Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
William H. Goodson(California Pacific Medical Center), Leroy Lowe(Lancaster University), David O. Carpenter(University at Albany, State University of New York), Michael Gilbertson(University of Guelph), Abdul Manaf Ali(Sultan Zainal Abidin University), Adela Lopez de Cerain Salsamendi(Universidad de Navarra), Ahmed Lasfar(Rutgers, The State University of New Jersey), Amancio Carnero(Instituto de Biomedicina de Sevilla), Amaya Azqueta(Universidad de Navarra), Amedeo Amedei(University of Florence), Amelia K. Charles(University of Reading), Andrew Collins(University of Oslo), Andrew Ward(University of Bath), Anna C. Salzberg(Pennsylvania State University), Annamaria Colacci(Health Protection Agency), Ann‐Karin Olsen(Norwegian Institute of Public Health), Arthur Berg(Pennsylvania State University), Barry J. Barclay(Planet Biotechnology (United States)), Binhua P. Zhou(University of Kentucky), Carmen Blanco‐Aparicio(Spanish National Cancer Research Centre), Carolyn J. Baglole(McGill University), Chenfang Dong(University of Kentucky), Chiara Mondello(Istituto di Genetica Molecolare), Chia-Wen Hsu(National Institutes of Health), Christian C. Naus(University of British Columbia), Clément G. Yedjou(Jackson State University), Colleen S. Curran(University of Wisconsin–Madison), Dale W. Laird(Western University), Daniel C. Koch(Stanford Medicine), Danielle J. Carlin(National Institute of Environmental Health Sciences), Dean W. Felsher(Stanford Medicine), Debasish Roy(City University of New York), Dustin G. Brown(Colorado State University), Edward A. Ratovitski(Johns Hopkins University), Elizabeth P. Ryan(Colorado State University), Emanuela Corsini(University of Milan), Emilio Rojas(National Institute of Genomic Medicine), Eun‐Yi Moon(Sejong University), Ezio Laconi(University of Cagliari), Fabio Marongiu(University of Cagliari), Fahd Al‐Mulla(Kuwait University), Ferdinando Chiaradonna(University of Milano-Bicocca), F. Darroudi(University of Doha for Science and Technology), Francis Martin(Lancaster University), Frederik‐Jan van Schooten(Maastricht University), Gary S. Goldberg(Rowan University), Gerard Wagemaker(Hacettepe University), Gladys N. Nangami(Meharry Medical College), Gloria M. Calaf(University of Tarapacá), Graeme P. Williams(University of Reading), Gregory T. Wolf(University of Michigan), Gudrun Koppen(Flemish Institute for Technological Research), Gunnar Brunborg(Norwegian Institute of Public Health), H. Kim Lyerly(Duke University), Harini Krishnan(Rowan University), Hasiah Ab Hamid(Universiti Putra Malaysia), Hemad Yasaei(Brunel University of London), Hideko Sone(National Institute for Environmental Studies), Hiroshi Kondoh(Kyoto University Hospital), Hosni Salem(Cairo University), Hsue‐Yin Hsu(Tzu Chi University), Hyun Ho Park(Yeungnam University), Igor Koturbash(University of Arkansas for Medical Sciences), Isabelle R. Miousse(University of Arkansas for Medical Sciences), A. Ivana Scovassi(Istituto di Genetica Molecolare), James E. Klaunig(Indiana University Bloomington), Jan Vondráček(Czech Academy of Sciences), Jayadev Raju(Health Canada), Jesse Roman(University of Louisville), John Pierce Wise(University of Southern Maine), Jonathan R. Whitfield(CIBBIM-Nanomedicine), Jordan Woodrick(Georgetown University), Joseph Christopher(University of Cambridge), Josiah Ochieng(Meharry Medical College), Juan Fernando Martínez-Leal(PharmaMar (Spain)), Judith Weisz(Pennsylvania State University), Julia Kravchenko(Duke University), Jun Sun(Rush University), Kalan R. Prudhomme(Oregon State University), Kannan Badri Narayanan(Yeungnam University), Karine Cohen-Solal(Rutgers, The State University of New Jersey), Kim Moorwood(University of Bath), Laetitia Gonzalez(Vrije Universiteit Brussel), Laura Soucek(Institució Catalana de Recerca i Estudis Avançats), Le Jian(Curtin University), Leandro S. D’Abronzo(University of California, Davis), Liang Lin(Taipei Medical University), Lin Li(Chinese University of Hong Kong), Linda Gulliver(University of Otago), Lisa J. McCawley(Vanderbilt University), Lorenzo Memeo(Mediterranean