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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]

The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data. This guide provides a higher-level hierarchy of tumor types or categories correlating the tumor names from the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer's guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature; as SEND and INHAND terminology and information evolve, this guide will be updated. [ABSTRACT FROM AUTHOR]

Aminocarboxylic acid (monoamine-based) chelating agents such as GLDA, MGDA, NTA, and EDG are widely used in a variety of products and processes. In the European Union, based on the Green Deal and the Chemicals Strategy for Sustainability (CSS), there is an increasing tendency to speed up chemical hazard evaluation and to regulate chemicals by grouping substances based on molecular structure similarity. Recently, it was proposed to group polycarboxylic acid monoamines, hydroxy derivatives and their salts with monovalent cations, and to consider all group members as potential carcinogens based on the official CLP classification of one group member, viz. NTA, which is classified as suspected carcinogen Cat. 2. In this review, we show that a grouping approach for harmonized classification and labeling based on molecular structure alone, disregarding existing animal test data as well as current scientific and regulatory knowledge, would result in incorrect classification. Using such a simplistic, although considered pragmatic approach, classification of all group members upfront would not improve protection of human health. Instead, it could not only lead to unnecessary additional vertebrate animal testing but also to onerous and disproportionate restrictions being placed on the use of these valuable substances; some of these even being considered as green chemicals. [ABSTRACT FROM AUTHOR]

The kinetically-derived maximal dose (KMD) is defined as the maximal external dose at which kinetics are unchanged relative to lower doses, e.g., doses at which kinetic processes are not saturated. Toxicity produced at doses above the KMD can be qualitatively different from toxicity produced at lower doses. Here, we test the hypothesis that neoplastic lesions reported in the National Toxicology Program's (NTP) rodent cancer bioassay with ethylbenzene are a high-dose phenomenon secondary to saturation of elimination kinetics. To test this, we applied Bayesian modeling on kinetic data for ethylbenzene from rats and humans to estimate the Vmax and Km for the Michaelis–Menten equation that governs the elimination kinetics. Analysis of the Michaelis–Menten elimination curve generated from those Vmax and Km values indicated KMD ranges for venous ethylbenzene of 8–17 mg/L in rats and 10–18 mg/L in humans. Those venous concentrations are produced by inhalation concentrations of around 200 ppm ethylbenzene, which is well above typical human exposures. These KMD estimates support the hypothesis that neoplastic lesions seen in the NTP rodent bioassay occur secondary to saturation of ethylbenzene elimination pathways and are not relevant for human risk assessment. Thus, ethylbenzene does not pose a credible cancer risk to humans under foreseeable exposure conditions. Cancer risk assessments focused on protecting human health should avoid endpoint data from rodents exposed to ethylbenzene above the KMD range and future toxicological testing should focus on doses below the KMD range. [ABSTRACT FROM AUTHOR]

Triclosan is a widely used antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Due to its extensive use, there is potential for humans in all age groups to receive lifetime exposures to triclosan, yet data on the chronic dermal toxicity/carcinogenicity of triclosan are still lacking. We evaluated the toxicity/carcinogenicity of triclosan administered dermally to B6C3F1 mice for 104 weeks. Groups of 48 male and 48 female B6C3F1 mice received dermal applications of 0, 1.25, 2.7, 5.8, or 12.5 mg triclosan/kg body weight (bw)/day in 95% ethanol, 7 days/week for 104 weeks. Vehicle control animals received 95% ethanol only; untreated, naïve control mice did not receive any treatment. There were no significant differences in survival among the groups. The highest dose of triclosan significantly decreased the body weight of mice in both sexes, but the decrease was ≤ 9%. Minimal-to-mild epidermal hyperplasia, suppurative inflammation (males only), and ulceration (males only) were observed at the application site in the treated groups, with the highest incidence occurring in the 12.5 mg triclosan/kg bw/day group. No tumors were identified at the application site. Female mice had a positive trend in the incidence of pancreatic islet adenoma. In male mice, there were positive trends in the incidences of hepatocellular carcinoma and hepatocellular adenoma or carcinoma (combined), with the increase of carcinoma being significant in the 5.8 and 12.5 mg/kg/day groups and the increase in hepatocellular adenoma or carcinoma (combined) being significant in the 2.7, 5.8, and 12.5 mg/kg/day groups. [ABSTRACT FROM AUTHOR]

Acrylamide, a food-borne chemical toxicant, has raised global concern in recent decades. It mainly originated from reducing sugar and free amino acid interactions in the carbohydrate-rich foodstuffs heated at high temperatures. Due to the neurotoxicity and carcinogenicity of AA, the mechanism of formation, toxic effects on health, and mitigation strategies, including conventional approaches and innovative technologies, have been of great interest since its discovery in food. Potato products (especially French fries and crisps), coffee, and cereals(bread and biscuit) are renowned contributors to AA's daily intake. The best preventive methods discussed in the literature include time/temperature optimization, blanching, enzymatic treatment, yeast treatment, additives, pulsed electric fields, ultrasound, vacuum roasting, air frying, and irradiation, exhibiting a high efficacy in AA elimination in food products. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) are pervasive environmental contaminants, with benzo(a)pyrene (B(a)P) standing out as a prototypical example. B(a)P is a known mutagen and carcinogen that, upon metabolic activation stimulated by cytochromes P450 (CYP1A) with microsomal epoxide hydrolase, reacts with DNA. In this study, common carp (Cyprinus carpio) were subjected to three different doses of B(a)P (1µg/kg and 10µg/kg) to investigate the mutagenic effects on B(a)Pderived DNA in vivo. Blood samples were collected, followed by thorough DNA extraction and polymerase chain reaction analysis. The findings revealed a pronounced mutational impact of B(a)P on the amplified segment of the CYP1A gene. Specifically, at a concentration of 1µg/kg, B(a)P induced 8 mutations, 3 amino acid alterations, and the emergence of 5 new haplotype patterns. In contrast, at a concentration of 10µg/kg, B(a)P resulted in 21 mutations, 10 changes in amino acids, and the generation of 7 new haplotype patterns. Additionally, alterations in the three-dimensional protein composition were observed in both dosage groups. This study underscores the significant mutagenic potential of B(a)P, shedding light on its capacity to induce genetic changes and protein structure modifications, thereby emphasizing the importance of monitoring and addressing the environmental presence of PAHs for both ecological and human health considerations. [ABSTRACT FROM AUTHOR]

