Kuwait Medical Electronic Library

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

William H Goodson 3rd 1, Leroy Lowe 2, David O Carpenter 3, Michael Gilbertson 4, Abdul Manaf Ali 5, Adela Lopez de Cerain Salsamendi 6, Ahmed Lasfar 7, Amancio Carnero 8, Amaya Azqueta 6, Amedeo Amedei 9, Amelia K Charles 10, Andrew R Collins 11, Andrew Ward 12, Anna C Salzberg 13, Annamaria Colacci 14, Ann-Karin Olsen 15, Arthur Berg 13, Barry J Barclay 16, Binhua P Zhou 17, Carmen Blanco-Aparicio 18, Carolyn J Baglole 19, Chenfang Dong 17, Chiara Mondello 20, Chia-Wen Hsu 21, Christian C Naus 22, Clement Yedjou 23, Colleen S Curran 24, Dale W Laird 25, Daniel C Koch 26, Danielle J Carlin 27, Dean W Felsher 28, Debasish Roy 29, Dustin G Brown 30, Edward Ratovitski 31, Elizabeth P Ryan 30, Emanuela Corsini 32, Emilio Rojas 33, Eun-Yi Moon 34, Ezio Laconi 35, Fabio Marongiu 35, Fahd Al-Mulla 36, Ferdinando Chiaradonna 37, Firouz Darroudi 38, Francis L Martin 39, Frederik J Van Schooten 40, Gary S Goldberg 41, Gerard Wagemaker 42, Gladys N Nangami 43, Gloria M Calaf 44, Graeme Williams 45, Gregory T Wolf 46, Gudrun Koppen 47, Gunnar Brunborg 15, H Kim Lyerly 48, Harini Krishnan 41, Hasiah Ab Hamid 49, Hemad Yasaei 50, Hideko Sone 51, Hiroshi Kondoh 52, Hosni K Salem 53, Hsue-Yin Hsu 54, Hyun Ho Park 55, Igor Koturbash 56, Isabelle R Miousse 56, A Ivana Scovassi 20, James E Klaunig 57, Jan Vondráček 58, Jayadev Raju 59, Jesse Roman 60, John Pierce Wise Sr 61, Jonathan R Whitfield 62, Jordan Woodrick 63, Joseph A Christopher 64, Josiah Ochieng 43, Juan Fernando Martinez-Leal 65, Judith Weisz 66, Julia Kravchenko 48, Jun Sun 67, Kalan R Prudhomme 68, Kannan Badri Narayanan 55, Karine A Cohen-Solal 69, Kim Moorwood 12, Laetitia Gonzalez 70, Laura Soucek 71, Le Jian 72, Leandro S D'Abronzo 73, Liang-Tzung Lin 74, Lin Li 75, Linda Gulliver 76, Lisa J McCawley 77, Lorenzo Memeo 78, Louis Vermeulen 79, Luc Leyns 70, Luoping Zhang 80, Mahara Valverde 33, Mahin Khatami 81, Maria Fiammetta Romano 82, Marion Chapellier 83, Marc A Williams 84, Mark Wade 85, Masoud H Manjili 86, Matilde E Lleonart 87, Menghang Xia 21, Michael J Gonzalez 88, Michalis V Karamouzis 89, Micheline Kirsch-Volders 70, Monica Vaccari 14, Nancy B Kuemmerle 90, Neetu Singh 91, Nichola Cruickshanks 92, Nicole Kleinstreuer 93, Nik van Larebeke 94, Nuzhat Ahmed 95, Olugbemiga Ogunkua 43, P K Krishnakumar 96, Pankaj Vadgama 97, Paola A Marignani 98, Paramita M Ghosh 73, Patricia Ostrosky-Wegman 33, Patricia A Thompson 99, Paul Dent 92, Petr Heneberg 100, Philippa Darbre 101, Po Sing Leung 75, Pratima Nangia-Makker 102, Qiang Shawn Cheng 103, R Brooks Robey 104, Rabeah Al-Temaimi 105, Rabindra Roy 63, Rafaela Andrade-Vieira 98, Ranjeet K Sinha 106, Rekha Mehta 59, Renza Vento 107, Riccardo Di Fiore 108, Richard Ponce-Cusi 109, Rita Dornetshuber-Fleiss 110, Rita Nahta 111, Robert C Castellino 112, Roberta Palorini 37, Roslida Abd Hamid 49, Sabine A S Langie 47, Sakina E Eltom 43, Samira A Brooks 113, Sandra Ryeom 114, Sandra S Wise 61, Sarah N Bay 115, Shelley A Harris 116, Silvana Papagerakis 46, Simona Romano 82, Sofia Pavanello 117, Staffan Eriksson 118, Stefano Forte 78, Stephanie C Casey 26, Sudjit Luanpitpong 119, Tae-Jin Lee 120, Takemi Otsuki 121, Tao Chen 122, Thierry Massfelder 123, Thomas Sanderson 124, Tiziana Guarnieri 125, Tove Hultman 126, Valérian Dormoy 127, Valerie Odero-Marah 128, Venkata Sabbisetti 129, Veronique Maguer-Satta 84, W Kimryn Rathmell 113, Wilhelm Engström 126, William K Decker 130, William H Bisson 68, Yon Rojanasakul 131, Yunus Luqmani 132, Zhenbang Chen 43, Zhiwei Hu 133

