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  • Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
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  • Goodson, W. H., Lowe, L., Carpenter, D. O., Gilbertson, M., Ali, A. M., de Cerain Salsamendi, A. L., ... & Hu, Z. (2015). Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis, 36(Suppl 1), S254-S296. doi:10.1093/carcin/bgv039
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  • 36
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  • Supp. 1
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  • We gratefully acknowledge the support of the National Instituteof Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276); GlennRice, Office of Research and Development, United StatesEnvironmental Protection Agency, Cincinnati, OH, USA alsodeserves thanks for his thoughtful feedback and inputs on themanuscript; William H.Goodson III was supported by theCalifornia Breast Cancer Research Program, Clarence HellerFoundation and California Pacific Medical Center Foundation;Abdul M.Ali would like to acknowledge the financial support ofthe University of Sultan Zainal Abidin, Malaysia; Ahmed Lasfarwas supported by an award from the Rutgers Cancer Institute ofNew Jersey; Ann-Karin Olsen and Gunnar Brunborg were supportedby the Research Council of Norway (RCN) through itsCentres of Excellence funding scheme (223268/F50), AmancioCarnero’s lab was supported by grants from the Spanish Ministryof Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC:RD12/0036/0028) co-funded by FEDER from Regional DevelopmentEuropean Funds (European Union), Consejeria de Ciencia eInnovacion (CTS-1848) and Consejeria de Salud of the Junta deAndalucia (PI-0306-2012); Matilde E. Lleonart was supported by atrienal project grant PI12/01104 and by project CP03/00101 for personalsupport. Amaya Azqueta would like to thank the Ministeriode Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) ofthe Spanish Government for personal support; Amedeo Amedeiwas supported by the Italian Ministry of University and Research(2009FZZ4XM_002), and the University of Florence (ex60%2012);Andrew R.Collins was supported by the University of Oslo;Annamaria Colacci was supported by the Emilia-Romagna Region- Project ‘Supersite’ in Italy; Carolyn Baglole was supported by asalary award from the Fonds de recherche du Quebec-Sante (FRQS);Chiara Mondello’s laboratory is supported by FondazioneCariplo in Milan, Italy (grant n. 2011-0370); Christian C.Naus holdsa Canada Research Chair; Clement Yedjou was supported by agrant from the National Institutes of Health (NIH-NIMHD grantno. G12MD007581); Daniel C.Koch is supported by the BurroughsWellcome Fund Postdoctoral Enrichment Award and the TumorBiology Training grant: NIH T32CA09151; Dean W. Felsher wouldlike to acknowledge the support of United States Department ofHealth and Human Services, NIH grants (R01 CA170378 PQ22, R01CA184384, U54 CA149145, U54 CA151459, P50 CA114747 andR21 CA169964); Emilio Rojas would like to thank CONACyT support152473; Ezio Laconi was supported by AIRC (ItalianAssociation for Cancer Research, grant no. IG 14640) and by theSardinian Regional Government (RAS); Eun-Yi Moon was supportedby grants from the Public Problem-Solving Program(NRF-015M3C8A6A06014500) and Nuclear R&D Program(#2013M2B2A9A03051296 and 2010-0018545) through the NationalResearch Foundation of Korea (NRF) and funded by the Ministryof Education, Science and Technology (MEST) in Korea;Fahd Al-Mulla was supported by the Kuwait Foundation forthe Advancement of Sciences (2011-1302-06); FerdinandoChiaradonna is supported by SysBioNet, a grant for the ItalianRoadmap of European Strategy Forum on Research Infrastructures(ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro; IG15364); Francis L.Martin acknowledges funding from RosemereCancer Foundation; he also thanks Lancashire Teaching HospitalsNHS trust and the patients who have facilitated the studies hehas undertaken over the course of the last 10 years; GaryS.Goldberg would like to acknowledge the support of the NewJersey Health Foundation; Gloria M.Calaf was supported by FondoNacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA);Gudrun Koppen was supported by the Flemish Institute forTechnological Research (VITO), Belgium; Hemad Yasaei was supportedfrom a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction(NC3Rs) of animals in research (NC.K500045.1 and G0800697);Hiroshi Kondoh was supported in part by grants from the Ministryof Education, Culture, Sports, Science, and Technology of Japan,Japan Science and Technology Agency and by JST, CREST; Hsue-Yin Hsu was supported by the Ministry of Science and Technologyof Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002);Hyun Ho Park was supported by the Basic Science ResearchProgram through the National Research Foundation of Korea(NRF) of the Ministry of Education, Science and Technology(2012R1A2A2A01010870) and a grant from the Korea HealthcareTechnology R&D project, Ministry of Health and Welfare, Republicof Korea (HI13C1449); Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 andKL2TR000063) and the Arkansas Biosciences Institute, the majorresearch component of the Arkansas Tobacco SettlementProceeds Act of 2000; Jan Vondráček acknowledges funding fromthe Czech Science Foundation (13-07711S); Jesse Roman thanksthe NIH for their support (CA116812); John Pierce Wise Sr. andSandra S.Wise were supported by National Institute ofEnvironmental Health Sciences (ES016893 