title: Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.
abstract: 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.
authors.affiliation: 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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mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced*; D002274:Carcinogens, Environmental / Q000009:adverse effects*; D004781:Environmental Exposure / Q000009:adverse effects*; D015386:Hazardous Substances / Q000009:adverse effects*; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced* / Q000209:etiology*
chemical_list: D002274:Carcinogens, Environmental; D015386:Hazardous Substances