Recent publications on the KC Framework
*Arose from work led by UC Berkeley
Rusyn et al. (2021). “Key Characteristics of Human Hepatotoxicants as a Basis for Identification and Characterization of the Causes of Liver Toxicity”. 2021 Jun 9. Online ahead of print. PMID: 34105804 DOI: 10.1002/hep.31999
Abstract: Hazard identification regarding adverse effects on the liver is a critical step in safety evaluations of drugs and other chemicals. Current testing paradigms for hepatotoxicity rely heavily on pre-clinical studies in animals and human data (epidemiology and clinical trials). Mechanistic understanding of the molecular and cellular pathways that may cause or exacerbate hepatotoxicity is well advanced, and holds promise for identification of hepatotoxicants. One of the challenges in translating mechanistic evidence into robust decisions about potential hepatotoxicity is the lack of a systematic approach to integrate these data to help identify liver toxicity hazards. Recently, marked improvements were achieved in the practice of hazard identification of carcinogens, female and male reproductive toxicants, and endocrine disrupting chemicals using the key characteristics approach. Here, we describe the methods by which key characteristics of human hepatotoxicants were identified and provide examples for how they could be used to systematically identify, organize and utilize mechanistic data when identifying hepatotoxicants.
Barupal et al., (2021). “Prioritizing cancer hazard assessments for IARC Monographs using an integrated approach of database fusion and text mining”. Environ Int. 156:106624. Online ahead of print May 10. PMID: 33984576 doi: 10.1016/j.envint.2021.106624.
Abstract: Background: Systematic evaluation of literature data on the cancer hazards of human exposures is an essential process underlying cancer prevention strategies. The scope and volume of evidence for suspected carcinogens can range from very few to thousands of publications, requiring a complex, systematically planned, and critical procedure to nominate, prioritize and evaluate carcinogenic agents. To aid in this process, database fusion, cheminformatics and text mining techniques can be combined into an integrated approach to inform agent prioritization, selection, and grouping.
Results: We have applied these techniques to agents recommended for the IARC Monographs evaluations during 2020-2024. An integration of PubMed filters to cover cancer epidemiology, key characteristics of carcinogens, chemical lists from 34 databases relevant for cancer research, chemical structure grouping and a literature data-based clustering was applied in an innovative approach to 119 agents recommended by an advisory group for future IARC Monographs evaluations. The approach also facilitated a rational grouping of these agents and aids in understanding the volume and complexity of relevant information, as well as important gaps in coverage of the available studies on cancer etiology and carcinogenesis.
Conclusion: A new data-science approach has been applied to diverse agents recommended for cancer hazard assessments, and its applications for the IARC Monographs are demonstrated. The prioritization approach has been made available at www.cancer.idsl.me site for ranking cancer agents.
Madia et al., (2021). “Integration of data across toxicity endpoints for improved safety assessment of chemicals: the example of carcinogenicity assessment”. Arch Tox. 95(6):1971-1993 PMID: 33830278. doi: 10.1007/s00204-021-03035-x. Online ahead of print.
Abstract: In view of the need to enhance the assessment of consumer products called for in the EU Chemicals Strategy for Sustainability, we developed a methodology for evaluating hazard by combining information across different systemic toxicity endpoints and integrating the information with new approach methodologies. This integrates mechanistic information with a view to avoiding redundant in vivo studies, minimising reliance on apical endpoint tests and ultimately devising efficient testing strategies. Here, we present the application of our methodology to carcinogenicity assessment, mapping the available information from toxicity test methods across endpoints to the key characteristics of carcinogens. Test methods are deconstructed to allow the information they provide to be organised in a systematic way, enabling the description of the toxicity mechanisms leading to the adverse outcome. This integrated approach provides a flexible and resource-efficient means of fully exploiting test methods for which test guidelines are available to fulfil regulatory requirements for systemic toxicity assessment as well as identifying where new methods can be integrated.
*Rider CV et al. (2021). “Using the Key Characteristics of Carcinogens to Develop Research on Chemical Mixtures and Cancer”. Environmental Health Perspectives. 129(3):35003. Epub 2021 Mar 30. PMID: 33784186. doi: 10.1289/EHP8525.
Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design. Objectives: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches. Methods: A working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development. Results and Discussion: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed.
