Risk Of Toxicity Research Articles

Stereotactic Body Radiotherapy for Renal Cell Carcinoma-A Review of Use in the Primary, Cytoreductive and Oligometastatic Settings.

Renal cell carcinoma (RCC) has been increasing in incidence by around 1.5% per year for several years. However, the mortality rate has been decreasing by 1.6% per year, and this can be attributed to stage migration and improvements in treatment. One treatment modality that has emerged in recent years is stereotactic body radiotherapy (SBRT), which is an advanced radiotherapy technique that allows the delivery of high-dose radiation to the tumor while minimizing doses to the organs at risk. SBRT has developed a role in the treatment of early-stage, oligometastatic and oligoprogressive RCC. In localized disease, phase II trials and meta-analyses have shown that SBRT provides a very high probability of long-term local control with a low risk of severe late toxicity. In oligometastatic (OMD) RCC, the same level of evidence has similarly shown good local control and minimal toxicity. SBRT could also delay the necessity to start or switch systemic treatments. Medical societies have started to incorporate SBRT in their guidelines in the treatment of localized disease and OMD. A possible future role of SBRT involves cytoreduction. It is theorized that SBRT can lower tumor burden and enhance immune-related response, but it cannot be recommended until the results of the phase II trials are published.

Exploring the therapeutic potential of lipid-based nanoparticles in the management of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a highly malignant and invasive tumor with significant mortality and morbidity. Current treatment modalities such as surgery, radiotherapy, and chemotherapy encounter significant limitations, such as poor targeting, systemic toxicity, and drug resistance. There is an urgent need for novel therapeutic strategies that offer targeted delivery, enhanced efficacy, and reduced side effects. The advent of lipid-based nanoparticles (LNPs) offers a promising tool for OSCC therapy, potentially overcoming the limitations of current therapeutic approaches. LNPs are composed of biodegradable and biocompatible lipids, which minimize the risk of toxicity and adverse effects. LNPs can encapsulate hydrophobic drugs, improving their solubility and stability in the biological environment, thereby enhancing their bioavailability. LNPs demonstrate significantly higher ability to encapsulate lipophilic drugs than other nanoparticle types. LNPs offer excellent storage stability, minimal drug leakage, and controlled drug release, making them highly effective nanoplatforms for the delivery of chemotherapeutic agents. Additionally, LNPs can be modified by complexing them with specific target ligands on their surface. This surface modification allows the active targeting of LNPs to the tumors in addition to the passive targeting mechanism. Furthermore, the PEGylation of LNPs improves their hydrophilicity and enhances their biological half-life by reducing clearance by the reticuloendothelial system. This review aims to discuss current treatment approaches and their limitations, as well as recent advancements in LNPs for better management of OSCC.

Coronary artery calcium score and other risk factors in patients at moderate and high risk of cancer therapy-related cardiovascular toxicity

BackgroundThe presence and burden of coronary artery calcium (CAC) is a strong predictor of cardiovascular events. Current guidelines of the European Society of Cardiology (ESC) for cardio-oncology do not recommend the use of the CAC score to determine the status of risk in cancer patients. The aim of this study is to evaluate the presence and burden of CAC on cardiac tomography and the distribution of the cardiovascular toxicity risk factors in patients with moderate and high baseline risk of cancer therapy-related cardiovascular toxicity.MethodsThe study prospectively included cancer patients, diagnosed and qualified for systemic treatment with anthracycline chemotherapy. Clinical data and blood samples were collected from all patients. Additionally, the echocardiography and coronary computed tomography (CCTA) with the calculation of the coronary artery calcium (CAC) score were performed.ResultsA total of 80 patients (mean age 60.5 years, 75 female) were included in the study. The majority of patients (62, 77.5%) had breast cancer, 11 (13.8%) were diagnosed with sarcoma, and 7 (8.8%) with lymphoma. There were 42 (52.5%) patients classified as having moderate (MR) and 38 (47.5%) as having high risk (HR) of cancer therapy-related cardiovascular toxicity according to current ESC guidelines. In comparison with moderate risk, high risk patients were older and more likely to have hypertension, hyperlipidaemia and chronic kidney disease. The mean coronary artery calcium score was significantly higher in the HR group (150.4 vs. 24.8; p = 0.000). Furthermore, cardiac biomarkers were also higher in high-risk patients (p = 0.000). In echocardiographic parameters global longitudinal strain (GLS) was lower (p = 0.012), and diastolic dysfunction was more common in the HR group. However, the left ventricle ejection fraction (LVEF) was similar in the MR and HR groups.ConclusionsIn patients at high and moderate risk for cancer therapy-related cardiovascular toxicity, cardiovascular toxicity risk factors were common and more prevalent in the high-risk group. The coronary artery calcium score was also significantly higher in the high-risk group. Assessing the presence and burden of coronary artery calcium is an attractive option to assess additional cardiovascular risk in cancer patients.

