Occupational exposure to carcinogens in Brazil: An approach.

This study aims to estimate the prevalence of the primary occupational exposures, considered risk factors for Cancer in Brazil. We elaborated two exposure scenarios considering the agents' classification and the intensity of exposure, stratified by Brazilian regions and sex. Two pairs of specialists performed the classification of economic activities and occupations due to exposure. There was an excellent overall agreement (94%) and acceptable overall reliability (kappa 0.92, 95% CI 0.89-0.95). There is a notable difference (595%) in occupational exposure between the north (with a higher concentration of rural areas and extractivism) and southeast (with a higher level of industrial activities). There is a difference in prevalence from 833% for solvents to 1170% for inorganic dust between the two scenarios. There is a heterogeneity of exposures according to location, sex, circumstance, and sensitiveness of classification.

Butylated hydroxyanisole: Carcinogenic food additive to be avoided or harmless antioxidant important to protect food supply?

Tumor data from rodent bioassays are used for cancer hazard classification with wide-ranging consequences. This paper presents a case study of the synthetic antioxidant butylated hydroxyanisole (BHA), which IARC classified as Group 2B ("possibly carcinogenic to humans") on the basis of forestomach tumors in rodents following chronic dietary exposure to high levels. IARC later determined that the mechanism by which BHA induces forestomach tumors is not relevant to humans; however, the classification has not been revoked. BHA was listed on California Proposition 65 as a direct consequence of the IARC classification, and there is widespread concern among consumers regarding the safety of BHA driven by the perception that it is a carcinogen. While many regulatory agencies have established safe exposure limits for BHA, the IARC classification and Proposition 65 listing resulted in the addition of BHA to lists of substances banned from children's products and products seeking credentials such as EPA's Safer Choice program, as well as mandatory product labeling. Classifications have consequences that many times pre-empt the ability to conduct an exposure-based risk-based assessment., It is imperative to consider human relevance of both the endpoint and exposure conditions as fundamental to hazard identification.

A tiered approach to prioritizing registered pesticides for potential cancer hazard evaluations: implications for decision making.

BACKGROUND: Over 800 pesticides are registered for use in the United States. Human studies indicate concern that some pesticides currently in use in large quantities may also pose a carcinogenic hazard. Our objective is to identify candidates for future hazard evaluations among pesticides used in high volumes in the United States and also classified as potential carcinogens by U.S. Environmental Protection Agency (USEPA). We also identify data gaps where further research is needed. METHODS: We used a systematic, two-tiered review approach to prioritize pesticides. First, we identified currently registered pesticides classified by USEPA as "possible", "suggestive", or "likely" human carcinogens. Among these, we selected pesticides USEPA has listed as commonly used by volume in at least one sector (agriculture, home and garden, or industry, commercial, and/or government), and those without a published hazard evaluation in the past 5 years. Second, we searched primary literature databases for peer-reviewed human cancer studies reporting pesticide-specific data published since the last USEPA carcinogenicity evaluation for each pesticide, and created evidence maps of the number of studies meeting our criteria for each identified pesticide. No evaluation of study results or risk-of-bias assessments were conducted. RESULTS: We identified 18 pesticides meeting our selection criteria, 16 pesticides had information from human cancer studies published after their initial carcinogenicity review. Of these, eight pesticides had at least three studies for one or more cancer sites: carbaryl, dichloropropene, dimethoate, mancozeb, metolachlor, pendimethalin, permethrin, and trifluralin. A major limitation in the literature revealed a shortage of studies reporting risk estimates for individual pesticides, rather pesticides were grouped by chemical class. CONCLUSIONS: Our scoping report provides a map of the existing literature on real-world exposures and human cancer that has accumulated on pesticides classified as potential carcinogens by USEPA and used in high volumes. We also illustrate that several pesticides which are "data-rich" may warrant updated authoritative hazard evaluations. Our two-tiered approach and utilization of evidence mapping can be used to inform future decision-making to update cancer hazard evaluations.

A retrospective study on EU harmonised classifications for carcinogenicity to guide future research.

