Carcinogenic and non-carcinogenic health hazards of potentially toxic elements in commonly consumed rice cultivars in Dhaka city, Bangladesh.

The study aimed to assess the level of potentially toxic elements (As, Cd, Pb, Zn, Cu, Cr, Mn, and Ni) and associated health implications through commonly consumed rice cultivars of Bangladesh available in Capital city, Dhaka. The range of As, Cd, Pb, Zn, Cu, Cr, Mn, and Ni in rice grains were 0.04-0.35, 0.01-0.15, 0.01-1.18, 10.74-34.35, 1.98-13.42, 0.18-1.43, 2.51-22.08, and 0.21-5.96 mg/kg fresh weight (FW), respectively. The principal component analysis (PCA) identified substantial anthropogenic activities to be responsible for these elements in rice grains. The estimated daily intake (EDI) of the elements was below the maximum tolerable daily intake (MTDI) level. The hazard index (HI) was above the threshold level, stating non-carcinogenic health hazards from consuming these rice cultivars. The mean target cancer risk (TCR) of As and Pb exceeded the USEPA acceptable level (10-6), revealing carcinogenic health risks from the rice grains.

Toxicology and carcinogenesis study of triclosan administered dermally to B6C3F1/N mice.

Triclosan is a broad-spectrum antimicrobial agent to which humans are widely exposed. Very limited data are available regarding the dermal toxicity and the carcinogenic potential of triclosan. In this study, groups of 48 male and 48 female B6C3F1/N mice were untreated or were dermally administered 0 (vehicle), 1.25, 2.7, 5.8, or 12.5 mg triclosan/kg body weight/day (mg/kg/day) in 95% ethanol, 7 days per week for 2 years. Vehicle control animals received 95% ethanol only; untreated, naive control mice were not dosed. There were no significant differences in survival among the groups. The highest dose of triclosan decreased the body weights of mice in both sexes, but the decrease was ≤8%. (Abstract Abridged).

Aspartame carcinogenic potential revealed through network toxicology and molecular docking insights.

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

Genotoxicity assessments of N-nitrosoethylisopropylamine (NEIPA) and N-nitrosodiisopropylamine (NDIPA) in the C57BL/6J mouse.

N-Nitrosamines, known as drug impurities and suspected carcinogens, have drawn significant public concern. In response to drug regulatory needs, the European Medicines Agency (EMA) has previously proposed a carcinogenic potency categorization approach based on the N-nitrosamine α-hydroxylation hypothesis, i.e., that N-nitrosamine mutagenicity increases with the number of α-hydrogen atoms. However, this structure-activity relationship has not been fully tested in vivo. NEIPA (N-nitrosoethylisopropylamine) and NDIPA (N-nitrosodiisopropylamine) are small N-Nitrosamines with similar structures, differing in that the former compound has an additional α-hydrogen atom. In this study, NEIPA and NEIPA doses, 25-100 mg/kg, were administered orally to C57BL/6 J mice for seven consecutive days, and their mutation and DNA damage effects were compared. Compared with NDIPA, the mutagenicity and DNA damage potencies of NEIPA (which contains one more α-hydrogen) were much greater. These differences may be related to their distinct metabolic pathways and target organs. This case study confirms the role of α-hydroxyl modification in the mutagenicity of nitrosamines, with oxidation at the α-hydrogen being a crucial step in the formation of mutagens from N-Nitrosamines, and can inform mutagenicity risk assessment and the formulation of regulatory standards for N-nitrosamine impurities.

Alkylating agents are possible inducers of glioblastoma and other brain tumors.

