Search Results (40)

Polyethylene (PE) is the most widely produced plastic globally. It is extensively used as packaging in both the food and pharmaceutical industries. Its use can result in the formation of emerging contaminants—microplastics (MPs). This review summarizes current knowledge on PE and PE-derived microplastics (PE–MPs) and highlights existing gaps. It discusses the factors influencing PE degradation, with particular emphasis on interactions with packaged contents and food products. The role of PE–MPs as vectors for environmental contaminants is also examined, focusing on their adsorption and desorption behavior. Finally, we explore the toxicity and bioaccessibility of PE–MPs. Our findings indicate that pH, temperature, and exposure time are the most significant factors driving PE degradation. However, comparative studies examining a broad spectrum of parameter values remain scarce. The process of PE–MP generation remains largely unexplored. Adsorption mechanisms on PE–MPs are well documented in the literature. In contrast, desorption has received significantly less scientific attention, and its relevance to human exposure is still unclear. Numerous studies have suggested potential links between human exposure to PE–MPs and the development of non-communicable diseases, including cardiovascular and neurodegenerative disorders. Nevertheless, no studies have yet examined the bioavailability of PE–MPs. Similarly, the dose-response relationship between PE and MP exposure and toxicological outcomes in humans remains unclear. As a result, it is currently not possible to establish safety thresholds for PE–MP contamination in food products. This review offers a novel polymer-specific approach to MPs research and outlines specific recommendations for future studies. Full article

Background: There is substantial evidence supporting the role of genetic alterations in chemically induced carcinogenesis. We analyzed the existing literature to gather data on genetic alterations linked to human carcinogens and their possible connection to genotoxic outcomes. The review emphasizes carcinogenic substances and occupational exposures identified as “carcinogenic to humans”. In particular, we searched for studies describing genotoxic alterations linked to agents and occupational exposures for which the International Agency for Research on Cancer has found sufficient evidence of an association with bladder cancer. Methods: The review was carried out in compliance with the PRISMA standards. A comprehensive search of the PubMed database was conducted to identify studies published through March 2024. Results: We identified 60 studies that evaluated genetic alterations for 16 carcinogenic agents and occupations (such as aluminum production, 4-aminobiphenyl, auramine production, benzidine, chlornaphazine, cyclophosphamide, firefighters, magenta production, 2-naphthylamine, opium consumption, ortho-toluidine, painters, the rubber manufacturing industry, Schistosoma haematobium infection, X-radiation, gamma-radiation) in healthy humans. Conclusions: The genotoxic effects of chemical agents in healthy individuals have been well studied and characterized. Additionally, this review presents numerous studies concerning occupational exposure but not exclusively. Genotoxicity assessments have mainly been conducted on biological materials such as blood, peripheral blood lymphocytes, urine, and buccal epithelial cells. The most frequently examined genotoxic effects were DNA damage, chromosomal abnormalities, and micronuclei. Standardized data to clearly define a dose–response relationship for predicting delayed health effects are still lacking. Full article

Objectives: HangAmDan-B1 (HAD-B1), a blended herbal mixture, has been investigated as an adjuvant therapy with afatinib (AFT) to treat non-small lung cancer (NSCLC). Although preclinical studies demonstrated promising synergistic results, clinical trials have not yet confirmed the expected benefits. This study aims to quantitatively examine the exposure–response relationship and synergistic interactions through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: A PK/PD model was established and validated based on tumor growth profiles from a xenograft mouse study of gefitinib-resistant HCC827. Model-based simulations were performed to predict and assess therapeutic effects across different treatment groups. Results: The PK/PD model confirmed HAD-B1 enhances the potency of AFT by 1.45-fold. Model-based simulations predicted that combination treatment maintains a lower tumor size compared to AFT monotherapy. Conclusions: This study quantitatively demonstrated the synergistic interaction between HAD-B1 and AFT. The developed PK/PD model provides insights into potential dosing strategies to treat NSCLC resistant to EGFR-TKIs. Further clinical trials are warranted to validate these findings and refine dosing strategies to improve therapeutic outcomes. Full article