University), Louis Vermeulen(Amsterdam UMC Location University of Amsterdam), Luc Leyns(Vrije Universiteit Brussel), Luoping Zhang(University of California, Berkeley), Mahara Valverde(National Institute of Genomic Medicine), Mahin Khatami(National Institutes of Health), Maria Fiammetta Romano(University of Naples Federico II), Marion Chapellier(Université Claude Bernard Lyon 1), Marc A. Williams(U.S. Army Center for Health Promotion and Preventive Medicine), Mark Wade(Italian Institute of Technology), Masoud H. Manjili(Virginia Commonwealth University), Matilde E. Lleonart(Vall d'Hebron Institut de Recerca), Menghang Xia(National Institutes of Health), Michael J. Guzman(University of Puerto Rico, Medical Sciences Campus), Michalis V. Karamouzis(National and Kapodistrian University of Athens), Micheline Kirsch‐Volders(Vrije Universiteit Brussel), Monica Vaccari(Health Protection Agency), Nancy B. Kuemmerle(Dartmouth College), Neetu Singh(King George's Medical University), Nichola Cruickshanks(Virginia Commonwealth University), Nicole Kleinstreuer(National Center for Toxicological Research), Nicolas Van Larebeke(Vrije Universiteit Brussel), Nuzhat Ahmed(The University of Melbourne), Olugbemiga Ogunkua(Meharry Medical College), P K Krishnakumar(King Fahd University of Petroleum and Minerals), Pankaj Vadgama(Queen Mary University of London), Paola A. Marignani(Dalhousie University), P. Ghosh(University of California, Davis), Patricia Ostrosky‐Wegman(National Institute of Genomic Medicine), Patricia A. Thompson(State University of New York), Paul Dent(Virginia Commonwealth University), Petr Heneberg(Charles University), Philippa D. Darbre(University of Reading), Po Sing Leung(Chinese University of Hong Kong), Pratima Nangia‐Makker(Wayne State University), Qiang Cheng(Southern Illinois University Carbondale), R. Brooks Robey(Dartmouth College), Rabeah Al‐Temaimi(Kuwait University), Rabindra Roy(Georgetown University), Rafaela Andrade-Vieira(Dalhousie University), Ranjeet Kumar Sinha(Scripps Research Institute), Rekha Mehta(Health Canada), Renza Vento(Temple University), Riccardo Di Fiore(University of Palermo), Richard Ponce‐Cusi(University of Tarapacá), Rita Dornetshuber-Fleiss(University of Vienna), Rita Nahta(Emory University), Robert C. Castellino(Emory University), Roberta Palorini(University of Milano-Bicocca), Roslida Abd Hamid(Universiti Putra Malaysia), Sabine A. S. Langie(Flemish Institute for Technological Research), Sakina E. Eltom(Meharry Medical College), Samira A. Brooks(University of North Carolina at Chapel Hill), Sandra Ryeom(University of Pennsylvania), Sandra S. Wise(University of Southern Maine), Sarah Bay(Emory University), Shelley A. Harris(University of Toronto), Silvana Papagerakis(University of Michigan), Simona Romano(University of Naples Federico II), Sofia Pavanello(University of Padua), Staffan Eriksson(Swedish University of Agricultural Sciences), Stefano Forte(Mediterranean University), Stephanie C. Casey(Stanford Medicine), Sudjit Luanpitpong(Siriraj Hospital), Tae Jin Lee(Yeungnam University), Takemi Otsuki(Kawasaki Medical School), Tao Chen(National Center for Toxicological Research), Thierry Massfelder(Inserm), J. Thomas Sanderson(Institut National de la Recherche Scientifique), Tiziana Guarnieri(IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola), Tove Hultman(Swedish University of Agricultural Sciences), Valérian Dormoy(Inserm), Valerie Odero‐Marah(Center for Cancer Research), Venkata Sabbisetti(Brigham and Women's Hospital), Véronique Maguer‐Satta(U.S. Army Center for Health Promotion and Preventive Medicine), W. Kimryn Rathmell(University of North Carolina at Chapel Hill), Wilhelm Engström(Swedish University of Agricultural Sciences), William K. Decker(Baylor College of Medicine), William H. Bisson(Oregon State University), Yon Rojanasakul(West Virginia University), Yunus A. Luqmani(Kuwait University), Zhenbang Chen(Meharry Medical College), Zhiwei Hu(The Ohio State University)
Cited by 317Open Access
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.
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