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.

Advanced Molecular Science Research Centre King George's Medical University Lucknow Uttar Pradesh 226 003 India

Analytische Milieu en Geochemie Vrije Universiteit Brussel Brussel B1050 Belgium

Baylor College of Medicine Houston TX 77030 USA

California Pacific Medical Center Research Institute 2100 Webster Street 401 San Francisco CA 94115 USA Getting to Know Cancer Room 229A 36 Arthur Street Truro Nova Scotia B2N 1X5 Canada Lancaster Environment Centre Lancaster University Bailrigg Lancaster LA1 4AP UK Institute for Health and the Environment University at Albany 5 University Pl Rensselaer NY 12144 USA Getting to Know Cancer Guelph N1G 1E4 Canada School of Biotechnology Faculty of Agriculture Biotechnology and Food Sciences Sultan Zainal Abidin University Tembila Campus 22200 Besut Terengganu Malaysia Department of Pharmacology and Toxicology Faculty of Pharmacy University of Navarra Pamplona 31008 Spain Department of Pharmacology and Toxicology Ernest Mario School of Pharmacy Rutgers State University of New Jersey Piscataway NJ 08854 USA Instituto de Biomedicina de Sevilla Consejo Superior de Investigaciones Cientificas Hospital Universitario Virgen del Rocio Univ de Sevilla Avda Manuel Siurot sn 41013 Sevilla Spain Department of Experimental and Clinical Medicine University of Firenze Florence 50134 Italy School of Biological Sciences University of Reading Hopkins Building Reading Berkshire RG6 6UB UK Department of Nutrition University of Oslo Oslo Norway Department of Biochemistry and Biology University of Bath Claverton Down Bath BA2 7AY UK Department of Public Health Sciences College of Medicine Pennsylvania State University Hershey PA 17033 USA Center for Environmental Carcinogenesis and Risk Assessment Environmental Protection and Health Prevention Agency 40126 Bologna Italy Department of Chemicals and Radiation Division of Environmental Medicine Norwegian Institute of Public Health Oslo N 0403 Norway Planet Biotechnologies Inc St Albert Alberta T8N 5K4 Canada Department of Molecular and Cellular Biochemistry University of Kentucky Lexington KY 40508 USA Spanish National Cancer Research Centre CNI

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Center for Environment and Water Research Institute King Fahd University of Petroleum and Minerals Dhahran 3126 Saudi Arabia

Center for Environmental Carcinogenesis and Risk Assessment Environmental Protection and Health Prevention Agency 40126 Bologna Italy

Center for Experimental Molecular Medicine Academic Medical Center Meibergdreef 9 Amsterdam 1105 AZ The Netherlands

Center for Genomic Science of Fondazione Istituto Italiano di Tecnologia Via Adamello 16 20139 Milano Italy

Center for Radiological Research Columbia University Medical Center New York NY 10032 USA Instituto de Alta Investigacion Universidad de Tarapaca Arica Chile

Centre De Recherche En Cancerologie De Lyon Lyon U1052 UMR5286 France

Charles University Prague 3rd Faculty of Medicine CZ 100 00 Prague 10 Czech Republic

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Department of Biological Chemical and Pharmaceutical Sciences and Technologies Polyclinic Plexus University of Palermo Palermo 90127 Italy

Department of Biological Chemical and Pharmaceutical Sciences and Technologies Polyclinic Plexus University of Palermo Palermo 90127 Italy Sbarro Institute for Cancer Research and Molecular Medicine Temple University Philadelphia PA 19122 USA

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Department of Microbiology and Immunology Virginia Commonwealth University Massey Cancer Center Richmond VA 23298 USA

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Department of Molecular and Experimental Medicine The Scripps Research Institute La Jolla CA 92037 USA

Department of Molecular Biology School of Osteopathic Medicine Rowan University Stratford NJ 08084 USA

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Department of Natural Science The City University of New York at Hostos Campus Bronx NY 10451 USA

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Department of Otolaryngology Head and Neck Surgery University of Michigan Medical School Ann Arbor MI 48109 USA

Department of Pathology Kuwait University Safat 13110 Kuwait

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Department of Pharmacology and Toxicology University of Vienna Vienna A 1090 Austria Institute of Cancer Research Department of Medicine Medical University of Vienna Wien 1090 Austria

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Geisel School of Medicine at Dartmouth Hanover NH 03755 USA Geisel School of Medicine at Dartmouth Hanover NH 03755 USA

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Hacettepe University Center for Stem Cell Research and Development Ankara 06640 Turkey

Harvard Medical School Brigham and Women's Hospital Boston MA 02115 USA

Human Genetics Unit Department of Pathology Faculty of Medicine Kuwait University Jabriya 13110 Kuwait

Human Safety and Environmental Research Department of Health Sciences College of North Atlantic Doha 24449 State of Qatar

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INSERM U1113 team 3 'Cell Signalling and Communication in Kidney and Prostate Cancer' University of Strasbourg Faculté de Médecine 67085 Strasbourg France

INSERM U1113 team 3 'Cell Signalling and Communication in Kidney and Prostate Cancer' University of Strasbourg Faculté de Médecine 67085 Strasbourg France Department of Cell and Developmental Biology University of California Irvine CA 92697 USA

Institut De Recerca Hospital Vall D'Hebron Passeig Vall d'Hebron 119 129 08035 Barcelona Spain

Institute for Health and the Environment University at Albany 5 University Pl Rensselaer NY 12144 USA

Instituto de Alta Investigacion Universidad de Tarapaca Arica Chile

Instituto de Biomedicina de Sevilla Consejo Superior de Investigaciones Cientificas Hospital Universitario Virgen del Rocio Univ de Sevilla Avda Manuel Siurot sn 41013 Sevilla Spain

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Laboratory for Cell Genetics Vrije Universiteit Brussel 1050 Brussels Belgium

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Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill NC 27599 USA

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Mouse Models of Cancer Therapies Group Vall d'Hebron Institute of Oncology 08035 Barcelona Spain

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School of Biotechnology Yeungnam University Gyeongbuk 712 749 South Korea

School of Engineering and Materials Science Queen Mary University of London Mile End Road London E1 4NS UK

School of Public Health Curtin University Bentley WA 6102 Australia Department of Urology University of California Davis Sacramento CA 95817 USA

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