Epidemiological evidence of an association between exposure to chemical carcinogens and an increased risk for development of glioblastoma (GBM) is limited to weak statistical associations in cohorts of firefighters, farmers, residents exposed to air pollution, and soldiers exposed to toxic chemicals (e.g., military burn pits, oil-well fire smoke). A history of ionizing radiation therapy to the head or neck is associated with an increased risk of GBM. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Data on 16 agents (15 chemicals and radio frequency radiation) that induced tumors in the rodent brain were extracted from 602 Technical Reports on 2-years cancer bioassays found in the National Toxicology Program database. Ten of the 15 chemical agents that induce brain tumors are alkylating agents. Three of the 15 chemical agents have idiosyncratic structures and might be alkylating agents. Only two of the 15 chemical agents are definitively not alkylating agents. The rat model is thought to be of possible relevance to humans suggesting that exposure to alkylating chemicals should be considered in epidemiology studies on GBM and other brain tumors.

Occupational exposure, carcinogenic and non-carcinogenic risk assessment of formaldehyde in the pathology labs of hospitals in Iran.

Formaldehyde, a known carcinogenic compound, is commonly used in various medical settings. The objective of this study was to assess the carcinogenic and non-carcinogenic risks associated with occupational exposure to formaldehyde. This study was conducted in the pathology labs of four hospitals in Tehran. Cancer and non-cancer risks were evaluated using the quantitative risk assessment method proposed by the United States environmental protection agency (USEPA), along with its provided database known as the integrated risk information system (IRIS). Respiratory symptoms were assessed using the American thoracic society (ATS) questionnaire. The results indicated that 91.23% of exposure levels in occupational groups exceed the NIOSH standard of 0.016 ppm. Regarding carcinogenic risk, 41.03% of all the studied subjects were in the definite carcinogenic risk range (LCR > 10-4), 23.08% were in the possible carcinogenic risk range (10-5 < LCR < 10-4), and 35.90% were in the negligible risk range (LCR < 10-6). The highest index of occupational carcinogenesis was observed in the group of lab technicians with a risk number of 3.7 × 10-4, followed by pathologists with a risk number of 1.7 × 10-4. Furthermore, 23.08% of the studied subjects were within the permitted health risk range (HQ < 1.0), while 76.92% were within the unhealthy risk range (HQ > 1.0). Overall, the findings revealed significantly higher carcinogenic and non-carcinogenic risks among lab technicians and pathologists. Therefore, it is imperative to implement control measures across various hospital departments to mitigate occupational formaldehyde exposure levels proactively. These findings can be valuable for policymakers in the health sector, aiding in the elimination or reduction of airborne formaldehyde exposure in work environments.

EDUCATION FROM DERMATOLOGISTS: THE SIMULTANEOUSLY DEVELOPMENT OF 16 KERATINOCYTIC CANCERS AFTER USE OF METFORMIN IN COMBINATION WITH LOSARTAN/ HYDROCHLOROTHIAZIDE, METOPROLOL AND NIFEDIPINE- IMPORTANT LINKS TO DRUG RELATED (PHOTO)-NITROSO-CARCINOGENESIS AND ONCOPHARMACOGENESIS.

