William H. GoodsonLeroy LoweDavid O. CarpenterMichael GilbertsonAbdul Manaf AliAdela Lopez de Cerain SalsamendiAhmed LasfarAmancio CarneroAmaya AzquetaAmedeo AmedeiAmelia K. CharlesAndrew R. CollinsAndrew WardAnna C. SalzbergAnnamaria ColacciAnn Karin OlsenArthur BergBarry J. BarclayBinhua P. ZhouCarmen Blanco-AparicioCarolyn J. BagloleChenfang DongChiara MondelloChia Wen HsuChristian C. NausClement YedjouColleen S. CurranDale W. LairdDaniel C. KochDanielle J. CarlinDean W. FelsherDebasish RoyDustin G. BrownEdward RatovitskiElizabeth P. RyanEmanuela CorsiniEmilio RojasEun Yi MoonEzio LaconiFabio MarongiuFahd Al-MullaFerdinando ChiaradonnaFirouz DarroudiFrancis L. MartinFrederik J. Van SchootenGary S. GoldbergGerard WagemakerGladys NangamiGloria M. CalafGraeme WilliamsGregory T. WolfGudrun KoppenGunnar BrunborgH. Kim LyerlyHarini KrishnanHasiah Ab HamidHemad YasaeiHideko SoneHiroshi KondohHosni K. SalemHsue Yin HsuHyun Ho ParkIgor KoturbashIsabelle R. MiousseA. Ivana ScovassiJames E. KlaunigJan VondráčekJayadev RajuJesse RomanJohn Pierce WiseJonathan R. WhitfieldJordan WoodrickJoseph A. ChristopherJosiah OchiengJuan Fernando Martinez-LealJudith WeiszJulia KravchenkoJun SunKalan R. PrudhommeKannan Badri NarayananKarine A. Cohen-SolalKim MoorwoodLaetitia GonzalezLaura SoucekLe JianLeandro S. D'AbronzoLiang Tzung LinLin LiLinda GulliverLisa J. McCawleyLorenzo MemeoLouis VermeulenLuc LeynsLuoping ZhangGetting to Know CancerLancaster UniversityUniversity at Albany State University of New YorkGetting to Know CancerUniversiti Sultan Zainal AbidinUniversidad de NavarraRutgers Biomedical and Health SciencesHospital Universitario Virgen del RocioUniversita degli Studi di FirenzeUniversity of ReadingUniversitetet i OsloUniversity of BathPenn State College of MedicineEnvironmental Protection and Health Prevention AgencyNorwegian Institute of Public HealthNational Research Council CanadaUniversity of KentuckyCentro Nacional de Investigaciones OncologicasMcGill UniversityConsiglio Nazionale delle RicercheNational Center for Advancing Translational SciencesThe University of British ColumbiaJackson State UniversityUniversity of Wisconsin MadisonWestern UniversityStanford University School of MedicineNational Institute of Environmental Health SciencesCity University of New YorkColorado State UniversityThe Johns Hopkins School of MedicineUniversita degli Studi di MilanoUniversidad Nacional Autonoma de MexicoSejong UniversityUniversita degli Studi di CagliariUniversity of KuwaitUniversity of Milano - BicoccaCollege of North AtlanticMaastricht UniversityRowan UniversityHacettepe UniversitesiMeharry Medical CollegeColumbia University Medical CenterUniversidad de Tarapaca de AricaUniversity of Michigan Medical SchoolFlemish Institute for Technological ResearchDuke University Medical CenterUniversiti Putra MalaysiaBrunel University LondonNational Institute for Environmental Studies of JapanKyoto University HospitalCairo UniversityTzu Chi UniversityYeungnam UniversityUniversity of Arkansas for Medical SciencesIndiana UniversityAcademy of Sciences of the Czech RepublicToxicology Research DivisionUniversity of LouisvilleLouisville Veterans Administration Medical CenterUniversity of Southern MaineVall d`Hebron Institut de OncologiaLombardi Comprehensive Cancer CenterUniversity of CambridgeDepartment of Cell BiologyRush UniversityOregon State UniversityThe Cancer Institute of New JerseyVrije Universiteit BrusselInstitucio Catalana de Recerca I Estudis AvancatsCurtin UniversityDepartment of Health Western AustraliaUniversity of California, DavisTaipei Medical UniversityChinese University of Hong KongUniversity of OtagoVanderbilt UniversityMediterranean Institute of OncologyAcademic Medical Centre, University of AmsterdamUniversity of California, BerkeleyNational Cancer InstituteUniversita degli Studi di Napoli Federico IICentre de recherche en cancérologie de LyonUnited States ArmyIstituto Italiano di TecnologiaCalifornia Pacific Medical Center2018-11-232018-11-232015-06-01Carcinogenesis. Vol.36, (2015), S254-S29614602180014333342-s2.0-84937708474https://repository.li.mahidol.ac.th/handle/20.500.14594/35451© The Author 2015. 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1093/carcin/bgv039