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

• Type of Material: Article
• Authors: William H. Goodson, lll, California Pacific Medical Center; Leroy Lowe, Getting to Know Cancer; David O. Carpenter, University of Albany; Michael Gilbertson, Getting to Know Cancer; Abdul Manaf Ali, Sultan Zainal Abidin University; Adela Lopez de Cerain Salsamendi, University of Navarra; Ahmed Lasfar, Rutgers State University; Amancio Carnero, University of Seville; Amaya Azqueta, University of Navarra; Amedeo Amedei, University of Florence; Amelia K. Charles, University of Reading; Andrew R. Collins, University of Oslo; Andrew Ward, University of Bath; Anna C. Salzberg, Pennsylvania State University; Anna Maria Colacci, Environmental Protection and Health Prevention Agency; Ann -Karin Olsen, Norwegian Institute of Public Health; Arthur Berg, Pennsylvania State University; Barry J. Barclay, Planet Biotechnologies Inc.; Robert Craig Castellino, Emory University; Rita Nahta, Emory University
• Language: English
• Date: 2015-06-01
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
• Publication Version: Final Published Version
• Copyright Statement: © The Author 2015.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/carcin/bgv039
• Title of Journal or Parent Work: Carcinogenesis
• ISSN: 0143-3334
• Volume: 36
• Issue: Suppl 1
• Start Page: S254
• End Page: S296
• Grant/Funding Information: Complete funding list available in full text.
• Keywords: ACTIVATED PROTEIN-KINASES; ENDOCRINE-DISRUPTING CHEMICALS; Oncology; Life Sciences & Biomedicine; TARGETING TISSUE FACTOR; VASCULAR ENDOTHELIAL-CELLS; Science & Technology; EPITHELIAL-MESENCHYMAL TRANSITION; BREAST-CANCER CELLS; METHOXYCHLOR-INDUCED ALTERATIONS; ESTROGEN-RECEPTOR-ALPHA; MIGRATION INHIBITORY FACTOR; POLYBROMINATED DIPHENYL ETHERS
• Research Categories: Health Sciences, Oncology

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.