Spatial distribution, ecological and ecotoxicity evaluation of heavy metals in agricultural soils along Lala-Manjo Highway, Cameroon Volcanic Line

This study aims at assessing the spatial distribution, ecological and toxicity levels of heavy metals in agricultural soils of Lala-Manjo Highway in Cameroon. The soil samples were collected and analyzed by inductively coupled plasma-mass spectrometry. The result shows that Co, Cr, Cu, Hg, Mn, Ni, Sr, V and Zn concentrations are higher than those of the upper continental crust reference values except those of As, Cd and Pb. Correlation coefficient indicate similar input sources governed by same geochemical characteristics. Spatial distribution maps show high concentration of heavy metals in east, south and western part of the study area. Pollution indicators show that enrichment factor varied from moderate to high enrichment of heavy metals. The contamination degree (27.12–35.59), geo-accumulation index (0.01–4.94), and potential ecological risk index (RI = < 150) revealed a low to moderate levels of metallic pollution. The majority of stations have pollution load index and Nemerow integrated pollution index values greater than one, indicating serious pollution. Modified hazard quotient and toxic risk index suggest significant severity of pollution and low toxicity risk of heavy metals, pointing low toxicity effects of heavy metals to fauna and flora in the soil ecosystem. Considering the factors governing soils accumulation such as geology, climate and anthropogenic activities as well as the correlation with commonly used environmental background, it is proposed that the data from this study can be considered as a baseline of pollution to plan major agricultural developments in the area. The study underlines the importance of continuous monitoring and adaptive management for the preservation of soil ecosystem. The results may assist companies and local population in setting realistic targets for monitoring and remediation programs.

Association between hydroxychloroquine intake and damage to the outer nuclear layer in eyes without manifest retinal toxicity

BackgroundHydroxychloroquine (HCQ) is widely used to treat various autoimmune diseases but carries a risk of retinal toxicity, particularly with prolonged use. Despite advancements, uncertainty persists regarding optimal screening methods. Recent advances in OCT have enabled early detection of retinal damage, with studies suggesting that thinning of specific retinal layers may be an early indicator of toxicity. However, there is a gap in research on outer nuclear layer (ONL) thinning in HCQ users without apparent retinal toxicity. This information is crucial for improving screening and identifying the ONL as a reliable biomarker for screening. Therefore, this study aimed to investigate the association between HCQ intake and ONL damage in eyes without manifest retinal toxicity.MethodsA case‒control study was conducted at the ophthalmology department of Eye and Ear Hospital International from July 2022 to June 2023. The study included 20 individuals on HCQ and 20 age-matched controls. The data were obtained through chart reviews, and participants underwent comprehensive ophthalmic assessments.ResultsA total of 80 eyes were analyzed. Patients on HCQ exhibited significantly thinner perifoveal, parafoveal, and overall ONL compared to controls (P < .001, P < .012, and P < .004, respectively). Similarly, this association was found in the nasal, inferior, and temporal quadrants of both the inner (region 3: P < .01, region 4: P < .001, and region 5: P < .03) and outer zones (region 7: P < .04, region 8: P < .001, region 9: P < .02), most pronounced in the inferior regions. The cumulative dose was weakly associated with decreased ONL thickness only in the nasal quadrant of the inner zone (region 3: P < .047). Correlation analysis of the initial and most recent OCT scans in the same individuals revealed a weak association with ONL thinning in the central zone (region 1: P < .0048).ConclusionThe thickness of the ONL can significantly decrease in patients taking HCQ, even in the absence of of manifest retinal toxicity. This study is the first to evaluate this association in eyes with negative screening and diagnostic tests for HCQ retinopathy. The findings suggest that ONL thickness could serve as an early diagnostic indicator for HCQ retinal toxicity.

