Carcinogenic Potential Research Articles

Quantum chemical calculations of nitrosamine activation and deactivation pathways for carcinogenicity risk assessment.

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.

Assessing the genotoxicity of N-nitrosodiethylamine with three in vivo endpoints in male Big Blue® transgenic and wild-type C57BL/6N mice.

The detection of N-nitrosamines in drug products has raised global regulatory interest in recent years due to the carcinogenic potential of some nitrosamines in animals and a need to identify a testing strategy has emerged. Ideally, methods used would allow for the use of quantitative analysis of dose-response data from in vivo genotoxicity assays to determine a compound-specific acceptable intake for novel nitrosamines without sufficient carcinogenicity data. In a previous study we compared the dose-response relationships of N-nitrosodiethylamine (NDEA) in three in vivo genotoxicity endpoints in rats. Here we report a comparison of NDEA's genotoxicity profile in mice. Big Blue® mice were administered NDEA at doses of 0.001, 0.01, 0.1, 1 and 3 mg/kg/day by oral gavage for 28 days followed by 3 days of expression. Statistically significant increases in the NDEA induced mutations were detected by both the transgenic rodent mutation assay (TGR) using the cII endpoint and by duplex sequencing in the liver but not bone marrow of mice. In addition, administration of NDEA for two consecutive days in male C57BL/6N mice caused elevated DNA damage levels in the liver as measured by % tail DNA in comet assay. The benchmark dose (BMD) analysis shows a BMDL50 of 0.03, 0.04 and 0.72 mg/kg/day for TGR, duplex sequencing and comet endpoints, respectively. Overall, this study demonstrated a similar genotoxicity profile of NDEA between mice and rats and provides a reference that can be used to compare the potential potency of other novel nitrosamines for the induction of gene mutations.

PHARMA'S NITROSAMINE CHALLENGE: A REVIEW OF A CALL FOR VIGILANCE

Nitrosamines are potential carcinogens (cancer-causing agents) that can form in medications under specific conditions. The British Pharmacopoeia (BP) and the United States Pharmacopeia (USP) both set strict guidelines to minimize their presence. Nitrosamines form when nitrites and amines react in acidic environments, potentially occurring in the stomach or during drug production. They are classified as probable human carcinogens, meaning long-term exposure at high levels may increase cancer risk. Fortunately, nitrosamine levels in most medications are very low and unlikely to pose significant health risks. Both BP and USP have implemented a new general chapter: Nitrosamine Impurities (BP: 5.20 and USP: <1469>).These chapters outline acceptable intake limits for six specific nitrosamines and a four-step risk assessment and control strategy. They also detail testing procedures and analytical methods for detecting and measuring nitrosamines in medications. There are similarities between BP and USP as both set comparable acceptable intake limits for the same six nitrosamines. Also, both employ a similar four-step risk management approach. Moreover, both provide information on testing procedures and analytical methods. Nevertheless, there are few differences between both references. There may be slight variations in the specifics of analytical procedures (e.g., detection limits, chromatographic conditions).Regulatory agencies are actively monitoring and controlling nitrosamine levels in medications, ensuring patient safety. Both BP and USP play crucial roles in setting stringent standards and ensuring their consistent implementation across the pharmaceutical industry. Peer Review History: Received 28 March 2024; Revised 2 May 2024; Accepted 25 June; Available online 15 July 2024 Academic Editor: Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Maya Shaaban Eissa Hussein, Egyptian Russian University, Egypt, maya-shaaban@hotmail.com Dr. Michael Otakhor Erhunmwunse, St. Philomena Catholic Hospital, Nigeria,dedoctor4life@yahoo.com

Per- and Polyfluorinated Substances (PFAS); a Literature Review

This literature review aims to assess contemporary research on human exposure to Per- and Polyfluorinated Substances (PFAS) using the PubMed database. A series of research papers were acquired and examined, revealing novel exposure routes (firefighting, blood transfusions), associations with renal cell carcinoma, impact on DNA methylation, and links to pregnancy and early infant health. PFAS is also associated with adiposity, heart disease, and impaired immune response post-vaccination. The literature suggests potential interventions through blood and plasma donations. Limitations in the scope and scale of research, along with gaps in the understanding of the carcinogenic potential of PFAS and the efficacy of interventions in reducing PFAS exposure, were identified. Further public health research should address these gaps and limitations to enhance our understanding and address the negative health outcomes associated with PFAS exposure.

