Search

Aspartame, invented in 1965 by GD-Searle, is an intense artificial sweetener taste approximately 200 times as sweet as sucrose and used as an additive in more than 6,000 products. Aspartame (APM) was submitted for pre-marketing safety evaluation in early 1980. The studies, performed by GD-Searle, produced controversial results. Because of the great commercial diffusion of aspartame, in 1997 the Ramazzini Institute (RI) started a large experimental project on rodents to test the carcinogenic effects of aspartame following an experimental model with more sensitive characteristics, namely a large number of rat and mice, starting treatment from prenatal life, observation until spontaneous death. Overall, the project included studying 2270 rats and 852 mice. These studies have shown that aspartame is a carcinogenic agent in experimental animals, inducing a significant dose-related increased incidence of several types of malignant tumors and, among them, hematological neoplasia, and liver cancer. The results of these studies on aspartame by the Ramazzini Institute opened a real front on the evaluation of artificial sweeteners and their possible health risks. Adequate long-term carcinogenicity bioassays on other diffuse artificial sweeteners such as acesulfame-k, sucralose, saccharin, including their blends, are likewise important for public health. [ABSTRACT FROM AUTHOR]

AbstractInterest in the role of dietary nitrate in human health and disease has grown exponentially in recent years. However, consensus is yet to be reached as to whether consuming nitrate from various food sources is beneficial or harmful to health. Global authorities continue to recommend an acceptable daily intake (ADI) of nitrate of 3.7 mg/kg-bw/day due to concerns over its carcinogenicity. This is despite evidence showing that nitrate consumption from vegetable sources, exceeding the ADI, is associated with decreased cancer prevalence and improvements in cardiovascular, oral, metabolic and neurocognitive health. This review examines the paradox between dietary nitrate and health and disease and highlights the key role of the dietary source and food matrix in moderating this interaction. We present mechanistic and epidemiological evidence to support the notion that consuming vegetable-derived nitrate promotes a beneficial increase in nitric oxide generation and limits toxic N-nitroso compound formation seen with high intakes of nitrate added during food processing or present in contaminated water. We demonstrate the need for a more pragmatic approach to nitrate-related nutritional research and guidelines. Ultimately, we provide an overview of our knowledge in this field to facilitate the various therapeutic applications of dietary nitrate, whilst maintaining population safety. [ABSTRACT FROM AUTHOR]

AbstractMineral oils, untreated or mildly treated, have been classified in group 1 as a potential source of cancer by the International Agency for Research on Cancer (IARC). Although numerous studies have implicated metalworking fluids (MWFs) as human carcinogens, toxicology data regarding the mechanism of carcinogenicity are limited. This study is intended to examine the systemic effects of machining workers’ exposure to MWFs. The potential toxicity of mineral oils was investigated in 65 lathe workers compared to controls (66 men). The occupational exposure was measured by the National Institute for Occupational Safety and Health (NIOSH) 5026. The DNA damage has been examined by the comet assay method. According to the field assessments, the time-weighted average (TWA) exposure to mineral oil mist was 7.67 ± 3.21 mg/m3. A comet assay of peripheral blood cells showed that tail length (TL) and olive moment (OM) were significantly higher in the exposed group (p < 0.05). A multiple logistic regression analysis revealed that, within subjects with over 10 years of exposure, the odds ratio of worker with high TL, percent of DNA in tail, OM, and tail moment (TM) were 1.68, 1.41, 1.71, and 2.71, respectively. DNA strand break in exposed workers was associated with higher exposure time in years. Mineral oil toxicity could be altered in the presence of by-products and impurities. For a better understanding of genotoxicity, further studies are required. [ABSTRACT FROM AUTHOR]

AbstractNano-sized titanium dioxide particles (TiO2 NPs) are a high-production volume nanomaterial widely used in the paints, cosmetics, food and photovoltaics industry. However, the potential carcinogenic effects of TiO2 NPs in the lung are still unclear despite the vast number of in vitro and in vivo studies investigating TiO2 NPs. Here, we systematically reviewed the existing in vitro and in vivo mechanistic evidence of TiO2 NP lung carcinogenicity using the ten key characteristics of carcinogens for identifying and classifying carcinogens. A total of 346 studies qualified for the quality and reliability assessment, of which 206 were considered good quality. Using a weight-of-evidence approach, these studies provided mainly moderate to high confidence for the biological endpoints regarding genotoxicity, oxidative stress and chronic inflammation. A limited number of studies investigated other endpoints important to carcinogenesis, relating to proliferation and transformation, epigenetic alterations and receptor-mediated effects. In summary, TiO2 NPs might possess the ability to induce chronic inflammation and oxidative stress, but it was challenging to compare the findings in the studies due to the wide variety of TiO2 NPs differing in their physicochemical characteristics, formulation, exposure scenarios/test systems, and experimental protocols. Given the limited number of high-quality and high-reliability studies identified within this review, there is a lack of good enough mechanistic evidence for TiO2 NP lung carcinogenicity. Future toxicology/carcinogenicity research must consider including positive controls, endotoxin testing (where necessary), statistical power analysis, and relevant biological endpoints, to improve the study quality and provide reliable data for evaluating TiO2 NP-induced lung carcinogenicity. [ABSTRACT FROM AUTHOR]

Regulators and industry are actively seeking improvements and alternatives to current models and approaches to evaluate potential carcinogenicity of gene therapies (GTs). A meeting of invited experts was organized by NC3Rs/UKEMS (London, March 2023) to discuss this topic. This article describes the consensus reached among delegates on the definition of vector genotoxicity, sources of uncertainty, suitable toxicological endpoints for genotoxic assessment of GTs, and future research needs. The collected recommendations should inform the further development of regulatory guidelines for the nonclinical toxicological assessment of GT products. [ABSTRACT FROM AUTHOR]

A modular strategy is described for the testing and assessment (MoSt) of non-genotoxic carcinogenicity (NGTxC) that is suitable for regulatory applications. It utilizes and builds upon work conducted by the OECD expert group on NGTxC. The approach integrates relevant test methods from the molecular- to cellular- and further to tissue level, many of which have been recently reviewed. Six progressive modules are included in the strategy. Advice is provided for the iterative selection of the next appropriate test method within each step of the strategy. Assessment is completed by a weight of evidence conclusion, which integrates the different streams of modular information. The assessment method gives higher weight to findings that are mechanistically linked with biological relevance to carcinogenesis. With a focus on EU-REACH, and pending upon successful test method validation and acceptance, this will also enable the MoSt for NGTxC to be applied for regulatory purposes across different regulatory jurisdictions. [ABSTRACT FROM AUTHOR]

The transition metal cadmium (Cd) is toxic to humans and can induce cellular redox stress and inflammation. Cd is a recognized carcinogen, but the molecular mechanisms associated with its genotoxicity and carcinogenicity are not defined. Therefore, a systematic review was undertaken to examine the scientific literature that has covered the molecular mechanism of Cd genotoxicity and its relationship to cellular redox stress and inflammation. An electronic database search of PubMed, Scopus, and the Web of Science Core Collection was conducted to retrieve the studies that had investigated if Cd genotoxicity was directly linked to the induction of redox stress and inflammation. Studies included exposure to Cd via in vitro and in vivo routes of administration. Of 214 publications retrieved, 10 met the inclusion criteria for this review. Preclinical studies indicate that Cd exposure causes the induction of reactive oxygen species (ROS) and, via concomitant activity of the transcription factor NF-κβ, induces the production of pro-inflammatory cytokines and a cytokine profile consistent with the induction of an allergic response. There is limited information regarding the impact of Cd on cellular signal transduction pathways, and the relationship of this to genotoxicity is still inconclusive. Nevertheless, pre-incubation with the antioxidants, N-acetylcysteine or sulforaphane, or the necroptosis inhibitor, necrostatin-1, reduces Cd toxicity; indicative that these agents may be a beneficial treatment adjunct in cases of Cd poisoning. Collectively, this review highlights that Cd-induced toxicity and associated tissue pathology, and ultimately the carcinogenic potential of Cd, may be driven by redox stress and inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Asbestos fibres have been considered an environmental hazard for decades. However, little is known about the attempts of circulating immune cells to counteract their toxicity. We addressed the early effects of fibre‐released soluble factors (i.e. heavy metals) in naïve immune cells, circulating immediately below the alveolar/endothelial cell layer. By comparison, the direct fibre effects on endotheliocytes were also studied since these cells are known to sustain inflammatory processes. The three mineral fibres analysed showed that mainly chrysotile (CHR) and erionite (ERI) were able to release toxic metals in extracellular media respect to crocidolite (CRO), during the first 24 h. Nevertheless, all three fibres were able to induce oxidative stress and genotoxic damage in indirectly challenged naïve THP‐1 monocytes (separated by a membrane). Conversely, only CHR‐released metal ions induced apoptosis, NF‐κB activation, cytokines and CD163 gene overexpression, indicating a differentiation towards the M0 macrophage phenotype. On the other hand, all three mineral fibres in direct contact with HECV endothelial cells showed cytotoxic, genotoxic and apoptotic effects, cytokines and ICAM‐I overexpression, indicating the ability of these cells to promote an inflammatory environment in the lung independently from the type of inhaled fibre. Our study highlights the different cellular responses to mineral fibres resulting from both the nature of the cells and their function, but also from the chemical–physical characteristics of the fibres. In conclusion, CHR represented the main pro‐inflammatory trigger, able to recruit and activate circulating naïve monocytes, through its released metals, already in the first 24 h after inhalation. The early effects of mineral fibre‐released heavy metals in THP‐1 cells, mimicking the immune cells in the alveolar capillaries, were investigated, and by comparison, also the direct fibre effects on the endothelial cell layer. The study highlights that the cellular responses result from the nature of the cells, their function and from the fibre chemical–physical characteristics. CHR represented the main pro‐inflammatory trigger, able to recruit and activate circulating monocytes, through its released metals, already at 24 h after inhalation. [ABSTRACT FROM AUTHOR]