Synthesis and characterization of chitosan-pectin fabricated nanoemulsion for ethylhexyl triazone topical delivery

This study aimed to investigate the stability of nanoemulsions for the UVB filter, ethylhexyl triazone (EHT) encapsulation followed by fabrication with chitosan and pectin. Four formulations were developed to assess the influence of hydrophile-lipophile balance (HLB) values on nanoemulsion stability for EHT encapsulation, targeting high Sun Protection Factor (SPF) values. The selected nanoemulsion was then subjected to fabrication with chitosan and pectin, followed by physical characterization and rheological behaviour study. Results indicated that all nanoemulsions exhibited particle sizes ranging from 137.7 nm to 206.0 nm and high entrapment efficiency from 88.76 % to 91.98 %. Sample N3, containing 1 % Tween 20 and 2 % polyethylene glycol (PEG) 400 with HLB of 12, demonstrated the highest stability, yielding a significantly elevated SPF value (10.33). Moreover, polymer-coated nanoemulsions with a low concentration of chitosan (0.1 %) showed enhanced stability when combined with different percentages of pectin. Polymer-coated nanoemulsions indicated shear-thinning behaviour at lower shear rates to Newtonian flow at higher shear rate. Furthermore, both polymer-coated and uncoated nanoemulsions exhibited decreased viscosity with increasing temperature. Also, polymer-coated nanoemulsions was found to enhance the sustainable release of EHT. These findings demonstrated the potential of polymer-coated nanoemulsions for skin application, offering enhanced stability and improved flow behaviour. The design of polymer-coated nanoemulsions could potentially minimize the risks of accumulation and toxicity of UV filters by providing a sustainable release behaviour.

Current Research Status, Opportunities, and Future Challenges of Nine Representative Persistent Herbicides.

Pesticides are extensively utilized in contemporary agriculture to manage pests, enhance crop yields, and sustain productivity. Nevertheless, the persistent herbicide represents a dual-edged weapon. On one hand, their prolonged efficacy enables reduced application frequency during crop growth seasons, resulting in cost savings on labor. However, the presence of these residues within fields poses safety risks to soil quality, sensitive crops in subsequent rotations, agricultural product quality, and the ecological environment. This review presents a comprehensive review on the mechanisms of action, application risks, ecotoxicology, and residue analysis methods of nine representative persistent herbicides (namely, atrazine, imazethapyr, imazapic, mesosulfuron-methyl, halosulfuron-methyl, fomesafen, diflufenican, quinclorac, and pyroxasulfone). The objective is to guide their scientific and rational utilization in agricultural practices while minimizing phytotoxicity risks and effectively monitoring and controlling soil pollution. These can not only provide practical recommendations for mitigating potential plant toxicity and ecological environmental risks but also contribute valuable technical insights for efficient soil pollution monitoring and prevention. Additionally, unaddressed research objectives were also anticipated.

Frequency of pharmacogenomic variants affecting safety and efficacy of immunomodulators and biologics in a South Asian population from Sri Lanka

BackgroundImmunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans.MethodsSri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database.ResultsSLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7–65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C9*3 (rs1057910) and NUD15*3 (rs116855232), with MAFs of 35.3% (32.7–37.9), 12.2% (10.4–13.9), 10.9% (9.2–12.6), 9.8% (8.2–11.4), 8.3% (6.8–9.8) respectively. Less commonly present variants included CYP2C9*2 (rs1799853) (2.5%[1.7–3.4]), TPMT*3C (rs1142345) (1.9%[1.1–2.6]), TPMT*3B (rs1800460) (0.2%[0–0.5]), CYP3A5*6 (rs10264272) (0.2%[0–0.4]) and CYP3A4*18 (rs28371759) (0.1%[0–0.2]). The SLC19A1 (rs1051266), NUD15*3 (rs116855232), CYP2C9*3 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT*3B (rs1800460), and CYP2C9*2 (rs1799853) were significantly less prevalent among Sri Lankans than in many other populations. Sri Lankans exhibited lower prevalence of TPMT*3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A4*18 (rs28371759) compared to East-Asians; and CYP3A5*6 (rs10264272) compared to African/African-Americans and Latino-Americans.ConclusionSri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT*3B, TPMT*3C), reduced tacrolimus efficacy (CYP3A4*18), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A5*6) are less common. This highlights need for targeted medication strategies to improve treatment outcomes.