McKeon et al. (2021). “Environmental exposomics and lung cancer risk assessment in the Philadelphia metropolitan area using ZIP code–level hazard indices”. Environmental Science and Pollution Research. PMID: 33611735. doi: 10.1007/s11356-021-12884-z. Online ahead of print.
Abstract: To illustrate methods for assessing environmental exposures associated with lung cancer risk, we investigated anthropogenic based air pollutant data in a major metropolitan area using United States-Environmental Protection Agency (US-EPA) Toxic Release Inventory (TRI) (1987-2017), and PM2.5 (1998-2016) and NO2 (1996-2012) concentrations from NASA satellite data. We studied chemicals reported according to the following five exposome features: (1) International Agency for Research on Cancer (IARC) cancer grouping; (2) priority EPA polycyclic aromatic hydrocarbons (PAHs); (3) component of diesel exhaust; (4) status as a volatile organic compound (VOC); and (5) evidence of lung carcinogenesis. Published articles from PubChem were tallied for occurrences of 10 key characteristics of cancer-causing agents on those chemicals. Zone Improvement Plan (ZIP) codes with higher exposures were identified in two ways: (1) combined mean exposure from all features, and (2) hazard index derived through a multi-step multi-criteria decision analysis (MMCDA) process. VOCs, IARC Group 1 carcinogens consisted 82.3% and 11.5% of the reported TRI emissions, respectively. ZIP codes along major highways tended to have greater exposure. The MMCDA approach yielded hazard indices based on imputed toxicity, occurrence, and persistence for risk assessment. Despite many studies describing environmental exposures and lung cancer risk, this study develops a method to integrate these exposures into population-based exposure estimates that could be incorporated into future lung cancer screening trials and benefit public health surveillance of lung cancer incidence. Our methodology may be applied to probe other hazardous exposures for other cancers.
Gualtieri AF (2021). “Bridging the gap between toxicity and carcinogenicity of mineral fibres by connecting the fibre crystal-chemical and physical parameters to the key characteristics of cancer”. Current Research in Toxicology. 2:42-52. https://doi.org/10.1016/j.crtox.2021.01.005
Airborne fibres and particularly asbestos represent hazards of great concern for human health because exposure to these peculiar particulates may cause malignancies such as lung cancer and mesothelioma. Currently, many researchers worldwide are focussed on fully understanding the patho-biological mechanisms leading to carcinogenesis prompted by pathogenic fibres. Along this line, the present work introduces a novel approach to correlate how and to what extent the physical/crystal-chemical and morphological parameters (including length, chemistry, biodurability, and surface properties) of mineral fibres cause major adverse effects with an emphasis on asbestos. The model described below conceptually attempts to bridge the gap between toxicity and carcinogenicity of mineral fibres and has several implications: 1) it provides a tool to measure the toxicity and pathogenic potential of asbestos minerals, allowing a quantitative rank of the different types (e.g. chrysotile vs. crocidolite); 2) it can predict the toxicity and pathogenicity of “unregulated” or unclassified fibres; 3) it reveals the parameters of a mineral fibre that are active in stimulating key characteristics of cancer, thus offering a strategy for developing specific cancer prevention strategies and therapies.
Chappell et al. (2021). “Lack of potential carcinogenicity for steviol glycosides – Systematic evaluation and integration of mechanistic data into the totality of evidence.” Food Chem Toxicol. 2021 Feb 12;112045. PMID: 33587976. DOI: 10.1016/j.fct.2021.112045
Steviol glycosides are present in the leaves of the Stevia rebaudiana plant, have a sweet taste, and have been used as a sweetener for centuries. To build on previous authoritative safety assessments of steviol glycosides, a systematic assessment of mechanistic data related to key characteristics of carcinogens (KCCs) was conducted. Over 900 KCC-relevant endpoints from peer-reviewed literature and high-throughput screening data (ToxCast/Tox21) were identified across individual steviol glycosides and derivatives, metabolites, and whole leaf extracts. Most data (both in vivo and in vitro, including human cells), showed inactivity. Studies were weighted according to quality and relevance. Although data were available for eight of the ten KCC, genotoxicity, oxidative stress, inflammation, and cell proliferation/cell death represent the KCCs with the most data. The data for these KCC primarily show beneficial activity (anti-inflammatory, antioxidant, and anti-proliferative). Following integration across all data, and accounting for study quality and relevance, the totality of the evidence demonstrated an overall lack of genotoxic and carcinogenic activity for steviol glycosides. This is in agreement with previous regulatory decisions, and is consistent with the lack of tumor response in two-year rodent cancer bioassays. The findings support prior conclusions that steviol glycosides are unlikely to be carcinogenic in humans.