The International Agency for Research on Cancer has classified N‐nitrosodiethylamine (NDEA) as a possible carcinogen and mutagenic substances, placing it in category 2A of compounds that are probably harmful to humans. It is found in nature and tobacco smoke, along with its precursors, and is also synthesized endogenously in the human body. The oral or parenteral administration of a minimal quantity of NDEA results in severe liver and kidney organ damage. The NDEA required bioactivation by CYP450 enzyme to form DNA adduct in the alkylation mechanism. Thus, this bioactivation directs oxidative stress and injury to cells due to the higher formation of reactive oxygen species and alters antioxidant system in tissues, whereas free radical scavengers guard the membranes from NDEA‐directed injury in many enzymes. This might be one of the reasons in the etiology of cancer that is not limited to a certain target organ but can affect various organs and organ systems. Although there are various possible approaches for the treatment of NDEA‐induced cancer, their therapeutic outcomes are still very dismal. However, several precautions were considered to be taken during handling or working with NDEA, as it considered being the best way to lower down the occurrence of NDEA‐directed cancers. The present review was designed to enlighten the general guidelines for working with NDEA, possible mechanism, to alter the antioxidant line to cause malignancy in different parts of animal body along with its protective agents. Thus, revelation to constant, unpredictable stress situations even in common life may remarkably augment the toxic potential through the rise in the oxidative stress and damage of DNA. N‐Nitrosodiethylamine (NDEA) is a potential carcinogen and mutagen. Their carcinogenic action is not limited to a certain target organ but can affect various organs and organ systems. It induces oxidative stress and cellular injury due to higher formation of reactive oxygen species and alters antioxidant system in the tissues. The present review was designed to enlighten the general guidelines for working with NDEA, possible mechanism, to alter antioxidant line to cause malignancy in different parts of animal body along with its protective agents. [ABSTRACT FROM AUTHOR]

N-nitrosamines and nitrosamine drug substance related impurities (NDSRIs) became a critical topic for the development and safety of small molecule medicines following the withdrawal of various pharmaceutical products from the market. To assess the mutagenic and carcinogenic potential of different N-nitrosamines lacking robust carcinogenicity data, several approaches are in use including the published carcinogenic potency categorization approach (CPCA), the Enhanced Ames Test (EAT), in vivo mutagenicity studies as well as read-across to analogue molecules with robust carcinogenicity data. We employ quantum chemical calculations as a pivotal tool providing insights into the likelihood of reactive ion formation and subsequent DNA alkylation for a selection of molecules including e.g., carcinogenic N-nitrosopiperazine (NPZ), N-nitrosopiperidine (NPIP), together with N-nitrosodimethylamine (NDMA) as well as non-carcinogenic N-nitrosomethyl-tert-butylamine (NTBA) and bis (butan-2-yl) (nitros)amine (BBNA). In addition, a series of nitrosomethylaminopyridines is compared side-by-side. We draw comparisons between calculated reaction profiles for structures representing motifs common to NDSRIs and those of confirmed carcinogenic and noncarcinogenic molecules with in vivo data from cancer bioassays. Furthermore, our approach enables insights into reactivity and relative stability of intermediate species that can be formed upon activation of several nitrosamines. Most notably, we reveal consistent differences between the free energy profiles of carcinogenic and non-carcinogenic molecules. For the former, the intermediate diazonium ions mostly react, kinetically controlled, to the more stable DNA adducts and less to the water adducts via transition-states of similar heights. Non-carcinogenic molecules yield stable carbocations as intermediates that, thermodynamically controlled, more likely form the statistically preferred water adducts. In conclusion, our data confirm that quantum chemical calculations can contribute to a weight of evidence approach for the risk assessment of nitrosamines. [ABSTRACT FROM AUTHOR]

The European Commission asked EFSA to update its 2011 risk assessment on tetrabromobisphenol A (TBBPA) and five derivatives in food. Neurotoxicity and carcinogenicity were considered as the critical effects of TBBPA in rodent studies. The available evidence indicates that the carcinogenicity of TBBPA occurs via non‐genotoxic mechanisms. Taking into account the new data, the CONTAM Panel considered it appropriate to set a tolerable daily intake (TDI). Based on decreased interest in social interaction in male mice, a lowest observed adverse effect level (LOAEL) of 0.2 mg/kg body weight (bw) per day was identified and selected as the reference point for the risk characterisation. Applying the default uncertainty factor of 100 for inter‐ and intraspecies variability, and a factor of 3 to extrapolate from the LOAEL to NOAEL, a TDI for TBBPA of 0.7 μg/kg bw per day was established. Around 2100 analytical results for TBBPA in food were used to estimate dietary exposure for the European population. The most important contributors to the chronic dietary LB exposure to TBBPA were fish and seafood, meat and meat products and milk and dairy products. The exposure estimates to TBBPA were all below the TDI, including those estimated for breastfed and formula‐fed infants. Accounting for the uncertainties affecting the assessment, the CONTAM Panel concluded with 90%–95% certainty that the current dietary exposure to TBBPA does not raise a health concern for any of the population groups considered. There were insufficient data on the toxicity of any of the TBBPA derivatives to derive reference points, or to allow a comparison with TBBPA that would support assignment to an assessment group for the purposes of combined risk assessment. [ABSTRACT FROM AUTHOR]

The potential carcinogenicity of talc has been evaluated in many studies in humans and experimental animals published in the scientific literature over the last several decades, with a number of these studies reporting no associations between talc exposure and any type of cancer. In order to fully understand the current state of the science regarding the potential for talc to induce human cancers, we conducted a comprehensive and systematic review of the available experimental animal and mechanistic evidence (in conjunction with a systematic review of the epidemiology evidence in a companion analysis) to evaluate whether it supports talc as being carcinogenic to humans. We considered study quality and its impact on the interpretation of results and evaluated all types of cancer and all exposure routes. We also evaluated the evidence on the potential for talc to migrate in the body to potential tumor sites. We identified seven experimental animal carcinogenicity studies and 11 mechanistic studies of talc to systematically review. We found that several of the experimental animal carcinogenicity studies of talc have limitations that preclude their sensitivity to detect increases in tumor incidence. Regardless, the studies cover multiple exposure routes, species, and exposure durations, and none indicate that talc is a carcinogen in experimental animals except in rats under conditions of extremely high exposure that likely resulted in lung particle overload, a nonspecific effect of high exposures to poorly soluble particles, and not from any carcinogenic properties of talc. Lung particle overload leading to lung tumor formation has only been observed in rats and not in any other species, including humans. The mechanistic studies indicate that talc is not genotoxic or mutagenic, but can induce some effects that could be events on a possible pathway to carcinogenicity, mainly at high exposures or in in vitro studies with exposures of unclear relevance in vivo, but these effects are not consistent across studies and cell types. This systematic review of the experimental animal carcinogenicity and mechanistic evidence for talc indicates that an association between talc exposure and cancer is not expected in humans. Talc carcinogenicity is not plausible in any species except rats, and only when the exposure conditions are high enough to induce lung particle overload, which is not relevant to human exposures. [ABSTRACT FROM AUTHOR]