Background: The relationship between sarcopenia and the incidence of coronary artery disease (CAD) is not well understood. This study aimed to investigate this relationship and the modifying effect of potential risk factors. Methods: We conducted a prospective study including 439,295 individuals from the UK Biobank. The primary outcome was the incidence of CAD. The main physical capability markers for sarcopenia, grip strength and muscle mass, were investigated as risk factors of interest. Grip strength was measured using a Jamar J00105 (Lafayette, IN, USA) hydraulic hand dynamometer, while muscle mass was estimated through bioelectrical impedance. Cox proportional hazard models were employed to analyze the associations between the exposures and the risk of CAD. Results: A total of 41,564 incident cases of CAD were identified after a median follow-up of 13.15 years (IQR 12.29–13.88 years). Compared with the lowest quintile of grip strength, the adjusted HRs for incidences of CAD from the second to the fifth quintile were 0.81 (95% CI: 0.79–0.83), 0.71 (95% CI: 0.69–0.73), 0.61 (95% CI: 0.60–0.63), and 0.49 (95% CI: 0.48–0.51). The association remained significant in subgroup analysis and interactions were observed between the two exposures and sex, age, smoking status, inflammatory diseases, metabolic syndrome, and genetic predisposition (all p for interactions < 0.05). Conclusions: Physical capability markers of sarcopenia, grip strength and muscle mass, were independently associated with a dose–response decreased risk for CAD incidence, regardless of genetic predisposition and potential modifying risk factors. Full article

The constrained disorder principle (CDP) defines complex biological systems based on inherent variability. Allostasis refers to the physiological processes that help maintain stability in response to changing environmental demands. Allostatic load describes the cumulative wear and tear on the body resulting from prolonged exposure to stress, and it has been suggested to mediate the relationship between stress and disease. This study presents the concepts of CDP and allostasis while discussing their similarities and differences. We reviewed the current literature on the potential benefits of introducing controlled doses of biological noise into interventions, which may enhance the effectiveness of therapies. The paper highlights the promising role of variability provided by a CDP-based second-generation artificial intelligence system in improving health outcomes. Full article

Introduction: This study investigates associations between fine particulate air pollution (PM_2.5) exposure and thyroid hormone levels during pregnancy in Puerto Rican individuals, a vulnerable population facing socioeconomic and environmental disparities. Methods: This research draws on data from the PROTECT cohort study and involves 1040 participants to measure the effect of PM_2.5 on developmentally important thyroid hormones (TSH, T3, T4, and FT4). Pollution concentrations were linked to participant locations using EPA air quality data and analyzed across two visits during gestational weeks 16–20 and 24–28. Results: The results suggest that PM_2.5 exposure is positively associated with maternal T3, T4, and FT4 levels but not TSH. These effects vary by timing, with T3 showing stronger associations later in pregnancy and T4/FT4 earlier. Nonlinear dose–response relationships were observed, suggesting thresholds for certain hormones. Discussion: These findings support previous studies linking altered thyroid hormones to adverse birth outcomes and highlight the potential role of air pollution in disrupting maternal thyroid function and its implications for fetal development, calling for further research into mechanisms and interventions to mitigate these risks. Full article