Chappell et al. (2021). Assessment of mechanistic data for hexavalent chromium-induced rodent intestinal cancer using the key characteristics of carcinogens. Toxicol Sci. Jan 6;kfaa187. PMID: 33404626. DOI: 10.1093/toxsci/kfaa187
Oral exposure to hexavalent chromium (Cr(VI)) induces intestinal tumors in mice. Mutagenic and non-mutagenic modes of action (MOAs) have been accepted by different regulatory bodies globally, the latter involving cytotoxicity-induced regenerative cell proliferation. However, concerns persist that all possible MOAs have not been fully considered. To address the potential for alternative MOAs, mechanistic data not represented in the existing two MOAs were evaluated. Relevant data were identified and organized by key characteristics of carcinogens (KCCs); literature related to epigenetics, immunosuppression, receptor-mediated effects, and immortalization were reviewed to identify potential key events associated with an alternative MOA. Over 200 references were screened for these four KCCs and further prioritized based on relevance to the research objective (i.e., in vivo, oral exposure, gastrointestinal tissue). Minimal data were available specific to the intestine for these KCCs, and there was no evidence of any underlying mechanisms or key events that are not already represented in the two proposed MOAs. For example, while epigenetic dysregulation of DNA repair genes has been demonstrated, epigenetic effects were not measured in intestinal tissue, and it has been shown that Cr(VI) does not cause DNA damage in intestinal tissue. High-throughput screening (HTS) data related to the KCCs were also evaluated, with activity generally limited to the two recognized MOAs. Collectively, no plausible alternative MOAs (or key events) were identified in addition to those previously proposed for Cr(VI) SI tumors.
Vandenberg and Bugos (2021). “Assessing the Public Health Implications of the Food Preservative Propylparaben: Has This Chemical Been Safely Used for Decades?” Curr Environ Health Rep. doi: 10.1007/s40572-020-00300-6. PMID: 33415721. DOI: 10.1007/s40572-020-00300-6
Purpose: Parabens are chemicals containing alkyl-esters of p-hydroxybenzoic acid, which give them antimicrobial, antifungal, and preservative properties. Propylparaben (PP) is one paraben that has been widely used in personal care products, cosmetics, pharmaceuticals, and food. In this review, we address the ongoing controversy over the safety of parabens, and PP specifically. These chemicals have received significant public attention after studies published almost 20 years ago suggested plausible associations between PP exposures and breast cancer.
Recent findings: Here, we use key characteristics, a systematic approach to evaluate the endocrine disrupting properties of PP based on features of “known” endocrine disruptors, and consider whether its classification as a “weak” estrogen should alleviate public health concerns over human exposures. We also review the available evidence from rodent and human studies to illustrate how the large data gaps that exist in hazard assessments raise concerns about current evaluations by regulatory agencies that PP use is safe. Finally, we address the circular logic that is used to suggest that because PP has been used for several decades, it must be safe. We conclude that inadequate evidence has been provided for the safe use of PP in food, cosmetics, and consumer products.
Vandenberg et al. (2020). “Agrochemicals with estrogenic endocrine disrupting properties: Lessons Learned?” Mol Cell Endocrinol. Dec 1;518:110860. doi: 10.1016/j.mce.2020.110860. PMID: 32407980. DOI: 10.1016/j.mce.2020.110860
Many agrochemicals have endocrine disrupting properties. A subset of these chemicals is characterized as “estrogenic”. In this review, we describe several distinct ways that chemicals used in crop production can affect estrogen signaling. Using three agrochemicals as examples (DDT, endosulfan, and atrazine), we illustrate how screening tests such as the US EPA’s EDSP Tier 1 assays can be used as a first-pass approach to evaluate agrochemicals for endocrine activity. We then apply the “Key Characteristics” approach to illustrate how chemicals like DDT can be evaluated, together with the World Health Organization’s definition of an endocrine disruptor, to identify data gaps. We conclude by describing important issues that must be addressed in the evaluation and regulation of hormonally active agrochemicals including mixture effects, efforts to reduce vertebrate animal use, chemical prioritization, and improvements in hazard, exposure, and risk assessments.