Formaldehyde is widely utilized across various industries such as food, textiles, and leather, yet its presence raises significant health concerns due to its irritation and carcinogenicity. Numerous methods have been developed to probe it in solution and gas states. Among them, absorption spectroscopy-based methods commonly employed. However, these methods require complex preprocessing for colored solutions to avoid interference. In response to this challenge, a novel interference-resistant detection kit leveraging surface-enhanced Raman spectroscopy (SERS) coupled with reaction-induced self-amplification for rapid and direct detection of formaldehyde was developed. The kit needed only ten minutes and achieved a limit of detection lower than 10−4 μg/mL with a handheld Raman spectrometer. Thanks to the kit's reaction with formaldehyde, colloidal nanoparticles were linked to form "hot-spots" to further enhance the SERS signals. The signal demonstrated outstanding resistance to interference, including different dyes, ensuring a practical tool for direct detection of formaldehyde in complex solutions. [ABSTRACT FROM AUTHOR]

Background: Carcinogenicity assessment of industrial chemicals is necessary because of the risk of workplaces exposure to these chemicals in humans. Objectives: We aimed to evaluation nongenotoxicity and epigenetic carcinogenicity of the industrial chemicals anisol, 2-methoxyethanol, and 1,2-dichlorobenzene. Results: Treatment of Bhas 42 cells with these chemicals did not induce cell transformation, and there was no significant methylation difference in the methylation of CpG islands between the treatment and control groups. Conclusion: Anisol, 2-methoxyethanol, and 1,2-dichlorobenzene do not exert nongenotoxic carcinogenicity or methylation-related epigenetic changes. [ABSTRACT FROM AUTHOR]

Abstract The research employed network toxicology and molecular docking techniques to systematically examine the potential carcinogenic effects and mechanisms of aspartame (l-α-aspartyl-l-phenylalanine methyl ester). Aspartame, a commonly used synthetic sweetener, is widely applied in foods and beverages globally. In recent years, its safety issues, particularly the potential carcinogenic risk, have garnered widespread attention. The study first constructed an interaction network map of aspartame with gastric cancer targets using network toxicology methods and identified key targets and pathways. Preliminary validation was conducted through microarray data analysis and survival analysis, and molecular docking techniques were employed to further examine the binding affinity and modes of action of aspartame with key proteins. The findings suggest that aspartame has the potential to impact various cancer-related proteins, potentially raising the likelihood of cellular carcinogenesis by interfering with biomolecular function. Furthermore, the study found that the action patterns and pathways of aspartame-related targets are like the mechanisms of known carcinogenic pathways, further supporting the scientific hypothesis of its potential carcinogenicity. However, given the complexity of the in vivo environment, we also emphasize the necessity of validating these molecular-level findings in actual biological systems. The study introduces a fresh scientific method for evaluating the safety of food enhancers and provides a theoretical foundation for shaping public health regulations.

The rodent cancer bioassays are conducted for agrochemical safety assessment yet they often do not inform regulatory decision-making. As part of a collaborative effort, the Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) developed a reporting framework to guide a weight of evidence (WOE)-based carcinogenicity assessment that demonstrates how to fulfill the regulatory requirements for chronic risk estimation without the need to conduct lifetime rodent bioassays. The framework is the result of a multi-stakeholder collaboration that worked through an iterative process of writing case studies (in the form of waivers), technical peer reviews of waivers, and an incorporation of key learnings back into the framework to be tested in subsequent case study development. The example waivers used to develop the framework were written retrospectively for registered agrochemical active substances for which the necessary data and information could be obtained through risk assessment documents or data evaluation records from the US EPA. This exercise was critical to the development of a framework, but it lacked authenticity in that the stakeholders reviewing the waiver already knew the outcome of the rodent cancer bioassay(s). Syngenta expanded the evaluation of the ReCAAP reporting framework by writing waivers for three prospective case studies for new active substances where the data packages had not yet been submitted for registration. The prospective waivers followed the established framework considering ADME, potential exposure, subchronic toxicity, genotoxicity, immunosuppression, hormone perturbation, mode of action (MOA), and all relevant information available for read-across using a WOE assessment. The point of departure was estimated from the available data, excluding the cancer bioassay results, with a proposed use for the chronic dietary risk assessment. The read-across assessments compared data from reliable registered chemical analogues to strengthen the prediction of chronic toxicity and/or tumorigenic potential. The prospective case studies represent a range of scenarios, from a new molecule in a well-established chemical class with a known MOA to a molecule with a new pesticidal MOA (pMOA) and limited read-across to related molecules. This effort represents an important step in establishing criteria for a WOE-based carcinogenicity assessment without the rodent cancer bioassay(s) while ensuring a health protective chronic dietary risk assessment. [ABSTRACT FROM AUTHOR]

Industry representatives on the ICH S1B(R1) Expert Working Group (EWG) worked closely with colleagues from the Drug Regulatory Authorities to develop an addendum to the ICH S1B guideline on carcinogenicity studies that allows for a weight-of-evidence (WoE) carcinogenicity assessment in some cases, rather than conducting a 2-year rat carcinogenicity study. A subgroup of the EWG composed of regulators have published in this issue a detailed analysis of the Prospective Evaluation Study (PES) conducted under the auspices of the ICH S1B(R1) EWG. Based on the experience gained through the Prospective Evaluation Study (PES) process, industry members of the EWG have prepared the following commentary to aid sponsors in assessing the standard WoE factors, considering how novel investigative approaches may be used to support a WoE assessment, and preparing appropriate documentation of the WoE assessment for presentation to regulatory authorities. The commentary also reviews some of the implementation challenges sponsors must consider in developing a carcinogenicity assessment strategy. Finally, case examples drawn from previously marketed products are provided as a supplement to this commentary to provide additional examples of how WoE criteria may be applied. The information and opinions expressed in this commentary are aimed at increasing the quality of WoE assessments to ensure the successful implementation of this approach. [ABSTRACT FROM AUTHOR]

Cyanides and nitriles, characterized by their R-CN chains, are known for their toxicity, mutagenicity, and carcinogenicity, posing significant threats to environmental and human health. This study aims to explore the biodegradation capabilities of Rhodococcus sp. in breaking down cyanide and nitrile bonds. Rhodococcus pyridinivorans strain I-benzo was isolated from tanning waste and cultured in mineral media with a 20 mM benzonitrile substrate. The activity of this strain was tested using substrates such as benzonitrile, acetonitrile, acrylonitrile, benzamide, acetamide, and acrylamide, revealing positive reactions of nitrile hydratase and amidase enzymes through the Nessler measurement method, which indicated the production of ammonia and carboxylic acids. Furthermore, the degradation tests showed that the Vmax values for the biodegradation of potassium cyanide and sodium cyanide were 0.56 ppm/minute and 0.21 ppm/minute, respectively. These findings highlight the potential application of Rhodococcus pyridinivorans strain I-benzo in mitigating the environmental impact of cyanide and nitrile pollutants through efficient biodegradation. [ABSTRACT FROM AUTHOR]

The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell–cell and cell–matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose–response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals. [ABSTRACT FROM AUTHOR]