Acrylamide is a toxic substance that forms in food during high-temperature processing methods such as deep-frying, baking, and roasting, through the Maillard reaction or the acrolein pathway. Since acrylamide has been identified for its carcinogenicity, genotoxicity, and neurotoxicity, global food authorities have established benchmark levels for different food categories. Consequently, researchers have proposed various mitigation strategies, focusing on agronomical, chemical, physical, and microbial approaches. However, most of these approaches are associated with high cost, technology, extended time, and poor sensory and nutritional quality. In this context, application of various additives such as metal cations, organic and inorganic acids, and antioxidants in optimum amounts have been effective in reducing acrylamide formation. Additives contribute to reducing acrylamide either by interacting with its precursors and/or intermediate products or by breaking down acrylamide into other non-toxic substances. Since cations can form thermostable asparagine/matrix intermediates through chelation reaction between asparagine and metal cations, asparagine will be unavailable to react with carbonyl compounds to form the Schiff base. Lower pH conditions inhibit the acrylamide formation by blocking the protonation of the α-amino group of asparagine and reducing any possibility for nucleophilic addition reactions with carbonyl groups. Toxicity associated with Maillard products can be reduced by using antioxidants in the frying oil or the food. Polyphenols are capable of reducing the acrylamide formation by directly trapping acrylamide at elevated temperature. It is essential to identify the most appropriate additive, its concentration and the optimum process conditions when applying additives to get an optimal acrylamide inhibition. This review article highlights the effect of various additive applications, their effectiveness and possible future advances in food to control acrylamide formation within the accepted level. [ABSTRACT FROM AUTHOR]

Background: Rab1A not only regulates eukaryotic secretion, autophagy and intracellular traffic, but also extensively participates in the development of cancer. Thus, we collected data to investigate the clinical value of Rab1A in cancers. Methods: English web database was searched for appropriate studies. The role of Rab1A in cancer patients was evaluated by combining hazard ratios and odds ratios. Results: There were 15 studies in 14 articles, including 1,791 cancer patients. The results showed that up-regulated Rab1A led to poor prognosis in cancer patients (pooled HR = 2.545, 95% CI = 1.924 - 3.367, p < 0.001). Notably, a high level of Rab1A was associated with a poorer prognosis than patients with a low level of Rab1A in digestive system cancer (pooled HR = 2.484, 95% CI = 1.796 - 3.437, p < 0.001). In order to explore the possible carcinogenic mechanism, we further analyzed and confirmed that high expression of Rab1A was associated with worse histologic grade, deeper tumor invasion, higher TNM stage, positive LN metastasis, positive neural invasion, positive vascular invasion, and larger tumor size (p < 0.05). Conclusions: Rab1A overexpression was associated with poor prognosis and adverse clinicopathological parameters in cancer patients and had the potential to be a target for future cancer therapy. [ABSTRACT FROM AUTHOR]

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.

The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients (APIs), drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

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.

Laboratory studies were conducted to determine the embryotoxic effect and carcinogenicity of the veterinary drug “BTF plus” on white rats and white mice. The drug “BTF plus” is a complex vitamin-mineral drug based on butophosphane, L-carnitine, and cyanocobalamin, which is used to normalize and correct metabolic processes in animals and poultry. The drug is used for various types of animals and poultry as a stimulating, tonic and general strengthening agent for obstetric pathologies (complicated childbirth, postpartum complications, paresis, eclampsia, sexual cycle disorders); metabolic disorders caused by irrational feeding, malnutrition, asthenic syndrome, etc.; anemia with helminthiasis; secondary anemias, as an additional means in the treatment of magnesium and calcium deficiency; to increase muscle activity, with significant loads, overstrain and exhaustion in animals; to increase the body's resistance to various pathogens; to stimulate growth, development and live weight gain in young animals and poultry; as an additional means in the treatment of diseases caused by various factors (infectious and non-infectious origin). The drug “BTF plus”, under the conditions of subcutaneous administration to pregnant female rats in doses (based on the absolute weight of the drug) of 200.0 and 2000.0 mg/kg of body weight, does not cause death and pathological changes in embryos do not have an embryotoxic and teratogenic effect since indicators of total, preimplantation, and postimplantation embryonic lethality in rats of the experimental groups had no significant differences compared to indicators in control and also did not show changes in the weight of the placenta, fetuses, and their cranio-caudal size. The drug “BTF plus”, under conditions of 5-day subcutaneous administration to white mice in doses (based on the absolute weight of the drug) of 200.0 and 2000.0 mg/kg of body weight, does not show a carcinogenic effect (during microscopic studies, the proportion of polychromatophilic erythrocytes was not probable deviations between themselves and was 0.117-0.133%, which is within the normal range of up to 0.2 %). Further studies will be the next stage of pre-registration tests aimed at studying the ecotoxicity of “BTF plus”, which is a mandatory material of the “Safety and residue studies” section of the dossier for this drug.

