Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, ...cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.
In human beings, observational data showed slight but statistically significant associations with APC gene mutation or promoter methylation that were identified in 75 (43%) and 41 (23%) of 185 ...archival colorectal cancer samples, respectively.17 Consuming well done cooked red meat increases the bacterial mutagenicity of human urine. In three intervention studies in human beings, changes in oxidative stress markers (either in urine, faeces, or blood) were associated with consumption of red meat or processed meat.18 Red and processed meat intake increased lipid oxidation products in rodent faeces.13 Substantial supporting mechanistic evidence was available for multiple meat components (NOC, haem iron, and HAA).
Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, ...the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as “carcinogenic to humans” (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzoapyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzoapyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments.
Occupational use was associated with an increased risk of prostate cancer in a Canadian case-control study8 and in the AHS, which reported a significant trend for aggressive cancers after adjustment ...for other pesticides.9 In mice, malathion increased hepatocellular adenoma or carcinoma (combined).10 In rats, it increased thyroid carcinoma in males, hepatocellular adenoma or carcinoma (combined) in females, and mammary gland adenocarcinoma after subcutaneous injection in females.4 Malathion is rapidly absorbed and distributed. Red meat and processed meat Monograph Working Group Members A Blair (USA)--Meeting Chair; L Fritschi (Australia); J McLaughlin; C M Sergi (Canada); G M Calaf (Chile); F Le Curieux (Finland); I Baldi (France); F Forastiere (Italy); H Kromhout (Netherlands); A 't Mannetje (New Zealand); T Rodriguez unable to attend (Nicaragua); P Egeghy unable to attend, G D Jahnke; C W Jameson; M T Martin; M K Ross; I Rusyn; L Zeise (USA) Invited Specialists C Portier (Switzerland) Representatives M E Gouze, for the French Agency for Food, Environment and Occupational Health and Safety (France); J Rowland, for the US Environmental Protection Agency (USA) Observers M K Boye Jensen, for Cheminova (Denmark); B Fervers, for the Léon Bérard Centre (France); E Giroux, for University Jean-Moulin Lyon 3 (France); T Sorahan, for Monsanto Company (USA); C Strupp, for the European Crop Protection Association (Belgium); P Sutton, for the University of California, San Francisco (USA) IARC/WHO Secretariat L Benbrahim-Tallaa; R Carel; F El Ghissassi; Sonia El-Zaemey; Y Grosse; N Guha; K Z Guyton; C Le Cornet; M Leon; D Loomis; H Mattock; C Scoccianti; A Shapiro; K Straif; J Zavadil For the Preamble to the IARC Monographs see http://monographs.iarc.fr/ENG/Preamble/index.php For declarations of interests see http://monographs.iarc.fr/ENG/Meetings/vol112-participants.pdf We declare no competing interests.
For bladder cancer, there was no consistent evidence of an association with drinking coffee, or of an exposure-response gradient from ten cohort studies and several population-based case-control ...studies in Europe, the USA, and Japan.3-5 In several studies, relative risks were increased in men but were null or decreased in women, consistent with residual confounding from smoking or occupational exposures among men. Welding, welding fumes and some related chemicals IARC Monograph Working Group Members L T Stayner (USA)--meeting chair; E Milne (Australia); S Knasmüller (Austria); A Farah, L F Ribeiro Pinto (Brazil); D W Lachenmeier (Germany); C Bamia (Greece); A Tavani (Italy); M Inoue (Japan); N Djordjevic (Serbia); P C H Hollman, P A van den Brandt (Netherlands); J A Baron, E Gonzalez de Mejia, F Islami (unable to attend); C W Jameson, F Kamangar, D L McCormick, I Pogribny, I I Rusyn, R Sinha, M C Stern, K M Wilson (USA) Declaration of interests MI is the beneficiary of a financial contribution from AXA Research fund as chair holder of the AXA Department of Health and Human Security, Graduate School of Medicine, The University of Tokyo from Nov 1, 2012.
A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts ...A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens.
IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens.
These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply.
We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program.
Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.
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Two of three studies that assessed risk by duration of employment as a welder showed positive trends.3,4 These studies also showed increased ocular melanoma risk associated with eye burns-a proxy for ...UV exposure-and one reported a positive exposure-response association for cumulative occupational exposure to artificial UV radiation, including welding.3,4 Risks persisted after adjustment for sun exposure, sun bed use, or both.4-6 Welding fumes are produced when metals heated above their melting point vaporise and condense to fine particles (mostly <1 μm in size). In one oropharyngeal aspiration study and one inhalation study in male A/J mice, gas metal arc-stainless steel welding fumes promoted 3-methylcholanthrene-induced lung tumours.13,14 Absorption and excretion of metals (chromium, nickel, and manganese) was shown in people exposed to welding fumes, but data for particle deposition and clearance in welders were scarce. 2 International Agency for Research on Cancer, Chromium, nickel and welding, IARC Monogr Eval Carcinog Risks Hum, Vol. 49, 1990, 1-648 3 CM Vajdic, A Kricker, M Giblin, Artificial ultraviolet radiation and ocular melanoma in Australia, Int J Cancer, Vol. 112, 2004, 896-900 4 P Guenel, L Laforest, D Cyr, Occupational risk factors, ultraviolet radiation, and ocular melanoma: a case-control study in France, Cancer Causes Control, Vol. 12, 2001, 451-459 5 EA Holly, DA Aston, DK Ahn, AH Smith, Intraocular melanoma linked to occupations and chemical exposures, Epidemiology, Vol. 7, 1996, 55-61 6 JM Seddon, ES Gragoudas, RJ Glynn, KM Egan, DM Albert, PH Blitzer, Host factors, UV radiation, and risk of uveal melanoma. A case-control...
Occupational exposures associated with the Acheson process were classified as carcinogenic to humans (Group 1) on the basis of sufficient evidence in humans that they cause lung cancer. Since the ...correlation between exposures to SiC fibres and cristobalite made it difficult to disentangle their independent effects, the Working Group concluded that fibrous SiC is possibly carcinogenic to humans (Group 2B) based on limited evidence in humans that it causes lung cancer. Furthermore, the lack of coherent evidence across the various distinct CNTs precluded generalisation to other types of CNTs. ...MWCNT-7 was classified as possibly carcinogenic to humans (Group 2B); and SWCNTs and MWCNTs excluding MWCNT-7 were categorised as not classifiable as to their carcinogenicity to humans (Group 3).
The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International ...Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE.
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