{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T15:13:02Z","timestamp":1760541182524,"version":"build-2065373602"},"reference-count":93,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T00:00:00Z","timestamp":1551744000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Health Canada's CMP Monitoring and Surveillance fund"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>This study aimed to assess the impact of multi\u2010route co\u2010exposures to chemicals on interindividual variability in toxicokinetics. Probabilistic physiologically based pharmacokinetic multi\u2010route interaction models were developed for adults and four younger subpopulations. Drinking water\u2010mediated multi\u2010route exposures were simulated for benzene alone or in co\u2010exposure with toluene, ethylbenzene and m\u2010xylene, for trichloroethylene or vinyl chloride (VC), alone and in mixture. These simulations were performed for \u201clow\u201d and \u201chigh\u201d exposure scenarios, involving respectively the US EPA's short\u2010term drinking water health advisories, and 10 times these advisory values. Distributions of relevant internal dose metrics for benzene, trichloroethylene and VC were obtained using Monte Carlo simulations. Intergroup variability indexes (VI) were computed for the \u201clow\u201d (VI<jats:sub>L<\/jats:sub>) and \u201chigh\u201d (VI<jats:sub>H<\/jats:sub>) exposure scenarios, as the ratio between the 95th percentile in each subpopulation over the median in adults. Thus, for benzene, parent compound's area under the curve\u2010based VI<jats:sub>L<\/jats:sub> for single exposures vs. co\u2010exposures correspondingly varied between 1.7 (teenagers) and 2.8 (infants) vs. 1.9 and 3.1 respectively. VI<jats:sub>H<\/jats:sub> varied between 2.5 and 3.5 vs. 2.9 and 4.1. Inversely, VI<jats:sub>L<\/jats:sub> and VI<jats:sub>H<\/jats:sub> for the amount of benzene metabolized via CYP2E1 pathway decreased in co\u2010exposure compared to single exposure. For VC and trichloroethylene, similar results were obtained for the \u201chigh\u201d exposure, but \u201clow\u201d co\u2010exposures did not impact the toxicokinetics of individual substances. In conclusion, multi\u2010route co\u2010exposures can have an impact on the toxicokinetics of individual substances, but to an extent, that does not seem to challenge the default values attributed to the factors deemed at reflecting interindividual or child\/adult differences in toxicokinetics.<\/jats:p>","DOI":"10.1002\/jat.3787","type":"journal-article","created":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T04:25:14Z","timestamp":1551759914000},"page":"974-991","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["An assessment of the impact of multi\u2010route co\u2010exposures on human variability in toxicokinetics: A case study with binary and quaternary mixtures of volatile drinking water contaminants"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0670-7763","authenticated-orcid":false,"given":"Honesty","family":"Tohon","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health, ESPUM, IRSPUM Universit\u00e9 de Montr\u00e9al  Montreal QC Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5384-0877","authenticated-orcid":false,"given":"Mathieu","family":"Valcke","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, ESPUM, IRSPUM Universit\u00e9 de Montr\u00e9al  Montreal QC Canada"},{"name":"Institut national de sant\u00e9 publique du Qu\u00e9bec  Montr\u00e9al QC Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8906-9693","authenticated-orcid":false,"given":"Sami","family":"Haddad","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, ESPUM, IRSPUM Universit\u00e9 de Montr\u00e9al  Montreal QC Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,3,5]]},"reference":[{"volume-title":"Toxicological profile for vinyl chloride","year":"2006","author":"Agency for Toxic Substances and Disease Registry (ATSDR)","key":"e_1_2_7_2_1"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.15620\/cdc:11481"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.15620\/cdc:11481"},{"volume-title":"Toxicological profile for ethylbenzene","year":"2010","author":"Agency for Toxic Substances and Disease Registry (ATSDR)","key":"e_1_2_7_5_1"},{"volume-title":"Toxicological profile for trichloroethylene","year":"2014","author":"Agency for Toxic Substances and Disease Registry (ATSDR)","key":"e_1_2_7_6_1"},{"volume-title":"Toxicological profile for toluene","year":"2017","author":"Agency for Toxic Substances and Disease Registry (ATSDR)","key":"e_1_2_7_7_1"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(87)90281-X"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.1117"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408444.2017.1303818"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571\u2010200002000\u201000007"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfh109"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2007.10.012"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1997.2145"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/15459620590916198"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002040100216"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.021101031"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfi160"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.4314\/wsa.v43i4.08"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/0470096209"},{"key":"e_1_2_7_21_1","first-page":"1","article-title":"Anthropometric Reference Data for Children and Adults: United States, 2007\u20132010. National Center for Health Statistics","volume":"11","author":"Fryar C. D.","year":"2012","journal-title":"Vital and Health Statistics"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2006.10.013"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1080\/00984100050131350"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/63.1.125"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.2000.8991"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.22136"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/15287390600631789"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470686263.ch4"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1999.8803"},{"volume-title":"Guidelines for Canadian Drinking Water Quality: Supporting Documentations\u2014Trichloroethylene","year":"2005","author":"Health Canada","key":"e_1_2_7_30_1"},{"volume-title":"Guidelines for Canadian Drinking Water Quality: Guideline Technical Document\u2014Trihalomethanes","year":"2006","author":"Health Canada","key":"e_1_2_7_31_1"},{"volume-title":"Guidelines for Canadian Drinking Water Quality: Guideline Technical Document\u2014Dichloromethane","year":"2011","author":"Health Canada","key":"e_1_2_7_32_1"},{"volume-title":"Guidelines for Canadian Drinking Water Quality: Guideline Technical Document\u2014Vinyl chloride","year":"2013","author":"Health Canada","key":"e_1_2_7_33_1"},{"volume-title":"Guidelines for Canadian Drinking Water Quality\u2014Summary Table","year":"2017","author":"Health Canada","key":"e_1_2_7_34_1"},{"key":"e_1_2_7_35_1","unstructured":"Institut National de l\u2019Environnement Industriel et des RISques (INERIS). (2018).Portail Substances Chimiques. Ethylbenzene. Retrieved fromhttps:\/\/substances.ineris.fr\/fr\/substance\/952"},{"key":"e_1_2_7_36_1","unstructured":"International Panel on Chemical Safety (IPCS). (1994). Assessing human health risks of chemicals: Derivation of guidance values for health based exposure limits.Environmental Health Criteria 170. International Panel on Chemical Safety World Health Organization Geneva Switzerland."},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.053124"},{"key":"e_1_2_7_38_1","first-page":"149","volume-title":"Principles and methods of toxicology","author":"Krishnan K.","year":"1994"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470686263"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/10590500802343974"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.02110s6989"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088\u2010199835050\u201000003"},{"key":"e_1_2_7_43_1","first-page":"183","article-title":"Gasoline contaminated ground water as a source of residential benzene exposure: a case study","volume":"4","author":"Lindstrom A. B.","year":"1994","journal-title":"Journal of Exposure Analysis and Environmental Epidemiology"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2008.01.006"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1080\/15376510309821"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.11079"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1080\/10473289.1991.10466844"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300\u2010483X(02)00265\u20102"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfq116"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2004.06.006"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2007.04.015"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1080\/15287394.2012.625546"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1080\/10937400903158359"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2005.12.001"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1006\/rtph.2000.1436"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0272\u20100590(89)90290\u2010X"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1996.0015"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1080\/15287390306450"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408440390242324"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378\u20104274(90)90148\u2010F"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1006\/rtph.1997.1195"},{"key":"e_1_2_7_62_1","first-page":"211","volume-title":"Cytochrome P450 metabolic and toxicological aspects","author":"Ronis M. J. J.","year":"1996"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.50"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1080\/08958370390226350"},{"key":"e_1_2_7_65_1","unstructured":"Syracuse