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.

Phenylpropenes represent a major subclass of plant volatiles, including eugenol, and (E)-anethole. They contribute to the flavor and aroma of many chief herbs and spices, to exert distinct notes in food, i.e., spicy anise- and clove-like to fruit. Asides from their culinary use, they appear to exert general health effects, whereas some effects are specific, e.g., eugenol being a natural local anesthetic. This review represents the most comprehensive overview of phenylpropenes with respect to their chemical structures, different health effects, and their food applications as flavor and food preservatives. Side effects and toxicities of these compounds represent the second main part of this review, as some were reported for certain metabolites generated inside the body. Several metabolic reactions mediating for phenylpropenes metabolism in rodents via cytochrome P450 (CYP450) and sulfotransferase (SULT) enzymes are presented being involved in their toxicities. Such effects can be lessened by influencing their pharmacokinetics through a matrix-derived combination effect via administration of herbal extracts containing SULT inhibitors, i.e., nevadensin in sweet basil. Moreover, structural modification of phenylpropanes appears to improve their effects and broaden their applications. Hence, such review capitalizing on phenylpropenes can help optimize their applications in nutraceuticals, cosmeceuticals, and food applications. [ABSTRACT FROM AUTHOR]

Electronic cigarettes that are currently popular are used as nicotine replacement therapy. There are several substances contained in electronic cigarette liquid that have carcinogenic effects. These substances can also increase free radicals which in turn can cause oxidative stress. Nicotine, propylene glycol, and glycerol can cause disturbances in male reproductive function. Infertility can occur due to lifestyle factors, one of which is smoking. Nicotine found in cigarettes can reduce sperm quality, including concentration, mobility, viability, and sperm morphology. The purpose of this study was to determine the effect of electronic cigarettes on sperm quality. The research method uses a literature review system. The twelve studies that are in accordance with the topic of discussion are experimental studies on mice and rats, two studies on human, and one study on both human and rats. Five journals showed a significant decrease in sperm count and testosterone serum level, three other journals showed a significant decrease in sperm morphology and viability, six journals showed a decrease in sperm motility, seven journals showed a significant impairment of testis histological structure, four journals showed a decrease of steroidogenesis enzymes, and one journal showed a significant increase of DNA fragmentation due to the use of electronic cigarettes. Electronic cigarettes had an effect on sperm quality. [ABSTRACT FROM AUTHOR]

In Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) the criterion for deciding the studies that must be performed is the annual tonnage of the chemical manufactured or imported into the EU. The annual tonnage may be considered as a surrogate for levels of human exposure but this does not take into account the physico-chemical properties and use patterns that determine exposure. Chemicals are classified using data from REACH under areas of health concern covering effects on the skin and eye; sensitisation; acute, repeated and prolonged systemic exposure; effects on genetic material; carcinogenicity; and reproduction and development. We analysed the mandated study lists under REACH for each annual tonnage band in terms of the information they provide on each of the areas of health concern. Using the European Chemicals Agency (ECHA) REACH Registration data base of over 20,000 registered substances, we found that only 19% of registered substances have datasets on all areas of health concern. Information limited to acute exposure, sensitisation and genotoxicity was found for 62%. The analysis highlighted the shortfall of information mandated for substances in the lower tonnage bands. Deploying New Approach Methodologies (NAMs) at this lower tonnage band to assess health concerns which are currently not covered by REACH, such as repeat and extended exposure and carcinogenicity, would provide additional information and would be a way for registrants and regulators to gain experience in the use of NAMs. There are currently projects in Europe aiming to develop NAM-based assessment frameworks and they could find their first use in assessing low tonnage chemicals once confidence has been gained by their evaluation with data rich chemicals. [ABSTRACT FROM AUTHOR]

Enarodustat (JTZ-951) is an oral hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor for the treatment of anemia with chronic kidney disease. Carcinogenicity of enarodustat was evaluated in a 26-week repeated oral dose study in Transgenic rasH2 (Tg.rasH2) mice and a 2-year repeated oral dose study in Sprague-Dawley (SD) rats. The highest dose levels were set at 6 mg/kg in the Tg.rasH2 mouse study and at 1 mg/kg in the SD rat study based on the maximum tolerated doses in the 3-month and 6-month dose-range finding studies, respectively. Enarodustat did not increase the incidence of any tumors or affect survival in these carcinogenicity studies. Pharmacology-related findings including increases in blood RBC parameters were observed at the highest dose levels for each study. The AUC-based exposure margins as protein-unbound drug base are 16.3-/26.0-fold multiple (males/females) for Tg.rasH2 mice and 1.6-/1.1-fold multiple for SD rats when compared with the estimated exposure in human with chronic kidney disease at 8 mg/day (maximum recommended human dose). In conclusion, enarodustat was considered to have no carcinogenic potential at the clinical dose. [ABSTRACT FROM AUTHOR]

