Exposure Threshold Research Articles

Initial assessment of multi-compound antineoplastic drug surface contamination in Argentinean healthcare centers: Insights into occupational exposures in South America.

Antineoplastic drug contamination can result in severe health effects for healthcare workers exposed to them. Despite the worldwide growing concern regarding these drugs and sustained monitoring efforts in developed countries, there is almost no data about surface contamination levels in Argentina, in particular, and South America, in general. Antineoplastic drug contamination was measured in three Argentinean public hospitals (pharmacy and daycare center areas) by surface wiping and liquid chromatography coupled with tandem mass spectrometry. Eleven drugs were detected, in 51 of 58 sampled surfaces, in variable concentrations from 0.00064 to 7.3 ng cm-2, with cyclophosphamide, gemcitabine, and paclitaxel as the most prevalent drugs. This highly variable antineoplastic distribution reflects differences in facility layout, number of patients, antineoplastic drug use, etc., at each hospital. Values exceeding the 1 ng cm-2 threshold were detected in 13 surfaces of the two hospitals handling the largest amounts of antineoplastic drugs. The cyclophosphamide 75th percentile averaged 0.030 ng cm-2 comparable to the high values reported more than 10 years ago for developed countries, emphasizing the potential of reducing antineoplastic contamination by implementing routine monitoring and improved cleaning and handling procedures. This study is the first survey of multi-compound surface antineoplastic contamination in Argentinean (and South American) hospitals, providing a baseline against which future studies can be compared. Widespread antineoplastic contamination has been detected on numerous surfaces, with concentrations surpassing suggested threshold exposure levels (1 ng cm-1) for some surfaces in two of the sampled hospitals.

A Hybrid Method for Enhancement of Both Contrast Distorted and Low-Light Images

Many different histogram equalization (HE)-based image enhancement methods have been developed to overcome the problems of low or high image brightness, contrast sensitivity, and difficulty in revealing details of dark areas under low-light environments. In this paper, a novel image enhancement method based on HE and adaptive gamma correction with weight distribution (AGCWD) is proposed for natural and effective image enhancement. In this method, histogram stretching is performed on Red–Green–Blue (RGB) color components of image, and then the color space of RGB image is converted to Hue–Saturation–Intensity (HSI) color space. The histograms of S and I components are divided into sub-histograms according to the exposure threshold. The underexposure regions are enhanced with a new AGCWD. Then, the color space of HSI image is converted to RGB color space. Finally, the HE is applied to the input image with the obtained image histogram map. Thus, the method has not only effectively prevented the over-enhancement of the contrast but also obtained the quality and natural enhanced image. The proposed method is compared with the most known contrast enhancement methods and low-light enhancement methods. Experimental results have supported that the proposed method outperforms other methods in terms of both visual perception and objective evaluation.

Threshold Effect in the Bank Lending Channel of Monetary Policy Transmission and the Role of Bank Portfolio Deterioration: A PSTR Specification in the WAEMU Zone

The objective of this paper is to analyse the influence of monetary policy on credit supply in the WAEMU zone over the period 1996-2017. The study focuses on the WAEMU countries, except for Guinea-Bissau, due to the unavailability of sufficient data. We apply the Panel Smooth Transition Regression (PSTR) model of Gonzalez et al. (2005). The results reveal the non-linearity of the link between monetary policy and credit supply. There is a threshold of credit risk exposure of 8.726% above which monetary policy loses its effectiveness. Indeed, monetary policy has a positive effect on the supply of credit when the value of the gross bank portfolio deterioration rate is less than or equal to the threshold of 8.726% and an insignificant effect above this threshold. Above this threshold, the link between monetary policy and bank credit supply is distended. In this case, it is the level of economic activity that stimulates the supply of bank credit in this area. These results indicate that the effectiveness of the monetary policy conducted by the Central Bank of West African States (BCEAO), through the bank credit channel, should take into account the level of credit risk attained by banks. Thus, the study recommends that the authorities further strengthen prudential supervision within the WAEMU.

Establishment and Evaluation of a Parametric Population Pharmacokinetic Model Repository for Ganciclovir and Valganciclovir.

Ganciclovir and valganciclovir are used for prophylaxis and treatment of cytomegalovirus infection. However, there is great interindividual variability in ganciclovir's pharmacokinetics (PK), highlighting the importance of individualized dosing. To facilitate model-informed precision dosing (MIPD), this study aimed to establish a parametric model repository of ganciclovir and valganciclovir by summarizing existing population pharmacokinetic information and analyzing the sources of variability. (2) Methods: A total of four databases were searched for published population PK models. We replicated these models, evaluated the impact of covariates on clearance, calculated the probability of target attainment for each model based on a predetermined dosing regimen, and developed an area under the concentration-time curve (AUC) calculator using maximum a posteriori Bayesian estimation. (3) Results: A total of 16 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area) and renal function. The results show that 5 mg/kg/12 h of ganciclovir could make the AUC0-24h within 40-80 mg·h/L for 50.03% pediatrics but cause AUC0-24h exceeding the exposure thresholds for toxicity (120 mg·h/L) in 51.24% adults. (4) Conclusions: Dosing regimens of ganciclovir and valganciclovir should be adjusted according to body size and renal function. This model repository has a broad range of potential applications in MIPD.