• This study presents the development of several deep-learning models to evaluate different types of compound toxicity. • The models were tailored to specific types of toxicity, each with a unique GCN binary classification. • Evaluation metrics indicate that developed models were reliable in predicting compounds toxicity. • The models were integrated into a virtual screening pipeline to facilitate drug discovery. Ensuring the safety and efficacy of chemical compounds is crucial in small-molecule drug development. In the later stages of drug development, toxic compounds pose a significant challenge, losing valuable resources and time. Early and accurate prediction of compound toxicity using deep learning models offers a promising solution to mitigate these risks during drug discovery. In this study, we present the development of several deep-learning models aimed at evaluating different types of compound toxicity, including acute toxicity, carcinogenicity, hERG_cardiotoxicity (the human ether-a-go-go related gene caused cardiotoxicity), hepatotoxicity, and mutagenicity. To address the inherent variations in data size, label type, and distribution across different types of toxicity, we employed diverse training strategies. Our first approach involved utilizing a graph convolutional network (GCN) regression model to predict acute toxicity, which achieved notable performance with Pearson R 0.76, 0.74, and 0.65 for intraperitoneal, intravenous, and oral administration routes, respectively. Furthermore, we trained multiple GCN binary classification models, each tailored to a specific type of toxicity. These models exhibited high area under the curve (AUC) scores, with an impressive AUC of 0.69, 0.77, 0.88, and 0.79 for predicting carcinogenicity, hERG_cardiotoxicity, mutagenicity, and hepatotoxicity, respectively. Additionally, we have used the approved drug dataset to determine the appropriate threshold value for the prediction score in model usage. We integrated these models into a virtual screening pipeline to assess their effectiveness in identifying potential low-toxicity drug candidates. Our findings indicate that this deep learning approach has the potential to significantly reduce the cost and risk associated with drug development by expediting the selection of compounds with low toxicity profiles. Therefore, the models developed in this study hold promise as critical tools for early drug candidate screening and selection. [ABSTRACT FROM AUTHOR]

The research employed network toxicology and molecular docking techniques to systematically examine the potential carcinogenic effects and mechanisms of aspartame (l-α-aspartyl-l-phenylalanine methyl ester). Aspartame, a commonly used synthetic sweetener, is widely applied in foods and beverages globally. In recent years, its safety issues, particularly the potential carcinogenic risk, have garnered widespread attention. The study first constructed an interaction network map of aspartame with gastric cancer targets using network toxicology methods and identified key targets and pathways. Preliminary validation was conducted through microarray data analysis and survival analysis, and molecular docking techniques were employed to further examine the binding affinity and modes of action of aspartame with key proteins. The findings suggest that aspartame has the potential to impact various cancer-related proteins, potentially raising the likelihood of cellular carcinogenesis by interfering with biomolecular function. Furthermore, the study found that the action patterns and pathways of aspartame-related targets are like the mechanisms of known carcinogenic pathways, further supporting the scientific hypothesis of its potential carcinogenicity. However, given the complexity of the in vivo environment, we also emphasize the necessity of validating these molecular-level findings in actual biological systems. The study introduces a fresh scientific method for evaluating the safety of food enhancers and provides a theoretical foundation for shaping public health regulations. [ABSTRACT FROM AUTHOR]

Intensified sanitation practices amid the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak might result in the increased release of chloramine disinfectants into surface water, significantly promoting the formation of nitrosamine disinfection by-products (DBPs) in drinking water. Unfortunately, these nitrosamine DBPs exhibit significant genotoxic, carcinogenic, and mutagenic properties, whereas chlorinating disinfectants remain in global practice. The current review provides valuable insights into the occurrence, identification, contamination status, exposure limits, and toxicity of the new unregulated disinfection by-products (nitrosamine DBPs) in drinking water. As a result, concentrations of nitrosamine DBPs far exceed allowable limits in drinking water, and prolonged exposure has the potential to cause metabolic disorders, a critical step in tumor initiation and progression. Importantly, based on recent research, we have concluded the role of nitrosamines DBPs in different metabolic pathways. Remarkably, nitrosamine DBPs can induce chronic inflammation and initiate tumors by activating sphingolipid and polyunsaturated fatty acid metabolism. Regarding amino acid and nucleotide metabolism, nitrosamine DBPs can inhibit tryptophan metabolism and de novo nucleotide synthesis. Moreover, inhibition of de novo nucleotide synthesis fails to repair DNA damage induced by nitrosamines. Additionally, the accumulation of lactate induced by nitrosamine DBPs may act as a pivotal signaling molecule in communication within the tumor microenvironment. However, with the advancement of tumor metabolomics, understanding the role of nitrosamine DBPs in causing cancer by inducing metabolic abnormalities significantly lags behind, and specific mechanisms of toxic effects are not clearly defined. Urgently, further studies exploring this promising area are needed. [ABSTRACT FROM AUTHOR]

Torsional stress in double-stranded DNA enables and regulates facets of chromosomal metabolism, replication, and transcription and requires regulatory enzymatic systems including topoisomerases and histone methyltransferases. As such, this machinery may be subject to deleterious effects from reactive mutagens, including ones from carcinogenic polycyclic aromatic hydrocarbon (PAH) adduct formation with DNA. Supercoiled plasmid DNA was investigated for its torsional responses to adducts formed in vitro from PAH benzylic carbocation reactive intermediates created spontaneously by release of leaving groups. PAH sulfate esters were found to (1) unwind DNA in a concentration dependent manner, and (2) provide maximum unwinding in a pattern consistent with known carcinogenicities of the parent PAHs, that is, 6-methylbenzo[a]pyrene > 7,12-methylbenz[a]anthracene > 3-methylcholanthrene > 9-methylanthracene > 7-methylbenz[a]anthracene > 1-methylpyrene. Supercoil unwinding was demonstrated to be dependent on the presence of sulfate or chloride leaving groups such that reactive carbocations were generated in situ by hydrolysis. In silico modeling of intercalative complex topology showed PAH benzylic carbocation reactive functional groups in alignment with target nucleophiles on guanine bases in a 5'-dCdG-3' pocket in agreement with known formation of nucleotide adducts. Inhibitory or modulatory effects on PAH-induced supercoil unwinding were seen with ascorbic acid and an experimental antineoplastic agent Antineoplaston A10 in agreement with their known anticarcinogenic properties. In summary, the reactive PAH intermediates studied here undoubtedly participate in well-known mutational mechanisms such as frameshifts and apurinic site generation. However, they are also capable of random disruption of chromosomal supercoiling in a manner consistent with the known carcinogenicities of the parent compounds, and this mechanism may represent an additional detrimental motif worthy of further study for a more complete understanding of chemical carcinogenicity. [ABSTRACT FROM AUTHOR]

Background: The current manuscript's aim was to determine the human papillomavirus (HPV) genotype-specific prevalence and distribution among individuals, males, and females, of different ages in the region of Apulia, Italy, highlighting the possible variables involved in the carcinogenicity mechanism. In addition, we proposed two hypothetical models of HPV's molecular dynamics, intending to clarify the impact of prevention and therapeutic strategies, explicitly modeled by recent survey data. Methods: We presented clinical data from 9647 participants tested for either high-risk (HR) or low-risk (LR) HPV at the affiliated Bari Policlinic University Hospital of Bari from 2011 to 2022. HPV DNA detection was performed using nested-polymerase chain reaction (PCR) and multiplex real-time PCR assay. Statistical analysis showed significant associations for all genders and ages and both HR- and LR-HPV types. A major number of significant pairwise associations were detected for the higher-risk types and females and lower-risk types and males. Results: The overall prevalence of HPV was 50.5% (n-4.869) vs. 49.5% (n-4.778) of the study population, of which 74.4% (n-3621) were found to be HPV high-risk (HR-HPV) genotypes and 57.7% (n-2.807) low-risk HPV (LR-HPV) genotypes, of which males were 58% and females 49%; the three most prevalent HR-HPV genotypes were HPV 53 (n707-15%), 16 (n704-14%), and 31 (n589-12%), and for LR-HPV, they were 42 (19%), 6 (16%), and 54 (13%); 56% of patients screened for HPV were ≤ 30 years old, 53% were between 31 and 40 years old, 46% were 41–50 and 51–60 years old, and finally, 44% of subjects were >60 years old. Conclusions: Our study provided comprehensive epidemiological data on HPV prevalence and genotype distribution among 9647 participants, which could serve as a significant reference for clinical practice, and it implied the necessity for more effective screening methods for HPV carcinogenesis covering the use of more specific molecular investigations. Although this is a predominantly descriptive and epidemiological study, the data obtained offer not only a fairly unique trend compared to other studies of different realities and latitudes but also lead us to focus on the HPV infection within two groups of young people and adults and hypothesize the possible involvement of dysbiosis, stem cells, and the retrotransposition mechanism. [ABSTRACT FROM AUTHOR]

The tobacco-specific nitrosamines N ʹ-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered 'carcinogenic to humans' by the International Agency for Research on Cancer (IARC) and are believed to be important in the carcinogenic effects of both smokeless tobacco and combusted tobacco products. This short review focuses on the results of recent studies on the formation of NNN and NNK in tobacco, and their carcinogenicity and toxicity in laboratory animals. New mechanistic insights are presented regarding the role of dissimilatory nitrate reductases in certain microorganisms involved in the conversion of nitrate to nitrite that leads to the formation of NNN and NNK during curing and processing of tobacco. Carcinogenicity studies of the enantiomers of the major NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and the enantiomers of NNN are reviewed. Recent toxicity studies of inhaled NNK and co-administration studies of NNK with formaldehyde, acetaldehyde, acrolein and CO2, all of which occur in high concentrations in cigarette smoke, are discussed. [ABSTRACT FROM AUTHOR]