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Affiliations

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
2Getting to Know Cancer, Room 229A, 36 Arthur Street, Truro, Nova Scotia B2N 1X5, Canada, Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4AP, UK.
3Institute for Health and the Environment, University at Albany, 5 University Pl., Rensselaer, NY 12144, USA.
4Getting to Know Cancer, Guelph N1G 1E4, Canada.
5School of Biotechnology, Faculty of Agriculture Biotechnology and Food Sciences, Sultan Zainal Abidin University, Tembila Campus, 22200 Besut, Terengganu, Malaysia.
6Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31008, Spain.
7Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA.
8Instituto de Biomedicina de Sevilla, Consejo Superior de Investigaciones Cientificas. Hospital Universitario Virgen del Rocio, Univ. de Sevilla., Avda Manuel Siurot sn. 41013 Sevilla, Spain.
9Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy.
10School of Biological Sciences, University of Reading, Hopkins Building, Reading, Berkshire RG6 6UB, UK.
11Department of Nutrition, University of Oslo, Oslo, Norway.
12Department of Biochemistry and Biology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
13Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
14Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy.
15Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo N-0403, Norway.
16Planet Biotechnologies Inc., St Albert, Alberta T8N 5K4, Canada.
17Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40508, USA.
18Spanish National Cancer Research Centre, CNIO, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain.
19Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.
20Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
21Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3375, USA.
22Department of Cellular and Physiological Sciences, Life Sciences Institute, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
23Department of Biology, Jackson State University, Jackson, MS 39217, USA.
24Department of Molecular and Environmental Toxicology, University of Wisconsin-Madison, Madison, WI 53706, USA.
25Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 3K7, Canada.
26Stanford University Department of Medicine, Division of Oncology, Stanford, CA 94305, USA.
27Superfund Research Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27560, USA.
28Department of Medicine, Oncology and Pathology, Stanford University, Stanford, CA 94305, USA.
29Department of Natural Science, The City University of New York at Hostos Campus, Bronx, NY 10451, USA.
30Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1680, USA.
31Department of Head and Neck Surgery/Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
32Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy.
33Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México.
34Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea.
35Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy.
36Department of Pathology, Kuwait University, Safat 13110, Kuwait.
37Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy, SYSBIO Centre of Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy.
38Human Safety and Environmental Research, Department of Health Sciences, College of North Atlantic, Doha 24449, State of Qatar.
39Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4AP, UK.
40Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht 6200, The Netherlands.
41Department of Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA.
42Hacettepe University, Center for Stem Cell Research and Development, Ankara 06640, Turkey.
43Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
44Center for Radiological Research, Columbia University Medical Center, New York, NY 10032, USA, Instituto de Alta Investigacion, Universidad de Tarapaca, Arica, Chile.
45School of Biological Sciences, University of Reading, Reading, RG6 6UB, UK.
46Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
47Environmental Risk and Health Unit, Flemish Institute for Technological Research, 2400 Mol, Belgium.
48Department of Surgery, Pathology, Immunology, Duke University Medical Center, Durham, NC 27710, USA.
49Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, 43400 Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
50Department of Life Sciences, College of Health and Life Sciences and the Health and Environment Theme, Institute of Environment, Health and Societies, Brunel University Kingston Lane, Uxbridge, Middlesex UB8 3PH, UK.
