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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).

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.

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.

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.

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...

Benchmark dose (BMD) modeling computes the dose associated with a prespecified response level. While offering advantages over traditional points of departure (PODs), such as no-observed-adverse-effect-levels (NOAELs), BMD methods have lacked consistency and transparency in application, interpretation, and reporting in human health assessments of chemicals. We aimed to apply a standardized process for conducting BMD modeling to reduce inconsistencies in model fitting and selection. We evaluated 880 dose-response data sets for 352 environmental chemicals with existing human health assessments. We calculated benchmark doses and their lower limits [10% extra risk, or change in the mean equal to 1 SD (BMD/L10/1SD)] for each chemical in a standardized way with prespecified criteria for model fit acceptance. We identified study design features associated with acceptable model fits. We derived values for 255 (72%) of the chemicals. Batch-calculated BMD/L10/1SD values were significantly and highly correlated (R2 of 0.95 and 0.83, respectively, n = 42) with PODs previously used in human health assessments, with values similar to reported NOAELs. Specifically, the median ratio of BMDs10/1SD:NOAELs was 1.96, and the median ratio of BMDLs10/1SD:NOAELs was 0.89. We also observed a significant trend of increasing model viability with increasing number of dose groups. BMD/L10/1SD values can be calculated in a standardized way for use in health assessments on a large number of chemicals and critical effects. This facilitates the exploration of health effects across multiple studies of a given chemical or, when chemicals need to be compared, providing greater transparency and efficiency than current approaches.

In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) completed a toxicological review of trichloroethylene (TCE) in September 2011, which was the result of an effort spanning > 20 years. We summarized the key findings and scientific issues regarding the human health effects of TCE in the U.S. EPA's toxicological review. In this assessment we synthesized and characterized thousands of epidemiologic, experimental animal, and mechanistic studies, and addressed several key scientific issues through modeling of TCE toxicokinetics, meta-analyses of epidemiologic studies, and analyses of mechanistic data. Toxicokinetic modeling aided in characterizing the toxicological role of the complex metabolism and multiple metabolites of TCE. Meta-analyses of the epidemiologic data strongly supported the conclusions that TCE causes kidney cancer in humans and that TCE may also cause liver cancer and non-Hodgkin lymphoma. Mechanistic analyses support a key role for mutagenicity in TCE-induced kidney carcinogenicity. Recent evidence from studies in both humans and experimental animals point to the involvement of TCE exposure in autoimmune disease and hypersensitivity. Recent avian and in vitro mechanistic studies provided biological plausibility that TCE plays a role in developmental cardiac toxicity, the subject of substantial debate due to mixed results from epidemiologic and rodent studies. TCE is carcinogenic to humans by all routes of exposure and poses a potential human health hazard for noncancer toxicity to the central nervous system, kidney, liver, immune system, male reproductive system, and the developing embryo/fetus.

Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment. Our goal was to explore how next-generation human health risk assessments may better characterize variability in the context of the conceptual framework for the source-to-outcome continuum. This review was informed by a National Research Council workshop titled \"Biological Factors that Underlie Individual Susceptibility to Environmental Stressors and Their Implications for Decision-Making.\" We considered current experimental and in silico approaches, and emerging data streams (such as genetically defined human cells lines, genetically diverse rodent models, human omic profiling, and genome-wide association studies) that are providing new types of information and models relevant for assessing interindividual variability for application to human health risk assessments of environmental chemicals. One challenge for characterizing variability is the wide range of sources of inherent biological variability (e.g., genetic and epigenetic variants) among individuals. A second challenge is that each particular pair of health outcomes and chemical exposures involves combinations of these sources, which may be further compounded by extrinsic factors (e.g., diet, psychosocial stressors, other exogenous chemical exposures). A third challenge is that different decision contexts present distinct needs regarding the identification-and extent of characterization-of interindividual variability in the human population. Despite these inherent challenges, opportunities exist to incorporate evidence from emerging data streams for addressing interindividual variability in a range of decision-making contexts.

DCM was classified as probably carcinogenic to humans (Group 2A) on the basis of limited evidence that it causes biliary-tract cancer and non-Hodgkin lymphoma in humans and sufficient evidence of carcinogenicity in experimental animals (malignant lung and hepatocellular tumours in male and female mice).2,3,6-9 In making its overall assessment, the working group also took into account the strong evidence that DCM metabolism via glutathione-S-transferase T1 (GSTT1) leads to the formation of reactive metabolites, that GSTT1 activity is strongly associated with genotoxicity of DCM in vitro and in vivo, and that GSTT1-mediated metabolism of DCM does occur in humans. DNA reactivity was evident in various genotoxicity assays, including in animals and in human cells in vitro. Because 1,3-PS does not require metabolic activation and reacts directly with DNA and other macromolecules, the working group concluded that this mechanism probably operates both in animals and humans.