Health risks associated with hazardous airborne chemicals in beauty salons: A pilot study in Kuwaiti salons

The beauty industry has become increasingly popular in recent years, leading to a surge in salon visits for various beauty treatments. However, public concerns were raised about the possible health dangers linked to the widespread use of harmful chemicals in beauty salons. To address these concerns, a pilot study was conducted in Kuwait to evaluate and identify the ten most commonly occurring hazardous airborne chemicals in different beauty salons. Air samples were gathered from inside and outside ten beauty salons situated in diverse regions of Kuwait, covering various periods, including working hours, non-working hours, and a continuous 24-h period. The study used diffusion tubes for sampling and employed the thermo-desorption gas chromatograph/mass spectroscopy technique (TD-GC/MS) to identify the chemical compounds. In addition, the measured concentration of compounds was utilized to assess the potential inhalation health risks associated with both carcinogenic and non-carcinogenic substances, employing the USEPA Cancer Risk Indicator (CRI) and Hazard Quotient Indicator (HQI). The findings indicated that indoor concentrations of hazardous chemicals were significantly higher than those recorded outdoors. A total of 55 hazardous chemicals were detected in the indoor air quality inside beauty salons, and benzene concentrations exceeded ACGIH thresholds, suggesting a potential health concern. Although concentrations of toluene, ethylbenzene, m/p-xylene, and o-xylene remained below NIOSH recommendations, health risk assessments indicated the potential carcinogenicity of three compounds in the indoor air of beauty salons: benzene, ethylbenzene, and 2-ethyl-1-hexanol. Additionally, 15 compounds were identified by non-carcinogenic risk assessments, such as ethyl acetate and 2-ethyl-1-hexanol. These findings emphasize the urgency of implementing measures to address the exposure in Kuwait's beauty salons and conducting further research.

Estimation of acceptable daily intake values based on modeling and in vivo mutagenicity of NDSRIs of fluoxetine, duloxetine and atomoxetine

Nitrosamine drug substance related impurities or NDSRIs can be formed if an active pharmaceutical ingredient (API) has an intrinsic secondary amine that can undergo nitrosation. This is a concern as 1) nitrosamines are potentially highly potent carcinogens, 2) secondary amines in API are common, and 3) NDSRIs that might form from such secondary amines will be of unknown carcinogenic potency. Approaches for evaluating NDSRIs include read across, quantum mechanical modeling of reactivity, in vitro mutation data, and transgenic in vivo mutation data. These approaches were used here to assess NDSRIs that could potentially form from the drugs fluoxetine, duloxetine and atomoxetine. Based on a read across informed by modeling of physicochemical properties and mechanistic activation from quantum mechanical modeling, NDSRIs of fluoxetine, duloxetine, and atomoxetine were 10-100-fold less potent compared with highly potent nitrosamines such as NDMA or NDEA. While the NDSRIs were all confirmed to be mutagenic in vitro (Ames assay) and in vivo (TGR) studies, the latter data indicated that the potency of the mutation response was ≥4400 ng/day for all compounds-an order of magnitude higher than published regulatory limits for these NDSRIs. The approaches described herein can be used qualitatively to better categorize NDSRIs with respect to potency and inform whether they are in the ICH M7 (R2) designated Cohort of Concern.

Periodontal pathogens and cancer development.

Increasing evidence suggests a significant association between periodontal disease and the occurrence of various cancers. The carcinogenic potential of several periodontal pathogens has been substantiated invitro and invivo. This review provides a comprehensive overview of the diverse mechanisms employed by different periodontal pathogens in the development of cancer. These mechanisms induce chronic inflammation, inhibit the host's immune system, activate cell invasion and proliferation, possess anti-apoptotic activity, and produce carcinogenic substances. Elucidating these mechanisms might provide new insights for developing novel approaches for tumor prevention, therapeutic purposes, and survival improvement.