Oncopharmacogenesis and Drug-Induced Skin cancer related Nitrosogenesis are newly introduced concepts in the medical literature that owe their genesis or presence to the carcinogens/ mutagens, also known as nitrosamines/NDSRIs, which are present in a heterogeneous class of drugs. The contribution to the origin of these 2 concepts is entirely due to 1) the functions and efficacy of FDA in terms of control and identification of these carcinogens, and 2) the establishment of clinicopathological correlations by the dermatologists, occurring during drug intake. According to recent FDA data, the concentration of NDMA in just one metformin tablet could be up to more than 5-fold increased. The intake of 3 to 6 tablets per day should result in a carcinogen intake that is 15 to 30 times elevated within the day and within the monomedication alone. It is these circumstances that paraphrase/ ˝betonate˝ concepts such as Onco-Pharmacogenesis and Drug-mediated Nitrosogenesis of skin cancer. Although not officially declared, these mutagens are present and have been in forced tolerance mode for the last 30-40 years. And after their intake, multiple cancers have been found to develop. The concomitant use of other nitrosamine-contaminated drugs such as losartan/hydrochlorothiazide, metoprolol and nefidipine should certainly not be surprising when it could also be associated with the development of exactly 16 keratinocytic tumours as in the case presented by us. Recent evidence in medical literature has linked the nitrosamine N-nitrosomorpholine (NMOR) with the direct development of its subsequent mutagenic action in rodents following irradiation with UVA. This fact leaves open the question of the potentially available photocarcinogenic action of the other nitrosamines in humans found in medicinal preparations. This is what necessitates a clarification of the concept of Photo-Nitroso-Carcinogenesis/ Oncogenesis in humans and its relationship to skin cancer. The overlap of the mutational patterns of some of the nitrosamine-induced mutations in target genes such as p53 and RAS oncogenes, with those of UV light-induced mutations - or practically the same ones mentioned above, suggest a possible significant role of the Drug-Induced Photo-Nitroso-Carcinogenesis of keratinocyte cancer in the context of Onco-Pharmacogenesis. Future analyses should focus on elucidating the photocarcinogenic effect of nitrosamines in drug preparations and differentiating Skin cancer Nitrosogenesis from ˝pure˝ Photo-Carcinogenesis and Nitroso-Photo-Carcinogenesis. The localization of the tumors in the area of the UV-exposed sites within the potential/actual contamination of the 4 preparations (simultaneously) in the described patient are indicative of a possible pathogenetic influence in the context of the already mentioned Nitroso-(Photo)carcinogenesis. Polycontamination of polymedication remains a so far unresolvable problem.

A meta-analysis of the carcinogenic effects of particulate matter and polycyclic aromatic hydrocarbons.

Urbanization has numerous benefits to human society, but some aspects of urban environments, such as air pollution, can negatively affect human health. Two major air pollutants, particulate matter (PM) and polycyclic aromatic hydrocarbons (PAH), have been classified as carcinogens by the International Agency for Research on Cancer. Here, we answer two questions: (1) What are the carcinogenic effects of PM and PAH exposure? (2) How does carcinogenic risk vary across geographical regions? We performed a comprehensive literature search of peer-reviewed published studies examining the link between air pollution and human cancer rates. Focusing on studies published since 2014 when the last IARC monograph on air pollution was published, we converted the extracted data into relative risks and performed subgroup analyses. Exposure to PM2.5 (per 10 µg/m3) resulted in an 8.5% increase in cancer incidence when all cancer types were combined, and risk for individual cancer types (i.e. lung cancer and adenocarcinoma) was also elevated. PM2.5 was also associated with 2.5% higher mortality due to cancer when all types of cancer were combined, and for individual cancer types (i.e., lung and breast cancer). Exposure to PM2.5 and PM10 posed the greatest risk to lung cancer incidence and mortality in Europe (PM2.5 RR 2.15; PM10 RR 1.26); the risk in Asia and the Americas was also elevated. Exposure to PAH and benzo[a]pyrene significantly increased the pooled risk of cancer incidence (10.8% and 8.0% respectively) at the highest percentile of exposure concentration. Our meta-analyses of studies over the past decade shows that urban air pollution in the form of PM2.5, PM10, and PAH all elevate the incidence and mortality of cancer. We discuss the possible mechanisms of carcinogenesis of PM and PAH. These results support World Health Organization's conclusion that air pollution poses among the greatest health risks to humans living in cities.

M2 Macrophage Prominently Distributed in the Rat's Colon of DMH-Induced Inflammation Associated Colorectal Cancer.

OBJECTIVE: The aim of this study is to examine the M1 and M2 macrophages distribution in the rat's colon of DMH-induced inflammation associated colorectal cancer. METHODS: Colon tissue of three groups of 4 rats that induced using 1,2 dimethylhydrazine (DMH) at 30 mg/kg bw every week for 9, 11, and 13 weeks were used. The M1 and M2 distribution was examined by using antibody anti iNOS for M1 and anti-CD163 for M2 with immunohistochemistry method. The data was presents in figure and table in the form of percentage. RESULT: M1 macrophage was found in all groups in the low distribution level (25% - 50%), while M2 macrophage was observed in all groups with 100% distribution. In the longer period of DMH induction, M2 macrophages was distributed more abundant. CONCLUSION: All of the rat's colon showing chronic inflammation that led to the tumorigenesis.