Guyton and Smith (2020). “Identifying carcinogens from 10 key characteristics: A new approach based on mechanisms”. In: World Cancer Report: Cancer Research for Cancer Prevention, Chapter 3.11, pp.177-183, Wild CP, Weiderpass E, Stewart BW, editors, Published by the International Agency for Research on Cancer, Lyon, France. Available from: http://publications.iarc.fr/586.
*Guo et al. (2020). “Benzene-associated immunosuppression and chronic inflammation in humans: a systematic review.” Occup Environ Med 2020;oemed-2020-106517.
Objective: Recent evidence has accumulated that the immune system is intimately intertwined with cancer development. Two key characteristics of carcinogens in which the immune system plays a central role are chronic inflammation and immunosuppression. In this systematic review, we investigated the association of chronic inflammatory and immunosuppressive outcomes with benzene, a widely used industrial chemical. Benzene has been confirmed to cause acute myeloid leukaemia and suspected to cause non-Hodgkin lymphoma, two cancers of the blood-forming system that affect immune cells. Methods: We systematically searched PubMed and Embase for all relevant studies using a combination of Medical Subject Headings (MeSH) and selected key words. The detailed review protocol, including search strategy, was registered with PROSPERO, the international prospective register of systematic reviews (#CRD42019138611). Results: Based on all human studies selected in the final review, we report new evidence of a benzene-induced immunosuppressive effect on the adaptive immune system and activation of the innate immune system to cause inflammation. In particular, benzene significantly lowers the number of white blood cells, particularly lymphocytes such as CD4+ T-cells, B-cells and natural killer cells, and increases proinflammatory biomarkers at low levels of exposure.
Conclusion: To the best of our knowledge, this is the first comprehensive review of benzene’s immunotoxicity in humans. Based on results obtained from this review, we propose two potential immunotoxic mechanisms of how benzene induces leukaemia/lymphoma: (1) cancer invasion caused by proinflammatory cytokine production, and (2) cancer promotion via impaired immunosurveillance. Further studies will be required to confirm the connection between benzene exposure and its effects on the immune system.
Sone et al. (2020). “Hazard evaluation of air pollution by using the key characteristics approach.” IOP Conf. Ser.: Earth Environ. Sci. 496 012004.
The key characteristic (KC) as a new approach based on mechanistic evidence has been shown by the IARC Monographs Program working group. Human carcinogens like exhibit one or more key characteristics that are related to how they cause cancer, and different carcinogenic agents exhibit different spectra of these key characteristics. Air pollution is one of the major concerns of human health for the people who lives in Asia because air pollution contains many different human carcinogens including heavy metals, volatile compounds. electrophile compounds and polyaromatic hydrocarbon compounds. In this study, weinvestigated air pollution mixtures derived from diesel and gasoline engine exhausts by a mechanism-based approach. We first conducted a KC analysis of organic compounds of diesel exhaust in IARC monograph 105 using data of biological test results from the PubChem database. As a result, it was found that some PAH among those compounds is highly responsive to aryl hydrocarbon receptor, nuclear factor erythroid 2 like 2, NR1I2/3 nuclear receptor subfamily 1 group I member 2/3. Further, we analyzed KCs of water-extract mixtures from diesel exhaust particle (DEP-WM) using gene expression values in the mouse lung responded induced by exposures to DEP-WM. The KC of DEP-WM showed lipid related-nuclear receptor signaling and apoptotic pathway, suggesting that DEP-WM affects lipid metabolism in lung tissues. Thus, the KC method will be useful for high-precision assessment of a mixture of air pollution.
Calaf et al. (2020). “Endocrine disruptors from the environment affecting breast cancer (Review).” Oncology Letters 20: 19-32.