51National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan.
52Department of Geriatric Medicine, Kyoto University Hospital 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto, 606-8507, Japan.
53Department of Urology, Kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 11559, Egypt.
54Department of Life Sciences, Tzu-Chi University, Hualien 970, Taiwan.
55School of Biotechnology, Yeungnam University, Gyeongbuk 712-749, South Korea.
56Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
57Department of Environmental Health, Indiana University, School of Public Health, Bloomington, IN 47405, USA.
58Department of Cytokinetics, Institute of Biophysics Academy of Sciences of the Czech Republic, Brno, CZ-61265, Czech Republic.
59Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada.
60Department of Medicine, University of Louisville, Louisville, KY 40202, USA, Robley Rex VA Medical Center, Louisville, KY 40202, USA.
61Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth St., Portland, ME 04104, USA.
62Mouse Models of Cancer Therapies Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.
63Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA.
64Cancer Research UK. Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
65Department of Cell Biology, Pharmamar-SAU, Avda. De los Reyes, 1. 28770-Colmenar Viejo, Madrid, Spain.
66Departments of Obstetrics and Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey PA 17033, USA.
67Department of Biochemistry, Rush University, Chicago, IL 60612, USA.
68Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA.
69Department of Medicine/Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
70Laboratory for Cell Genetics, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
71Mouse Models of Cancer Therapies Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain, Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain.
72School of Public Health, Curtin University, Bentley, WA 6102, Australia, Department of Urology, University of California Davis, Sacramento, CA 95817, USA.
73Department of Urology, University of California Davis, Sacramento, CA 95817, USA.
74Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
75School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People's Republic of China.
76Faculty of Medicine, University of Otago, Dunedin 9054, New Zealand.
77Department of Biomedical Engineering and Cancer Biology, Vanderbilt University, Nashville, TN 37235, USA.
78Department of Experimental Oncology, Mediterranean Institute of Oncology, Via Penninazzo 7, Viagrande (CT) 95029, Italy.
79Center for Experimental Molecular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
80Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA.
81Inflammation and Cancer Research, National Cancer Institute (NCI) (Retired), National Institutes of Health, Bethesda, MD 20892, USA.
82Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy.
83Centre De Recherche En Cancerologie, De Lyon, Lyon, U1052-UMR5286, France.
84United States Army Institute of Public Health, Toxicology Portfolio-Health Effects Research Program, Aberdeen Proving Ground, Edgewood, MD 21010-5403, USA.
85Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Via Adamello 16, 20139 Milano, Italy.
86Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298, USA.
87Institut De Recerca Hospital Vall D'Hebron, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
88University of Puerto Rico, Medical Sciences Campus, School of Public Health, Nutrition Program, San Juan 00921, Puerto Rico.
89Department of Biological Chemistry, Medical School, University of Athens, Institute of Molecular Medicine and Biomedical Research, 10676 Athens, Greece.
90Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
91Advanced Molecular Science Research Centre (Centre for Advanced Research), King George's Medical University, Lucknow, Uttar Pradesh 226 003, India.
92Departments of Neurosurgery and Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
93Integrated Laboratory Systems Inc., in support of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, RTP, NC 27709, USA.
94Analytische, Milieu en Geochemie, Vrije Universiteit Brussel, Brussel B1050, Belgium.
95Department of Obstetrics and Gynecology, University of Melbourne, Victoria 3052, Australia.
96Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 3126, Saudi Arabia .
97School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London, E1 4NS, UK.
98Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
