Recent publications on the KC Framework
*Arose from work led by UC Berkeley
Borgert CJ (2023). Issue analysis: key characteristics approach for identifying endocrine disruptors. Arch Toxicol 97(10):2819-2822.
Abstract: For more than a decade, weight of evidence (WoE) evaluations have been the standard method for determining whether a chemical meets the definition of an endocrine disrupting chemical (EDC). WoE methods consider all data pertinent to satisfying the EDC definition and evaluating those data with respect to relevance, reliability, strength, and coherence with established endocrine physiology and pharmacology. A new approach for identifying EDC hazards has been proposed that organizes and evaluates data according to ten so-called “Key Characteristics (KCs) of EDCs”. The approach claims to address the lack of a widely accepted, systematic approach for identifying EDC hazards, but completely ignores the WoE literature for EDCs. In contrast to WoE methods, the KC approach fails to apply the consensus definition of EDC and is not amenable to empirical testing or validation, is fungible and ensures inconsistent and unreliable results, ignores principles of hormone action and characteristics of dose-response in endocrine pharmacology and toxicology, lacks a means of distinguishing endocrine-mediated from non-endocrine mediated mechanisms, lacks a means to reach a negative conclusion about a chemical’s EDC properties or to distinguish EDCs from non-EDCs, and provides no means for developing a valid consensus among experts nor provides a means of resolving conflicting interpretations of data. Instead of shortcuts like the KC approach, which are prone to bias, error, and arbitrary conclusions, identifying EDCs should rely on WoE evaluations that supply the critical components and scientific rigor lacking in the proposed KCs for EDCs.
Meek, MEB and Wikoff, D (2023). The need for good practice in the application of mechanistic constructs in hazard and risk assessment. Toxicol Sci 194(1):13-22.
Abstract: A series of recent and proposed workshops address the interface between key characteristics and mechanistic pathway descriptions (adverse outcome pathways and mode of action) to identify commonalities and potential for complementary application. Informed by different communities, these constructs have collective potential to increase confidence to support the application of mechanistic data in hazard assessment. This forum article summarizes concepts, introduces evolving understanding, and invites future collaboration to contribute to better common understanding and development of good practice in the use of mechanistic data in hazard assessment.
Muncke J et al., (2023). A vision for safer food contact materials: Public health concerns as drivers for improved testing. Environ Int 180:108161.
Abstract: Food contact materials (FCMs) and food contact articles are ubiquitous in today’s globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. To identify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs.
Rana, I et al., (2023). Mapping the key characteristics of carcinogens for glyphosate and its formulations: A systematic review. Chemosphere 339:139572.
Abstract: Glyphosate was classified as a probable human carcinogen (Group 2A) by the International Agency for Research on Cancer (IARC) partially due to strong mechanistic evidence in 2015. Since then, numerous studies of glyphosate and its formulations (GBF) have emerged. These studies can be evaluated for cancer hazard identification with the newly described ten key characteristics (KC) of carcinogens approach. Our objective was to assess all in vivo, ex vivo, and in vitro mechanistic studies of human and experimental animals (mammals) that compared exposure to glyphosate/GBF with low/no exposure counterparts for evidence of the ten KCs. A protocol with our methods adhering to PRISMA guidelines was registered a priori (INPLASY202180045). Two blinded reviewers screened all in vivo, ex vivo, and in vitro studies of glyphosate/GBF exposure in humans/mammals reporting any KC-related outcome available in PubMed before August 2021. Studies that met inclusion criteria underwent data extraction conducted in duplicate for each KC outcome reported along with key aspects of internal/external validity, results, and reference information. These data were used to construct a matrix that was subsequently analyzed in the program R to conduct strength of evidence and quality assessments. Of the 2537 articles screened, 175 articles met inclusion criteria, from which we extracted >50,000 data points related to KC outcomes. Data analysis revealed strong evidence for KC2, KC4, KC5, KC6, KC8, limited evidence for KC1 and KC3, and inadequate evidence for KC7, KC9, and KC10. Notably, our in-depth quality analyses of genotoxicity (KC2) and endocrine disruption (KC8) revealed strong and consistent positive findings. For KC2, we found: 1) studies conducted in humans and human cells provided stronger positive evidence than counterpart animal models; 2) GBF elicited a stronger effect in both human and animal systems when compared to glyphosate alone; and 3) the highest quality studies in humans and human cells consistently revealed strong evidence of genotoxicity. Our analysis of KC8 indicated that glyphosate’s ability to modulate hormone levels and estrogen receptor activity is sensitive to both exposure concentration and formulation. The modulations observed provide clear evidence that glyphosate interacts with receptors, alters receptor activation, and modulates the levels and effects of endogenous ligands (including hormones). Our findings strengthen the mechanistic evidence that glyphosate is a probable human carcinogen and provide biological plausibility for previously reported cancer associations in humans, such as non-Hodgkin lymphoma. We identified potential molecular interactions and subsequent key events that were used to generate a probable pathway to lymphomagenesis.