Evaluation of carcinogenic substances from the environment is a challenge for scientists. Recently, a novel approach based on 10 key characteristics of human carcinogens classified by the International Agency for Research on Cancer (IARC) has emerged. Carcinogenesis depends on different mechanisms and factors, including genetic, infectious (bacteria, viruses) and environmental (chemicals) factors. Endocrine disruptors are exogenous chemicals that can interfere and impair the function of the endocrine system due to their interaction with estrogen receptors or their estrogen signaling pathways inducing adverse effects in the normal mammary development, originating cancer. They are heterogeneous chemicals and include numerous synthetic substances used worldwide in agriculture, industry and consumer products. The most common are plasticizers, such as bisphenol A (BPA), pesticides, such as dichlorodiphenyltrichloroethane, and polychlorinated biphenyls (PCBs). Xenoestrogens appear to serve an important role in the increased incidence of breast cancer in the United States and numerous other countries. Several studies have demonstrated the role of organochlorine xenoestrogens in breast cancer. Therefore, the overall cumulative exposure of women to estrogens results in an increased risk for this type of cancer. Factors like lifestyle and diet also serve a role in the increased incidence of this disease. The aim of the present study was to analyze these chemical compounds based on the key characteristics given by the IARC, with a special focus on breast cancer, to establish whether these compounds are carcinogens, and to create a model for future analysis of other endocrine disruptors. doi: 10.1007/s10911-013-9275-7
Chappell G. A. et al. (2020). Lack of potential carcinogenicity for acesulfame potassium–Systematic evaluation and integration of mechanistic data into the totality of the evidence. Food and Chemical Toxicology 141: 111375
The safety of low- and no-calorie sweeteners remains a topic of general interest. Substantial evidence exists demonstrating a lack of carcinogenicity of the no-calorie sweetener acesulfame potassium (Ace K). The objective of this evaluation was to conduct a systematic assessment of available mechanistic data using a framework that quantitatively integrates proposed key characteristics of carcinogens (KCCs) into the totality of the evidence. Over 800 KCC-relevant endpoints from a variety of in vitro and in vivo assays were assessed for quality, relevance, and activity, and integrated to determine the overall strength of the evidence for plausibility that Ace K acts through the KCC. Overall, there was a lack of activity across the KCCs (overall integrated score <0 and no “strong” categorization for evidence of activity) in which data were identified. Together with the absence of treatment-related tumor effects in rodent bioassays, these results support the conclusion that Ace K is unlikely to induce a carcinogenic response. This assessment employed a weight of the evidence analysis that includes the consideration of factors such as reliability, strength of the model system, activity, and dose in a complex and heterogeneous dataset, and the ultimate integration of multiple data streams in the cancer hazard evaluation.
*La Merrill, M. A., et al. (2020). “Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification.” Nat Rev Endocrinol 16(1): 45-57.
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.
*Smith, M. T. et al. (2020). “The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them.” Cancer Epidemiol Biomarkers Prev. https://doi.org/10.1158/1055-9965.EPI-19-1346
Background: The key characteristics (KCs) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. Methods: We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and an examination of the literature to more clearly describe each KC; identify current and emerging assays and in vivo biomarkers that can be used to measure them; and, make recommendations for future assay development. Results: We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro. We identified gaps in coverage of the KCs by current assays. Conclusion: Future efforts should expand the breadth, specificity and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Impact: Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention.
Temkin, A. M. et al. (2020). “Application of the key characteristics of carcinogens to Per and Polyfluoroalkyl Substances.” Int Journal Env Res and Public Health 17, 1668.
Per- and polyfluoroalkyl substances (PFAS) constitute a large class of environmentally persistent chemicals used in industrial and consumer products. Human exposure to PFAS is extensive, and PFAS contamination has been reported in drinking water and food supplies as well as in the serum of nearly all people. The most well-studied member of the PFAS class, perfluorooctanoic acid (PFOA), induces tumors in animal bioassays and has been associated with elevated risk of cancer in human populations. GenX, one of the PFOA replacement chemicals, induces tumors in animal bioassays as well. Using the Key Characteristics of Carcinogens framework for cancer hazard identification, we considered the existing epidemiological, toxicological and mechanistic data for 26 different PFAS. We found strong evidence that multiple PFAS induce oxidative stress, are immunosuppressive, and modulate receptor-mediated effects. We also found suggestive evidence indicating that some PFAS can induce epigenetic alterations and influence cell proliferation. Experimental data indicate that PFAS are not genotoxic and generally do not undergo metabolic activation. Data are currently insufficient to assess whether any PFAS promote chronic inflammation, cellular immortalization or alter DNA repair. While more research is needed to address data gaps, evidence exists that several PFAS exhibit one or more of the key characteristics of carcinogens. https://doi.org/10.3390/ijerph17051668
Wikoff, D. S. et al. (2020). Lack of potential carcinogenicity for aspartame–Systematic evaluation and integration of mechanistic data into the totality of the evidence. Food and Chemical Toxicology 135: 110866
Despite repeated confirmation of aspartame safety in a variety of foods and beverages, there continues to be interest in researching the potential carcinogenic risk associated with its consumption. The objective of this evaluation was to conduct a systematic assessment of available mechanistic data using a framework for quantitatively integrating the key characteristics of carcinogens (KCCs). For aspartame, 1332 endpoints were appraised for quality and relevance and quantitatively integrated using an algorithm to determine the potential for individual KCC activity based on all available evidence, and subsequently assessed in the context of human and animal evidence streams. An overall lack of activity (integrated scores <0 and no “strong” categorizations) was observed for all KCCs except oxidative stressor (#5), for which activity was determined to be unlikely to be related to a carcinogenic response. Overall, the KCC-based analysis, together with the lack of consistent evidence of carcinogenicity in experimental animals, continue to support lack of carcinogenicity from aspartame consumption. This comprehensive evaluation of available mechanistic data demonstrates the need for a systematic approach to identify and appraise all avaialble data as part of weight-of-evidence determinations related use of KCC in evaluations of potential human carcinogenicity.