The Tumorigenic dose 50 (TD 50) is a widely used measure of carcinogenic potency representing the dosage at which 50 % of animals exposed to a compound will develop tumours. The popularity of the TD 50 is in part due to the large amount of publicly available data. TD 50 s were calculated for a large number of compounds in the Carcinogenic Potency Database, which has since been extended in the freely available Lhasa Carcinogenicity database, containing TD 50 s from over 7500 studies and 1700 compounds. However, due to the age of these studies many are of low quality, often comprising only a single test dosage, therefore raising questions about the applicability of such TD 50 s for toxicological risk assessment. We investigate whether the lower 99 % confidence interval is sufficient to produce conservative TD 50 estimates for these studies. [Display omitted] • TD50s are typically conservative when calculated from single dose studies. • The confidence interval for these TD50s does not cover the expected interval. • The lower 99 % confidence interval is conservative in 98.5 % of cases. [ABSTRACT FROM AUTHOR]

This study examined the sources, health risk and pollution status of selected inorganic contaminants such as iron (Fe), nickel (Ni), cadmium (Cd), cobalt (Co), arsenic (As), manganese (Mn), lead (Pb), copper (Cu), zinc (Zn), and chromium (Cr) in representative roadside uncontaminated soil (n = 72) from the Egi crude oil mining areas (Oboburu, Obagi, and Ogbogu), Niger Delta, Nigeria, using a combination of multiple models (Principle component analysis (PCA), correlation analysis, geo-accumulation index (Igeo), contamination factor (CF), enrichment factor (EF), pollution load index (PLI), cancer risk (CR), hazard quotient (HQ), and metal daily intake (MDIm)). A random sampling method was applied in the sampling and analysis using inductively coupled plasma mass spectroscopy. The result revealed that the mean (mg/kg) for Oboburu, was the highest for Fe (89.95 ± 28.83) and Mn (26.12 ± 7.642), whereas Obagi, had less Fe (28.90 ± 7.601) and Mn (16.80 ± 5.021), and Ogbogu, Fe (44.67 ± 28.15) and Pb (19.38 ± 8.731) was the second highest heavy metal. The order of contamination was F > Mn > Zn > Pb > Cu > Cr > Ni > Cd > Co. The Igeo and CF had cadmium as a metal of concern. The contamination level was low from the PLI estimation. The EF revealed anthropogenic sources for all the metals except for Ni, which was biogenic. The correlations at p < 0.05 and p < 0.01 showed much positive significance amongst the metals. Variations of the cumulative percentages, loading percentages, and eigenvalues from the regression plot gave a coefficients of determination (r 2) of 0.9936, 0.9995, and 0.9994, respectively. The PCA indicated that Cd and Ni were of anthropogenic origin; Mn, Fe, and Co were biogenic or natural, and Zn and Pb were of mixed origins. The CR assessment indicated a possible cancer risk due to Cr, Cd, and Ni, and the rest of elements have no carcinogenic risk. These findings suggest there should be regular monitoring, source control, and integrated environmental management of the study area. [Display omitted] • The GAI and C.F. were used to check the pollution status, P.C.A. and E.F. to check the pollution sources, and MDIm, C.R., and H.Q were employed to estimate the possible health risk of ingestion. • The findings of this research work indicate that majority of the parameters were within the safe limit. • The pollution level of the various parameters indicated that Cd is the only variable of concern due to its toxicity and amount in the soil. • The health risk assessments suggest possible risks for some variables via ingestion of the soil samples by children and adults. • There is a probable risk of one out of every one hundred thousand having cancer due to the ingestion of samples from the study area of this research work. • The research suggests the possible influence of human activity on the contamination of agricultural soil. [ABSTRACT FROM AUTHOR]

Background: Plastic debris pervades our environment. Some breaks down into microplastics (MPs) that can enter and distribute in living organisms causing effects in multiple target organs. MPs have been demonstrated to harm animals through environmental exposure. Laboratory animal studies are still insufficient to evaluate human impact. And while MPs have been found in human tissues, the health effects at environmental exposure levels are unclear. Aim: We reviewed and summarized existing evidence on health effects from occupational exposure to MPs. Additionally, the diverse effects documented for workers were organized by MP type and associated co‐contaminants. Evidence of the unique effects of polyvinyl chloride (PVC) on liver was then highlighted. Methods: We conducted two stepwise online literature reviews of publications focused on the health risks associated with occupational MP exposures. This information was supplemented with findings from animal studies. Results: Our analysis focused on 34 published studies on occupational health effects from MP exposure with half involving exposure to PVC and the other half a variety of other MPs to compare. Liver effects following PVC exposure were reported for workers. While PVC exposure causes liver toxicity and increases the risk of liver cancers, including angiosarcomas and hepatocellular carcinomas, the carcinogenic effects of work‐related exposure to other MPs, such as polystyrene and polyethylene, are not well understood. Conclusion: The data supporting liver toxicity are strongest for PVC exposure. Overall, the evidence of liver toxicity from occupational exposure to MPs other than PVC is lacking. The PVC worker data summarized here can be useful in assisting clinicians evaluating exposure histories from PVC exposure and designing future cell, animal, and population exposure‐effect research studies. [ABSTRACT FROM AUTHOR]