Rusyn, I and Wright, A (2023). Ten Years of Using Key Characteristics of Human Carcinogens to Organize and Evaluate Mechanistic Evidence in IARC Monographs on the Identification of Carcinogenic Hazards to Humans: Patterns and Associations. bioRxiv 2023.07.11.548354.
Abstract: Systematic review and evaluation of the mechanistic evidence only recently been instituted in cancer hazard identification step of decision-making. One example of organizing and evaluating mechanistic evidence is the Key Characteristics approach of the International Agency for Research on Cancer (IARC) Monographs on the Identification of Carcinogenic Hazards to Humans. The Key Characteristics of Human Carcinogens were proposed almost 10 years ago and have been used in every IARC Monograph since 2015. We investigated the patterns and associations in the use of Key Characteristics by the independent expert Working Groups. We examined 19 Monographs (2015-2022) that evaluated 73 agents. We extracted information on the conclusions by each Working Group on the strength of evidence for agent-Key Characteristic combinations, data types that were available for decisions, and the role mechanistic data played in the final cancer hazard classification. We conducted both descriptive and association analyses within and across data types. We found that IARC Working Groups were cautious when evaluating mechanistic evidence: for only ∼13% of the agents was strong evidence assigned for any Key Characteristic. Genotoxicity and cell proliferation were most data-rich, while little evidence was available for DNA repair and immortalization Key Characteristics. Analysis of the associations among Key Characteristics revealed that only chemical’s metabolic activation was significantly co-occurring with genotoxicity and cell proliferation/death. Evidence from exposed humans was limited, while mechanistic evidence from rodent studies in vivo was often available. Only genotoxicity and cell proliferation/death were strongly associated with decisions on whether mechanistic data was impactful on the final cancer hazard classification. The practice of using the Key Characteristics approach is now well-established at IARC Monographs and other government agencies and the analyses presented herein will inform the future use of mechanistic evidence in regulatory decision-making.
Zhang, L. et al., (2023). A systematic evidence map of chronic inflammation and immunosuppression related to per- and polyfluoroalkyl substance (PFAS) exposure. Environ Res 220:115188.
Abstract: Background: The ability to induce chronic inflammation and immunosuppression are two key characteristics of carcinogens and important forms of immunotoxicity. The National Toxicology Program (NTP) evaluated the immunotoxicity of two per- and polyfluoroalkyl substances (PFASs), PFOA (perfluorooctanoic acid) and PFOS (perfluorooctane sulfonate), in 2016. However, the potential pro-inflammatory and immunosuppressive effects of other PFASs remain largely uncharacterized.
Methods: We developed an expanded set of search terms pertaining to the chronic inflammatory and immunosuppressive effects of PFASs based on those of the International Agency for Research on Cancer (IARC) and NTP. To confirm searching effectiveness and scope, we compared our search term results with those of IARC and NTP for both PFASs and two other known carcinogens, chromium (VI) and benzene. Systematic evidence maps (SEMs) were also produced using Tableau to visualize the distribution of study numbers and types reporting immunotoxic effects and specific biomarkers elicited by PFAS exposures. Results: In total, 1155 PFAS studies were retrieved, of which 321 qualified for inclusion in our dataset. Using our search terms, we identified a greater number of relevant studies than those obtained using IARC and NTP’s search terms. From the SEM findings, increased cytokine production strengthened an association between PFAS exposure and chronic inflammation, and decreased B-cell activation and altered levels of T-cell subtypes and immunoglobulins confirmed PFAS-induced immunosuppression. Conclusion: Our SEM findings confirm that several PFASs commonly found in both in the environment, including those that are lesser-known, may induce immunosuppression and chronic inflammation, two key characteristics of carcinogens. This approach, including development of search terms, study screening process, data coding, and evidence mapping visualizations, can be applied to other key characteristics of chemical carcinogens.