to J.P.W.) and the MaineCenter for Toxicology and Environmental Health; JonathanWhitfield acknowledges support from the FERO Foundation inBarcelona, Spain; Joseph Christopher is funded by CancerResearch UK and the International Journal of ExperimentalPathology; Julia Kravchenko is supported by a philanthropicdonation by Fred and Alice Stanback; Jun Sun is supported by aSwim Across America Cancer Research Award; Karine A.Cohen-Solal is supported by a research scholar grant from the AmericanCancer Society (116683-RSG-09-087-01-TBE); Laetitia Gonzalezreceived a postdoctoral fellowship from the Fund for ScientificResearch–Flanders (FWO-Vlaanderen) and support by anInterUniversity Attraction Pole grant (IAP-P7-07); Laura Soucek issupported by grant #CP10/00656 from the Miguel Servet ResearchContract Program and acknowledges support from the FEROFoundation in Barcelona, Spain; Liang-Tzung Lin was supportedby funding from the Taipei Medical University (TMU101-AE3-Y19);Linda Gulliver is supported by a Genesis Oncology Trust (NZ)Professional Development Grant, and the Faculty of Medicine,University of Otago, Dunedin, New Zealand; Louis Vermeulen issupported by a Fellowship of the Dutch Cancer Society (KWF,UVA2011-4969) and a grant from the AICR (14–1164); MaharaValverde would like to thank CONACyT support 153781; MasoudH. Manjili was supported by the office of the Assistant Secretaryof Defense for Health Affairs (USA) through the Breast CancerResearch Program under Award No. W81XWH-14-1-0087 NeetuSingh was supported by grant #SR/FT/LS-063/2008 from theDepartment of Science and Technology, Government of India;Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES35504 and HHSN27320140003C); P.K. Krishnakumar is supportedby the Funding (No. T.K. 11-0629) of King Abdulaziz City forScience and Technology, Riyadh, Saudi Arabia; Paola A.Marignaniis supported by the Dalhousie Medical Research Foundation, TheBeatrice Hunter Cancer Institute and CIHR and the Nova ScotiaLung Association; Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported withfunds from PHS grants from the NIH (R01-CA141704,R01-CA150214, R01-DK52825 and R01-CA61774); Petr Henebergwas supported by the Charles University in Prague projects UNCE204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y; Po Sing Leungwas supported by the Health and Medical Research Fund of Foodand Health Bureau, Hong Kong Special Administrative Region,Ref. No: 10110021; Qiang Cheng was supported in part by grant NSF IIS-1218712; R. Brooks Robey is supported by the UnitedStates Department of Veterans Affairs; Rabindra Roy was supportedby United States Public Health Service Grants (RO1CA92306, RO1 CA92306-S1 and RO1 CA113447); Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer ResearchInstitute and the Nova Scotia Health Research Foundation; RenzaVento was partially funded by European Regional DevelopmentFund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163PO 037, OP Italia-Malta 2007–13) and grants from the ItalianMinistry of Education, University and Research (MIUR) ex-60%,2007; Riccardo Di Fiore was a recipient of fellowship granted byEuropean Regional Development Fund, European TerritorialCooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta2007–2013); Rita Dornetshuber-Fleiss was supported by theAustrian Science Fund (FWF, project number T 451-B18) and theJohanna Mahlke, geb.-Obermann-Stiftung; Roberta Palorini issupported by a SysBioNet fellowship; Roslida Abd Hamid is supportedby the Ministry of Education, Malaysia-ExploratoryResearch Grant Scheme-Project no: ERGS/1-2013/5527165; SabineA.S.Langie is the beneficiary of a postdoctoral grant from the AXAResearch Fund and the Cefic-LRI Innovative Science Award 2013;Sakina Eltom is supported by NIH grant SC1CA153326; SamiraA.Brooks was supported by National Research Service Award (T32ES007126) from the National Institute of Environmental HealthSciences and the HHMI Translational Medicine Fellowship;Sandra Ryeom was supported by The Garrett B. Smith Foundationand the TedDriven Foundation; Thierry Massfelder was supportedby the Institut National de la Santé et de la Recherche MédicaleINSERM and Université de Strasbourg; Thomas Sanderson is supportedby the Canadian Institutes of Health Research (CIHR; MOP-115019), the Natural Sciences and Engineering Council of Canada(NSERC; 313313) and the California Breast Cancer ResearchProgram (CBCRP; 17UB-8703); Tiziana Guarnieri is supported by agrant from Fundamental Oriented Research (RFO) to the AlmaMater Studiorum University of Bologna, Bologna, Italy and thanksthe Fondazione Cassa di Risparmio di Bologna and the FondazioneBanca del Monte di Bologna e Ravenna for supporting the Centerfor Applied Biomedical Research, S.Orsola-Malpighi UniversityHospital, Bologna, Italy; W.Kimryn Rathmell is supported by the VFoundation for Cancer Research and the American CancerSociety; William K.Decker was supported in part by grantRP110545 from the Cancer Prevention Research Institute of Texas;William H.Bisson was supported with funding from the NIH P30ES000210; Yon Rojanasakul was supported with NIH grantR01-ES022968; Zhenbang Chen is supported by NIH grants(MD004038, CA163069 and MD007593); Zhiwei Hu is grateful forthe grant support from an institutional start-up fund from TheOhio State University College of Medicine and The OSU JamesComprehensive Cancer Center (OSUCCC) and a Seed Award fromthe OSUCCC Translational Therapeutics Program.
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