*Arzuaga, X., et al. (2019). “Proposed Key Characteristics of Male Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Evidence in Human Health Hazard Assessments.” Environ Health Perspect 127(6): 65001.
BACKGROUND: Assessing chemicals for their potential to cause male reproductive toxicity involves the evaluation of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in hazard identification and evidence integration, the process of identifying, screening and analyzing mechanistic studies and outcomes is a challenging exercise due to the diversity of research models and methods and the variety of known and proposed pathways for chemical-induced toxicity. Ten key characteristics of carcinogens provide a valuable tool for organizing and assessing chemical-specific data by potential mechanisms for cancer-causing agents. However, such an approach has not yet been developed for noncancer adverse outcomes. OBJECTIVES: The objective in this study was to identify a set of key characteristics that are frequently exhibited by exogenous agents that cause male reproductive toxicity and that could be applied for identifying, organizing, and summarizing mechanistic evidence related to this outcome. DISCUSSION: The identification of eight key characteristics of male reproductive toxicants was based on a survey of known male reproductive toxicants and established mechanisms and pathways of toxicity. The eight key characteristics can provide a basis for the systematic, transparent, and objective organization of mechanistic evidence relevant to chemical-induced effects on the male reproductive system. https://doi.org/10.1289/EHP5045.
Atwood, S. T., et al. (2019). “New Perspectives for Cancer Hazard Evaluation by the Report on Carcinogens: A Case Study Using Read-Across Methods in the Evaluation of Haloacetic Acids Found as Water Disinfection By-Products.” Environ Health Perspect 127(12): 125003.
BACKGROUND: Due to the large number of chemicals not yet tested for carcinogenicity but to which people are exposed, the limited number of human and animal cancer studies conducted each year, and the frequent need for a timely response, mechanistic data are playing an increasingly important role in carcinogen hazard identification. OBJECTIVES: To provide a targeted approach to identify relevant mechanistic data in our cancer evaluation of haloacetic acids (HAAs), we used several approaches including systematic review, the 10 key characteristics of carcinogens (KCs), and read-across methods. Our objective in this commentary is to discuss the strengths, limitations, and challenges of these approaches in a cancer hazard assessment. METHODS: A cancer hazard assessment for 13 HAAs found as water disinfection by-products was conducted. Literature searches for mechanistic studies focused on the KCs and individual HAAs. Studies were screened for relevance and categorized by KCs and other relevant data, including chemical properties, toxicokinetics, and biological effects other than KCs. Mechanistic data were organized using the KCs, and strength of evidence was evaluated; this information informed potential modes of action (MOAs) and read-across-like approaches. Three read-across options were considered: evaluating HAAs as a class, as subclass(es), or as individual HAAs (analog approach). DISCUSSION: Because of data limitations and uncertainties, listing as a class or subclass(es) was ruled out, and an analog approach was used. Two brominated HAAs were identified as target (untested) chemicals based on their metabolism and similarity to source (tested) chemicals. In addition, four HAAs with animal cancer data had sufficient evidence for potential listing in the Report on Carcinogens (RoC). This is the first time that the KCs and other relevant data, in combination with read-across principles, were used to support a recommendation to list chemicals in the RoC that did not have animal cancer data. https://doi.org/10.1289/EHP5672.
Chappell, G. A., et al. (2019). “Lack of potential carcinogenicity for sucralose – Systematic evaluation and integration of mechanistic data into the totality of the evidence.” Food Chem Toxicol: 110898.
