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Review
. 2015 Jun;36 Suppl 1(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

William H Goodson 3rd  1 Leroy Lowe  2 David O Carpenter  3 Michael Gilbertson  4 Abdul Manaf Ali  5 Adela Lopez de Cerain Salsamendi  6 Ahmed Lasfar  7 Amancio Carnero  8 Amaya Azqueta  6 Amedeo Amedei  9 Amelia K Charles  10 Andrew R Collins  11 Andrew Ward  12 Anna C Salzberg  13 Annamaria Colacci  14 Ann-Karin Olsen  15 Arthur Berg  13 Barry J Barclay  16 Binhua P Zhou  17 Carmen Blanco-Aparicio  18 Carolyn J Baglole  19 Chenfang Dong  17 Chiara Mondello  20 Chia-Wen Hsu  21 Christian C Naus  22 Clement Yedjou  23 Colleen S Curran  24 Dale W Laird  25 Daniel C Koch  26 Danielle J Carlin  27 Dean W Felsher  28 Debasish Roy  29 Dustin G Brown  30 Edward Ratovitski  31 Elizabeth P Ryan  30 Emanuela Corsini  32 Emilio Rojas  33 Eun-Yi Moon  34 Ezio Laconi  35 Fabio Marongiu  35 Fahd Al-Mulla  36 Ferdinando Chiaradonna  37 Firouz Darroudi  38 Francis L Martin  39 Frederik J Van Schooten  40 Gary S Goldberg  41 Gerard Wagemaker  42 Gladys N Nangami  43 Gloria M Calaf  44 Graeme Williams  45 Gregory T Wolf  46 Gudrun Koppen  47 Gunnar Brunborg  15 H Kim Lyerly  48 Harini Krishnan  41 Hasiah Ab Hamid  49 Hemad Yasaei  50 Hideko Sone  51 Hiroshi Kondoh  52 Hosni K Salem  53 Hsue-Yin Hsu  54 Hyun Ho Park  55 Igor Koturbash  56 Isabelle R Miousse  56 A Ivana Scovassi  20 James E Klaunig  57 Jan Vondráček  58 Jayadev Raju  59 Jesse Roman  60 John Pierce Wise Sr  61 Jonathan R Whitfield  62 Jordan Woodrick  63 Joseph A Christopher  64 Josiah Ochieng  43 Juan Fernando Martinez-Leal  65 Judith Weisz  66 Julia Kravchenko  48 Jun Sun  67 Kalan R Prudhomme  68 Kannan Badri Narayanan  55 Karine A Cohen-Solal  69 Kim Moorwood  12 Laetitia Gonzalez  70 Laura Soucek  71 Le Jian  72 Leandro S D'Abronzo  73 Liang-Tzung Lin  74 Lin Li  75 Linda Gulliver  76 Lisa J McCawley  77 Lorenzo Memeo  78 Louis Vermeulen  79 Luc Leyns  70 Luoping Zhang  80 Mahara Valverde  33 Mahin Khatami  81 Maria Fiammetta Romano  82 Marion Chapellier  83 Marc A Williams  84 Mark Wade  85 Masoud H Manjili  86 Matilde E Lleonart  87 Menghang Xia  21 Michael J Gonzalez  88 Michalis V Karamouzis  89 Micheline Kirsch-Volders  70 Monica Vaccari  14 Nancy B Kuemmerle  90 Neetu Singh  91 Nichola Cruickshanks  92 Nicole Kleinstreuer  93 Nik van Larebeke  94 Nuzhat Ahmed  95 Olugbemiga Ogunkua  43 P K Krishnakumar  96 Pankaj Vadgama  97 Paola A Marignani  98 Paramita M Ghosh  73 Patricia Ostrosky-Wegman  33 Patricia A Thompson  99 Paul Dent  92 Petr Heneberg  100 Philippa Darbre  101 Po Sing Leung  75 Pratima Nangia-Makker  102 Qiang Shawn Cheng  103 R Brooks Robey  104 Rabeah Al-Temaimi  105 Rabindra Roy  63 Rafaela Andrade-Vieira  98 Ranjeet K Sinha  106 Rekha Mehta  59 Renza Vento  107 Riccardo Di Fiore  108 Richard Ponce-Cusi  109 Rita Dornetshuber-Fleiss  110 Rita Nahta  111 Robert C Castellino  112 Roberta Palorini  37 Roslida Abd Hamid  49 Sabine A S Langie  47 Sakina E Eltom  43 Samira A Brooks  113 Sandra Ryeom  114 Sandra S Wise  61 Sarah N Bay  115 Shelley A Harris  116 Silvana Papagerakis  46 Simona Romano  82 Sofia Pavanello  117 Staffan Eriksson  118 Stefano Forte  78 Stephanie C Casey  26 Sudjit Luanpitpong  119 Tae-Jin Lee  120 Takemi Otsuki  121 Tao Chen  122 Thierry Massfelder  123 Thomas Sanderson  124 Tiziana Guarnieri  125 Tove Hultman  126 Valérian Dormoy  127 Valerie Odero-Marah  128 Venkata Sabbisetti  129 Veronique Maguer-Satta  84 W Kimryn Rathmell  113 Wilhelm Engström  126 William K Decker  130 William H Bisson  68 Yon Rojanasakul  131 Yunus Luqmani  132 Zhenbang Chen  43 Zhiwei Hu  133
Affiliations
Free PMC article
Review

Assessing the Carcinogenic Potential of Low-Dose Exposures to Chemical Mixtures in the Environment: The Challenge Ahead

William H Goodson 3rd et al. Carcinogenesis. .
Free PMC article

Erratum in

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.

Figures

Figure 1.
Figure 1.
Disruptive potential of environmental exposures to mixtures of chemicals. Note that some of the acquired hallmark phenotypes are known to be involved in many stages of disease development, but the precise sequencing of the acquisition of these hallmarks and the degree of involvement that each has in carcinogenesis are factors that have not yet been fully elucidated/defined. This depiction is therefore only intended to illustrate the ways in which exogenous actions might contribute to the enablement of these phenotypes.

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References

    1. (2014) World cancer report 2014. In Wild C.P. and Stewart B.W. (eds). World Health Organization.
    1. Malhotra J. (2014) Molecular and genetic epidemiology of cancer in low- and medium-income countries. Ann. Glob. Health, 80, 418–425. - PubMed
    1. McGuinn L.A., et al. (2012) Cancer and environment: definitions and misconceptions. Environ. Res., 112, 230–234. - PMC - PubMed
    1. Sankpal U.T., et al. (2012) Environmental factors in causing human cancers: emphasis on tumorigenesis. Tumour Biol., 33, 1265–1274. - PubMed
    1. Trosko J.E., et al. (2005) The emperor wears no clothes in the field of carcinogen risk assessment: ignored concepts in cancer risk assessment. Mutagenesis, 20, 81–92. - PubMed

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