Systematic literature review of heavy metal contamination of the Nigerian environment from e-waste management: Associated health and carcinogenic risk assessment.

E-waste -the aftermath of large amount of electrical and electronic equipment ferried into Africa from which Nigeria receives a significant chunk, is composed of components known to be hazardous to health. Composition of series of heavy metals (HMs) in e-waste is traceable to many health conditions including cancer which is hitherto incompletely understood. This study harmonizes primary data on HMs from e-waste in different Nigerian environmental media including the air, soil, surface dust, water and plant. We estimated the possible health implications, single and aggregative soil and water pollution indices both in adult and children categories, carcinogenic and non-carcinogenic risks secondary to HM exposure and mapped out the possible mechanism of carcinogenesis. Analysis showed that soil, water, surface dust and plant matrices in Nigerian environment are variedly but considerably contaminated with combination of HMs. The significantly high values of the hazard quotient and hazard index of both water and surface dust matrices are indicative of adverse health effect of the non-carcinogenic risk. The highest HQ is generated by Pb and Cr through dermal exposure to soil and surface dust with mean values of 1718.48, 1146.14, 1362.10 and 1794.61 respectively among Nigerian children followed by the oral exposure. This pattern of observation is similar to that obtained for adult category. HI due to Pb and Cr in soil constitutes the highest HI (2.05E+03 and 1.18E+03 respectively) followed by surface dust. However, this study precipitates the observation that children are more at health risk than adults in contaminated environment. Carcinogenic risk also follows the same pattern of expression in the Nigerian environment. We conclude that exposure to e-waste poses significant carcinogenic and non-carcinogenic health risks and the induction of toxicity may be mediated via DNA damage, oxidative stress and inflammatory/immune cells dysfunction in Nigerian environment.

The Risk of Oral Cancer and the High Consumption of Thermally Processed Meat Containing Mutagenic and Carcinogenic Compounds.

The International Agency for Research on Cancer has classified the consumption of heat-processed meat as a direct human carcinogen and the consumption of red meat as a probable carcinogen. Mutagenic and carcinogenic compounds present in meat dishes include, among others, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs). These compounds can cause the development of gastrointestinal cancer. Oral cancer is one of the world's research priorities due to the ever-increasing incidence rate. However, the effect of diet on oral cancer is still a poorly recognized issue. The aim of this study was to assess the relationship between the risk of oral cancer and dietary ingredients with a particular emphasis on red meat and thermally processed meat. This study was conducted among patients with oral cancer in 2022 and 2023. The shortened standardized Food Frequency Questionnaire (FFQ) and a multivariate regression statistical analysis were used. The high consumption of red meat in general and thermally processed meat, especially smoked, fried, roasted and boiled, increases the risk of oral cavity cancer. Limiting the consumption of meat products and modifying the methods of preparing meat dishes may reduce exposure to carcinogenic compounds from the diet and thus reduce the risk of developing oral cancer.

Intestinal carcinogenicity screening of environmental pollutants using organoid-based cell transformation assay.

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

Single-cell and multi-omics analyses highlight cancer-associated fibroblasts-induced immune evasion and epithelial mesenchymal transition for smoking bladder cancer.