A Hybrid Metaheuristic based Feature Selection Framework for In-silico Mutagenicity Prediction

Mutagenicity is both a toxic risk to humans and an indicator of carcinogenicity. Hence, estimating mutagenicity in the early stages of drug design is crucial to minimize last-stage failures and withdrawals in drug discovery. Recently, in-silico methods have started to play critical and essential roles in the drug development process because they are low cost and low effort procedures. This study aims to predict mutagenicity of chemicals using in-silico methods. To achieve this goal, a two-phased flexible framework was proposed: 1) searching the effective and representative descriptors subset with Butterfly Optimization Algorithm (BOA) and Particle Swarm Optimization and 2) predicting mutagenicity of chemicals by the selected descriptor using gradient boosted tree-based ensemble methods. The study used two datasets: one including 8167 compounds for descriptor selection and modelling, and another containing 716 external compounds to validate the efficacy of our models. The datasets comprise 162 descriptors calculated using PaDEL. The results of both the cross-validation and the external data showed that descriptors reduced by nearly one-third by BOA (51 descriptors) yielded similar or slightly better predictive results than results obtained with the entire data set. The accuracy range attained by the proposed approach using BOA is approximately 91.9% to 97.91% for the external set and 83.35% to 86.47% for the test set. This research contributes that using optimization techniques for improving early drug design and minimizing risks in drug discovery can be considered as a valuable insights and advances in the field of drug toxicity prediction, based on the findings.

Reactivity, Pathways, and Iodinated Disinfection Byproduct Formation during Chlorination of Iodotyrosines Derived from Edible Seaweed.

Iodine derived from edible seaweed significantly enhances the formation of iodinated disinfection byproducts (I-DBPs) during household cooking. Reactions of chlorine with monoiodotyrosine (MIT) and diiodotyrosine (DIT) derived from seaweed were investigated. Species-specific second-order rate constants (25 °C) for the reaction of hypochlorous acid with neutral and anionic MIT were calculated to be 23.87 ± 5.01 and 634.65 ± 75.70 M-1 s-1, respectively, while the corresponding rate constants for that with neutral and anionic DIT were determined to be 12.51 ± 19.67 and 199.12 ± 8.64 M-1 s-1, respectively. Increasing temperature facilitated the reaction of chlorine with MIT and DIT. Based on the identification of 59 transformation products/DBPs from iodotyrosines by HPLC/Q-Orbitrap HRMS, three dominant reaction pathways were proposed. Thermodynamic results of computational modeling using density functional theory revealed that halogen exchange reaction follows a stepwise addition-elimination pathway. Among these DBPs, 3,5-diiodo-4-hydroxy-benzaldehyde and 3,5-diiodo-4-hydroxy-benzacetonitrle exhibited high toxic risk. During chlorination of MIT and DIT, iodinated trihalomethanes and haloacetic acids became dominant species at common cooking temperature (80 °C). These results provide insight into the mechanisms of halogen exchange reaction and imply important implications for the toxic risk associated with the exposure of I-DBPs from household cooking with iodine-containing food.