Features of the expression of the transcription factor NF-kB in patients with secondary edematous breast cancer with various pro-inflammatory cytokines

Background. One of the most prominent features of secondary edematous breast cancer (SEBC), which is the most malignant form of this type of cancer, is severity of chronic inflammation that is important for pathogenesis and progression of the disease. As of now, there is evidence of association of carcinogenesis and inflammation. The transcription factor (NF-kB) and pro-inflammatory cytokines play a pivotal role in both inflammation and carcinogenesis. The regulation of NF-kB signal pathways is impaired in a lot of malignant diseases, including breast cancer (BC). Thus, the study of the content of pro-inflammatory cytokines and NF-kB is of high priority, as it can provide valuable information about the course of the tumor process. However, there are few research papers that deal with association of cytokine profile and NF-kB in breast tumors. Purpose – is to study the content of NF-kB-р105 and pro-inflammatory cytokines (IL-6, IL-8, TNFα) in the blood serum of patients with secondary edematous breast cancer. Materials and Methods. 87 patients (42 with SEBC, 45 with BC) were examined prior to treatment. The age of 42 patients with T4bN0-3M0 SEBC ranged from 34 to 71 years (median 53.1). The ductal cancer was found in 30 patients (71.43%), the lobular cancer – in 12 patients (28.57%). The tumor of more than 5 cm was detected in 20 individuals (47.6%), the tumor of less than 5 cm – in 22 individuals (52.4%). The comparison group consisted of 45 patients with BC, with their age ranging from 30 to 67 years (median 52.3). They had T3-4N1-3M0 non-edematous locally advanced BC. The tumor of more than 5 cm was detected in 12 patients (26.7%), the tumor of less than 5 cm – in 33 patients (73.3%). The ductal cancer was diagnosed in 33 patients (73.3%), the lobular cancer – in 12 patients (26.7%). The control group consisted of 10 patients with fibroadenomas. The content of cytokines (IL-1B, IL-2, IL-6, IL-8, TNFα) in the blood serum of patients was measured using the ELISA assay and CJSC «Vektor-Best» standard assay kits. The content of NF-kB1 subunit (р105 → р50) was measured using the ELISA assay and the Human NFkB – p105 (Nuclear factor NF-kappa-B p 105 subunit) ELISA Kit. The measurement was performed using the Immunochem-2100 American semi-automatic immunoassay analyzer. Results. It was found that in SEBC, the levels of pro-inflammatory cytokines IL-6, IL-8, TNFα were increased by 1.4 times, compared to the parameters in BC, and the level of IL-8 was the highest. The total level of NF-kB increased by 14,7 times in patients with SEBC and by 2,4 times in patients with BC, compared to individuals with fibroadenomas. The level of NF-kB in SEBC in groups with IL-6, TNFα was higher than in groups with BC by 3.1 and 1,7 times, respectively. It was found that the highest level of NF-kB was in the group with cytokine IL-8. In SEBC, it was higher by 5.7 times than in BC. In patients with SEBC, correlations between NF-kB and cytokines were established: NF-kB and IL-8 (r = 0.80; p < 0.05); NF-kB and IL-6 (r = 0.60; p < 0.05); NF-kB and TNFα (r = 0.60; p < 0.05). Thus, one feature of SEBC is the increase in the content of NF-kB, IL-6, and TNFα, and also a significant increase in the level of NF-kB and IL-8, compared to the parameters in patients with BC as well as in patients with fibroadenomas. Conclusions. It was found that there was activation of the transcription factor NF-kB-p105 and a significant increase in the levels of pro-inflammatory cytokines (IL-6, IL-8, TNFα) in the blood serum of patients with SEBC, compared to patients with fibroadenomas, which indicates high carcinogenic potential of the tumor and the presence of the inflammatory component. It was demonstrated that the highest level of NF-kB-p105 was detected in the group of patients with SEBC with the highest level of cytokines IL-8. It was also found that in patients with SEBC, the level of the transcription factor and pro-inflammatory cytokines IL-6, IL-8, TNFα in the blood serum was significantly higher than in patients with BC, thereby confirming severe aggressiveness of this form of the disease.