Due to groundwater contamination and runoff from certain mining operations, populations are exposed to detrimental levels of arsenic daily. The effects of arsenic exposure on the human epigenome are extensive, and some are still unknown. It can alter DNA methylation, inhibiting specific tumor suppressor genes and increasing the risk of neoplasia. This can be drawn back to certain crucial factors of DNA methylation, such as CpG Binding Proteins or DNA Methyl-transferases, all of which have shown linkage to carcinogenesis. Arsenic can also cause an overproduction of free radicals and a reduction of antioxidant production, causing oxidative stress. Lastly, it has also been associated with specific chromosomal abnormalities. All of these factors, which will be discussed in further detail, have been shown to contribute to the progression of cancer. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the deadliest carcinogenic diseases affecting people all over the world. The majority of patients are usually detected at Stage III or Stage IV, and the chances of survival are very low once detected at the late stages. This study focuses on building an efficient data-driven analytical predictive model based on the associated risk factors and identifying the most contributing factors influencing the survival times of patients diagnosed with pancreatic cancer using the XGBoost (eXtreme Gradient Boosting) algorithm. The grid-search mechanism was implemented to compute the optimum values of the hyper-parameters of the analytical model by minimizing the root mean square error (RMSE). The optimum hyperparameters of the final analytical model were selected by comparing the values with 243 competing models. To check the validity of the model, we compared the model's performance with ten deep neural network models, grown sequentially with different activation functions and optimizers. We also constructed an ensemble model using Gradient Boosting Machine (GBM). The proposed XGBoost model outperformed all competing models we considered with regard to root mean square error (RMSE). After developing the model, the individual risk factors were ranked according to their individual contribution to the response predictions, which is extremely important for pancreatic research organizations to spend their resources on the risk factors causing/influencing the particular type of cancer. The three most influencing risk factors affecting the survival of pancreatic cancer patients were found to be the age of the patient, current BMI, and cigarette smoking years with contributing percentages of 35.5%, 24.3%, and 14.93%, respectively. The predictive model is approximately 96.42% accurate in predicting the survival times of the patients diagnosed with pancreatic cancer and performs excellently on test data. The analytical methodology of developing the model can be utilized for prediction purposes. It can be utilized to predict the time to death related to a specific type of cancer, given a set of numeric, and non-numeric features. [ABSTRACT FROM AUTHOR]

Tobacco smoking is carcinogenic to humans. Besides cigarettes, the most common form of tobacco smoking, there was sparse evidence of waterpipe's carcinogenicity-induced nasopharyngeal cancer (NPC). This study investigated the association between waterpipe smoking and NPC mortality. Our study followed up with 20,144 eligible man participants from nine northern Vietnam communes between 2007 and 2019. Face-to-face interviews were conducted to gather data on exclusive waterpipe and cigarette smoking and dietary intake using structured semi-quantitative food frequency and lifestyle questionnaires. Nasopharyngeal cancer was determined by accessing the medical records at the state health facilities. We estimated the Cox proportional hazard ratio and 95% confidence intervals, HR (95% CI). The proportion of never smokers, exclusive waterpipe, exclusive cigarette, and dual waterpipe and cigarette smokers was 55.8%, 14.5%, 16.6%, and 13.1%, respectively. Exclusively waterpipe smokers increased the risk of NPC death compared to exclusively cigarette smokers, HR (95% CI): 4.51 (1.25, 16.31), p = 0.022. A dose-dependent positive relationship between NPC and exclusive waterpipe smoking was significantly seen for higher intensity HR (95% CI): 1.35 (1.07, 1.71), earlier age of smoking initiation HR (95% CI): 1.26 (1.06, 1.50), longer duration HR (95% CI): 1.31 (1.04, 1.66), and the cumulative number of a smoke lifetime HR (95% CI): 1.37 (1.08, 1.74). We observed a significant positive association between exclusive waterpipe smoking and NPC in men. The findings suggested that waterpipe smoking is likely more harmful than cigarettes in developing this cancer. A firm tobacco control against waterpipe smoking is highly recommended. [ABSTRACT FROM AUTHOR]

The effective management of municipal solid waste is a persistent challenge within emerging nations. The observed phenomenon can be attributed to a multitude of reasons, encompassing swift economic growth, urban population development, garbage output, the substantial costs associated with waste treatment, and the design and functionality of containment systems. Methane, being the second most significant greenhouse gas following carbon dioxide, is prominently emitted into the environment by municipal solid waste dumps. This study use the IPCC model to assess the methane emissions generated by landfills. Additionally, Simapro 9.5 software is utilised in conjunction with the ReCiPe 2016 Midpoint approach to evaluate the corresponding environmental consequences. The Klotok landfill was found to generate the maximum quantity of methane, specifically 3.518 Mg CO2 eq, as determined by the composition analysis of paper waste. Additionally, the largest environmental impact was observed in the category of human toxicity carcinogenicity, as indicated by the life cycle assessment (LCA) analysis with a value of 3733.057. [ABSTRACT FROM AUTHOR]

Occurrence of cancer is driving up on a global scale that exerts greater implications on the physical, psychological and economic stability of the human population. In the present context, numerous research studies are being conducted to explore and discover the drug molecule as an anticancer agent. Diverse scales of flavonoids entail the human diet, and they displayed prospective curative effects against an array of ailments. Among different categories of flavonoids, apigenin a trihydroxy flavone has been proven to have various pharmacological effects. Molecular docking is a key tool in structural molecular biology and computer assisted drug design. In this study, HDAC inhibitory action of apigenin and its probable toxicity was assessed by docking study using Auto dock platform. Molecular dynamics simulation was done by using iMODS server for elucidating the stability of the receptor-ligand complex. Toxicity predictions were evaluated by using tools such as CarcinoPred for carcinogenicity study, pkCSM for ADMET analysis, ProTox-II for rodent oral toxicity, lazar for estimating mutagenicity, BOILED Egg plot analysis for examining the gastrointestinal absorption and blood brain permeability, PASS prediction to identify the various biological functions and DruLiTo program to compute the drug likeness property. [ABSTRACT FROM AUTHOR]