CARDIOMIOPATIA INDUZIDA POR QUIMIOTERAPIA: UMA REVISÃO INTEGRATIVA SOBRE MECANISMOS, DIAGNÓSTICO E TRATAMENTO

Chemotherapy-induced cardiomyopathy is a significant complication associated with the use of chemotherapeutic agents, particularly anthracyclines such as doxorubicin. This condition adversely affects cardiac function and can limit cancer treatment due to the increased risk of cardiac side effects. Studies have shown that doxorubicin and other agents, such as paclitaxel, are effective in cancer treatment but also present a high risk of cardiac toxicity. Mechanisms of cardiotoxicity include oxidative stress, mitochondrial dysfunction, and cellular signaling alterations. Prevention and management of cardiotoxicity have evolved, with the use of cardiac protectors such as dexrazoxane and carvedilol, as well as ACE inhibitors like captopril and enalapril. Clinical guidelines recommend rigorous monitoring of cardiac function using echocardiography and magnetic resonance imaging for early detection of toxicity. This integrative review examines the mechanisms, diagnosis, and treatment options for chemotherapy-induced cardiomyopathy, highlighting the importance of preventive strategies and therapeutic interventions to improve the management of this condition.

Antioxidant and antidiabetic potentials of methoxy-substituted Schiff bases using in vitro, in vivo, and molecular simulation approaches

Abstract The current study attempted to synthesize methoxy-substituted Schiff’s bases, namely MK1 and MK2, and evaluate their antidiabetic effects using in vitro, in vivo, and molecular docking studies. Experimental animals (rat model) received the synthetic compounds, MK1 and MK2, orally in doses of 25 and 50 mg/kg body weight, respectively. When comparing compound MK2 at the tested doses to glibenclamide on day 28, the diabetic rats’ blood glucose levels were nearly normal (139.02 and 121.23 mg/dL at 25 and 50 mg/kg body weight doses). The IC50 for MK1 against α-glucosidase inhibitory potential was found to be 281.29 μg/mL, while for MK2, it is reported to be 204.69 μg/mL. Furthermore, the acute toxicity, lipid profile, and its effect on blood biochemical parameters were also examined. In addition, through in silico analysis, the binding of MK1 and MK2 was elucidated with α-glucosidase enzyme, showcasing its antidiabetic mechanism at molecular levels. The in silico studies also predicted the two compounds to be inactive toward the human hERGs cardiac potassium channel, which indicates no potential risk of cardiac toxicity. Overall, the toxicity predictions suggest that compounds MK1 and MK2 are non-toxic and non-carcinogenic.

Abstract C137: Exploring cardiotoxicity risk factors among patients diagnosed with breast cancer

Abstract Introduction Heart disease is the second most common cause of death for cancer survivors after their cancer diagnosis. Patients diagnosed with cancer, especially those with left-side breast cancer are at higher risk for treatment related toxicity. This burden is exacerbated for vulnerable patients that experience structural and chronic risk factors such as language barriers and disability which contribute to poorer survival. This study compared multi-level factors and their effect on age of diagnosis. Methods We explored a diverse population of N=1795 patient electronic medical records for patients diagnosed with left-side breast cancer and compared characteristics of patients by age, race, ethnicity, history of heart disease, disability status. Descriptive and Kruskal-Wallis ANOVA models were used to compare groups. Results The mostly female cohort of language diverse patients had an average of 66 years, most were White (64.5%), retired (52.1%), and on Medicare (43.2%). Approximately 17.8% were Latine and 13.3% needed an interpreter. Disability status was 9.7% and 8.8% had a history of heart disease. Patients diagnosed with breast cancer who were disabled were younger compared to those without a disability (60 yrs vs 67, p&amp;lt;.0001). When we compared language proficiency, we found this difference persisted as patients with a disability and were limited English were younger compared to patients that experienced neither (61yrs vs 67, p&amp;lt;.0001). Discussion This exploratory analysis is one of the first to explore the role of disability among minoritized and limited English proficient patients with breast cancer. More research is necessary to understand how to best plan and support diverse and disabled patients diagnosed with cancer to minimize their risk and improve outcomes. Citation Format: Melody K Schiaffino, Van "Vannie" K. Nguyen, Dominique Rash, Alicia Fernandez. Exploring cardiotoxicity risk factors among patients diagnosed with breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C137.

Exploring the temporal toxicity signature: A baseline evaluation of the heavy metal concentration in estuarine core sediments in the coastal region of cauvery delta, bay of bengal.