The ten key characteristics (KCs) of carcinogens are based on characteristics of known human carcinogens and encompass many types of endpoints. We propose that an objective review of the large amount of cancer mechanistic evidence for the chemical bisphenol A (BPA) can be achieved through use of these KCs. A search on metabolic and mechanistic data relevant to the carcinogenicity of BPA was conducted and web-based software tools were used to screen and organize the results. We applied the KCs to systematically identify, organize, and summarize mechanistic information for BPA, and to bring relevant carcinogenic mechanisms into focus. For some KCs with very large data sets, we utilized reviews focused on specific endpoints. Over 3000 studies for BPA from various data streams (exposed humans, animals, in vitro and cell-free systems) were identified. Mechanistic data relevant to each of the ten KCs were identified, with receptor-mediated effects, epigenetic alterations, oxidative stress, and cell proliferation being especially data rich. Reactive and bioactive metabolites are also associated with a number of KCs. This review demonstrates how the KCs can be applied to evaluate mechanistic data, especially for data-rich chemicals. While individual entities may have different approaches for the incorporation of mechanistic data in cancer hazard identification, the KCs provide a practical framework for conducting an objective examination of the available mechanistic data without a priori assumptions on mode of action. This analysis of the mechanistic data available for BPA suggests multiple and inter-connected mechanisms through which this chemical can act. [ABSTRACT FROM AUTHOR]

Aerobic glycolysis is a typical metabolic rearrangement for tumorigenesis. Arecoline is of explicit carcinogenicity, numerous works demonstrate its mutagenicity, genotoxicity, and cytotoxicity. However, the effects of arecoline on aerobic glycolysis of esophageal epithelial cells remain unclear. In the present study, 5 μM arecoline efficiently increased HK2 expression to induce aerobic glycolysis in Het‐1A‐Are and NE2‐Are cells. The mechanistic analysis showed that arecoline activated the Akt‐c‐Myc signaling pathway and reduced the GSK3β‐mediated phosphorylation of c‐Myc on Thr58 to prevent its ubiquitination and destruction, subsequently promoting HK2 transcription and expression. Taken together, these results suggest that arecoline can induce aerobic glycolysis of esophageal epithelial cells and further confirm that arecoline is a carcinogen harmful to human health. [ABSTRACT FROM AUTHOR]

[Display omitted] • The highly produced bisphenol A can disrupt the homeostasis of the endocrine system. • Previous finding confirmed a higher concentration of bisphenol A in the young persons. • Conventional methods for bisphenol A elimination are not cost-efficient. • Plants naturally develop an efficient mechanism for contaminant removal. • Various advanced strategies can be applied to eliminate bisphenol A. Bisphenol A (BPA) accumulates in the environment at lethal concentrations because of its high production rate and utilization. BPA, originating from industrial effluent, plastic production, and consumer products, poses serious risks to both the environment and human health. The widespread aggregation of BPA leads to endocrine disruption, reactive oxygen species-mediated DNA damage, epigenetic modifications and carcinogenicity, which can disturb the normal homeostasis of the body. The living being in a population is subjected to BPA exposure via air, water and food. Globally, urinary analysis reports have shown higher BPA concentrations in all age groups, with children being particularly susceptible due to its occurrence in items such as milk bottles. The conventional methods are costly with a low removal rate. Since there is no proper eco-friendly and cost-effective degradation of BPA reported so far. The phytoremediation, green-biotechnology based method which is a cost-effective and renewable resource can be used to sequestrate BPA. Phytoremediation is observed in numerous plant species with different mechanisms to remove harmful contaminants. Plants normally undergo several improvements in genetic and molecular levels to withstand stress and lower levels of toxicants. But such natural adaptation requires more time and also higher concentration of contaminants may disrupt the normal growth, survival and yield of the plants. Therefore, natural or synthetic amendments and genetic modifications can improve the xenobiotics removal rate by the plants. Also, constructed wetlands technique utilizes the plant's phytoremediation mechanisms to remove industrial effluents and medical residues. In this review, we have discussed the limitations and futuristic advancement strategies for degrading BPA using phytoremediation-associated mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) initiated a process in 2012 to revise the S1B Guideline "Testing for Carcinogenicity of Pharmaceuticals". Previous retrospective analysis indicated the importance of histopathological risk factors in chronic toxicity studies, evidence of endocrine perturbation, and positive genetic toxicology results as potentially predictive indicators of carcinogenic risk. In addition, a relationship between pharmacodynamic activity and carcinogenicity outcome in long-term rodent studies has been reported. It was postulated that these factors could be evaluated in a Weight-of-Evidence (WoE) approach to predict the outcome of a 2-year rat study. Methods: The ICH S1B(R1) Expert Working Group (EWG) conducted a Prospective Evaluation Study (PES) to determine the regulatory feasibility of this WoE approach. Drug Regulatory Authorities (DRAs) evaluated 49 Carcinogenicity Assessment Documents (CADs), which describe the WoE for submitted pharmaceutical compounds. Each compound was categorized into a carcinogenic risk category including a statement of the value of the 2-year rat study. The outcome of the completed 2-year rat studies was evaluated in relation to the prospective CAD to determine the accuracy of predictions. Results: Based on the results of the PES, the EWG concluded that the evaluation process for assessing human carcinogenic risk of pharmaceuticals described in ICH S1B could be expanded to include a WoE approach. Approximately 27% of 2-year rat studies could be avoided in cases where DRAs and sponsors unanimously agreed that such a study would not add value. Discussion: Key factors supporting a WoE assessment were identified: data that inform carcinogenic potential based on drug target biology and the primary pharmacologic mechanism of the parent compound and major human metabolites; results from secondary pharmacology screens for this compound and major human metabolites that inform carcinogenic risk; histopathology data from repeated-dose toxicity studies; evidence for hormonal perturbation; genotoxicity data; and evidence of immune modulation. The outcome of the PES indicates that a WoE approach can be used in place of conducting a 2-year rat study for some pharmaceuticals. These data were used by the ICH S1B(R1) EWG to write the R1 Addendum to the S1B Guideline published in August 2022. [ABSTRACT FROM AUTHOR]

Ethidium Bromide (EtBr) serves as an interpolating agent utilized for its fluorescent properties in gel electrophoresis, aiding in the detection of various DNA fragments. However, its usage has been associated with DNA mutations, inhibition of mitochondrial protein synthesis and other alterations, particularly at high concentrations. Due to its remarkable stability in the environment and propensity to degrade into mutagenic compounds, especially when exposed to bleaching agents, there are significant concerns regarding its widespread use. Given the potential toxic and mutagenic effects of EtBr and the possibility of its entry into the food chain, it becomes crucial to monitor its concentration at emission sources across different ecosystems, including aquatic, terrestrial, and plant environments. Improper disposal of EtBr poses substantial risks, including the induction of mutations and cancer. Various disposal methods have been explored, such as phytoremediation and employing bacteria capable of degrading this chemical. Proper management of EtBr disposal is paramount to mitigate its harmful impact on the environment and living organisms. [ABSTRACT FROM AUTHOR]

The ICH S1B carcinogenicity global testing guideline has been recently revised with a novel addendum that describes a comprehensive integrated Weight of Evidence (WoE) approach to determine the need for a 2-year rat carcinogenicity study. In the present work, experts from different organizations have joined efforts to standardize as much as possible a procedural framework for the integration of evidence associated with the different ICH S1B(R1) WoE criteria. The framework uses a pragmatic consensus procedure for carcinogenicity hazard assessment to facilitate transparent, consistent, and documented decision-making and it discusses best-practices both for the organization of studies and presentation of data in a format suitable for regulatory review. First, it is acknowledged that the six WoE factors described in the addendum form an integrated network of evidence within a holistic assessment framework that is used synergistically to analyze and explain safety signals. Second, the proposed standardized procedure builds upon different considerations related to the primary sources of evidence, mechanistic analysis, alternative methodologies and novel investigative approaches, metabolites, and reliability of the data and other acquired information. Each of the six WoE factors is described highlighting how they can contribute evidence for the overall WoE assessment. A suggested reporting format to summarize the cross-integration of evidence from the different WoE factors is also presented. This work also notes that even if a 2-year rat study is ultimately required, creating a WoE assessment is valuable in understanding the specific factors and levels of human carcinogenic risk better than have been identified previously with the 2-year rat bioassay alone. [ABSTRACT FROM AUTHOR]

Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but negative in vivo , this can contribute to unnecessary testing in animals used to confirm erroneous in vitro positive results. Current in vitro tests typically evaluate only genotoxicity endpoints, which limits their potential to detect non-genotoxic carcinogens. The frequency of misleading in vitro positive results can be high, leading to a requirement for more informative in vitro tests. It is now recognized that multiple-endpoint genotoxicity testing may aid more accurate detection of carcinogens and non-carcinogens. The objective of this review was to evaluate the utility of our novel, multiple-endpoint in vitro test, which uses multiple cancer-relevant endpoints to predict carcinogenic potential. The tool assessed micronucleus frequency, p53 expression, p21 expression, mitochondrial respiration, cell cycle abnormalities and, uniquely, cell morphology changes in human lymphoblastoid cell lines, TK6 and MCL-5. The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. Adoption of the approach could enable reduced animal use in carcinogenicity testing. [ABSTRACT FROM AUTHOR]

Simple Summary: Total hip arthroplasty is a well-established orthopaedic procedure, the use of which is on the increase worldwide. Since implants used in arthroplasty are usually made of metals including cobalt, chromium and titanium. These metals have since been classified as potentially carcinogenic and may cause cancers in humans. This retrospective study aimed to investigate whether patients with hip implants have a higher risk of developing any type of cancer. The findings will better inform patients and doctors about the risks and benefits of the type of implants and if patients with implants are at a higher risk of malignancy, then patients with implants may benefit from closer medical monitoring. Background: Metal implants have been preferentially used in THA due to its biocompatibility, mechanical stability and durability. Yet concerns have emerged regarding their potential to release metallic ions, leading to long-term adverse effects, including carcinogenicity. This study aimed to investigate the risk of cancer development in patients with orthopaedic metal implants in total hip arthroplasty (THA). Methods: Patients with THA conducted at a local tertiary implant centre from 2001–2008 were linked to the local cancer registry and followed up to the end of 2023. Standardized incidence ratios (SIRs) for cancer incidence and its confidence interval by Poisson distribution were calculated. Survival analysis was depicted using the Kaplan–Meier method, and the log-rank test was used to assess the differences across groups. Results: The study cohort included 388 patients and 53 cancers diagnosed during follow-up, at least 5 years post THA. All-site cancer risks were increased in patients with THA (SIR: 1.97; 95% CI: 1.48–2.46), validated with chi-square analysis (chi-square = 15.2551, N = 100,388, p < 0.01). A statistically significant increase in multiple site-specific cancers including haematological cancers were identified. Conclusions: Patients with THA were found to have an increased risk for cancer compared to the general population during a mean follow-up of 16 years. [ABSTRACT FROM AUTHOR]

Because of their high nutritional value, meat and processed meat products play a crucial role in human dietary habits, offering a wide variety of options in today's market. Consumers seek these products to meet specific sensory standards, including appearance, color, flavour, and aroma, while also prioritizing safety. This has led the meat industry to rely on various additives, with nitrites being extensively used in meat processing. Nitrites, classified as preservatives, exhibit antimicrobial effects by impeding the proliferation of microorganisms, specifically the bacterium Clostridium botulinum. From a technological perspective, nitrites are pivotal for color enhancement and stability, prevention of fat oxidation, and contribution to the aroma in meat products. Despite these positive contributions, nitrites can have adverse effects on consumer health. Their reaction with proteins at elevated temperatures results in the formation of N-nitrosamines, known for their carcinogenic and mutagenic qualities. According to a recent classification by the World Health Organization, processed meat has been categorized as carcinogenic. It has been found that consuming 50g of processed meat daily can lead to an 18% higher risk of developing colon cancer. Nitrites, viewed from a health standpoint, can be toxic, causing the conversion of hemoglobin into methemoglobin, leading to methemoglobinemia and potential fatality with elevated methemoglobin levels. Adhering to legal regulations regarding the permissible levels of added nitrites and nitrates in processed meat products is crucial to mitigate the risk of carcinogenic N-nitroso compound formation. [ABSTRACT FROM AUTHOR]

Since 1974, Bayer's Roundup remains the world's most popular herbicide and pervades United States farmland and food production. However, in 2015, Roundup landed centerstage in an international and presently unsettled debate over whether its active ingredient, glyphosate, causes cancer. Environmental groups regularly call for the de-registration of glyphosate due to the plethora of ailments, ecological harm, and weed resistance resulting from glyphosate use. Dissenting experts, however, believe that strict bans would devastate agriculture because of global dependence and the lack of any popular alternatives. Faced with mounting litigation, silence from the highest court, and unreliable regulators, Bayer continues to effect risk-management strategies while the world enacts increasingly more restrictions over glyphosate's use. This Note argues that modification of agricultural practices is inevitable and appropriate due to rising concerns around the safety and efficacy of glyphosate-based herbicides, not-withstanding the compound's carcinogenicity. This Note ultimately calls for long-term deterrence of glyphosate use and the immediate development of alternative herbicides to minimize future industry hardship and protect consumers. As litigation and regulatory petitions still fail to produce results, Congress and state legislatures are the last venues to implement effective and lawful solutions proposed in this Note to one of the most unparalleled toxic torts dilemmas of our lifetime. [ABSTRACT FROM AUTHOR]

The use of 3D printing technologies by industry and consumers is expanding. However, the approaches to assess the risk of lung carcinogenesis from the emissions of 3D printers have not yet been developed. The objective of the study was to demonstrate a methodology for modeling lung cancer risk related to specific exposure levels as derived from an experimental study of 3D printer emissions for various types of filaments (ABS, PLA, and PETG). The emissions of 15 filaments were assessed at varying extrusion temperatures for a total of 23 conditions in a Class 1,000 cleanroom following procedures described by ANSI/CAN/UL 2904. Three approaches were utilized for cancer risk estimation: (a) calculation based on PM2.5 and PM10 concentrations, (b) a proximity assessment based on the pulmonary deposition fraction, and (c) modeling based on the mass‐weighted aerodynamic diameter of particles. The combined distribution of emitted particles had the mass median aerodynamic diameter (MMAD) of 0.35 μm, GSD 2.25. The average concentration of PM2.5 was 25.21 μg/m3. The spline‐based function of aerodynamic diameter allowed us to reconstruct the carcinogenic potential of seven types of fine and ultrafine particles (crystalline silica, fine TiO2, ultrafine TiO2, ambient PM2.5 and PM10, diesel particulates, and carbon nanotubes) with a correlation of 0.999, P < 0.00001. The central tendency estimation of lung cancer risk for 3D printer emissions was found at the level of 14.74 cases per 10,000 workers in a typical exposure scenario (average cumulative exposure of 0.3 mg/m3 – years), with the lowest risks for PLA filaments, and the highest for PETG type. The approaches to assess risk of lung carcinogenesis for particles emitted by 3D printers have been proposed. The emission from 15 filaments were assessed at varying extrusion temperatures. The spline‐based function of aerodynamic diameter allowed for reconstruction of the carcinogenic potential of seven types of fine and ultrafine particles. The central tendency estimation of lung cancer risk for 3D printer emissions was found at the level of 14.74 cases per 10,000 workers for average cumulative exposure of 0.3 mg/m3 – years. [ABSTRACT FROM AUTHOR]

