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Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health. A genomic analysis of tumors in mice caused by known or suspected carcinogens shows that most carcinogens do not generate distinct mutational signatures.

Carcinogen exposure has been associated with enhanced cancer immunogenicity that is often attributed to neoantigen generation. However, the broader, neoantigen-independent impact of carcinogens on immune responses to cancer cells remains underexplored. In this issue of the JCI, Huang et al. uncover a mechanism wherein carcinogen-treated cancer cells exhibit an inability to establish an immunosuppressive tumor microenvironment (TME) due to reduced M-CSF expression. Intriguingly, the so-called carcinogen-induced tumor-associated macrophages (TAMs) within this TME exhibited anti-tumor properties instead of the conventional immunosuppressive phenotype. This phenomenon extended to human lung cancers, as evidenced by TAM reprogramming in smokers versus nonsmokers. This study substantially advances our understanding of carcinogen-mediated effects on cancer immunogenicity, potentially redirecting approaches to cancer immunotherapy.

While much research has been done to identify individual workplace lung carcinogens, little is known about joint effects on risk when workers are exposed to multiple agents. We investigated the pairwise joint effects of occupational exposures to asbestos, respirable crystalline silica, metals (i.e., nickel, chromium-VI), and polycyclic aromatic hydrocarbons (PAH) on lung cancer risk, overall and by major histologic subtype, while accounting for cigarette smoking. In the international 14-center SYNERGY project, occupational exposures were assigned to 16,901 lung cancer cases and 20,965 control subjects using a quantitative job-exposure matrix (SYN-JEM). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for ever vs. never exposure using logistic regression models stratified by sex and adjusted for study center, age, and smoking habits. Joint effects among pairs of agents were assessed on multiplicative and additive scales, the latter by calculating the relative excess risk due to interaction (RERI). All pairwise joint effects of lung carcinogens in men were associated with an increased risk of lung cancer. However, asbestos/metals and metals/PAH resulted in less than additive effects; while the chromium-VI/silica pair showed marginally synergistic effect in relation to adenocarcinoma (RERI: 0.24; CI: 0.02, 0.46; = 0.05). In women, several pairwise joint effects were observed for small cell lung cancer including exposure to PAH/silica (OR = 5.12; CI: 1.77, 8.48), and to asbestos/silica (OR = 4.32; CI: 1.35, 7.29), where exposure to PAH/silica resulted in a synergistic effect (RERI: 3.45; CI: 0.10, 6.8). Small or no deviation from additive or multiplicative effects was observed, but co-exposure to the selected lung carcinogens resulted generally in higher risk than exposure to individual agents, highlighting the importance to reduce and control exposure to carcinogens in workplaces and the general environment. https://doi.org/10.1289/EHP13380.

The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches. We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them. An expert working group was convened to discuss mechanisms associated with CV toxicity. The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1-4 below), the vascular system (5-7), or both (8-12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling. These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM in aerodynamic diameter ( )] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321.

Extremely low frequency magnetic fields (ELF-MFs) are classified as a possible carcinogenic factor (Group 2B). This study assessed the association between ELF-MFs and childhood cancer through a systematic review and meta-analysis. Three databases were searched in January 2020. We conducted a meta-analysis for the association between the ELF-MFs exposure level and childhood cancer. A total of 33 studies were identified. Thirty studies with 186,223 participants were included in the meta-analysis. Children exposed to 0.2-, 0.3-, and 0.4-μT ELF-MFs had a 1.26 (95% confidence interval [CI] 1.06-1.49), 1.22 (95% CI 0.93-1.61), and 1.72 (95% CI 1.25-2.35) times higher odds of childhood leukemia. In childhood brain tumors, children exposed to 0.2-μT had a 0.95 (95% CI 0.59-1.56) times higher odds, and those exposed to 0.4-μT ELF-MFs had a 1.25 (95% CI 0.93-1.61). Children exposed to 0.2- and 0.4-μT ELF-MFs had a 1.10 (95% CI 0.70-1.75) and 2.01 (95% CI 0.89-4.52) times higher odds of any childhood cancers. Significant associations were observed between exposure to ELF-MFs and childhood leukemia. Furthermore, a possible dose-response effect was also observed.

The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.

Chemicals that induce mammary tumors in rodents or activate estrogen or progesterone signaling are likely to increase breast cancer (BC) risk. Identifying chemicals with these activities can prompt steps to protect human health. We compiled data on rodent tumors, endocrine activity, and genotoxicity to assess the key characteristics (KCs) of rodent mammary carcinogens (MCs), and to identify other chemicals that exhibit these effects and may therefore increase BC risk. Using authoritative databases, including International Agency for Research on Cancer (IARC) Monographs and the US Environmental Protection's (EPA) ToxCast, we selected chemicals that induce mammary tumors in rodents, stimulate estradiol or progesterone synthesis, or activate the estrogen receptor (ER) . We classified these chemicals by their genotoxicity and strength of endocrine activity and calculated the overrepresentation (enrichment) of these KCs among MCs. Finally, we evaluated whether these KCs predict whether a chemical is likely to induce mammary tumors. We identified 279 MCs and an additional 642 chemicals that stimulate estrogen or progesterone signaling. MCs were significantly enriched for steroidogenicity, ER agonism, and genotoxicity, supporting the use of these KCs to predict whether a chemical is likely to induce rodent mammary tumors and, by inference, increase BC risk. More MCs were steroidogens than ER agonists, and many increased both estradiol and progesterone. Enrichment among MCs was greater for strong endocrine activity vs. weak or inactive, with a significant trend. We identified hundreds of compounds that have biological activities that could increase BC risk and demonstrated that these activities are enriched among MCs. We argue that many of these should not be considered low hazard without investigating their ability to affect the breast, and chemicals with the strongest evidence can be targeted for exposure reduction. We describe ways to strengthen hazard identification, including improved assessments for mammary effects, developing assays for more KCs, and more comprehensive chemical testing. https://doi.org/10.1289/EHP13233.

