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Carcinogenesis. 2015 Jun;36 Suppl 1:S254-96. doi: 10.1093/carcin/bgv039.

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

Goodson WH 3rd1, Lowe L2, Carpenter DO3, Gilbertson M4, Manaf Ali A5, Lopez de Cerain Salsamendi A6, Lasfar A7, Carnero A8, Azqueta A6, Amedei A9, Charles AK10, Collins AR11, Ward A12, Salzberg AC13, Colacci A14, Olsen AK15, Berg A13, Barclay BJ16, Zhou BP17, Blanco-Aparicio C18, Baglole CJ19, Dong C17, Mondello C20, Hsu CW21, Naus CC22, Yedjou C23, Curran CS24, Laird DW25, Koch DC26, Carlin DJ27, Felsher DW28, Roy D29, Brown DG30, Ratovitski E31, Ryan EP30, Corsini E32, Rojas E33, Moon EY34, Laconi E35, Marongiu F35, Al-Mulla F36, Chiaradonna F37, Darroudi F38, Martin FL39, Van Schooten FJ40, Goldberg GS41, Wagemaker G42, Nangami GN43, Calaf GM44, Williams G45, Wolf GT46, Koppen G47, Brunborg G15, Lyerly HK48, Krishnan H41, Ab Hamid H49, Yasaei H50, Sone H51, Kondoh H52, Salem HK53, Hsu HY54, Park HH55, Koturbash I56, Miousse IR56, Scovassi AI20, Klaunig JE57, Vondráček J58, Raju J59, Roman J60, Wise JP Sr61, Whitfield JR62, Woodrick J63, Christopher JA64, Ochieng J43, Martinez-Leal JF65, Weisz J66, Kravchenko J48, Sun J67, Prudhomme KR68, Narayanan KB55, Cohen-Solal KA69, Moorwood K12, Gonzalez L70, Soucek L71, Jian L72, D'Abronzo LS73, Lin LT74, Li L75, Gulliver L76, McCawley LJ77, Memeo L78, Vermeulen L79, Leyns L70, Zhang L80, Valverde M33, Khatami M81, Romano MF82, Chapellier M83, Williams MA84, Wade M85, Manjili MH86, Lleonart ME87, Xia M21, Gonzalez MJ88, Karamouzis MV89, Kirsch-Volders M70, Vaccari M14, Kuemmerle NB90, Singh N91, Cruickshanks N92, Kleinstreuer N93, van Larebeke N94, Ahmed N95, Ogunkua O43, Krishnakumar PK96, Vadgama P97, Marignani PA98, Ghosh PM73, Ostrosky-Wegman P33, Thompson PA99, Dent P92, Heneberg P100, Darbre P101, Sing Leung P75, Nangia-Makker P102, Cheng QS103, Robey RB104, Al-Temaimi R105, Roy R63, Andrade-Vieira R98, Sinha RK106, Mehta R59, Vento R107, Di Fiore R108, Ponce-Cusi R109, Dornetshuber-Fleiss R110, Nahta R111, Castellino RC112, Palorini R37, Abd Hamid R49, Langie SA47, Eltom SE43, Brooks SA113, Ryeom S114, Wise SS61, Bay SN115, Harris SA116, Papagerakis S46, Romano S82, Pavanello S117, Eriksson S118, Forte S78, Casey SC26, Luanpitpong S119, Lee TJ120, Otsuki T121, Chen T122, Massfelder T123, Sanderson T124, Guarnieri T125, Hultman T126, Dormoy V127, Odero-Marah V128, Sabbisetti V129, Maguer-Satta V84, Rathmell WK113, Engström W126, Decker WK130, Bisson WH68, Rojanasakul Y131, Luqmani Y132, Chen Z43, Hu Z133.

Author information

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

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.

PMID:
26106142
PMCID:
PMC4480130
DOI:
10.1093/carcin/bgv039
[Indexed for MEDLINE]
Free PMC Article

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