Objectives: Differences in cancer incidence between men and women are often explained by differences in environmental exposure, or the influence of sex hormones. However, there is little research on the intrinsic differences in sensitivity to chemical carcinogens. Methods: To predict and consider related in vivo carcinogenicity tests, changes in gene expression were examined in rats and mice (by gender and organ) due to exposure to carcinogenic chemicals such as phenyl compounds, which among chemicals are the main cause of carcinogenesis. Results: In the case of male SD rats, the genes IL1B, TNF, NOS2, IL6, and NGF were related, and the probability of carcinogenesis in the urinary bladder, kidney, and oral cavity was high. In female SD rats, the genes ADRB2, TNF, HMOX1, CYP1A1, PTGS2, ILB1, CASP3, POR, PRL, TSC22D1, ATEG, REG1, HRH2, NFE2L2, AKR1C2, ADRB2, NR3C1, IL6, ADRB1, ADRB3, and LPO showed high probability of carcinogenesis in the stomach, liver, and nasal cavity. In the male F344 rat, the genes ACACA, ACSL1, ALB, ALCAM, CYP19A1, PPARA, CYP4A1, ACAA1, and ACOX1 were related, and showed a high probability of carcinogenesis in the liver, kidney, stomach, and urinary bladder. In the female F344 rat, no related genes were found, but a high probability of carcinogenesis was shown in the kidney, ear, Zymbal's gland, stomach, and liver. In male ICR mice, no related genes and organs with a high probability of carcinogenesis were found, while in female ICR mice, genes for KRAS, ACHE, CAT, CYP3A4, and GPT were involved, and carcinogenesis occurred in the stomach, thyroid gland, ovary, liver, etc. The probability was shown to be high. In BALBc mice, no related genes and organs with a high probability of carcinogenesis were found, while in female BALBc mice, the genes NR1I2, CYP3A4, ABCB1, CYP2B6, PRKDC, CYP2C9, and NCOA1 were related, and the liver, etc., had a high probability of carcinogenesis. Conclusion: Differences in the epigenetics of each sex begin at the moment of fertilization due to differences in sex chromosome gene expression and metabolic profiles between XX and XY embryos. These fundamental sex differences in nutrient utilization and mitochondrial activity may contribute to sex differences in the metabolic reprogramming of cancer cells, which is important during cancer development, cancer progression, and response to anticancer treatment. Purpose of review: In this study, I compared and considered the degree of toxicity and genome expression in each male and female gender and organ due to exposure to phenyl compounds (PAH, etc.), which are the basis of benzene toxicity as aromatic hydrocarbons, and conducted future inhalation toxicity tests and related carcinogenicity tests. Recent findings: Differences in the epigenetics of each sex begin at the moment of fertilization due to differences in sex chromosome gene expression and metabolic profiles between XX and XY embryos. Throughout development, additional processes, such as X-chromosome inactivation and gonadal steroid exposure, further distinguish the sexes. [ABSTRACT FROM AUTHOR]

N-nitrosamines and nitrosamine drug substance related impurities (NDSRIs) became a critical topic for the development and safety of small molecule medicines following the withdrawal of various pharmaceutical products from the market. To assess the mutagenic and carcinogenic potential of different N-nitrosamines lacking robust carcinogenicity data, several approaches are in use including the published carcinogenic potency categorization approach (CPCA), the Enhanced Ames Test (EAT), in vivo mutagenicity studies as well as read-across to analogue molecules with robust carcinogenicity data. We employ quantum chemical calculations as a pivotal tool providing insights into the likelihood of reactive ion formation and subsequent DNA alkylation for a selection of molecules including e.g., carcinogenic N-nitrosopiperazine (NPZ), N-nitrosopiperidine (NPIP), together with N-nitrosodimethylamine (NDMA) as well as non-carcinogenic N-nitrosomethyl-tert-butylamine (NTBA) and bis (butan-2-yl) (nitros)amine (BBNA). In addition, a series of nitroso-methylaminopyridines is compared side-by-side. We draw comparisons between calculated reaction profiles for structures representing motifs common to NDSRIs and those of confirmed carcinogenic and non-carcinogenic molecules with in vivo data from cancer bioassays. Furthermore, our approach enables insights into reactivity and relative stability of intermediate species that can be formed upon activation of several nitrosamines. Most notably, we reveal consistent differences between the free energy profiles of carcinogenic and non-carcinogenic molecules. For the former, the intermediate diazonium ions mostly react, kinetically controlled, to the more stable DNA adducts and less to the water adducts via transition-states of similar heights. Non-carcinogenic molecules yield stable carbocations as intermediates that, thermodynamically controlled, more likely form the statistically preferred water adducts. In conclusion, our data confirm that quantum chemical calculations can contribute to a weight of evidence approach for the risk assessment of nitrosamines.

The Ramazzini Institute (RI) has been conducting animal carcinogenicity studies for decades, many of which have been considered by authoritative bodies to determine potential carcinogenicity in humans. Unlike other laboratories, such as the U.S. National Toxicology Program (NTP), the RI does not provide a report or record of historical control data. Transparently documenting historical control data is critical in the interpretation of individual study results within the same laboratory. Historical control data allow an assessment of significant trends, either increasing or decreasing, resulting from changes in laboratory methods or genetic drift. In this investigation: (1) we compiled a dataset of the tumors reported in control groups of Sprague-Dawley rats and Swiss mice based on data included in published RI studies on specific substances, and (2) conducted case studies to compare data from this RI control dataset to the findings from multiple RI studies on sweeteners and corresponding breakdown products. We found considerable variability in the tumor incidence across multiple tumor types when comparing across control groups from RI studies. When compared to the tumor incidence in treated groups from multiple studies, the incidence of some tumors considered to be treatment-related fell within the variability of background incidence from the RI control dataset. [ABSTRACT FROM AUTHOR]

In the European Union, Occupational Safety and Health legislation generally refers to European Regulation (CE) n. 1272/2008 to define and classify carcinogens of concern for occupational risk assessment and exposure assessment. In Europe, the current reference is Directive (UE) 2022/431, regarding carcinogen, mutagen, and reprotoxic agent (CMR) exposure. However, at the worldwide level, different classification approaches are used to establish carcinogenicity of substances and it is often difficult to compare the classifications of carcinogenicity (CoCs) proposed by different international bodies. This study aims to investigate a list of carcinogens of concern in occupational settings based on the CLP (Classification Labelling Packaging) CoC and to create a tool that allows a rapid translation–comparison of some international CoCs with the reference one. CoCs proposed by various sources were consulted and used to apply a translation method, to favor an alignment of different CoCs according to a reference. Results outlined that, considering diverse sources, CoCs can result in different classifications of the same chemicals. Overall, this may have implications for the hazard assessment process, which is the base of risk assessment. The proposed tool is expected to help risk assessors in the occupational field when it is needed to have a comparison with different CoC systems. [ABSTRACT FROM AUTHOR]

Mycotoxins are toxic metabolites produced by fungi that may cause serious health problems in humans and animals. Zearalenone is an estrogenic mycotoxin produced by Fusarium species that leads to huge economic losses in the food industry and livestock husbandry. Contamination of food and feed with zearalenone has reproductive problems, carcinogenicity, immunotoxicity, and other cytotoxic effects. At present, microorganisms and enzymes derived from microbial strains have been widely used for the degradation of zearalenone in food and feed. Researchers have developed biodegradation of zearalenone by the use of microbial and their enzyme derivatives, which offers harmless products and is environmentally friendly. Development of recombinant enzymes improves enzymatic detoxification of zearalenone to a non-toxic product without damaging the nutritional content. This review summarizes biodegradation and detoxification strategies of zearalenone using microorganisms and enzyme derivatives to nontoxic products. [ABSTRACT FROM AUTHOR]

Heavy metals are chemical elements with unique properties that are toxic even in low concentrations and affect human health with different functions. Agricultural and industrial activities, improper disposal of household solid waste and residues related to industrial producers, discharge of household wastewater and agricultural fertilizers are the most important ways in which toxic heavy metals enter the environment, which harms human health and life. A narrative review of the literature was done from 2000 to 2022 based on searched databases included Google Scholar, PubMed, Springer, Web of Science, and Science Direct (Scopus). All relevant studies published 2000 until 2022 gathered. According to the databases, 820 articles were retrieved. 186 and 50 articles were found and selected based on records identified through database searching and additional records identified through other sources. In the next stage, 97 studies were screened after review and 64 full-text articles entered into the analysis process. Finally, 45 articles were selected in this study. Adverse effects of heavy metals on various conditions in the body depend on a number of factors, including dose, route of exposure and chemical species, as well as age, sex, genetics, nutritional status, and duration of exposure to the heavy metal. The existence of significant relationships between long-term and short-term exposure to toxic heavy metals and their adverse effects, including carcinogenicity, has been extensively studied and proven through numerous experiments. However, the mechanisms associated with this complication have not been properly identified, so in future research, there is a great need for comprehensive studies on the carcinogenicity of heavy metals. [ABSTRACT FROM AUTHOR]