Under European Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP), chemicals can be classified as carcinogenic if they are considered to induce tumours, increase tumour incidence and/or malignancy, or shorten the time to tumour occurrence. Cancer classifications are divided into different hazard categories: Carc. 1A (known human carcinogen), Carc. 1B (presumed human carcinogen), Carc. 2 (suspected human carcinogen), and chemicals not classified for carcinogenicity. Selecting which classification is appropriate can be challenging, as judgements need to be made both on the existing hazard data and on its relevance to humans. One aspect to be considered in defining human relevance is a chemical's mode of action (MoA); the series of necessary key events that lead from an exposure to the adverse effect (in this case, tumours). This work aims to identify and discuss some of the features that have led ECHA's Committee for Risk Assessment (RAC) to decide upon harmonised cancer classifications for chemicals, and to prioritise future research on MoA and/or human relevance. RAC bases its decisions on cancer classification on both the weight-of-evidence (WoE) and strength-of-evidence (SoE) of this particular activity. Multiple factors contribute, including the species in which tumours are seen, and the relevance of the MoA to human health.

Classifying polycyclic aromatic hydrocarbons by carcinogenic potency using in vitro biosignatures.

One of the most difficult challenges for risk assessment is evaluation of chemicals that predominately co-occur in mixtures like polycyclic aromatic hydrocarbons (PAHs). We previously developed a classification model in which systems biology data collected from mice short-term after chemical exposure accurately predict tumor outcome. The present study demonstrates translation of this approach into a human in vitro model in which chemical-specific bioactivity profiles from 3D human bronchial epithelial cells (HBEC) classify PAHs by carcinogenic potency. Gene expression profiles were analyzed from HBEC exposed to carcinogenic and non-carcinogenic PAHs and classification accuracies were identified for individual pathway-based gene sets. Posterior probabilities of best performing gene sets were combined via Bayesian integration resulting in a classifier with four gene sets, including aryl hydrocarbon receptor signaling, regulation of epithelial mesenchymal transition, regulation of angiogenesis, and cell cycle G2-M. In addition, transcriptional benchmark dose modeling of benzo[a]pyrene (BAP) showed that the most sensitive gene sets to BAP regulation were largely dissimilar from those that best classified PAH carcinogenicity challenging current assumptions that BAP carcinogenicity (and subsequent mode of action) is reflective of overall PAH carcinogenicity. These results illustrate utility of using systems toxicology approaches to analyze global gene expression towards carcinogenic hazard assessment.

Efficacy of sodium hypochlorite in the degradation antineoplastic drugs by NMR spectroscopy.

SUMMARY: Antineoplastic drugs are used to treat cancer, having their therapeutic effect by inhibiting the cell division process. Although cancer cells, due to their rapid growth, are more sensitive to the toxic effects of chemotherapeutic agents, healthy cells and tissues may also be damaged. Many studies show acute and chronic toxicity both in patients treated with chemotherapy and in exposed workers. In fact, exposure to these substances can also be linked to the formation of different types of secondary tumors. The International Agency on Research on Cancer (IARC) included some antineplastic drugs in Group 1 (carcinogenic to humans), in Group 2A (probable carcinogens for In recent years, many studies have evidenced the presence of antineoplastic drug contamination on work surfaces, materials and floors and based on these observations, international and national guidelines have been published to limit occupational exposure, with particular attention to procedures post-preparation of chemotherapy to limit as much as possible the accumulation of contaminated residues. The aim of the following study is to determine the effectiveness of the degradation of four antineoplastic drugs: 5-fluorouracil, azacitidine, cytarabine and irinotecan using a low concentration of sodium hypochlorite solution (0.115%). The analytical platform used to monitor the degradation course of the substances under examination was hydrogen nuclear magnetic spectroscopy (1H NMR). In the same experimental conditions the effectiveness of the degradation of the same antineoplastic drugs with a 99.9% ethanol solution was also evaluated. The study showed that the best degradation efficiency (> 90% ) is obtained with the hypochlorite solution after 15 minutes.

How the 62-year old Delaney Clause continues to thwart science: Case study of the flavor substance ß-myrcene.