Sucralose is widely used as a sugar substitute. Many studies and authoritative reviews have concluded that sucralose is non-carcinogenic, based primarily on animal cancer bioassays and genotoxicity data. To add to the body of knowledge on the potential carcinogenicity of sucralose, a systematic assessment of mechanistic data was conducted. This entailed using a framework developed for the quantitative integration of data related to the proposed key characteristics of carcinogens (KCCs). Data from peer-reviewed literature and the ToxCast/Tox21 database were evaluated using an algorithm that weights data for quality and relevance. The resulting integration demonstrated an overall lack of activity for sucralose across the KCCs, with no “strong” activity observed for any KCC. Almost all data collected demonstrated inactivity, including those conducted in human models. The overall lack of activity in mechanistic data is consistent with findings from animal cancer bioassays. The few instances of activity across the KCC were generally accompanied by limitations in study design in the context of either quality and/or dose and model relevance, highlighted upon integration of the totality of the evidence. The findings from this comprehensive and integrative evaluation of mechanistic data support prior conclusions that sucralose is unlikely to be carcinogenic in humans. https://doi.org/10.1016/j.fct.2019.110898
Iyer, S. et al. (2019). “An Integrated Approach Using Publicly Available Resources for Identifying and Characterizing Chemicals of Potential Toxicity Concern: Proof-of-
Concept With Chemicals That Affect Cancer Pathways.” Toxicol Sci, 169(1), 2019, 14–24.
We developed an integrated, modular approach to predicting chemical toxicity relying on in vitro assay data, linkage of molecular targets to disease categories, and software for ranking chemical activity and examining structural features (chemotypes). We evaluate our approach in a proof-of-concept exercise to identify and prioritize chemicals of potential carcinogenicity concern. We identified 137 cancer pathway-related assays from a subset of U.S. EPA’s ToxCast platforms. We mapped these assays to key characteristics of carcinogens and found they collectively assess 5 of 10 characteristics. We ranked all 1061 chemicals screened in Phases I and II of ToxCast by their activity in the selected cancer pathway-related assays using Toxicological Prioritization Index software. More chemicals used as biologically active agents (eg, pharmaceuticals) ranked in the upper 50% versus lower 50%. Twenty-three chemotypes are enriched in the top 5% (n 1⁄4 54) of chemicals; these features may be important for their activity in cancer pathway-related assays. The biological coverage of the ToxCast assays related to cancer pathways is limited and short-term assays may not capture the biology of some key characteristics. Metabolism is also minimal in the assays. The ability of our approach to identify chemicals with cancer hazard is limited with the current input data, but we expect that our approach can be applied with future iterations of ToxCast and other data for improved chemical prioritization and characterization. The novel approach and proof-of- concept exercise described here for ranking chemicals for potential carcinogenicity concern is modular, adaptable, and amenable to evolving data streams. https://doi.org/10.1093/toxsci/kfz017
*Luderer, U., et al. (2019). “Proposed Key Characteristics of Female Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Data in Hazard Assessment.” Environ Health Perspect 127(7): 75001.
BACKGROUND: Identification of female reproductive toxicants is currently based largely on integrated epidemiological and in vivo toxicology data and, to a lesser degree, on mechanistic data. A uniform approach to systematically search, organize, integrate, and evaluate mechanistic evidence of female reproductive toxicity from various data types is lacking. OBJECTIVE: We sought to apply a key characteristics approach similar to that pioneered for carcinogen hazard identification to female reproductive toxicant hazard identification. METHODS: A working group of international experts was convened to discuss mechanisms associated with chemical-induced female reproductive toxicity and identified 10 key characteristics of chemicals that cause female reproductive toxicity: 1) alters hormone receptor signaling; alters reproductive hormone production, secretion, or metabolism; 2) chemical or metabolite is genotoxic; 3) induces epigenetic alterations; 4) causes mitochondrial dysfunction; 5) induces oxidative stress; 6) alters immune function; 7) alters cell signal transduction; 8) alters direct cell-cell interactions; 9) alters survival, proliferation, cell death, or metabolic pathways; and 10) alters microtubules and associated structures. As proof of principle, cyclophosphamide and diethylstilbestrol (DES), for which both human and animal studies have demonstrated female reproductive toxicity, display at least 5 and 3 key characteristics, respectively. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), for which the epidemiological evidence is mixed, exhibits 5 key characteristics. DISCUSSION: Future efforts should focus on evaluating the proposed key characteristics against additional known and suspected female reproductive toxicants. Chemicals that exhibit one or more of the key characteristics could be prioritized for additional evaluation and testing. A key characteristics approach has the potential to integrate with pathway-based toxicity testing to improve prediction of female reproductive toxicity in chemicals and potentially prevent some toxicants from entering common use. https://doi.org/10.1289/EHP4971.