To investigate the presence of metal elements and assess their health risk for the populace in the Nandong Underground River Basin (NURB), we conducted an analysis of eleven common heavy metals in the water body. A Health risk assessment (HRA) model was employed to analyze 84 water samples from the NURB. The detection results revealed the following order of heavy metals concentrations: Fe > Al > Mn > Zn > As > Cd > Pb > Cr > Ni > Cu > Hg. Correlation analysis indicated a certain similarity in material source and migration transformation among these eleven metal elements. Our study identified that the health risks for local residents exposed to metal elements in the water of NURB primarily stem from carcinogenic risk (10−6 –10−4 a −1) through the drinking water pathway. Moreover, the health risk of heavy metal exposure for children through drinking water was notably higher than for adults. The maximum health risks of Cr in both underground and surface water exceeded the recommendation standard (5.0×10−5 a −1) from ICRP, surpassing the values recommended by the Swedish Environmental Protection Agency, the Dutch Ministry of Construction and Environment and the British Royal Society (5.0×10−6 a −1). The results of the health risk assessment indicate that Cr in the water of NURB is the primary source of carcinogenic risk for local residents, followed by Cd and As. Consequently, it is imperative to control these three carcinogenic metals when the water was used as drinking water resource. [ABSTRACT FROM AUTHOR]

Background: The role of Acyl-CoA dehydrogenase long chain (ACADL) in different tumor types had different inhibiting or promoting effect. However, its role in non-small cell lung cancer (NSCLC) carcinogenicity is not clear. Method: In this study, we utilized The Cancer Genome Atlas (TCGA) database to analyze ACADL expression in NSCLC and its correlation with overall survival. Furthermore, we investigated the function of ACADL on cellular proliferation, invasion, colony, apoptosis, cell cycle in vitro with NSCLC cells. Mechanistically, we evaluated the regulatory effect of ACADL expression on its downstream factor yes-associated protein (YAP) by assessing YAP phosphorylation levels and its cellular localization. Finally, we verified the tumorigenic effect of ACADL on NSCLC cells through xenograft experiments in vivo. Results: Compared to adjacent non-cancerous samples, ACADL significantly down-regulated in NSCLC. Overexpression of ACADL, effectively reduced the proliferative, colony, and invasive capabilities of NSCLC cells, while promoting apoptosis and inducing cell cycle arrest. Moreover, ACADL overexpression significantly enhanced YAP phosphorylation and hindered its nuclear translocation. However, the inhibitory effect of the overexpression of ACADL in NSCLC cells mentioned above can be partially counteracted by YAP activator XMU-MP-1 application both in vitro and in vivo. Conclusion: The findings suggest that ACADL overexpression could suppress NSCLC development by modulating YAP phosphorylation and limiting its nuclear shift. This role of ACADL-YAP axis provided novel insights into NSCLC carcinogenicity and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

A retrospective analysis in C57BL6/J mice used in dietary carcinogenicity studies was performed to determine the survival rate, causes of death and incidences of spontaneous non-tumoral and tumoral findings. Data were collected from 1600 mice from control dose groups of sixteen 18-month carcinogenicity assays performed between 2003 and 2021 at the same test facility with similar environmental conditions and experimental procedures. The survival rate was high in both sexes (81%-85%) and the causes of humane euthanasia or death were mainly non-tumoral (chronic ulcerative dermatitis, atrial thrombosis). Benign tumors were more frequent than malignant tumors and females were more affected than males. Pituitary gland adenoma in females, lymphoma, bronchioloalveolar adenoma, and harderian gland adenoma in both sexes were the most common tumors. Systemic amyloidosis, the most frequent non-tumoral lesion, was observed variably across studies without sex predilection. The analysis by cohort (3 time periods of 6 years) showed a tendency toward higher incidences of lymphoma and pituitary gland adenoma and lower incidences of amyloidosis over time. The results presented here provide for the first time a robust set of control historical data in untreated C57BL/6J mice kept for 18 months contributing to build in depth knowledge of this animal model. [ABSTRACT FROM AUTHOR]

INTRODUCTION The addition of cooling substances, such as menthol, might be attractive for youth to start smoking waterpipe by reducing the harshness of the smoke, thereby facilitating inhalation. These compounds simultaneously increase the addictiveness of tobacco and related products by stimulating nicotine uptake. Some menthol-like compounds also increase attractiveness by imparting a menthol/mint flavor. We provide an overview of the frequency and quantities of use of menthollike substances in waterpipe tobacco, herbal molasses and steam stones. METHODS The primary data source of this study was the European Common Entry Gate (EU-CEG). Product names and ingredients were obtained for 282 waterpipe tobacco products notified to The Netherlands in 2020. Subsequently, gas-chromatography-mass spectrometry (GC-MS) analysis was used to quantify seven menthol-like substances and nicotine in waterpipe tobacco (n=5), herbal molasses (n=1) and steam stones (n=12). RESULTS Of the 282 EU-CEG-notified products, 39% have a menthol/mint declared flavor. GC-MS showed that 15 of the 18 investigated waterpipe products contained one or more menthol-like ingredients. GC-MS analysis showed that products termed 'freeze', 'ice' or 'mint' contained higher median menthol concentrations than products without these terms. CONCLUSIONS Nearly all investigated waterpipe products contained menthol-like compounds, irrespective of their flavor. Such compounds are known to provide flavoring or cooling effects, and some are known to be carcinogenic. Our results can support the regulation of these substances in waterpipe products. Regulators should screen all waterpipe products, not only those with menthol or a similar indicator in product names. [ABSTRACT FROM AUTHOR]

Water makes up most of the Earth, although just 0.3% is usable for people and animals. The huge oceans, icecaps, and other non-potable water resources make up the remaining 99.7%. Water quality has declined in recent decades due to pollution from population growth, industry, unplanned urbanization, and poor water management. The textile industry has significant global importance, although it also stands as a major contributor to wastewater generation, leading to water depletion and ecotoxicity. This issue arises from the extensive utilization of harmful chemicals, notably dyes. The main aim of this review article is to combine and assess the impacts of textile wastewater that contains dyes and chemicals, and to examine their potential consequences on human health, aquatic health, and the environment. Moreover, the dedicated section presents an in-depth review of various environmentally sustainable approaches for the management and treatment of wastewater in the textile industry. These approaches encompass bio adsorbents, biological methods, membrane technology, ion exchange, advanced oxidation processes, as well as physicochemical and biochemical processes. Furthermore, this study also evaluates the contemporary progressions in this particular domain, taking into account the corresponding advantages and disadvantages. Finally, this article highlights the significance of recovering and reusing dyes, alkalis, and electrolytes in wastewater treatment. Additionally, it emphasizes the necessity of performing technoeconomic analyses and life cycle assessments (LCA) on wastewater treatment plants. [ABSTRACT FROM AUTHOR]

Ochratoxin A (OTA) is a well-known mycotoxin that adversely affects different human cells. Inhalational exposure to OTA and subsequent pulmonary diseases have been previously reported, yet its potential carcinogenicity and underlying molecular mechanisms have not been fully elucidated. This study aimed to evaluate the OTA-induced cytotoxicity and the epigenetic changes underlying its potential carcinogenicity in fetal lung fibroblast (WI-38) cells. OTA cytotoxicity was assessed by MTT assay; RT-qPCR was used to determine the expression of BAX, BCL-2, TP53, and miR-155, while ELISA was used for measuring 5-methyl cytosine percentage to assess global DNA methylation in OTA-treated versus control cells. WI-38 cells demonstrated sensitivity to OTA with IC50 at 22.38 μM. Though BAX and Bcl-2 were downregulated, with low BAX/BCL-2 ratio, and TP53 was upregulated, their fold changes showed decline trend with increasing OTA concentration. A significant dose-dependent miR-155 upregulation was observed, with dynamic time-related decline. Using subtoxic OTA concentrations, a significant global DNA hypermethylation with significant dose-dependent and dynamic alterations was identified. Global DNA hypermethylation and miR-155 upregulation are epigenetic mechanisms that mediate OTA toxicity on WI-38 cells. BAX downregulation, reduced BAX/BCL-2 ratio together with miR-155 upregulation indicated either the inhibition of TP53-dependent apoptosis or a tissue specific response to OTA exposure. The aforementioned OTA-induced variations present a new molecular evidence of OTA cytotoxicity and possible carcinogenicity in lung fibroblast cells. [ABSTRACT FROM AUTHOR]