The carcinogenicity of drugs can have a serious impact on human health, so carcinogenicity testing of new compounds is very necessary before being put on the market. Currently, many methods have been used to predict the carcinogenicity of compounds. However, most methods have limited predictive power and there is still much room for improvement. In this study, we construct a deep learning model based on capsule network and attention mechanism named DCAMCP to discriminate between carcinogenic and non‐carcinogenic compounds. We train the DCAMCP on a dataset containing 1564 different compounds through their molecular fingerprints and molecular graph features. The trained model is validated by fivefold cross‐validation and external validation. DCAMCP achieves an average accuracy (ACC) of 0.718 ± 0.009, sensitivity (SE) of 0.721 ± 0.006, specificity (SP) of 0.715 ± 0.014 and area under the receiver‐operating characteristic curve (AUC) of 0.793 ± 0.012. Meanwhile, comparable results can be achieved on an external validation dataset containing 100 compounds, with an ACC of 0.750, SE of 0.778, SP of 0.727 and AUC of 0.811, which demonstrate the reliability of DCAMCP. The results indicate that our model has made progress in cancer risk assessment and could be used as an efficient tool in drug design. [ABSTRACT FROM AUTHOR]

Shampooing is a universal daily hair care routine in this modern era. In todays' market, shampoo products have been advertised and commercialized for different purposes and grades like medicated, professional, baby, or regular shampoo for everyday use. These shampoos typically contain a range of core ingredients, such as, surfactants, foaming agents, conditioners, pearlescent agents, sequestrants, pH adjuster, antidandruff agents, colorants, perfumes, and preservatives. Most of these ingredients present in shampoos are synthetically made. For example, diethylamine, triethylamine, cocamide diethanolamine and some other by-products like 1,4-dioxane. Although regulatory agency has controlled the application of these synthetic ingredients in cosmetics, they are still capable of being dermally absorbed and elicit allergic reactions, skin irritation, contact dermatitis below restricted concentrations. Prolonged exposure to these synthetic ingredients is also associated with carcinogenicity and mutagenicity. This review mainly focuses on elucidating the common synthetic ingredients used in the shampoo formulation, their functions and their potential health risks following long term exposure. [ABSTRACT FROM AUTHOR]

Since heavy metals (HM) exist in the soil due to industrial activity and the usage of pesticides and fertilizers, monitoring the content of these pollutants is very significant. The current research aimed to determine the concentrations of cadmium (Cd) and lead (Pb) in the tea plant leaves, black tea, and soil and look for their correlations. Twenty-seven (27) samples were divided into three groups of tea plant leaves, black tea, and soil from the same tea plantations originating from Lahijan, Iran. The concentrations of Pb and Cd in samples were determined using a flame atomic absorption spectrophotometer. After that, some analyses were conducted to find the correlation between the content of Pb and Cd in tea plant leaves, black tea, and soil, and their health risks were evaluated. In leaves, black tea, and soil, the mean contents for Cd were 0.001, 0.044, and 0.044 ppm, whereas those for Pb were 0.501, 0.939, and 2.093 ppm, respectively. The results showed that Cd and Pb concentration means in tea plant leaves, black tea, and soil samples were lower than the guidelines recommended by EU, WHO, and national Iranian standards (P < 0.05). The values of the non-carcinogenic hazard quotients (HQ) and the hazard index (HI) were below 1, indicating that these two HMs will not adversely affect consumers' health through the oral pathway of drinking tea. However, more attention should be paid to monitoring the content of HMs in soil. This research recommends that soil Pb contamination should be managed to ensure safe tea production in the study area. An effective management strategy appears necessary to ensure the quality and safety of tea plantations, as well as to reduce the risk of the accumulation of HMs in tea. [ABSTRACT FROM AUTHOR]

Toxicogenomic technologies query the genome, transcriptome, proteome, and the epigenome in a variety of toxicological conditions. Due to practical considerations related to the dynamic range of the assays, sensitivity, cost, and technological limitations, transcriptomic approaches are predominantly used in toxicogenomics. Toxicogenomics is being used to understand the mechanisms of toxicity and carcinogenicity, evaluate the translational relevance of toxicological responses from in vivo and in vitro models, and identify predictive biomarkers of disease and exposure. In this session, a brief overview of various transcriptomic technologies and practical considerations related to experimental design was provided. The advantages of gene network analyses to define mechanisms were also discussed. An assessment of the utility of toxicogenomic technologies in the environmental and pharmaceutical space showed that these technologies are being increasingly used to gain mechanistic insights and determining the translational relevance of adverse findings. Within the environmental toxicology area, there is a broader regulatory consideration of benchmark doses derived from toxicogenomics data. In contrast, these approaches are mainly used for internal decision-making in pharmaceutical development. Finally, the development and application of toxicogenomic signatures for prediction of apical endpoints of regulatory concern continues to be area of intense research. [ABSTRACT FROM AUTHOR]