Holographic Fabrication of 3D Moiré Photonic Crystals Using Circularly Polarized Laser Beams and a Spatial Light Modulator.

A moiré photonic crystal is an optical analog of twisted graphene. A 3D moiré photonic crystal is a new nano-/microstructure that is distinguished from bilayer twisted photonic crystals. Holographic fabrication of a 3D moiré photonic crystal is very difficult due to the coexistence of the bright and dark regions, where the exposure threshold is suitable for one region but not for the other. In this paper, we study the holographic fabrication of 3D moiré photonic crystals using an integrated system of a single reflective optical element (ROE) and a spatial light modulator (SLM) where nine beams (four inner beams + four outer beams + central beam) are overlapped. By modifying the phase and amplitude of the interfering beams, the interference patterns of 3D moiré photonic crystals are systemically simulated and compared with the holographic structures to gain a comprehensive understanding of SLM-based holographic fabrication. We report the holographic fabrication of phase and beam intensity ratio-dependent 3D moiré photonic crystals and their structural characterization. Superlattices modulated in the z-direction of 3D moiré photonic crystals have been discovered. This comprehensive study provides guidance for future pixel-by-pixel phase engineering in SLM for complex holographic structures.

Multi-scale risk assessment and mitigations comparison for COVID-19 in urban public transport: A combined field measurement and modeling approach

The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused an unparalleled disruption to daily life. Given that COVID-19 primarily spreads in densely populated indoor areas, urban public transport (UPT) systems pose significant risks. This study presents an analysis of the air change rate in buses, subways, and high speed trains based on measured CO2 concentrations and passenger behaviors. The resulting values were used as inputs for an infection risk assessment model, which was used to quantitatively evaluate the effects of various factors, including ventilation rates, respiratory activities, and viral variants, on the infection risk. The findings demonstrate that ventilation has a negligible impact on reducing average risks (less than 10.0%) for short-range scales, but can result in a reduction of average risks by 32.1%–57.4% for room scales. When all passengers wear masks, the average risk reduction ranges from 4.5-folds to 7.5-folds. Based on our analysis, the average total reproduction numbers (R) of subways are 1.4-folds higher than buses, and 2-folds higher than high speed trains. Additionally, it is important to note that the Omicron variant may result in a much higher R value, estimated to be approximately 4.9-folds higher than the Delta variant. To reduce disease transmission, it is important to keep the R value below 1. Thus, two indices have been proposed: time-scale based exposure thresholds and spatial-scale based upper limit warnings. Mask wearing provides the greatest protection against infection in the face of long exposure duration to the omicron epidemic.

The role of salience in the suppression of distracting stimuli.

Researchers have long debated whether salient distractors have the power to automatically capture attention. Recent research has suggested a potential resolution, called the signal suppression hypothesis, whereby salient distractors produce a bottom-up salience signal, but can be suppressed to prevent visual distraction. This account, however, has been criticized on the grounds that previous studies may have used distractors that were only weakly salient. This claim has been difficult to empirically test because there are currently no well-established measures of salience. The current study addresses this by introducing a psychophysical technique to measure salience. First, we generated displays that aimed to manipulate the salience of two color singletons via color contrast. We then verified that this manipulation was successful using a psychophysical technique to determine the minimum exposure duration required to detect each color singleton. The key finding was that high-contrast singletons were detected at briefer exposure thresholds than low-contrast singletons, suggesting that high-contrast singletons were more salient. Next, we evaluated the participants' ability to ignore these singletons in a task in which they were task irrelevant. The results showed that, if anything, high-salience singletons were more strongly suppressed than low-salience singletons. These results generally support the signal suppression hypothesis and refute claims that highly salient singletons cannot be ignored.