Globally, the concentration of heavy metals and sediment toxicity analysis are significant liabilities to aquatic environments. This scrutiny outlines the sediment textures, heavy metals and toxicity status associated with environmental pollution indices in the core sediment of the Cauvery and Vettar estuaries, East coast of India. The impact of rapid industrialization, urbanization, harbour activities and agricultural activities influences on the twain estuary is a significant concern to designate the environment. The contamination status of the sediments affects the potential biodiversity, ecological risks and human health. A total of two core sediments were recovered from the Cauvery and Vettar estuaries in March 2023 to decipher the environmental pollution status. Meticulous observation of the textural studies underscores the prevalence of sand content in Cauvery, and Vettar sediments consist of predominate clay content and minor silt contents. Furthermore, the organic matter is augmented in the Vettar River due to the higher input of waste disposal, seaweeds and algae due to the surrounding landmass. Twain core sediments argue that heavy metal concentration is decreasing in order as Fe > Zn > Ni > Pb > Cu > Cr by using portable X-ray fluorescence (pXRF) spectrometry. Remarkable results of environmental pollution indices such as Igeo, Ef, Cf, Cd and mCd state very highly polluted, extreme enrichments, high contamination and very high degree of contamination. Furthermore, the potential ecological risk indices such as PLI, SQGs, and PERI argue polluted, medium to high toxicity and moderate adverse ecological risk to the estuarine regions. Statistical analysis of the heavy metal affirms the enrichment of Fe metals may derive from lithogenic and/or anthropogenic influences, and the other studied metals such as Cu, Ni, Zn, Pb and Cr may be influenced by the anthropogenic activities in the aspect of point and non-point pollution sources. This could result from both estuaries undergoing higher pollution, in which the Vettar estuary is a considerable environmental risk zone compared to the Cauvery river due to the impact of industrial effluents and rapid urbanization activities. This finding underscores the urgent need for enhanced estuarine sediment quality study and comprehensive assessment of sediment toxicity, regulating the beneficial acumen for the government to follow the suitable remediation on the embellish policy of river and marine environments.

Insights into the occurrence, distribution and dissipation of widespread agrochemicals in celery agrosystems for joint risk assessment

Elucidating exposure risks associated with the most widely used agrochemicals and their metabolites in celery agrosystems are vital for food safety and human health. The occurrence, distribution, dissipation and metabolism of imidacloprid (IMI), acetamiprid (ACE), thiamethoxam (THM) and difenoconazole (DIF) in celery tissues reflected by initial depositions, uptake characteristics, half-lives, concentration variations. DIF exhibited unacceptable ecological risk to soil organisms under multi-risk evaluation models, including toxicity exposure ratio, risk quotient, and BITSSD model. The joint dietary risks of target pesticides were 37.273–647.454% and 0.400–2522.016% based on deterministic and probabilistic models, with non-carcinogenic risks of 30.207–85.522% and 1.229–2524.662%, respectively. Children aged 1–6 years suffered the highest exposure, with the leaves posing higher risk than other tissues. Long-term exposure risks should be continuously assessed for ecological sustainability and human health, given the widespread usage and cumulative effects of target pesticides, especially for rural children.

Effect of polypharmacy and potentially inappropriate medications on physical functional decline among older adults with advanced cancer receiving systemic treatment.