The 10 key characteristics (KCs) of carcinogens form the basis of a framework to identify, organize, and evaluate mechanistic evidence relevant to carcinogenic hazard identification. The 10 KCs are related to mechanisms by which carcinogens cause cancer. The ( ) programme has successfully applied the KCs framework for the mechanistic evaluation of different types of exposures, including chemicals, metals, and complex exposures, such as environmental, occupational, or dietary exposures. The use of this framework has significantly enhanced the identification and organization of relevant mechanistic data, minimized bias in evaluations, and enriched the knowledge base regarding the mechanisms of known and suspected carcinogens. We sought to report the main outcomes of an IARC Scientific Workshop convened by the IARC to establish appropriate, transparent, and uniform application of the KCs in future evaluations. A group of experts from different disciplines reviewed the experience with the KCs of carcinogens, discussing three main themes: ) the interpretation of end points forming the evidence base for the KCs, ) the incorporation of data from novel assays on the KCs, and ) the integration of the mechanistic evidence as part of cancer hazard identification. The workshop participants assessed the relevance and the informativeness of multiple KCs-associated end points for the evaluation of mechanistic evidence in studies of exposed humans and experimental systems. Consensus was reached on how to enhance the use of , molecular, and cellular high-output and high-throughput data. In addition, approaches to integrate evidence across the KCs and opportunities to improve methodologies of mechanistic evaluation of cancer hazards were explored. The findings described herein and in a forthcoming IARC technical report will support future working groups of experts in reporting and interpreting results under the KCs framework within the or in other contexts. https://doi.org/10.1289/EHP15389.

Black carbon (BC), a component of fine particulate matter [particles with an aerodynamic diameter ( )], may contribute to carcinogenic effects of air pollution. Until recently however, there has been little evidence to evaluate this hypothesis. This study aimed to estimate the associations between long-term exposure to BC and risk of cancer. This study was conducted within the French Gazel cohort of 20,625 subjects. We assessed exposure to BC by linking subjects' histories of residential addresses to a map of European black carbon levels in 2010 with back- and forward-extrapolation between 1989 and 2015. We used extended Cox models, with attained age as time-scale and time-varying cumulative exposure to BC, adjusted for relevant sociodemographic and lifestyle variables. To consider latency between exposure and cancer diagnosis, we implemented a 10-y lag, and as a sensitivity analysis, a lag of 2 y. To isolate the effect of BC from that of total , we regressed BC on and used the residuals as the exposure variable. During the 26-y follow-up period, there were 3,711 incident cancer cases (all sites combined) and 349 incident lung cancers. Median baseline exposure in 1989 was 2.65 [interquartile range (IQR): 2.23-3.33], which generally slightly decreased over time. Using 10 y as a lag-time in our models, the adjusted hazard ratio per each IQR increase of the natural log-transformed cumulative BC was 1.17 (95% confidence interval: 1.06, 1.29) for all-sites cancer combined and 1.31 (0.93, 1.83) for lung cancer. Associations with BC residuals were also positive for both outcomes. Using 2 y as a lag-time, the results were similar. Our findings for a cohort of French adults suggest that BC may partly explain the association between and lung cancer. Additional studies are needed to confirm our results and further disentangle the effects of BC, total , and other constituents. https://doi.org/10.1289/EHP8719.

Purpose This scoping review examines controllable predisposing factors attributable to cancer in the Middle East and North Africa (MENA) region’s adult population, highlighting opportunities to enhance cancer prevention programs. Design We systematically searched the PubMed, Science Direct, and CINAHL, EMBASE, and Cochrane Library databases from 1997 to 2022 for articles reporting on the impact of modifiable risk factors on adult patients with cancer in the MENA region. Results The review identified 42 relevant articles, revealing that tobacco consumption, obesity, physical inactivity, and diet are significant modifiable risk factors for cancer in the region. Tobacco smoking is a leading cause of lung, bladder, squamous cell carcinoma, and colorectal cancer. A shift towards a westernized, calorie-dense diet has been observed, with some evidence suggesting that a Mediterranean diet may be protective against cancer. Obesity is a known risk factor for cancer, particularly breast malignancy, but further research is needed to determine its impact in the MENA region. Physical inactivity has been linked to colorectal cancer, but more studies are required to establish this relationship conclusively. Alcohol consumption, infections, and exposure to environmental carcinogens are additional risk factors, although the literature on these topics is limited. Conclusion The review emphasizes the need for further research and the development of targeted cancer prevention strategies in the MENA region.