Tobacco carcinogens are recognized as critical hazard factors for bladder tumorigenesis, affecting the prognosis of patients through aromatic amines components. However, the specific function of tobacco carcinogens and systematic assessment models in the prognosis of bladder cancer remains poorly elucidated. We retrieved bladder cancer specific tobacco carcinogens-related genes from Comparative Toxicogenomic Database, our Nanjing Bladder Cancer cohort and TCGA database. Gene×Gene interaction method was utilized to establish a prognostic signature. Integrative assessment of immunogenomics, tumor microenvironments and single-cell RNA-sequencing were performed to illustrate the internal relations of key events from different levels. Finally, we comprehensively identified 33 essential tobacco carcinogens-related genes to construct a novel prognostic signature, and found that high-risk patients were characterized by significantly worse overall survival (HR=2.25; Plog-rank < 0.01). Single-cell RNA-sequencing and multi-omics analysis demonstrated that cancer-associated fibroblasts mediated the crosstalk between epithelial-mesenchymal transition progression and immune evasion. Moreover, an adverse outcome pathway framework was established to facilitate our understanding to the tobacco carcinogens-triggered bladder tumorigenesis. Our study systematically provided immune microenvironmental alternations for smoking-induced adverse survival outcomes in bladder cancer. These findings facilitated the integrative multi-omics insights into risk assessment and toxic mechanisms of tobacco carcinogens.

Pathologists' perspective on the study design, analysis, and interpretation of proliferative lesions in a lifetime rodent carcinogenicity bioassay of sucralose.

Sucralose, a sugar substitute first approved for use in 1991, is a non-caloric sweetener regulated globally as a food additive. Based on numerous experimental animal studies (dating to the 1980s) and human epidemiology studies, international health agencies have determined that sucralose is safe when consumed as intended. A single lifetime rodent carcinogenicity bioassay conducted by the Ramazzini Institute (RI) reported that mice fed diets containing sucralose develop hematopoietic neoplasia, but controversy continues regarding the validity and relevance of these data for predicting health effects in humans. The present paper addresses the controversy by providing the perspective of experienced pathologists on sucralose-related animal toxicity and carcinogenicity data generally, and the RI carcinogenicity bioassay findings specifically, using results from publicly available papers and international regulatory authority decisions. In the authors' view, flaws in the design, methodology, data evaluation, and reporting of the RI carcinogenicity bioassay for sucralose diminish the value of the data as evidence that this agent represents a carcinogenic hazard to humans. This limitation will remain until the RI bioassay is repeated under Good Laboratory Practices and the design, data, and accuracy of the pathology diagnoses and interpretations are reviewed by qualified pathologists with experience in evaluating potential chemically-induced carcinogenic hazards.

An update on the formation in tobacco, toxicity and carcinogenicity of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

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

Assessment of associations between inhaled formaldehyde and lymphohematopoietic cancer through the integration of epidemiological and toxicological evidence with biological plausibility.

Formaldehyde is recognized as carcinogenic for the portal of entry sites, though conclusions are mixed regarding lymphohematopoietic (LHP) cancers. This systematic review assesses the likelihood of a causal relationship between formaldehyde and LHP cancers by integrating components recommended by NASEM. Four experimental rodent bioassays and 16 observational studies in humans were included following the implementation of the a priori protocol. All studies were assessed for risk of bias (RoB), and meta-analyses were conducted on epidemiological studies, followed by a structured assessment of causation based on GRADE and Bradford Hill. RoB analysis identified systemic limitations precluding confidence in the epidemiological evidence due to inadequate characterization of formaldehyde exposure and a failure to adequately adjust for confounders or effect modifiers, thus suggesting that effect estimates are likely to be impacted by systemic bias. Mixed findings were reported in individual studies; meta-analyses did not identify significant associations between formaldehyde inhalation (when measured as ever/never exposure) and LHP outcomes, with meta-SMRs ranging from 0.50 to 1.51, depending on LHP subtype. No associations with LHP-related lesions were reported in reliable animal bioassays. No biologically plausible explanation linking the inhalation of FA and LHP was identified, supported primarily by the lack of systemic distribution and in vivo genotoxicity. In conclusion, the inconsistent associations reported in a subset of the evidence were not considered causal when integrated with the totality of the epidemiological evidence, toxicological data, and considerations of biological plausibility. The impact of systemic biases identified herein could be quantitatively assessed to better inform causality and use in risk assessment.