The Delaney Clause is a provision of the 1958 Food Additive Amendment to the Food, Drug and Cosmetic Act of 1938 which stipulates that if a substance is found by the Food and Drug Administration to be carcinogenic in any species of animal or in humans, then it cannot be used as a food additive. This paper presents a case study of ß-myrcene, one of seven synthetic substances that was challenged under the Delaney Clause, ultimately resulting in revocation of its regulatory approval as a food additive despite a lack of safety concern. While it is listed as a synthetic flavor in 21 CFR 172.515, ß-myrcene is also a substance naturally occurring in a number of dietary plants. The exposure level to naturally-occurring ß-myrcene is orders of magnitude higher (estimated to be 16,500 times greater) than the exposure via ß-myrcene added to food as a flavoring substance. The National Toxicology Program conducted genotoxicity testing (negative), a 13-week range-finding study, and a two-year cancer bioassay in B6C3F1 mice and F344/N rats. An increase in liver tumors was seen in male mice and kidney tumors in male rats, ultimately resulting in ß-myrcene being classified by IARC as a Class 2B carcinogen and being listed on California Proposition 65; in contrast, ß-myrcene is not classified as a carcinogen by any other regulatory authority. The doses administered in the NTP bioassay were five-six orders of magnitude higher than human exposures, and the FDA concluded after a thorough evaluation that there was no safety concern associated with the use of ß-myrcene as a flavor substance at the current use level. The Delaney Clause, however, does not consider the exposure potential or the human health relevance of effects observed in animals. The lack of options available to the US FDA led to the 2018 decision to remove ß-myrcene from the list of approved food additives. This revocation has contributed to the ongoing erosion of trust in regulatory agencies (and industry), which has both economic implications for food manufacturers and consumers alike, and implications for consumer perception of safety of the US food supply. It is time for us to reconsider the rationale behind any legislation that relies on classification alone, and whether there is, in fact, a reason to still classify nongenotoxic carcinogens at all.

Curation of cancer hallmark-based genes and pathways for in silico characterization of chemical carcinogenesis.

Exposure to toxic substances in the environment is one of the most important causes of cancer. However, the time-consuming process for the identification and characterization of carcinogens is not applicable to a huge amount of testing chemicals. The data gaps make the carcinogenic risk uncontrollable. An efficient and effective way of prioritizing chemicals of carcinogenic concern with interpretable mechanism information is highly desirable. This study presents a curation work for genes and pathways associated with 11 hallmarks of cancer (HOCs) reported by the Halifax Project. To demonstrate the usefulness of the curated HOC data, the interacting HOC genes and affected HOC pathways of chemicals of the three carcinogen lists from IARC, NTP and EPA were analyzed using the in silico toxicogenomics ChemDIS system. Results showed that a higher number of affected HOCs were observed for known carcinogens than the other chemicals. The curated HOC data is expected to be useful for prioritizing chemicals of carcinogenic concern. Database URL: The HOC database is available at https://github.com/hocdb-KMU-TMU/hocdb and the website of Database journal as Supplementary Data.

Hazard identification, classification, and risk assessment of carcinogens: too much or too little? - Report of an ECETOC workshop.

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) organized a workshop "Hazard Identification, Classification and Risk Assessment of Carcinogens: Too Much or Too Little?" to explore the scientific limitations of the current binary carcinogenicity classification scheme that classifies substances as either carcinogenic or not. Classification is often based upon the rodent 2-year bioassay, which has scientific limitations and is not necessary to predict whether substances are likely human carcinogens. By contrast, tiered testing strategies founded on new approach methodologies (NAMs) followed by subchronic toxicity testing, as necessary, are useful to determine if a substance is likely carcinogenic, by which mode-of-action effects would occur and, for non-genotoxic carcinogens, the dose levels below which the key events leading to carcinogenicity are not affected. Importantly, the objective is not for NAMs to mimic high-dose effects recorded in vivo, as these are not relevant to human risk assessment. Carcinogenicity testing at the "maximum tolerated dose" does not reflect human exposure conditions, but causes major disturbances of homeostasis, which are very unlikely to occur at relevant human exposure levels. The evaluation of findings should consider biological relevance and not just statistical significance. Using this approach, safe exposures to non-genotoxic substances can be established.

Biomedical Research Meets Toxicology: How In Vitro Chromosome Instability Methods Can Contribute to Carcinogenicity Prediction.

Cancer is a major health concern and a leading cause of mortality. The reliable identification of carcinogens and understanding of carcinogenicity has become a main focus of biomedical research and regulatory toxicology. While biomedical research applies cellular in vitro methods to uncover the underlying mechanisms causing cancer, regulatory toxicology relies on animal testing to predict carcinogenicity of chemicals, often with limited human relevance. Exemplified by chromosome instability-mediated carcinogenicity, we discuss the need to combine the strengths of both fields to develop highly predictive and mechanism-derived in vitro methods that facilitate risk assessment in respect to relevant human diseases.

The NTP Report on Carcinogens: A valuable resource for public health, a challenge for regulatory science.