Practical Experience of Using the Index of Comparative Health Hazard to Substantiate the List of Pollutants for Monitoring

Introduction: When selecting the most hazardous pollutants for inclusion in air quality monitoring programs, it is important to consider criteria of population health risk. Objective: To substantiate the list of priority air pollutants for 10 new cities of the Krasnoyarsk and Irkutsk Regions enrolled in the Clean Air Federal Project using the index of comparative hazard to population health and results of air quality testing to elaborate monitoring programs for the period until the results of summary calculations for the territory are obtained. Materials and methods: We used data provided by the Federal Supervisory Natural Resources Management Service (Rosprirodnadzor) on actual annual emissions (Form No. 2-TP (Air) for 2022) from sources of air pollution located in the cities of Angarsk, Achinsk, Zima, Irkutsk, Lesosibirsk, Minusinsk, Svirsk, Usolye-Sibirskoye, Cheremkhovo, and Shelekhov. Compliance with sanitary and epidemiological requirements for ambient air quality was established based on data from monitoring sites of the Federal Service for Hydrometeorology and Environmental Monitoring (Roshydromet) and the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing (Rospotrebnadzor) for 2020–2022. To substantiate the lists of air pollutants to be monitored within the framework of public health surveillance, we ranked chemicals according to Russian Risk Assessment Guidelines R 2.1.10.3968–23. Results: Based on the results of assessing contributions to the total index of comparative carcinogenic hazard, certain chemicals were proposed to be included into monitoring programs due to their carcinogenic potential when inhaled (acetaldehyde, benzo(a)pyrene, benzene, buta-1,3-diene, lead, carbon, formaldehyde, chromium (IV), etc.). Evaluation of percent contributions to the total index of comparative non-carcinogenic hazard revealed the need to expand monitoring programs to include the following highly hazardous chemicals: dialuminum trioxide, dihydrosulfide, dimethylamine, manganese and its compounds, sulfuric acid, fluorides, and chlorine. According to the findings, 10 to 24 pollutants were recommended for inclusion in the 2023–2024 public health surveillance program. Conclusion: The use of comparative hazard indices and consideration of their contributions to the corresponding total indices of comparative carcinogenic and/or non-carcinogenic hazard allowed us to substantiate the lists of pollutants to be included in the public health surveillance programs in 10 new cities enrolled in the Clean Air Federal Project for 2023–2024 and to expand them by including admixtures posing human health risks.

Reliability of the chemical, metabolic, and molecular methods in discriminating aflatoxigenic from non-aflatoxigenic Aspergillus isolates

Aflatoxins, potent carcinogens produced by Aspergillus species (A. flavus and A. parasiticus), are primarily consumed through dietary sources. Aflatoxin management using non-aflatoxigenic Aspergillus to outcompete their aflatoxigenic congeneric to achieve low residual toxin levels is a promising biological control (BC) field intervention. A prerequisite for the BC program is the accurate delineation of aflatoxigenic fungi from their non-aflatoxigenic relatives. In this study, we use three methods: Chemical (Dichlorvos-ammonia), Metabolic (ELISA coupled live cultures), and Molecular (10 aflatoxin biosynthetic genes) to determine the aflatoxigenicity of Aspergillus spp. previously collected from Eastern Kenya, an aflatoxin hotspot. Thirty-six different Aspergillus isolates were identified and studied microscopically from a total of 314 fungal cultures. The chemical method reported 21 aflatoxigenic and 15 non-aflatoxigenic isolates, while the metabolic technique distinguished 20 aflatoxigenic and 16 non-aflatoxigenic isolates. A large proportion (97.22 %) of the isolates harboured the aflR, aflO, and aflM genes, while 91.67 % of the isolates possessed the aflS gene. All isolates (100 %) harboured the aflD, aflQ, aflP, and aflK genes. ELISA-coupled live cultures positively correlated with Dichlorvos-ammonia (p > 0.01), only differing in one sample, indicating a strong concurrence between the two methods at segregating toxigenic A. flavus isolates. Cluster analysis based on Multiple Correspondence revealed that the non-aflatoxigenic group exhibited similar characteristics correlating with the absence of aflR, aflS, aflI, and aflO genes. These findings indicate the reliability of the Chemical and Metabolic methods and can function as confirmatory assays to complement the molecular detection approach in determining aflatoxigenicity among Aspergillus spp.

