Recent publications on the KC Framework
*Arose from work led by UC Berkeley
Guyton and Schubauer-Berigan (2021). “Invited Perspective: Prioritizing Chemical Testing and Evaluation Using Validated in Vitro Assays Relevant to Key Characteristics”. Environmental Health Perspectives. 129(7): 71303. Epub Jul 21. PMID: 34287027. PMCID: PMC8312475. doi: 10.1289/EHP9507.
Abstract: None available.
Rusyn et al. (2021). “Key Characteristics of Human Hepatotoxicants as a Basis for Identification and Characterization of the Causes of Liver Toxicity”. Hepatology. 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.