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

• Main Authors: Goodson III, William H., Lowe, Leroy, Carpenter, David O., Gilbertson, Michael, Ali, Abdul Manaf, Salsamendi, Adela Lopez de Cerain, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K., Collins, Andrew R., Ward, Andrew, Salzberg, Anna C., Colacci, Anna Maria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J., Zhou, Binhua P., Aparicio, Carmen Blanco, Baglole, Carolyn J., Dong, Chenfang, Mondello, Chiara, Chia, Wen Hsu, Naus, Christian C., Yedjou, Clement, Curran, Colleen S., Laird, Dale W., Koch, Daniel C., Carlin, Danielle J., Felsher, Dean W., Roy, Debasish, Brown, Dustin G., Ratovitski, Edward, Ryan, Elizabeth P., Corsini, Emanuela, Rojas, Emilio, Eun, Yi Moon, Laconi, Ezio, Marongiu, Fabio, Al-Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L., Schooten, Frederik J. Van, Goldberg, Gary S., Wagemaker, Gerard, Nangami, Gladys N., Calaf, Gloria M., Williams, Graeme P., Wolf, Gregory T., Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab. Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K., Hsue, Yin Hsu, Hyun, Ho Park, Koturbash, Igor, Miousse, Isabelle R., Scovassi, A. Ivana, Klaunig, James E., Vondrá ček, Jan, Raju, Jayadev, Roman, Jesse, Wise Sr., John Pierce, Whitfield, Jonathan R., Woodrick, Jordan, Christopher, Joseph A., Ochieng, Josiah, Martinez-Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Sun, Jun, Prudhomme, Kalan R., Narayanan, Kannan Badri, Cohen-Solal, Karine A., Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D’Abronzo, Leandro S., Liang, Tzung Lin, Li, Lin, Gulliver, Linda, McCawley, Lisa J., Memeo, Lorenzo, Vermeulen, Louis, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, Maria Fiammetta, Chapellier, Marion, Williams, Marc A., Wade, Mark, Manjili, Masoud H., Lleonart, Matilde E., Xia, Menghang, Gonzalez Guzma, Michael J., Karamouzis, Michalis V., Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B., Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, Larebeke, Nik van, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K., Vadgama, Pankaj, Marignani, Paola A., Ghosh, Paramita M., Ostrosky Wegman, Patricia, Thompson, Patricia A., Dent, Paul, Darbre, Philippa, Heneberg, Petr, Po, Sing Leung, Nangia Makker, Pratima, Cheng, Qiang, Robey, R. Brooks, Al-Temaimi, Rabeah, Roy, Rabindra, Andrade Vieira, Rafaela, Sinha, Ranjeet K., Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce Cusi, Richard, Dornetshuber Fleiss, Rita, Nahta, Rita, Castellino, Robert C., Palorini, Roberta, Abd Hamid @ Abdul Razak, Roslida, Langie, Sabine A. S., Eltom, Sakina E., Brooks, Samira A., Ryeom, Sandra, Wise, Sandra S., Bay, Sarah N., Harris, Shelley A., Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Eriksson, Staffan, Forte, Stefano, Casey, Stephanie C., Luanpitpong, Sudjit, Tae, Jin Lee, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thomas, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Mara, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K., Bisson, William H., Rojanasakul, Yon, Luqmani, Yunus, Chen, Zhenbang, Hu, Zhiwei
• Format: Article
• Language: English
• Published: Oxford University Press 2015
• Online Access: http://psasir.upm.edu.my/id/eprint/43847/1/Assessing%20the%20carcinogenic%20potential%20of%20low-dose%20exposures%20to%20chemical%20mixtures%20in%20the%20.pdf; http://psasir.upm.edu.my/id/eprint/43847/; http://carcin.oxfordjournals.org/content/36/Suppl_1/S254.full.pdf+html

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.