Résumé: La manipulation des anticancéreux dans les services d'oncologie médicale est multiple et quotidienne. Ces médicaments peuvent être destinés à la voie orale, mais sont principalement administrés par voie intraveineuse. La directive européenne 2022/431 réglemente l'utilisation des agents mutagènes et cancérigènes, ainsi que les substances reprotoxiques en incluant les médicaments. L'exposition des professionnels de santé à ces derniers lors de leur manipulation se fait principalement par absorption cutanée et elle est possible tout au long du circuit, de la réception à la pharmacie jusqu'à la gestion des excreta du patient et des déchets. Les risques sont différents en fonction de la molécule, mais des mesures de protection collective et individuelle permettent de limiter l'exposition. [ABSTRACT FROM AUTHOR]

Background: Kidney transplantation remains the best possible solution for patients with chronic kidney disease, providing better long-term outcomes and drastically improving quality of life. However, it comes with its own set of risks. The use of immunosuppressives following renal transplants has been shown to increase the development of malignancies and infections, and the occurrence of post-transplant malignancies is now the third most common cause of death in transplant patients. This involves multiple mechanisms, including the carcinogenic tendency of some immunosuppressive drugs, along with the induction and promotion of post-transplant malignancies by certain viruses. The quantification of Cancer risk must be made an integral part of the overall management of transplant patients, and appropriate follow-up screening needs to be adopted. Kaposi's sarcoma, lymphoma, and non-melanoma skin cancers have a greater incidence. If a malignancy develops immediately after transplantation, it may have been transmitted from the donor; donor-transmitted and donor-derived tumours may be differentiated based on a two-year time limit. Immunosuppressive medications with carcinogenic tendencies, reduced immunological control of oncogenic viruses, and poor immunosurveillance remain the most important risk factors. The gravity of this situation is further exacerbated by the fact that not only is there an increased risk of developing these malignancies in the post-transplant period, but the prognosis is also worsened when compared to non-transplant patients. All transplant centers should therefore adopt a multidisciplinary approach including early detection and prompt treatment, to improve outcomes in transplanted patients. [ABSTRACT FROM AUTHOR]

Background: /objectives: Potentially toxic elements (PTEs) are one of the dangerous pollutants in the environment that can cause morbidity and mortality in humans. This study was designed to evaluate the concentration of PTEs, assessment its human health risk assessment and carcinogenicity in the north of Ahvaz, the southwest of Iran. Methods: The soil samples were collected from the agricultural fields and riversides for investigating the health effects of the selected PTEs on the soil of the Weiss and Arab Assad regions in Ahvaz. Results: According to the result of this study, the highest level of Fe was observed in the soil samples of the Weiss and Arab Assad regions, 9013.70 and 9208.93 mg/kg, while Cd showed the lowest concentration in the soils of Weiss and Arab Assad fields, 1.58 and 1.56 mg/kg, respectively. Potentially toxic elements hazard quotient (HQ), non-carcinogenic risk (HI), and risk index (RI)) in the soil of agricultural fields in the Arab Assad and Weiss regions showed that Cd, Pb, Ni, Cu, Cr, Zn, Fe, Mn, and Co posed a significant risk to human health. Thus, it is recommended to observe health issues due to the non-carcinogenic risk index of metals. Conclusion: Generally, the excessive use of agricultural fertilizers (phosphate and nitrate), industrial, and human activities can increase the contamination of the resources and products, which has irreversible effects on human health, especially in carcinogenic risk.

Living systems, whether healthy or diseased, must obey the laws of chemistry. The purpose of this review is to identify the interpretive limits of cellular biochemistry using, largely, the tools of physical chemistry. We illustrate this approach using two major concepts in cancer: carcinogenicity and cancer recurrences. Cells optimize the chemical performance of enzymes and pathways during cancer recurrences. Biology has been primarily concerned with the analysis of high affinity interactions, such as ligand–receptor interactions. Collective weak interactions (such as van der Waals forces) are also important in determining biosystem behaviors, although they are infrequently considered in biology. For example, activity coefficients determine the effective concentrations of biomolecules. The in vivo performance of enzymes also depends upon intracellular conditions such as high protein concentrations and multiple regulatory factors. Phase separations within membranes (two dimensions) and nucleoli (three dimensions) are a fundamental regulatory factor within cells, as phase separations can alter reactant concentrations, local dielectric constants, and other factors. Enzyme agglomeration also affects the performance of biochemical pathways. Although there are many examples of these phenomena, we focus on the key steps of cancer: carcinogenicity and the biochemical mechanism of cancer recurrences. We conjecture that oxidative damage to histones contributes to carcinogenicity, which is followed by nucleolar phase separations and subsequent DNA damage that, in turn, contributes to the redistribution of enzymes mediating metabolic changes in recurrent breast cancer.