Risks assessment to the health of the population in the area of emissions pollutants influence of carbon graphite production enterprises

Risk assessment of the impact of the enterprise's activities on the environment includes risk assessment of the impact of the activity on the health of the population. Risk as the probability of undesirable events is an integral component of any person's life. Risk characterization integrates data on the danger of the analyzed chemical substances, the amount of exposure, parameters of "dose-response" dependence, with the aim of quantitative and qualitative assessment of risk, identification and assessment of the comparative significance of existing problems for the health of the population. In scientific terms, hazard identification is the process of establishing a causal relationship between the action of a chemical substance and the development of adverse effects on human health. The main goal of the hazard identification stage is the selection of priority, indicator chemical substances, the study of which allows to reliably characterize the sources of occurrence and the level of risk of public health impairment. Assessment of dose-response relationships is a process of quantitative characterization of toxicological information and establishment of a relationship between the likely influencing dose (concentration) of a pollutant and the incidence of adverse events in the exposed population. Characteristics of "dose-response" dependence, which are most often used to assess carcinogenic risk, have been sufficiently studied in epidemiological studies. Among them is the factor of carcinogenic potential (ICS), which reflects the probability of the development of a harmful reaction when the dose (concentration) increases by 1 mg/kg or 1 mg/m3 per exposure level, associated with a certain probability of effect (the indicators of this group are used for establishment of reference, i.e., reference doses and concentrations). The individual carcinogenic risk characterizes the upper limit of possible carcinogenic risk during the period corresponding to the average life expectancy of a person (70 years). Today, in the world, the classification and assessment of the acceptable risk to the health of the population caused by the chemical influence of chemical substances that pollute the environment is quite wide. the system of acceptance criteria recommended by WHO is used. In accordance with these criteria, the first range of risk (individual lifetime risk equal to or less than 1·10-6, which also corresponds to an additional case of serious illness or death per 1 million exposed persons) characterizes such levels of risk as are perceived by all strata population as quite small, which do not differ from ordinary everyday risks (De minimas level). Such risks do not require additional measures to reduce them and their levels are subject to periodic control. The second range (greater than 1·10-6 and less than 1·10-4) corresponds to the zone of conditionally accepted (acceptable) risk. It is at this level that most of the foreign and recommended by international organizations hygienic standards for the population as a whole are established. Levels of suitable risk belong to constant control. The third range (greater than 1·10-4 and less than 1·10-3) is suitable for professionals and unsuitable for the general population. The emergence of such a level of risk requires the development and implementation of planned health measures. The fourth range (equal to or greater than 1·10-3) is unsuitable neither for the population nor for professionals. This range is designated as De manifestis Risk, and when it is reached, it is necessary to carry out emergency health measures to reduce the risk on the part of the city authorities. During the assessment of the risk to the health of the population of Zaporizhzhia from the emissions of PJSC "Ukrgrafit", priority pollutants were identified: carbon oxides, nitrogen oxides, sulfur oxides, substances in the form of suspended solid particles of undifferentiated composition. Hazard indices were determined for individual HQ substances (non-carcinogenic risks) and in the case of combined exposure to HI, individual carcinogenic risks (ICR) and combined exposure (CRa) were calculated. Assessment of long-term effects (at the level of average annual concentration) on human health of the investigated substances. allowing to assess the chronic inhalation effect of the occurrence of negative effects in the health of the exposed population during the lifetime for the assessment and characterization of multistage risk showed that the hazard indices (HQ) do not exceed the norms.

Evaluation of Neuroprotective Activity of Delonix Regia Leaves on Haloperidol Induced Parkinsonism in Experimental Animals