A considerable quantity of microplastic debris exists in the environment and the toxicity of these materials has a notable impact on aquatic ecosystems. In this paper, 50–500 µm polystyrene microplastics (exposure concentrations were 200 µg/L, 800 µg/L, and 3200 µg/L concentrations) were selected to study the effects of polystyrene microplastics (PS-MPs) on cell morphology, detoxification enzyme activity, and mRNA expression in the liver tissues of crucian carp juveniles. The results demonstrated that: (1) Different concentrations of PS-MPs cause varying degrees of pathological and oxidative damage to liver tissue cells of crucian carp. The higher the concentration of microplastics, the lower the antioxidant enzyme (CAT, GST, SOD) activity and the greater the tissue cell damage. These results demonstrate a typical dose–effect relationship. (2) Principal component analysis and Spearman’s correlation analysis demonstrated that four components, namely glutathione S-transferase (GST) and its related genes (GSTpi, GSTα), along with catalase (CAT), contributed the most to the observed outcome. These four components demonstrated a relatively high level of responsiveness to PS-MP exposure and can be employed as ecotoxicological indicators of microplastics. (3) This experiment evaluated five genes in three treatments, which found that PS-MPs had different effects on gene expression in the liver and the tested genes were involved in different response pathways associated with virulence. In this study, the toxicity of PS-MPs to crucian carp was determined at the cellular, protein, and mRNA expression levels, and combined with principal component analysis and correlation analysis to identify response sensitivity indicators that provide a scientific basis for ecological risk assessment and the safe use of microplastics. Full article

Acute and short-term toxicity tests are foundational to toxicology research. These tests offer preliminary insights into the fundamental toxicity characteristics of the chemicals under evaluation and provide essential data for chronic toxicity assessments. Fluoride is a common chemical in aquatic environments; however, the findings of toxicological data, such as LC₅₀ for aquatic organisms, often exhibit inconsistency. Consequently, this study employed zebrafish as a model organism during their early life stages to assess the acute and short-term toxicity of fluoride exposure. Bayesian model averaging was utilized to calculate the LC₅₀/EC₅₀ values and establish baseline concentrations. The results indicated a dose–response relationship between water fluoride concentration and harmful outcomes. The 20 mg/L group was identified as the lowest observed adverse effect level (LOAEL) for the majority of toxicity indicators and warrants special attention. Based on the BBMD model averages, the LC₅₀ of fluoride for 1 to 5 days post-fertilization (dpf) zebrafish was 147.00, 80.80, 61.25, 56.50, and 37.50 mg/L, while the EC₅₀ of cumulative malformation rate for 5 dpf zebrafish was 59.75 mg/L. As the benchmark response (BMR) increased, both the benchmark concentrations (BMCs) and benchmark dose levels (BMDLs) also increased. The research aims to provide essential data for the development of environmental water guidelines and to mitigate ecological risks associated with fluoride in aquatic ecosystems. Full article

Background/Objective: Environmental exposures, such as heavy metals, can significantly affect physical activity, an important determinant of health. This study explores the effect of physical activity on combined exposure to cadmium, lead, and mercury (metals), using data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES). Methods: Physical activity was measured with ActiGraph GT3X+ devices worn continuously for 7 days, while blood samples were analyzed for metal content using inductively coupled plasma mass spectrometry. Descriptive statistics and multivariable linear regression were used to assess the impact of multi-metal exposure on physical activity. Additionally, Bayesian Kernel Machine Regression (BKMR) was applied to explore nonlinear and interactive effects of metal exposures on physical activity. Using a Gaussian process with a radial basis function kernel, BKMR estimates posterior distributions via Markov Chain Monte Carlo (MCMC) sampling, allowing for robust evaluation of individual and combined exposure-response relationships. Posterior Inclusion Probabilities (PIPs) were calculated to quantify the relative importance of each metal. Results: The linear regression analysis revealed positive associations between cadmium and lead exposure and physical activity. BKMR analysis, particularly the PIP, identified lead as the most influential metal in predicting physical activity, followed by cadmium and mercury. These PIP values provide a probabilistic measure of each metal’s importance, offering deeper insights into their relative contributions to the overall exposure effect. The study also uncovered complex relationships between metal exposures and physical activity. In univariate BKMR exposure-response analysis, lead and cadmium generally showed positive associations with physical activity, while mercury exhibited a slightly negative relationship. Bivariate exposure-response analysis further illustrated how the impact of one metal could be influenced by the presence and levels of another, confirming the trends observed in univariate analyses while also demonstrating the complexity varying doses of two metals can have on either increased or decreased physical activity. Additionally, the overall exposure effect analysis across different quantiles revealed that higher levels of combined metal exposures were associated with increased physical activity, though there was greater uncertainty at higher exposure levels as the 95% credible intervals were wider. Conclusions: Overall, this study fills a critical gap by investigating the interactive and combined effects of multiple metals on physical activity. The findings underscore the necessity of using advanced methods such as BKMR to capture the complex dynamics of environmental exposures and their impact on human behavior and health outcomes. Full article

