@article{3087605,
    title = "Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead",
    author = "Goodson, W.H., III and Lowe, L. and Carpenter, D.O. and Gilbertson, M. and Ali, A.M. and de Cerain Salsamendi, A.L. and Lasfar, A. and Carnero, A. and Azqueta, A. and Amedei, A. and Charles, A.K. and Collins, A.R. and Ward, A. and Salzberg, A.C. and Colacci, A. and Olsen, A.-K. and Berg, A. and Barclay, B.J. and Zhou, B.P. and Blanco-Aparicio, C. and Baglole, C.J. and Dong, C. and Mondello, C. and Hsu, C.-W. and Naus, C.C. and Yedjou, C. and Curran, C.S. and Laird, D.W. and Koch, D.C. and Carlin, D.J. and Felsher, D.W. and Roy, D. and Brown, D.G. and Ratovitski, E. and Ryan, E.P. and Corsini, E. and Rojas, E. and Moon, E.-Y. and Laconi, E. and Marongiu, F. and Al-Mulla, F. and Chiaradonna, F. and Darroudi, F. and Martin, F.L. and Van Schooten, F.J. and Goldberg, G.S. and Wagemaker, G. and Nangami, G. and Calaf, G.M. and Williams, G. and Wolf, G.T. and Koppen, G. and Brunborg, G. and Kim Lyerly, H. and Krishnan, H. and Hamid, H.A. and Yasaei, H. and Sone, H. and Kondoh, H. and Salem, H.K. and Hsu, H.-Y. and Park, H.H. and Koturbash, I. and Miousse, I.R. and Ivana Scovassi, A. and Klaunig, J.E. and Vondráček, J. and Raju, J. and Roman, J. and Wise, J.P., Sr. and Whitfield, J.R. and Woodrick, J. and Christopher, J.A. and Ochieng, J. and Martinez-Leal, J.F. and Weisz, J. and Kravchenko, J. and Sun, J. and Prudhomme, K.R. and Narayanan, K.B. and Cohen-Solal, K.A. and Moorwood, K. and Gonzalez, L. and Soucek, L. and Jian, L. and D'Abronzo, L.S. and Lin, L.-T. and Li, L. and Gulliver, L. and McCawley, L.J. and Memeo, L. and Vermeulen, L. and Leyns, L. and Zhang, L. and Valverde, M. and Khatami, M. and Romano, M.F. and Chapellier, M. and Williams, M.A. and Wade, M. and Manjili, M.H. and Lleonart, M. and Xia, M. and Gonzalez, M.J. and Karamouzis, M.V. and Kirsch-Volders, M. and Vaccari, M. and Kuemmerle, N.B. and Singh, N. and Cruickshanks, N. and Kleinstreuer, N. and Van Larebeke, N. and Ahmed, N. and Ogunkua, O. and Krishnakumar, P.K. and Vadgama, P. and Marignani, P.A. and Ghosh, P.M. and Ostrosky-Wegman, P. and Thompson, P. and Dent, P. and Heneberg, P. and Darbre, P. and Leung, P.S. and Nangia-Makker, P. and Cheng, Q.S. and Brooks Robey, R. and Al-Temaimi, R. and Roy, R. and Andrade-Vieira, R. and Sinha, R.K. and Mehta, R. and Vento, R. and Di Fiore, R. and Ponce-Cusi, R. and Dornetshuber-Fleiss, R. and Nahta, R. and Castellino, R.C. and Palorini, R. and Hamid, R.A. and Langie, S.A.S. and Eltom, S. and Brooks, S.A. and Ryeom, S. and Wise, S.S. and Bay, S.N. and Harris, S.A. and Papagerakis, S. and Romano, S. and Pavanello, S. and Eriksson, S. and Forte, S. and Casey, S.C. and Luanpitpong, S. and Lee, T.-J. and Otsuki, T. and Chen, T. and Massfelder, T. and Sanderson, T. and Guarnieri, T. and Hultman, T. and Dormoy, V. and Odero-Marah, V. and Sabbisetti, V. and Maguer-Satta, V. and Kimryn Rathmell, W. and Engström, W. and Decker, W.K. and Bisson, W.H. and Rojanasakul, Y. and Luqmani, Y. and Chen, Z. and Hu, Z.",
    journal = "Journal of Carcinogenesis",
    year = "2015",
    volume = "36",
    pages = "S254-S296",
    publisher = "Oxford University Press",
    issn = "1477-3163",
    doi = "10.1093/carcin/bgv039",
    keywords = "carcinogen;  acrolein;  acrylamide;  atrazine;  benomyl;  benzo[a]pyrene;  biphenyl;  butyltin;  carbendazim;  carbon;  chlorothalonil;  chlorphenotane;  cobalt;  copper;  cotinine;  cypermethrin;  dichlorvos;  dimpylate;  enilconazole;  environmental chemical;  folpet;  hexachlorobenzene;  iron;  lead;  lindane;  linuron;  paracetamol;  phorbol 13 acetate 12 myristate;  phthalic acid dibutyl ester;  sudan I;  tributyltin;  carcinogen;  dangerous goods, angiogenesis;  Article;  carcinogenesis;  carcinogenicity;  cell death;  cell proliferation;  DNA damage;  DNA repair;  dose response;  environmental exposure;  metastasis;  phenotype;  phenotypic variation;  priority journal;  risk assessment;  tumor microenvironment;  basic research;  cancer resistance;  cell stress;  cholesterol metabolism;  concentration response;  cytokine production;  environmental factor;  enzyme activation;  genomic instability;  heredity;  human;  inflammation;  lipid metabolism;  metabolic disorder;  mitochondrion;  molecular mechanics;  natural killer cell;  oxidative stress;  Review;  signal transduction;  tumor escape;  tumor invasion;  adverse effects;  animal;  carcinogenesis;  chemically induced;  dangerous goods;  environmental exposure;  Neoplasms, Animals;  Carcinogenesis;  Carcinogens, Environmental;  Environmental Exposure;  Hazardous Substances;  Humans;  Neoplasms",
    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. © The Author 2015."
}