One of the most serious and fatal neurodegenerative disorders, Parkinson disease (PD) is characterized by low levels of dopamine. Reactive oxygen species (ROS) from both endogenous and exogenous sources have a role in the oxidative stress that leads to PD, which is a complex condition. Delo nix Regia is a prominent medicinal plant that is frequently used in Indian systems of medicine. The fruit, leaves, and bark of this plant have been utilised for its antifungal, antiemetic, larvicidal, hepatoprotective, antibacterial, antioxidant, anti-diarrheal, anti-inflammatory, wound-healing, and ant carcinogenic potential, according to Ayurvedic literature. The "antioxidant strategy" is the main topic of this study's therapeutic intervention for Parkinson's disease (PD). The investigation was completed in wistar rats, in which Parkinson’s disease (PD) was induced with haloperidol 2 mg/kg, P.O. The rats were randomly divided into six groups and the test animals received the ethanolic extract of Delo nix regia (DRLE) at a dose of 100, 250 and 500 mg/kg, orally for 15 days. Various behavioural and biochemical parameters were estimated in haloperidol exposed rats. The results of this study conclusively show that Delo nix regia has anti-oxidant activity and neuroprotective activity in haloperidol experimental model of PD.

Pesticides, Drinking Water and Cancer Risk: A Portrait of Paraná Southwest, Brazil

A 2018 report from the Water Quality for Human Consumption Vigilance Information System (SISÁGUA, Brazil) showed the presence of 27 pesticides in Brazilian drinking water, of which 11 have carcinogenic potential. We assessed the data for 27 municipalities in Paraná state southwest, a rural landscape with high cancer rates. We selected data from the carcinogenic potential of 11 pesticides provided by international agencies (alachlor, aldrin-diheldrin, atrazine, chlordane, DDT, diuron, glyphosate, lindane, mancozeb, molinate, and trifluralin) and estimated the number of cancer cases attributable to drinking water contamination by pesticides. Also, we correlated such findings with incidence and mortality cancer rates for ten topographies obtained from the Brazilian National Cancer Institute (INCA) database. A total of 9 cities were selected, corresponding to about 81,000 people. All towns had all pesticides quantified in the drinking water. About ten cancer cases were attributed to drinking water contamination by pesticides in 2014–2017, mainly linked to diuron and mancozeb. Concerning the consolidated incidence of cancer cases reported by the INCA, significant correlations were found regarding aldrin-diheldrin, alachlor, and atrazine for breast cancer, atrazine for prostate cancer, and mancozeb and diuron for colon cancer, among others. Regarding the consolidated mortality rates, some correlations were found between DDT and trifluralin for the breast, DDT and lindane for the prostate, and glyphosate for lung cancer. Moderate correlations were found between the estimated and consolidated cancer cases for several topographies. Our findings highlight the correlation between drinking water contamination in Paraná state southwest and its increased incidence of cancers with poor prognosis.

Brazilian Thoracic Society recommendations for the diagnosis and monitoring of asbestos-exposed individuals.

Asbestos was largely used in Brazil. It is a mineral that induces pleural and pulmonary fibrosis, and it is a potent carcinogen. Our objective was to develop recommendations for the performance of adequate imaging tests for screening asbestos-related diseases. We searched peer-reviewed publications, national and international technical documents, and specialists' opinions on the theme. Based on that, the major recommendations are: Individuals exposed to asbestos at the workplace for ≥ 1 year or those with a history of environmental exposure for at least 5 years, all of those with a latency period > 20 years from the date of initial exposure, should initially undego HRCT of the chest for investigation. Individuals with pleural disease and/or asbestosis should be considered for regular lung cancer monitoring. Risk calculators should be adopted for lung cancer screening, with a risk estimate of 1.5%.

Mutational and Carcinogenic Potential of Amaltas Fruit Via Oxidation

Long term intake of plant-based medicines without knowing their toxicities and mutagenic potentials is common globally. Therefore, current work is an extension of cancer patient survey at Nuclear Institute of Medicine and Radiotherapy (NIMRA), for long term utilization of medicinal plant. Genotoxic potential Amaltas fruit (AF) was tested by Cicer arietinum L. and Allium cepa L plant assay. Abnormality index (A.I.), types of abnormalities and oxidative damages were the major parameters of genotoxicity. Analysis of variance (ANOVA) revealed statistically significant differences (LSD) at p≤ 0.05 for A.I. and oxidative damage in both assay plants, except negative control. Both A.I. and oxidative damages revealed incubation dependent increase. In both assay plant the major chromosomal aberration induced was fragmentation. AF induced polyploid cells, apoptotic cells and elongated cells only in Cicer arietinum L. assay. Oxidative damages in the form of nuclear membrane and cell membrane damage were observed in aberrant cells along with ghost cells. It is concluded that AF is capable to cause genotoxic effect incubation dependent manner. High rate of fragmented cells reflects its mutagenicity and carcinogenicity mediated oxidation of DNA and membranes in both assay plants. Induction of more ghost cells and less frequent apoptosis reflects activation of oncogene. Development of Pilus like projections in ghost cells depicts proliferation potential of defected cells. Prolonged utilization of AF was the cause of cancer in surveyed patients. Allium cepa L. was more sensitive as assay plant to the genotoxin. It is recommended that AF must be used occasionally.