Research Corporation (SRC). (2013).SRC PhysProp Database. Retrieved fromhttp:\/\/esc.syrres.com\/fatepointer\/results.asp"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jes.7500540"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1080\/15287390306455"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004728\u2010199601000\u201000025"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1996.8096"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378\u20104274(02)00185\u20106"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1080\/15428119691015188"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/68.2.280"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.2000.9014"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0890\u20106238(00)00060\u20105"},{"volume-title":"Guidance for Applying Quantitative Data to Develop Data\u2010Derived Extrapolation Factors for Interspecies and Intraspecies Extrapolation","year":"2014","author":"US EPA","key":"e_1_2_7_75_1"},{"volume-title":"2012 Edition of the Drinking Water Standards and Health Advisories","year":"2012","author":"US EPA","key":"e_1_2_7_76_1"},{"key":"e_1_2_7_77_1","unstructured":"US EPA. (2011).Toxicological review of trichloroethylene(Document no. EPA\/635\/R\u201009\/011F). Retrieved fromhttps:\/\/cfpub.epa.gov\/ncea\/iris\/iris_documents\/documents\/toxreviews\/0199tr\/0199tr.pdf"},{"key":"e_1_2_7_78_1","unstructured":"US EPA. (2005).Supplemental Guidance for Assessing Susceptibility from Early\u2010Life Exposure to Carcinogens(Document no. EPA\/630\/R\u201003\/003F). Retrieved fromhttps:\/\/www3.epa.gov\/airtoxics\/childrens_supplement_final.pdf"},{"key":"e_1_2_7_79_1","unstructured":"US EPA. (2000).Toxicological review of vinyl chloride(Document no. EPA\/635R\u201000\/004). Retrieved fromhttps:\/\/cfpub.epa.gov\/ncea\/iris\/iris_documents\/documents\/toxreviews\/1001tr.pdf"},{"key":"e_1_2_7_80_1","doi-asserted-by":"publisher","DOI":"10.1080\/15287394.2014.971477"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph7114002"},{"key":"e_1_2_7_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2010.10.008"},{"key":"e_1_2_7_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2011.05.003"},{"key":"e_1_2_7_84_1","doi-asserted-by":"publisher","DOI":"10.3109\/08958378.2011.609918"},{"key":"e_1_2_7_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2012.11.006"},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2919"},{"key":"e_1_2_7_87_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/404329"},{"key":"e_1_2_7_88_1","doi-asserted-by":"publisher","DOI":"10.1080\/15287390701601202"},{"volume-title":"Retrieved from","year":"2004","author":"World Health Organization (WHO)","key":"e_1_2_7_89_1"},{"key":"e_1_2_7_90_1","unstructured":"World Health Organization (WHO). (2005).Trichloroethene in Drinking\u2010water. Background document for development of WHO Guidelines for Drinking\u2010water Quality (WHO\/SDE\/WSH\/05.08\/22). Retrieved fromhttp:\/\/www.who.int\/water_sanitation_health\/dwq\/chemicals\/trichloroethenemay05.pdf"},{"volume-title":"Chemical\u2010Specific Adjustment Factors (CSAFs) for Interspecies Differences and Human Variability: guidance document for the use of data in dose\/concentration\u2010response assessment","year":"2005","author":"World Health Organization\/International Panel on Chemical Safety (WHO\/IPCS)","key":"e_1_2_7_91_1"},{"key":"e_1_2_7_92_1","unstructured":"World Health Organization\/International Panel on Chemical Safety (WHO\/IPCS). (2010).Characterization and application of physiologically based pharmacokinetic models in risk assessment(IPCS Harmonization document no. 9). Retrieved fromhttp:\/\/www.who.int\/ipcs\/methods\/harmonization\/areas\/pbpk_models.pdf?ua=1."},{"key":"e_1_2_7_93_1","first-page":"49","volume-title":"Introduction to biochemical toxicology","author":"Yang R.","year":"1994"},{"key":"e_1_2_7_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2018.07.073"}],"container-title":["Journal of Applied Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjat.3787","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.3787","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jat.3787","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.3787","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T14:38:28Z","timestamp":1760539108000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jat.3787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,5]]},"references-count":93,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2019,7]]}},"alternative-id":["10.1002\/jat.3787"],"URL":"https:\/\/doi.org\/10.1002\/jat.3787","archive":["Portico"],"relation":{},"ISSN":["0260-437X","1099-1263"],"issn-type":[{"type":"print","value":"0260-437X"},{"type":"electronic","value":"1099-1263"}],"subject":[],"published":{"date-parts":[[2019,3,5]]},"assertion":[{"value":"2018-10-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}