Polypharmacy and potentially inappropriate medications (PIM) are common among older adults with advanced cancer, but their association with physical functional outcomes is understudied. This study aimed to estimate the risk of physical functional decline associated with medication measures in older adults with advanced cancer starting a new line of systemic treatment. This secondary analysis of GAP 70+ Trial (PI: Mohile) enrolled patients aged 70+ with advanced cancer, had ≥ 1 geriatric assessment domain impairment and planned to start a new antineoplastic regimen with a high risk of toxicity. Polypharmacy (concurrent use of ≥ 8 medications (meds)) was assessed before initiation of treatment. PIM were categorized using Screening Tool of Older Person's Prescriptions (STOPP) criteria and 2019 Beers criteria. Physical functional outcomes were assessed within 3months of treatment initiation: (1) Activity of Daily Living (ADL) decline: 1-point decrease in ADL score between baseline and 3months; (2) Instrumental ADL (IADL) decline: 1-point decrease in IADL score between baseline and 3months; (3) Short physical performance battery (SPPB) decline, defined as 1-point decrease on SPPB; (4) ≥ 1 falls within 3months of treatment. Separate multivariable, cluster-weighted Generalized Estimating Equations models adjusted for relevant covariates (e.g., age, baseline function/comorbidities). Among 616 participants, mean number of meds was 6 (range 0-24); 28% received ≥ 8 meds. Polypharmacy was associated with increased risk of ADL decline (adjusted risk ratio [aRR], 1.31; 95% CI, 1.00-1.71). Taking ≥ 1 PIM per STOPP was associated with increased risk of IADL decline (aRR, 1.21; 95% CI, 1.04-1.40) and falls (aRR, 1.93; 95% CI, 1.49-2.51). In a large cohort of vulnerable older adults with advanced cancer receiving systemic treatment, polypharmacy and PIM were independently associated with an increased risk of physical functional decline. This emphasizes the need to develop interventions to optimize medication use, intending to improve outcomes in these patients. ClinicalTrials.gov Identifier: NCT02054741. Registered 01-31-2014.

Influence of Pesticide Application Method, Timing, and Rate on Contamination of Nectar with Systemic and Nonsystemic Pesticides.

Exposure to pesticides is one potential factor contributing to the recent loss of pollinators and pollinator diversity. Few studies have specifically focused on the relationship between pesticide management during ornamental plant production and contamination of nectar. We evaluated contamination of nectar in Salvia 'Indigo Spires' (Salvia longispicata M. Martens & Galeotti × S. farinacea Benth.) associated with applications of the systemic insecticide thiamethoxam, and the nonsystemic fungicides boscalid and pyraclostrobin. Applications were made at the labeled rates for the commercially available products, and we compared the influence of application method (drench vs. spray), timing (relative to flowering), and rate (low vs. high) for each pesticide. Nectar was sampled using 50-µL microcapillary tubes and analyzed by liquid chromatography-tandem mass spectrometry. The results indicate that concentrations from the spray application resulted in the least contamination of nectar with the systemic thiamethoxam, with lower concentrations occurring when thiamethoxam was applied before blooming at the lowest rate. Concentrations of thiamethoxam and its metabolite clothianidin were detected in nectar in all treatments (regardless of the method, timing, or rate of application), and ranged from 3.6 ± 0.5 ng/mL (spray-applied before blooming, low rate) to 1720.0 ± 80.9 ng/mL (drench-applied after blooming, high rate). Residues of clothianidin in nectar ranged from below quantification limits (spray-applied before blooming, low rate) to 81.2 ± 4.6 ng/mL (drench-applied after blooming, high rate). Drench applications resulted in the highest levels of nectar contamination with thiamethoxam, and exceeded published median lethal concentrations (LC50s/median lethal doses for native bees and/or honeybees in all cases). Spray treatments resulted in nectar concentrations exceeding published LC50s for some bee species. In comparison, all nonsystemic treatments resulted in concentrations much lower than the published no-observable-effect doses and sublethal toxicity values, indicating low risks of toxicity. Environ Toxicol Chem 2024;001:1-12. © 2024 SETAC.

Toxicity Risks Associated With the Beta-Blocker Metoprolol in Marine and Freshwater Organisms: A Review.

The detection of pharmaceuticals in aquatic ecosystems has generated concern for wildlife and human health over the past several decades. β-adrenergic blocking agents are a class of drugs designed to treat cardiovascular diseases and high blood pressure. Metoprolol is a second-generation β1-adrenergic receptor inhibitor detected in effluent derived from sewage treatment plants. Our review presents an updated survey of the current state of knowledge regarding the sources, occurrence, and toxicity of metoprolol in aquatic ecosystems. We further aimed to summarize the current literature on the presence of metoprolol in various classes of aquatic species and to consider the trophic transfer of these contaminants in marine mammals. The biological impacts of metoprolol have been reported in 20 aquatic organisms, with a primary focus on cardiac function and oxidative stress. Our review reveals that concentrations of metoprolol that cause toxicity in aquatic species are above levels that are typical of marine and freshwater environments. Future studies should investigate the effects of metoprolol at lower concentrations in aquatic organisms. Other recommendations include (1) a further focus on noncardiac endpoints, because computational assessments of currently available molecular data identify gonadotropins, vitellogenin, collagen, and cytokines as potential targets of modulation, and (2) development of adverse outcome pathways for cardiac dysfunction in aquatic species to improve our understanding of molecular interactions and outcomes following exposure. As the next generation of β-blockers is developed, continued diligence is needed for assessing environmental impacts in aquatic ecosystems to determine their potential accumulation and long-term effects on wildlife and humans. Environ Toxicol Chem 2024;00:1-14. © 2024 SETAC.