Aflatoxin biosynthesis regulators AflR and AflS: DNA binding affinity, stoichiometry, and kinetics.

Aflatoxins (AFs), potent foodborne carcinogens produced by Aspergillus fungi, pose significant health risks worldwide and present challenges to food safety and productivity in the food chain. Novel strategies for disrupting AF production, cultivating resilient crops, and detecting contaminated food are urgently needed. Understanding the regulatory mechanisms of AF production is pivotal for targeted interventions to mitigate toxin accumulation in food and feed. The gene cluster responsible for AF biosynthesis encodes biosynthetic enzymes and pathway-specific regulators, notably AflR and AflS. While AflR, a DNA-binding protein, activates gene transcription within the cluster, AflS enhances AF production through mechanisms that are not fully understood. In this study, we developed protocols to purify recombinant AflR and AflS proteins and utilized multiple assays to characterize their interactions with DNA. Our biophysical analysis indicated that AflR and AflS form a complex. AflS exhibited no DNA-binding capability on its own but unexpectedly reduced the DNA-binding affinity of AflR. Additionally, we found that AflR achieves its binding specificity through a mechanism in which either two copies of AflR or its complex with AflS bind to target sites on DNA in a highly cooperative manner. The estimated values of the interaction parameters of AflR, AflS and DNA target sites constitute a fundamental framework against which the function and mechanisms of other AF biosynthesis regulators can be compared.

Onions, Salt and Palm Oil Marination Reduced Polycyclic Aromatic Hydrocarbon in Cooked Chevon and Beef Meat: A Risk Assessment Study

The roles of foods in human health can be greatly influenced by processing. The process of singeing deposits polycyclic aromatic hydrocarbons (PAHs) on meat. However, some food additives have shown tendencies to reduce PAHs levels in singed food. This study conducted a risk assessment study on the effect of onions, salt and palm oil marination on Polycyclic aromatic hydrocarbon in cooked chevon and beef meat. The singed meat samples were cooked with specific quantities of additives (onions, salt and palm oil). PAHs levels were analyzed using Gas Chromatography Mass spectrophotometer (GC-MS) and the health risk assessment was conducted as described by USEPA. Our findings revealed that meat samples singed with augmented fire wood accumulated more PAHs than those singed with only firewood; also chevon accumulated more PAHs than beef. PAHs content in all singed meat samples cooked with maximum quantity of additives (15 g) for 30 min had reduction in concentration of about 99%. The estimated daily intake (EDI) showed that PAHs concentration were higher in uncooked meat samples singed with augmented firewood. The least concentration of PAH was seen in cooked chevon singed with only firewood (9.39E-06 mg/kg/day). The hazard quotients (HQs) evaluated showed that cooking the meat samples with additives, notably decreased PAHs concentration (from between 10−1 and 10−3 to between 10−5 and 10−7). The hazard index (HI) observed showed that PAHs concentration in cooked samples were lower than in uncooked samples. The Carcinogenic potency showed that the uncooked singed meat samples could lead to health complications except for the chevon sample singed with only firewood. However, all cooked samples showed lower health hazards with potency index which were all less than one (<1). The findings suggest that chevon accumulated PAHs more than beef. However, the carcinogenic potency of the PAHs in chevon was less than beef after cooking with additives.

Integrating Transcriptomics and Proteomics to Characterize the Intestinal Responses to Cadmium Exposure Using a Piglet Model.