(1) Peanut allergy is associated with high risk of anaphylaxis which could be prevented by oral immunotherapy. Patients eligible for immunotherapy are selected on the basis of a food challenge, although currently the assessment of antibodies against main peanut molecules (Ara h 1, 2, 3 and 6) is thought to be another option. (2) The current study assessed the relationship between the mentioned antibodies, challenge outcomes, skin tests and some other parameters in peanut-sensitized children. It involved 74 children, divided into two groups, based on their response to a food challenge. (3) Both groups differed in results of skin tests, levels of component-specific antibodies and peanut exposure history. The antibody levels were then used to calculate thresholds for prediction of challenge results or symptom severity. While the antibody-based challenge prediction revealed statistical significance, it failed in cases of severe symptoms. Furthermore, no significant correlation was observed between antibody levels, symptom-eliciting doses and the risk of severe anaphylaxis. Although in some patients it could result from interference with IgG4, the latter would not be a universal explanation of this phenomenon. (4) Despite some limitations, antibody-based screening may be an alternative to the food challenge, although its clinical relevance still requires further studies. Full article

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) stands as one of the most potent halogenated polycyclic hydrocarbons, known to inflict substantial cytotoxic effects on both animal and human tissues. Its widespread presence and recalcitrance make it an environmental and health concern. Efforts are being intensively channeled to uncover strategies that could mitigate the adverse health outcomes associated with TCDD exposure. In the realm of counteractive agents, boron compounds are emerging as potential candidates. These compounds, which have found applications in a spectrum of industries ranging from agriculture to pharmaceutical and cosmetic manufacturing, are known to modulate several cellular processes and enzymatic pathways. However, the dose–response relationships and protective potentials of commercially prevalent boron compounds, such as boric acid (BA), ulexite (UX), and borax (BX), have not been comprehensively studied. In our detailed investigation, when peripheral blood mononuclear cells (PBMCs) were subjected to TCDD exposure, they manifested significant cellular disruptions. This was evidenced by compromised membrane integrity, a marked reduction in antioxidant defense mechanisms, and a surge in the malondialdehyde (MDA) levels, a recognized marker for oxidative stress. On the genomic front, increased 8-OH-dG levels and chromosomal aberration (CA) frequency suggested that TCDD had the potential to cause DNA damage. Notably, our experiments have revealed that boron compounds could act as protective agents against these disruptions. They exhibited a pronounced ability to diminish the cytotoxic, genotoxic, and oxidative stress outcomes instigated by TCDD. Thus, our findings shed light on the promising role of boron compounds. In specific dosages, they may not only counteract the detrimental effects of TCDD but also serve as potential chemopreventive agents, safeguarding the cellular and genomic integrity of PBMCs. Full article

Appropriate surgical antimicrobial prophylaxis (SAP) is an important measure in preventing surgical site infections (SSIs). Although antimicrobial pharmacokinetics–pharmacodynamics (PKPD) is integral to optimizing antibiotic dosing for the treatment of infections, there is less research on preventing infections postsurgery. Whereas clinical studies of SAP dose, preincision timing, and redosing are informative, it is difficult to isolate their effect on SSI outcomes. Antimicrobial PKPD aims to explain the complex relationship between antibiotic exposure during surgery and the subsequent development of SSI. It accounts for the many factors that influence the PKs and antibiotic concentrations in patients and considers the susceptibilities of bacteria most likely to contaminate the surgical site. This narrative review examines the relevance and role of PKPD in providing effective SAP. The dose–response relationship i.e., association between lower dose and SSI in cefazolin prophylaxis is discussed. A comprehensive review of the evidence for an antibiotic concentration–response (SSI) relationship in SAP is also presented. Finally, PKPD considerations for improving SAP are explored with a focus on cefazolin prophylaxis in adults and outstanding questions regarding its dose, preincision timing, and redosing during surgery. Full article