The Report on Carcinogens (RoC), from the National Toxicology Program of the USA, is one of the world-leading programs for the identification and acknowledgment of substances that represent a hazard of cancer to humans. RoC covers several essential topics concerning environmental, occupational, and pharmaceutical agents that are known to be, or reasonably anticipated to be carcinogenic to humans. To promote the highest exploitation by its potential users, several RoC aspects and features were put together into one article. For doing so, a comprehensive description is provided regarding RoC history, scope, general features, listing criteria, contents, handbook, and website. Secondary and tertiary aims for this work were (a) to point out some improvement opportunities for the RoC, and (b) to discuss pending issues in regulatory science and cancer hazard assessments. In this regard, for agents classified as probably, likely, reasonably anticipated, possibly or suspected to be a human carcinogen, there is a lack of quantitative knowledge concerning the likelihood of those agents actually being carcinogenic to humans. Elucidating these probabilities is necessary, because the duration of current regulations and the arrival of new acts may depend on it. On the other hand, there is a dramatic imbalance in priorities toward carcinogens, compared with non-carcinogens, in current cancer hazard identification programs. That vision may ignore that the availability on the market of chemicals classified as probably not carcinogenic to humans can also be important for the employment, alimentation, economy, quality of life of consumers, and human health.

Classification or non-classification of substances with positive tumor findings in animal studies: Guidance by the German MAK commission.

One of the important tasks of the German Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (known as the MAK Commission) is in the evaluation of a potential for carcinogenicity of hazardous substances at the workplace. Often, this evaluation is critically based on data on carcinogenic responses seen in animal studies and, if positive tumor responses have been observed, this will mostly lead to a classification of the substance under investigation into one of the classes for carcinogens. However, there are cases where it can be demonstrated with a very high degree of confidence that the tumor findings in the experimental animals are not relevant for humans at the workplace and, therefore, the MAK Commission will not classify the respective substance into one of the classes for carcinogens. This paper will summarize the general criteria used by the MAK Commission for the categorization into "carcinogen" and "non-carcinogen" and compare this procedure with those used by other national and international organizations.

Predicting the cytotoxicity of chemicals using ensemble learning methods and molecular fingerprints.

The prediction of compound cytotoxicity is an important part of the drug discovery process. However, it usually appears as poor predictive performance because the datasets are high-throughput and have a class-imbalance problem. In this study, several strategies of performing a structure-activity relationship study for a cytotoxic endpoint in the AID364 dataset were explored to solve the class-imbalance problem. Random forest adaboost was used as the base learners for 10 types of molecular fingerprints and an ensemble method and six data-balancing methods were applied to balance the classes. As a result, the ensemble model using MACCS fingerprint was found to be the best, giving area under the curve of 85.2% ± 0.35%, sensitivity of 81.8% ± 0.65%, and specificity of 76.0% ± 0.12% in fivefold cross-validation and area under the curve of 78.8%, sensitivity of 55.5% and specificity of 78.5% in external validation. Good performance also appeared on other datasets with different sizes/degrees of imbalance. To explore the structural commonality of cytotoxic compounds, several substructures were identified as an important reference for substructure alerts. The convincing results indicate that the proposed models are helpful in predicting the cytotoxicity of chemicals.

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.

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 = 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.

Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible.

Developments in the understanding of the etiology of cancer have undermined the 1970s concept that chemicals are either "carcinogens" or "non-carcinogens". The capacity to induce cancer should not be classified in an inflexible binary manner as present (carcinogen) or absent (non-carcinogen). Chemicals may induce cancer by three categories of mode of action: direct interaction with DNA or DNA replication including DNA repair and epigenetics; receptor-mediated induction of cell division; and non-specific induction of cell division. The long-term rodent bioassay is neither appropriate nor efficient to evaluate carcinogenic potential for humans and to inform risk management decisions. It is of questionable predicitiveness, expensive, time consuming, and uses hundreds of animals. Although it has been embedded in practice for over 50 years, it has only been used to evaluate less than 5% of chemicals that are in use. Furthermore, it is not reproducible because of the probabilisitic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design. The modes of action that lead to the induction of tumors are already considered under other hazardous property categories in classification (Mutagenicity/Genotoxicity and Target Organ Toxicity); a separate category for Carcinogenicity is not required and provides no additional public health protection.

Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice.