Multidimensional Approach for the Assessment of Environmental Pollution and Health Risk Associated With V, Ni, Cr, Cu, and Zn in the Recent Sediments of Kabini Interstate River, Southeastern Western Ghats, India

ABSTRACTThe present work intends to study the variation of heavy metals (HMs) to scrutinize the scenario of pollution index and associated environmental risk, as well as source weathering conditions along the Kabini River. The decreasing order of concentration of HMs along the basin is Cr &gt; V &gt; Ni &gt; Zn &gt; Cu. The paper spotlights the pollution grade in sediments, assessed by the geo‐accumulation index (Igeo), contamination factor (Cf), pollution load index (PLI), and enrichment factor (Ef). The assessment of ecological risk is studied as potential ecological risk index (RI), toxic risk index (TRI), and modified hazard quotients (mHQs). As per the Igeo and Cf, V and Cr concentrations are higher in the region. Further, PLI confirmed that 35% of samples exceeded the limits of sediment quality guidelines. The RI and TRI values show that a higher ecological risk is associated with Ni, V, and Cr and with Cu and Cr, respectively. Additionally, the 23% Ni and 20% Cu samples from mHQ indicate the severity of pollution in the aquatic environment. The inputs from anthropogenic and natural sources change the concentration of these HMs along the region. Moreover, the study of CIA and plagioclase index of alteration plots confirmed the low to intense weathering conditions. The statistical approach shows the linkage between Cr–V, Cu–Zn, and principal component analysis–derived prominent sources: industrial and agricultural runoff, as well as higher silicate weathering, contribute to the HMs concentration in the region. The Kabini River passes through different climatic and land‐use domains of Kerala and Karnataka, which eventually regulate the HM concentration and geo‐environmental processes in the region and affect the health risk to humans in one or the other way. The reference data generated from the present work are absolutely new and would be significant in the future for deriving sustainable development plans for the well‐being of human beings and precious natural resources.

Recoverability of zebrafish from decabromodiphenyl ether exposure: The persisted interference with extracellular matrix production and collagen synthesis and the enhancement of arrhythmias

As a widely used brominated flame retardant, the widespread presence of decabromodiphenyl ether (BDE-209) in the natural environment and the toxicity risks it poses are well established, but the recoverability of BDE-209-induced individual injuries remains unknown. Therefore, a 7-day depuration experiment following a 4-day exposure of zebrafish to BDE-209 was conducted to confirm the recoverability and its mode of action. Oxidative stress after depuration was significantly reduced compared with BDE-209 exposure as indicated by the decreased expression level of oxidative stress-related genes and the reduced MDA, Gpx, and GST in zebrafish, indicating a gradual recovery of antioxidant activity. However, BDE-209 inhibition of extracellular matrix (ECM) proteins worsened after depuration. Mechanistically, BDE-209 mediated ECM production and secretion by down-regulating integrin expression. Furthermore, BDE-209 inhibition of collagen synthesis worsened after depuration. Biochemical assays and histopathological observations revealed a same result in zebrafish. Mechanistically, lysine hydroxylation is inhibited thereby affecting collagen synthesis. Interestingly, zebrafish showed arrhythmia after depuration compared to BDE-209 exposure, and abnormal changes in ATPase levels indicated that disturbances in Ca2+ homeostasis contributed to arrhythmia. Collectively, BDE-209-induced interference with ECM production and collagen synthesis persisted after depuration, which will provide new insights for understanding the recovery patterns of individuals under BDE-209 stress.