Sodium–glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure–response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure–response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC_0–tau,ss) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, p < 0.001), systolic blood pressure (0.80 mmHg, p = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, p = 0.03), and filtration fraction (0.09%, p = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC_0–tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, p = 0.002), systolic blood pressure (0.65 mmHg, p = 0.045), and mGFR (0.78 mL/min, p = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables. Full article

Esophageal cancer is a common and aggressive cancer, with a five-year survival rate of approximately 20%. Therefore, identifying safe and effective medications that can reduce the risk of esophageal cancer is of great importance. Objective: To examine the association between H1-antihistamines (AHs) use and the incidence of esophageal squamous cell carcinoma (ESCC) in a head-to-head propensity score matching (PSM) comparative study. Design: Retrospective cohort study. Setting: Nationwide population-based study in Taiwan. Participants: 1289,526 adults from the National Health Insurance Research Database from 2008 to 2018. Exposures: AH use. Main Outcomes and Measures: Incidence rates (IRs), incidence rate ratios (IRRs), and adjusted hazard ratios (aHRs) of ESCC in AH users compared with nonusers. Results: AH users had a significantly higher IR of ESCC than nonusers (1.47 vs. 1.36 per 100,000 person-years). The IRR (95% CI) for ESCC was 1.18 (1.08–1.28) in AH users compared with nonusers. After adjustment for age, sex, income levels, urbanization, cigarettes smoking, alcoholic related diseases, comorbidities, medication use, and Charlson Comorbidity Index scores, the aHR (95% CI) for ESCC was 1.22 (1.12–1.33) in AH users compared with nonusers. A dose–response relationship was also observed, with aHRs for AH use at 28–182, 183–488, 489–1043, and >1043 cumulative defined daily doses (cDDDs) of 1.12, 1.20, 1.25, and 1.37, respectively, compared with <28 cDDDs. Conclusions and Relevance: Our study found a significant association between AH use and the increased risk of ESCC, with a dose–response relationship. This study suggests that AH use may increase the risk of ESCC, especially at high doses, and highlights the importance of caution when prescribing AHs. Full article

Elucidation of the mechanisms for the response of cancer stem cells (CSCs) to radiation exposure is of considerable interest for further improvement of radio- and chemoradiotherapy of cervical cancer (CC). The aim of this work is to evaluate the effects of fractionated radiation exposure on the expression of vimentin, which is one of the end-stage markers of epithelial-mesenchymal transition (EMT), and analyze its association with CSC radiation response and short-term prognosis of CC patients. The level of vimentin expression was determined in HeLa, SiHa cell lines, and scrapings from the cervix of 46 CC patients before treatment and after irradiation at a total dose of 10 Gy using real-time polymerase chain reaction (PCR) assay, flow cytometry, and fluorescence microscopy. The number of CSCs was assessed using flow cytometry. Significant correlations were shown between vimentin expression and postradiation changes in CSC numbers in both cell lines (R = 0.88, p = 0.04 for HeLa and R = 0.91, p = 0.01 for SiHa) and cervical scrapings (R = 0.45, p = 0.008). Associations were found at the level of tendency between postradiation increase in vimentin expression and unfavorable clinical outcome 3–6 months after treatment. The results clarify some of the relationships between EMT, CSCs, and therapeutic resistance that are needed to develop new strategies for cancer treatment. Full article