Background: Carbon fibers are high aspect ratio structures with diameters on the submicron scale. Vapor grown carbon fibers are contained within multi-walled carbon tubes, with VGCF™-H commonly applied as a conductive additive in lithium-ion batteries. However, several multi-walled carbon fibers, including MWNT-7, have been reported to induce lung carcinogenicity in rats. This study investigated the carcinogenic potential of VGCF™-H fibers in F344 rats of both sexes with the vapor grown carbon fibers VGCF™-H and MWNT-7 over 2 years. The carbon fibers were administered to rats by intratracheal instillation at doses of 0, 0.016, 0.08, and 0.4 mg/kg (total doses of 0, 0.128, 0.64, and 3.2 mg/kg) once per week for eight weeks and the rats were observed for up to 2 years after the first instillation. Results: Histopathological examination showed the induction of malignant mesothelioma on the pleural cavity with dose-dependent increases observed at 0, 0.128, 0.64, and 3.2 mg/kg in rats of both sexes that were exposed to MWNT-7. On the other hand, only two cases of pleural malignant mesothelioma were observed in the VGCF™-H groups; both rats that received 3.2 mg/kg in male. The animals in the MWNT-7 groups either died or became moribund earlier than those in the VGCF™-H groups, which is thought related to the development of malignant mesothelioma. The survival rates were higher in the VGCF™-H group, and more carbon fibers were observed in the pleural lavage fluid (PLF) of the MWNT-7 groups. These results suggest that malignant mesothelioma is related to the transfer of carbon fibers into the pleural cavity. Conclusions: The intratracheal instillation of MWNT-7 clearly led to carcinogenicity in both male and female rats at all doses. The equivocal evidence for carcinogenic potential that was observed in male rats exposed to VGCF™-H was not seen in the females. The differences in the carcinogenicities of the two types of carbon fibers are thought due to differences in the number of carbon fibers reaching the pleural cavity. The results indicate that the carcinogenic activity of VGCF™-H is lower than that of MWNT-7. [ABSTRACT FROM AUTHOR]

To evaluate lung toxicity due to inhalation of multi-walled carbon nanotubes (MWCNTs) in rats, we developed a unique MWCNT aerosol generator based on dry aerosolization using the aerodynamic cyclone principle. Rats were exposed to MWNT-7 (also known as Mutsui-7 and MWCNT-7) aerosolized using this device. We report here an analysis of previously published data and additional unpublished data obtained in 1-day, 2-week, 13-week, and 2-year inhalation exposure studies. In one-day studies, it was found that approximately 50% of the deposited MWNT-7 fibers were cleared the day after the end of exposure, but that clearance of the remaining fibers was markedly reduced. This is in agreement with the premise that the rapidly cleared fibers were deposited in the ciliated airways while the slowly cleared fibers were deposited beyond the ciliated airways in the respiratory zone. Macrophage clearance of MWNT-7 fibers from the alveoli was limited. Instead of macrophage clearance from the alveoli, containment of MWNT-7 fibers within induced granulomatous lesions was observed. The earliest changes indicative of pulmonary toxicity were seen in the bronchoalveolar lavage fluid. Macrophage-associated inflammation persisted from the one-day exposure to MWNT-7 to the end of the two-year exposure period. Correlation of lung tumor development with MWNT-7 lung burden required incorporating the concept of area under the curve for the duration of the study; the development of lung tumors induced by MWNT-7 correlated with lung burden and the duration of MWNT-7 residence in the lung. [ABSTRACT FROM AUTHOR]

The hepatitis C virus (HCV), a single-stranded RNA virus belonging to the Flaviviridae family, is a major cause of hepatocellular carcinoma (HCC) worldwide. Tumors caused by HCC have an increased mortality rate globally, which is more accentuated in Western countries. The carcinogenic potential of this virus is mediated through a wide range of mechanisms, spanning from the induction of chronic inflammation to oxidative stress and deregulation of cellular pathways by viral proteins. As the number of new infections continues unabated, HCC-related mortality should be prioritized through early detection, continued prevention of HCV transmission, and treatment of HCV with safe and efficacious direct antiviral agents (DAAs). People who inject drugs (PWID) are a significant reservoir of new HCV infections globally, and in order to eliminate hepatitis C as a global health threat, as set out by the World Health Organization, an integrated approach based on the optimization of care delivery and increased access to harm reduction and treatment for PWID is needed. Thanks to the development of safe and effective antiviral agents, eradication of the infection is now possible in almost all treated patients, leading to a significant reduction but not the elimination of the risk for HCC in cured patients. This is particularly relevant among aged populations who have cofactors of morbidity known to accelerate HCC progression, such as diabetes, obesity, and excessive alcohol consumption. Given the restless accumulation of individuals with cured HCV infection, the implementation of risk-stratified surveillance programs becomes impellent from a cost-effectiveness perspective, whereas the availability of a performant biomarker to predict HCC in cured patients remains an unmet clinical need. [ABSTRACT FROM AUTHOR]

One of the important issues in urban areas is air pollution which causes respiratory disorders. A signifi cant association between exposure to inhaled particulate matter (PM), mainly ultrafi ne particles, and increased neurological and pulmonary morbidity and mortality was observed in some research. This study aimed to demonstrate the relation between multi-wall carbon nanotubes (MWCNTs) inhalation and the carcinogenic effect of these materials in the brain and lungs. For this purpose, we investigated gene expression in rat brain and lung tissues induced by exposure to MWCNTs. Rats were exposed to MWCNTs in diameters of 10 and 100 nm (pure and impure) at a concentration of 5 mg/m3 . Exposure was done through a whole-body exposure chamber for 5 h/day, 5 days/week for 14 days. After exposure, both brain and lung tissues were isolated to evaluate certain gene expressions including Bax, Bcl2, Rac1, Tp53, Mmp12, and Arc. The results showed that exposure to impure and pure MWCNTs (10 and 100 nm) at a concentration of 5 mg/m3 causes up-regulation or down-regulation of some of these genes. The results suggest that impure and pure MWCNTs (10 and 100 nm) can increase the risk of central nervous system disorders such as Alzheimer’s disease and increase the risk of carcinogenesis in the lung tissues of rats exposed to MWCNTs (Tab. 2, Fig. 2, Ref. 64). Text in PDF www.elis.sk. [ABSTRACT FROM AUTHOR]