Cadmium (Cd) is a heavy metal element with a wide range of hazards and severe biotoxicity. Since Cd can be easily accumulated in the edible parts of plants, the exposure of humans to Cd is mainly through the intake of Cd-contaminated food. However, the intestinal responses to Cd exposure are not completely characterized. Herein, we simulated laboratory and environmental Cd exposure by feeding the piglets with CdCl2-added rice and Cd-contaminated rice (Cdcr) contained diet, as piglets show anatomical and physiological similarities to humans. Subsequent analysis of the metal element concentrations showed that exposure to the two types of Cd significantly increased Cd levels in piglets. After verifying the expression of major Cd transporters by Western blots, multi-omics further expanded the possible transporters of Cd and found Cd exposure causes wide alterations in the metabolism of piglets. Of significance, CdCl2 and Cdcr exhibited different body distribution and metabolic rewiring, and Cdcr had stronger carcinogenic and diabetes-inducing potential. Together, our results indicate that CdCl2 had a significant difference compared with Cdcr, which has important implications for a more intense study of Cd toxicity.

The FABD domain is critical for the oncogenicity of BCR/ABL in chronic myeloid leukaemia

BackgroundAbnormally expressed BCR/ABL protein serves as the basis for the development of chronic myeloid leukaemia (CML). The F-actin binding domain (FABD), which is a crucial region of the BCR/ABL fusion protein, is also located at the carboxyl end of the c-ABL protein and regulates the kinase activity of c-ABL. However, the precise function of this domain in BCR/ABL remains uncertain.MethodsThe FABD-deficient adenovirus vectors Ad-BCR/ABL△FABD, wild-type Ad-BCR/ABL and the control vector Adtrack were constructed, and 32D cells were infected with these adenoviruses separately. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were evaluated by a CCK-8 assay, colony formation assay, flow cytometry and DAPI staining. The levels of phosphorylated BCR/ABL, p73, and their downstream signalling molecules were detected by western blot. The intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin were identified by immunofluorescence and co-IP. The effect of FABD deletion on BCR/ABL carcinogenesis in vivo was explored in CML-like mouse models. The degree of leukaemic cell infiltration was observed by Wright‒Giemsa staining and haematoxylin and eosin (HE) staining.ResultsWe report that the loss of FABD weakened the proliferation-promoting ability of BCR/ABL, accompanied by the downregulation of BCR/ABL downstream signals. Moreover, the deletion of FABD resulted in a change in the localization of BCR/ABL from the cytoplasm to the nucleus, accompanied by an increase in cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Furthermore, we discovered that the absence of FABD alleviated leukaemic cell infiltration induced by BCR/ABL in mice.ConclusionsThese findings reveal that the deletion of FABD diminished the carcinogenic potential of BCR/ABL both in vitro and in vivo. This study provides further insight into the function of the FABD domain in BCR/ABL.

Structuring expert review using AOPs: Enabling robust weight-of-evidence assessments for carcinogenicity under ICH S1B(R1)

There is widespread acceptance that non-animal studies can be used to assess chemical safety in humans. These New Approach Methodologies (NAMs) typically integrate data from multiple sources including in silico and in vitro models. Regulatory guidelines are being updated to recognise that these scientific advances are allowing animal studies to be replaced without compromising human safety. One such regulation, ICH S1B(R1), was updated in 2022 to include the provision for a weight-of-evidence assessment for carcinogenicity, using six factors to determine if there was sufficient evidence to waive the need to run a rat carcinogenicity assay. The volume of data and evidence, however, can be hard to organise and interpret into a cohesive evaluation. To aid such assessments, software has been developed that combines adverse outcome pathways (AOPs) and reasoning, to organise and contextualise knowledge, and provide an outcome based on the data available. Using this framework, a workflow has been developed to assess the initial outcome and structure expert review to investigate the factors, and potential biological mechanisms which could contribute to a compound’s carcinogenic potential (or lack thereof). The framework was used to structure expert review of three examples of differing activity and levels of supporting evidence. This highlighted where AOPs supported expert review by showing 1) the value in using AOPs to analyse data, 2) the importance of expert review to strengthen confidence in outcomes, and 3) how this approach can accurately predict experimental results. Therefore, using this approach to assess evidence for ICH S1B(R1) will give transparent, scientifically robust, and reproducible calls, and thus reduce the need for rat carcinogenicity studies.