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

Journal Article (Journal Article;Review)

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.

Full Text

Duke Authors

Cited Authors

  • Goodson, WH; Lowe, L; Carpenter, DO; Gilbertson, M; Manaf Ali, A; Lopez de Cerain Salsamendi, A; Lasfar, A; Carnero, A; Azqueta, A; Amedei, A; Charles, AK; Collins, AR; Ward, A; Salzberg, AC; Colacci, A; Olsen, A-K; Berg, A; Barclay, BJ; Zhou, BP; Blanco-Aparicio, C; Baglole, CJ; Dong, C; Mondello, C; Hsu, C-W; Naus, CC; Yedjou, C; Curran, CS; Laird, DW; Koch, DC; Carlin, DJ; Felsher, DW; Roy, D; Brown, DG; Ratovitski, E; Ryan, EP; Corsini, E; Rojas, E; Moon, E-Y; Laconi, E; Marongiu, F; Al-Mulla, F; Chiaradonna, F; Darroudi, F; Martin, FL; Van Schooten, FJ; Goldberg, GS; Wagemaker, G; Nangami, GN; Calaf, GM; Williams, G; Wolf, GT; Koppen, G; Brunborg, G; Lyerly, HK; Krishnan, H; Ab Hamid, H; Yasaei, H; Sone, H; Kondoh, H; Salem, HK; Hsu, H-Y; Park, HH; Koturbash, I; Miousse, IR; Scovassi, AI; Klaunig, JE; Vondráček, J; Raju, J; Roman, J; Wise, JP; Whitfield, JR; Woodrick, J; Christopher, JA; Ochieng, J; Martinez-Leal, JF; Weisz, J; Kravchenko, J; Sun, J; Prudhomme, KR; Narayanan, KB; Cohen-Solal, KA; Moorwood, K; Gonzalez, L; Soucek, L; Jian, L; D'Abronzo, LS; Lin, L-T; Li, L; Gulliver, L; McCawley, LJ; Memeo, L; Vermeulen, L; Leyns, L; Zhang, L; Valverde, M; Khatami, M; Romano, MF; Chapellier, M; Williams, MA; Wade, M; Manjili, MH; Lleonart, ME; Xia, M; Gonzalez, MJ; Karamouzis, MV; Kirsch-Volders, M; Vaccari, M; Kuemmerle, NB; Singh, N; Cruickshanks, N; Kleinstreuer, N; van Larebeke, N; Ahmed, N; Ogunkua, O; Krishnakumar, PK; Vadgama, P; Marignani, PA; Ghosh, PM; Ostrosky-Wegman, P; Thompson, PA; Dent, P; Heneberg, P; Darbre, P; Sing Leung, P; Nangia-Makker, P; Cheng, QS; Robey, RB; Al-Temaimi, R; Roy, R; Andrade-Vieira, R; Sinha, RK; Mehta, R; Vento, R; Di Fiore, R; Ponce-Cusi, R; Dornetshuber-Fleiss, R; Nahta, R; Castellino, RC; Palorini, R; Abd Hamid, R; Langie, SAS; Eltom, SE; Brooks, SA; Ryeom, S; Wise, SS; Bay, SN; Harris, SA; Papagerakis, S; Romano, S; Pavanello, S; Eriksson, S; Forte, S; Casey, SC; Luanpitpong, S; Lee, T-J; Otsuki, T; Chen, T; Massfelder, T; Sanderson, T; Guarnieri, T; Hultman, T; Dormoy, V; Odero-Marah, V; Sabbisetti, V; Maguer-Satta, V; Rathmell, WK; Engström, W; Decker, WK; Bisson, WH; Rojanasakul, Y; Luqmani, Y; Chen, Z; Hu, Z

Published Date

  • June 2015

Published In

Volume / Issue

  • 36 Suppl 1 /

Start / End Page

  • S254 - S296

PubMed ID

  • 26106142

Pubmed Central ID

  • PMC4480130

Electronic International Standard Serial Number (EISSN)

  • 1460-2180

Digital Object Identifier (DOI)

  • 10.1093/carcin/bgv039


  • eng

Conference Location

  • England