The 6-month Tg.rasH2 mouse carcinogenicity model provides an acceptable alternative to the 2-year carcinogenicity study in CD-1 mice. However, key questions related to the use of this model for testing antisense oligonucleotides (ASOs) include the similarity in the biologic response between mouse strains and the feasibility of using data from the CD-1 mouse to set doses and dose schedules for a Tg.rasH2 carcinogenicity study. To evaluate the potential strain differences, four distinct 2'- O-(2-methoxyethyl) ASOs were administered to CByB6F1 (wild type), Tg.rasH2 (hemizygous), and CD-1 mice. There were no meaningful differences in clinical signs, body weight, food consumption, or serum chemistry and hematology parameters. Histopathology evaluation indicated little to no difference in the spectrum or magnitude of changes present. The cytokine/chemokine response was also not appreciably different between the strains. This was consistent with the similarity in ASO concentration in the liver between the mouse strains tested. As the class effects of the ASOs were not meaningfully different between CD-1, CByB6F1, or Tg.rasH2 mice, data from nonclinical studies in CD-1 mice can be used for dose selection and expectation of effect in the Tg.rasH2 mouse.

[Occupational cancers: Risks and prevention]. / Les cancers professionnels : risques et prévention.

Since 2008, cancer became the first cause of death in France, exceeding cardiovascular diseases. The part of occupational cancers is close to 5% of all cancers but may still be widely underestimated. The detection of occupational cancer risk factors remains complicated. Indeed, most occupational risk factors are also present in the general environment. Thus far, 36 substances and 13 activities have been classified as carcinogenic (Group 1) and 37 substances and 6 activities have been classified as probably carcinogenic (Group 2A) by the International Agency for Research on Cancer (IARC). The most common cancer site is the lung, followed by bladder and skin (except melanoma). The most frequently observed occupational exposure was chemicals, building and construction, mining, metal production and coal transformation. Thus far, preventive actions are mandatory in occupational health in France, and are about occupational exposure monitoring, protection of vulnerable populations and reinforced medical supervision. Research must be continued to improve the knowledge on occupational carcinogens, in order to better protect the health of workers.

To be or not to be a carcinogen; delving into the glyphosate classification controversy

The International Agency for Research on Cancer (IARC) placed the most widely used herbicide glyphosate (GLY) into the category 2A (probably carcinogenic to humans), a classification questioned by experts from academia and industry. This article critically appraised the epidemiological and experimental data that led the IARC working group (WG) to consider GLY a probable human carcinogen and the ensuing controversy. An association of GLY with non-Hodgkin lymphoma was suggested by some observational studies. A non-causal explanation for this weak association, however, cannot be excluded. Contrary to WG's view, long-term rodent assays yielded no convincing evidence that GLY is carcinogenic. The mechanistic evidence remains elusive as well. Bacterial reverse mutation tests (including tester strains sensitive to oxidative mutagens) were clearly negative, and so were rodent genotoxicity assays by oral route. Tests with mammalian cells in vitro yielded conflicting results at high (cytotoxic) concentrations of GLY-based formulations. Conflicting results were also obtained when high doses of GLY-based herbicides were administered to rodents by the intraperitoneal route. Such high doses are unlikely to be attained in realistic scenarios of exposure. Finally, the IARC classification is based on a conjectural hazard, and rational public health interventions must be based on estimated risks.

Adverse outcome pathway-driven identification of rat liver tumorigens in short-term assays.

Chemicals induce liver cancer in rodents through well characterized adverse outcome pathways (AOPs). We hypothesized that measurement of molecular initiating events (MIEs) and downstream key events (KEs) in liver cancer AOPs in short-term assays will allow early identification of chemicals and their associated doses that are likely to be tumorigenic in the liver in two-year bioassays. We tested this hypothesis using the rat in vivo TG-GATES study data to measure MIEs (genotoxicity, cytotoxicity, AhR, CAR, ER, PPARα) and associated KEs (oxidative stress, cell proliferation, liver to body weights) across 77 chemicals that could be linked to doses with previously established effects on rat liver tumor induction. Gene expression biomarkers for MIEs generally considered to be rodent specific and human irrelevant (CAR, PPARα) and for MIEs that would be considered of greater risk at human relevant exposures (ER, AhR) were built using microarray comparisons from the livers of rats treated with prototypical activators of the receptors. The genotoxicity biomarker, also a potentially human relevant MIE, was comprised of 7 p53-responsive genes known to be induced upon DNA damage. The ability of the biomarkers to accurately predict MIE activation ranged from 91% to 98%. The Toxicological Priority Index (ToxPi) was used to rank chemicals based on their ability to activate MIEs/KEs. Chemicals administered at tumorigenic doses clearly gave the highest ranked scores. Our AOP-directed approach could be used in short term assays to identify chemicals and their doses that would be predicted to cause liver tumors in rats.

Application of the key characteristics of carcinogens in cancer hazard identification.

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.