99Department of Pathology, Stony Brook School of Medicine, Stony Brook University, The State University of New York, Stony Brook, NY 11794-8691, USA.
100Charles University in Prague, Third Faculty of Medicine, CZ-100 00 Prague 10, Czech Republic.
101School of Biological Sciences, The University of Reading, Whiteknights, Reading RG6 6UB, England.
102Department of Pathology, Wayne State University, Detroit, MI 48201, USA.
103Computer Science Department, Southern Illinois University, Carbondale, IL 62901, USA.
104White River Junction Veterans Affairs Medical Center, White River Junction, VT 05009, USA, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
105Human Genetics Unit, Department of Pathology, Faculty of Medicine, Kuwait University, Jabriya 13110, Kuwait.
106Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
107Department 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.
108Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, Polyclinic Plexus, University of Palermo, Palermo 90127, Italy .
109Instituto de Alta Investigacion, Universidad de Tarapaca, Arica, Chile.
110Department 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.
111Departments of Pharmacology and Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA.
112Division of Hematology and Oncology, Department of Pediatrics, Children's Healthcare of Atlanta, GA 30322, USA, Department of Pediatrics, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA.
113Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.
114Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
115Program in Genetics and Molecular Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA.
116Population Health and Prevention, Research, Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, M5G 2L7, Canada, Departments of Epidemiology and Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada .
117Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy.
118Department of Anatomy, Physiology and Biochemistry, The Swedish University of Agricultural Sciences, PO Box 7011, VHC, Almas Allé 4, SE-756 51, Uppsala, Sweden.
119Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
120Department of Anatomy, College of Medicine, Yeungnam University, Daegu 705-717, South Korea.
121Department of Hygiene, Kawasaki Medical School, Matsushima Kurashiki, Okayama 701-0192, Japan.
122Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR 72079, USA.
123INSERM U1113, team 3 'Cell Signalling and Communication in Kidney and Prostate Cancer', University of Strasbourg, Faculté de Médecine, 67085 Strasbourg, France.
124INRS-Institut Armand-Frappier, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada.
125Department of Biology, Geology and Environmental Sciences, Alma Mater Studiorum Università di Bologna, Via Francesco Selmi, 3, 40126 Bologna, Italy, Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital, Via Massarenti, 9, 40126 Bologna, Italy, National Institute of Biostructures and Biosystems, Viale Medaglie d' Oro, 305, 00136 Roma, Italy.
126Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden.
127INSERM 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.
128Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA.
129Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115, USA.
130Baylor College of Medicine, Houston, TX 77030, USA.
131Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, 26506, USA.
132Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, PO Box 24923, Safat 13110, Kuwait and.
133Department of Surgery, The Ohio State University College of Medicine, The James Comprehensive Cancer Center, Columbus, OH 43210, USA.

06 January 2015

doi: 10.1093/carcin/bgv039

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.

Figures

Figure 1. Disruptive potential of environmental exposures to mixtures of chemicals. Note that some of the acquired hallmark phenotypes are known to be involved in many stages of disease development, but the precise sequencing of the acquisition of these hallmarks and the degree of involvement that each has in carcinogenesis are factors that have not yet been fully elucidated/defined. This depiction is therefore only intended to illustrate the ways in which exogenous actions might contribute to the enablement of these phenotypes.

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KMEL References

https://pubmed.ncbi.nlm.nih.gov/

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Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

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