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

William H Goodson (1) , Leroy Lowe (1) , David O Carpenter (1) , Michael Gilbertson (1) , Abdul Manaf Ali (1) , Adela Lopez de Cerain Salsamendi (1) , Ahmed Lasfar (1) , Amancio Carnero (1) , Amaya Azqueta (1) , Amedeo Amedei (1) , Amelia K Charles (1) , Andrew R Collins (1) , Andrew Ward (1) , Anna C Salzberg (1) , Annamaria Colacci (1) , Ann-Karin Olsen (1) , Arthur Berg (1) , Barry J Barclay (1) , Binhua P Zhou (1) , Carmen Blanco-Aparicio (1) , Carolyn J Baglole (1) , Chenfang Dong (1) , Chiara Mondello (1) , Chia-Wen Hsu (1) , Christian C Naus (1) , Clement Yedjou (1) , Colleen S Curran (1) , Dale W Laird (1) , Daniel C Koch (1) , Danielle J Carlin (1) , Dean W Felsher (1) , Debasish Roy (1) , Dustin G Brown (1) , Edward Ratovitski (1) , Elizabeth P Ryan (1) , Emanuela Corsini (1) , Emilio Rojas (1) , Eun-Yi Moon (1) , Ezio Laconi (1) , Fabio Marongiu (1) , Fahd Al-Mulla (1) , Ferdinando Chiaradonna (1) , Firouz Darroudi (1) , Francis L. Martin (1) , Frederik J van Schooten (1) , Gary S Goldberg (1) , Gerard Wagemaker (1) , Gladys N Nangami (1) , Gloria M Calaf (1) , Graeme Williams (1) , Gregory T Wolf (1) , Gudrun Koppen (1) , Gunnar Brunborg (1) , H Kim Lyerly (1) , Harini Krishnan (1) , Hasiah Ab Hamid (1) , Hemad Yasaei (1) , Hideko Sone (1) , Hiroshi Kondoh (1) , Hosni K Salem (1) , Hsue-Yin Hsu (1) , Hyun Ho Park (1) , Igor Koturbash (1) , Isabelle R Miousse (1) , a Ivana Scovassi (1) , James E Klaunig (1) , Jan Vondráček (1) , Jayadev Raju (1) , Jesse Roman (1) , John Pierce Wise (1) , Jonathan R Whitfield (1) , Jordan Woodrick (1) , Joseph A Christopher (1) , Josiah Ochieng (1) , Juan Fernando Martinez-Leal (1) , Judith Weisz (1) , Julia Kravchenko (1) , Jun Sun (1) , Kalan R Prudhomme (1) , Kannan Badri Narayanan (1) , Karine A Cohen-Solal (1) , Kim Moorwood (1) , Laetitia Gonzalez (1) , Laura Soucek (1) , Le Jian (1) , Leandro S d'Abronzo (1) , Liang-Tzung Lin (1) , Lin Li (1) , Linda Gulliver (1) , Lisa J Mccawley (1) , Lorenzo Memeo (1) , Louis Vermeulen (1) , Luc Leyns (1) , Luoping Zhang (1) , Mahara Valverde (1) , Mahin Khatami (1) , Maria Fiammetta Romano (1) , Marion Chapellier (2) , Marc A Williams (1) , Mark Wade (1) , Masoud H Manjili (1) , Matilde E Lleonart (1) , Menghang Xia (1) , Michael J Gonzalez (1) , Michalis V Karamouzis (1) , Micheline Kirsch-Volders (1) , Monica Vaccari (1) , Nancy B Kuemmerle (1) , Neetu Singh (1) , Nichola Cruickshanks (1) , Nicole Kleinstreuer (1) , Nik van Larebeke (1) , Nuzhat Ahmed (1) , Olugbemiga Ogunkua (1) , P K Krishnakumar (1) , Pankaj Vadgama (1) , Paola A Marignani (1) , Paramita M Ghosh (1) , Patricia Ostrosky-Wegman (1) , Patricia A Thompson (1) , Paul Dent (1) , Petr Heneberg (1) , Philippa Darbre (1) , Po Sing Leung (1) , Pratima Nangia-Makker (1) , Qiang Shawn Cheng (1) , R Brooks Robey (1) , Rabeah Al-Temaimi (1) , Rabindra Roy (1) , Rafaela Andrade-Vieira (1) , Ranjeet K Sinha (1) , Rekha Mehta (1) , Renza Vento (1) , Riccardo Di Fiore (1) , Richard Ponce-Cusi (1) , Rita Dornetshuber-Fleiss (1) , Rita Nahta (1) , Robert C Castellino (1) , Roberta Palorini (1) , Roslida Abd Hamid (1) , Sabine a S Langie (1) , Sakina E Eltom (1) , Samira A Brooks (1) , Sandra Ryeom (1) , Sandra S Wise (1) , Sarah N Bay (1) , Shelley A Harris (1) , Silvana Papagerakis (1) , Simona Romano (1) , Sofia Pavanello (1) , Staffan Eriksson (1) , Stefano Forte (1) , Stephanie C Casey (1) , Sudjit Luanpitpong (1) , Tae-Jin Lee (1) , Takemi Otsuki (1) , Tao Chen (1) , Thierry Massfelder (3) , Thomas Sanderson (4) , Tiziana Guarnieri (1) , Tove Hultman (1) , Valérian Dormoy (3) , Valerie Odero-Marah (1) , Venkata Sabbisetti (1) , Veronique Maguer-Satta (1) , W Kimryn Rathmell (1) , Wilhelm Engström (1) , William K Decker (1) , William H Bisson (1) , Yon Rojanasakul (1) , Yunus Luqmani (1) , Zhenbang Chen (1) , Zhiwei Hu (1)

1 Sans affiliation
2 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
3 UNISTRA - Université de Strasbourg
4 INRS-IAF - Institut Armand Frappier

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.

Domains: Life Sciences [q-bio]; Cancer; Health

William H Goodson, Leroy Lowe, David O Carpenter, Michael Gilbertson, Abdul Manaf Ali, et al.. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.. Carcinogenesis, 2015, 36 (Suppl 1), pp.S254-96. ⟨10.1093/carcin/bgv039⟩. ⟨pasteur-01352152⟩