Chronic exposure to low levels of phenanthrene induces histological damage and carcinogenic risk in the uterus of female mice.

Phenanthrene (Phe), a polycyclic aromatic hydrocarbon with low molecular weight, is detected in the environment at high frequency. To study the toxic effects of Phe on the uterine structure and function, female Kunming mice were exposed to Phe (0.05, 0.5, 5 ng/mL) for 270 days by drinking water. Pathological alterations and their action pathways were analyzed using immunohistochemical and biomolecular technology. Phe significantly increased the percentage of blood vessel area, the number of endometrial neutrophils (indicating the occurrence of inflammation), collagen deposition (indicating fibrosis), and the percentage of Ki-67-positive cells (indicating carcinogenesis) in the uterus. Transcriptome sequencing identified differentially expressed genes that were mainly enriched in some signaling pathways, including inflammation and carcinogenesis, suggesting a carcinogenic risk in the Phe-exposed uterus. Elevated serum estrogen levels and decreased progesterone levels exhibited a disturbance of steroid hormone balance, which might be related to uterine damage. Upregulated protein levels of uterine androgen receptor and estrogen receptor α were linked to the pathological effects. Most of the effects exhibited a nonmonotonic dose response, which might be attributed to the corresponding change in the serum levels of Phe. The results suggest that exposure to low levels of Phe could exert adverse effects on the uterus.

Risk characterization of N-nitrosodimethylamine in pharmaceuticals.

Since 2018, N-nitrosodimethylamine (NDMA) has been a reported contaminant in numerous pharmaceutical products. To guide the pharmaceutical industry, FDA identified an acceptable intake (AI) of 96 ng/day NDMA. The approach assumed a linear extrapolation from the Carcinogenic Potency Database (CPDB) harmonic-mean TD50 identified in chronic studies in rats. Although NDMA has been thought to act as a mutagenic carcinogen in experimental animals, it has not been classified as a known human carcinogen by any regulatory agency. Humans are exposed to high daily exogenous and endogenous doses of NDMA. Due to the likelihood of a threshold dose for NDMA-related tumors in animals, we believe that there is ample scientific basis to utilize the threshold-based benchmark dose or point-of-departure (POD) approach when estimating a Permissible Daily Exposure limit (PDE) for NDMA. We estimated that 29,000 ng/kg/day was an appropriate POD for calculating a PDE. Assuming an average bodyweight of 50 kg, we expect that human exposures to NDMA at doses below 5800 ng/day in pharmaceuticals would not result in an increased risk of liver cancer, and that there is little, if any, risk for any other type of cancer, when accounting for the mode-of-action in humans.

Differential effect of the duration of exposure on the carcinogenicity of cadmium in MCF10A mammary epithelial cells.

The carcinogenic role of cadmium (Cd2+) in breast cancer is still debatable. Current data points to duration of exposure as the most important element. In our study, we designed an in vitro model to investigate the effects of 3 weeks versus 6 weeks of low-level CdCl2 exposure on MCF10A cells. Our results demonstrated that after 3 weeks of CdCl2 exposure the cells displayed significant changes in the DNA integrity, but there was no development of malignant features. Interestingly, after 6 weeks of exposure, the cells significantly increased their invasion, migration and colony formation capacities. Additionally, MCF10A cells exposed for 6 weeks to CdCl2 had many dysregulated genes (4905 up-regulated and 4262 down-regulated). As follows, Cd-induced phenotypical changes are accompanied by a profound modification of the transcriptomic landscape. Furthermore, the molecular alterations driving carcinogenesis in MCF10A cells exposed to CdCl2 were found to be influenced by the duration of exposure, as in the case of MEG8. This long non-coding RNA was down-regulated at 3 weeks, but up-regulated at 6 weeks of exposure. In conclusion, even very low levels of Cd (0.5 µM) can have significant carcinogenic effects on breast cells in the case of subchronic exposure.