Samet, J. M. (2019). The IARC Monographs: Updated Procedures for Modern and Transparent Evidence Synthesis in Cancer Hazard Identification. J National Cancer Institute 112 (1): 30-37.
The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert advisory group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs program. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating, and integrating evidence to identify causes of human cancer. The advancements adopted include the strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals, and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention. https://doi.org/10.1093/jnci/djz169
*Smith, M.T. (2019). “Key characteristics of carcinogens.” Chapter 10 in Tumor site concordance and mechanisms of carcinogenesis. Robert A. Baan, Bernard W. Stewart and Kurt Straif, Eds. IARC Scientific Publication No. 165. IARC, Lyons, France.
*Fielden, M. R., et al. (2018). “Modernizing Human Cancer Risk Assessment of Therapeutics.” Trends Pharmacol Sci 39(3): 232-247.
Cancer risk assessment of therapeutics is plagued by poor translatability of rodent models of carcinogenesis. In order to overcome this fundamental limitation, new approaches are needed that enable us to evaluate cancer risk directly in humans and human-based cellular models. Our enhanced understanding of the mechanisms of carcinogenesis and the influence of human genome sequence variation on cancer risk motivates us to re-evaluate how we assess the carcinogenic risk of therapeutics. This review will highlight new opportunities for applying this knowledge to the development of a battery of human-based in vitro models and biomarkers for assessing cancer risk of novel therapeutics. https://doi.org/10.1016/j.tips.2017.11.005
Guyton, K. Z., et al. (2018). “Key Characteristics Approach to Carcinogenic Hazard Identification.” Chem Res Toxicol 31(12):1290-1292
Evaluating carcinogenic mechanisms is a challenging part of hazard identification, as mechanistic data are both voluminous and diverse. An evaluation approach based on 10 key characteristics of human carcinogens provides a holistic and unbiased way to tackle this challenge. https://doi.org/10.1021/acs.chemrestox.8b00321
*Guyton, K. Z., et al. (2018). “Application of the key characteristics of carcinogens in cancer hazard identification.” Carcinogenesis 39(4): 614-622.
Smith et al. (Env. Health Perspect. 124: 713, 2016) identified 10 key characteristics (KCs), one or more of which are commonly exhibited by established human carcinogens. The KCs reflect the properties of a cancer-causing agent, such as ‘is genotoxic,’ ‘is immunosuppressive’ or ‘modulates receptor-mediated effects,’ and are distinct from the hallmarks of cancer, which are the properties of tumors. To assess feasibility and limitations of applying the KCs to diverse agents, methods and results of mechanistic data evaluations were compiled from eight recent IARC Monograph meetings. A systematic search, screening and evaluation procedure identified a broad literature encompassing multiple KCs for most (12/16) IARC Group 1 or 2A carcinogens identified in these meetings. Five carcinogens are genotoxic and induce oxidative stress, of which pentachlorophenol, hydrazine and malathion also showed additional KCs. Four others, including welding fumes, are immunosuppressive. The overall evaluation was upgraded to Group 2A based on mechanistic data for only two agents, tetrabromobisphenol A and tetrachloroazobenzene. Both carcinogens modulate receptor-mediated effects in combination with other KCs. Fewer studies were identified for Group 2B or 3 agents, with the vast majority (17/18) showing only one or no KCs. Thus, an objective approach to identify and evaluate mechanistic studies pertinent to cancer revealed strong evidence for multiple KCs for most Group 1 or 2A carcinogens but also identified opportunities for improvement. Further development and mapping of toxicological and biomarker endpoints and pathways relevant to the KCs can advance the systematic search and evaluation of mechanistic data in carcinogen hazard identification. https://doi.org/10.1093/carcin/bgy031
Smith, M. T. et al. (2016). Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis. Environmental Health Perspectives 124 (6): 713-721.
Background: 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. Objectives and Methods: 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. Discussion:
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. Conclusion: 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.