Multigenerational impacts of EE2 on reproductive fitness and immune competence of marine medaka

Estrogenic endocrine disrupting chemicals (EEDC) have been suspected to impact offspring in a transgenerational manner via modifications of the germline epigenome in the directly exposed generations. A holistic assessment of the concentration/ exposure duration-response, threshold level, and critical exposure windows (parental gametogenesis and embryogenesis) for the transgenerational evaluation of reproduction and immune compromise concomitantly will inform the overall EEDC exposure risk. We conducted a multigenerational study using the environmental estrogen, 17α-ethinylestradiol (EE2), and the marine laboratory model fish Oryzias melastigma (adult, F0) and their offspring (F1-F4) to identify transgenerationally altered offspring generations and phenotype persistence. Three exposure scenarios were used: short parental exposure, long parental exposure, and a combined parental and embryonic exposure using two concentrations of EE2 (33ng/L, 113ng/L). The reproductive fitness of fish was evaluated by assessing fecundity, fertilization rate, hatching success, and sex ratio. Immune competence was assessed in adults via a host-resistance assay. EE2 exposure during both parental gametogenesis and embryogenesis was found to induce concentration/ exposure duration-dependent transgenerational reproductive effects in the unexposed F4 offspring. Furthermore, embryonic exposure to 113 ng/L EE2 induced feminization of the directly exposed F1 generation, followed by subsequent masculinization of the F2 and F3 generations. A sex difference was found in the transgenerationally impaired reproductive output with F4 females being sensitive to the lowest concentration of EE2 (33 ng/L) upon long-term ancestral parent exposure (21 days). Conversely, F4 males were affected by ancestral embryonic EE2 exposure. No definitive transgenerational impacts on immune competence were identified in male or female offspring. In combination, these results indicate that EEDCs can be transgenerational toxicants that may negatively impact the reproductive success and population sustainability of fish populations.

Spatial assessment of the attributable burden of disease due to transportation noise in England

BackgroundNoise pollution from transportation is one of the leading contributors to the environmental disease burden in Europe. We provide a novel assessment of spatial variations of these health impacts within a country, using England as an example. MethodsWe estimated the burden of annoyance (highly annoyed), sleep disturbance (highly sleep disturbed), ischemic heart disease (IHD), stroke, and diabetes attributable to long-term transportation noise exposures in England for the adult population in 2018 down to local authority level (average adult population: 136,000). To derive estimates, we combined literature-informed exposure-response relationships, with population data on noise exposures, disease, and mortalities. Long-term average noise exposures from road, rail and aircraft were sourced from strategic noise mapping, with a lower exposure threshold of 50 dB (decibels) Lden and Lnight. Results40 %, 4.5 % and 4.8 % of adults in England were exposed to road, rail, and aircraft noise exceeding 50 dB Lden. We estimated close to a hundred thousand (∼97,000) disability adjusted life years (DALY) lost due to road-traffic, ∼13,000 from railway, and ∼ 17,000 from aircraft noise. This excludes some noise-outcome pairs as there were too few studies available to provide robust exposure–response estimates. Annoyance and sleep disturbance accounted for the majority of the DALYs, followed by strokes, IHD, and diabetes. London, the South East, and North West regions had the greatest number of road-traffic DALYs lost, while 63 % of all aircraft noise DALYs were found in London. The strategic noise mapping did not include all roads, which may still have significant traffic flows. In sensitivity analyses using modelled noise from all roads in London, the DALYs were 1.1x to 2.2x higher. ConclusionTransportation noise exposures contribute to a significant and unequal environmental disease burden in England. Omitting minor roads from the noise exposure modelling leads to underestimation of the disease burden.

Phytotoxic Effects of Kerosene on Plants of Forest and Bog Phytocenoses of Southern Taiga

One of the most important problems of environmental sciences is to determine limits for the sustainable functioning of affected ecosystems. The effects of volatile hydrocarbons (such as gasoline and kerosene) on plants in natural ecosystems have been poorly studied to date. The present work outlines the data of a field experiment on the effects of kerosene on the plants of forest and bog communities in Central Russia. In this paper, we model the influence of kerosene spillage on plants growing in a coniferous broad-leaved (aspen–spruce) forest and a raised bog with a subshrub–sphagnum pine forest. We used TS-1 kerosene, which is the most commonly used fuel for commercial aviation in Russia. The applied pollutant (loads of 1 to 100 g/kg) had a significant impact on herbaceous plants, leading to the death of individuals even at minimal doses. The shrubs of the bog community as well as the mosses of both communities were more resistant to kerosene. The recovery processes of plant communities were clearly pronounced as early as 2 years after the application of the pollutant. The level of kerosene threshold exposure, which significantly affects the dominant plants of the herb–shrub layer, can be defined as 1–5 g/kg for the forest community and 5–10 g/kg for the bog community.

The problem of validation of toxicological models in pharmacy

Animal toxicity testing is widely used in the chemical, pharmaceutical and research industries as a part of preclinical laboratory testing of substances to ensure that chemicals are safe for humans and animals. Under preclinical conditions, the safe and effective dose, acceptable dose, and exposure threshold of a substance can be established using mammals and rodents. There are enough materials on the introduction of biomodels in experiments. To summarize this knowledge, a polythematic abstract-bibliographic base was analyzed. The main attention was paid to such scientometric databases as: Web of Science Core Collection, Medline, PubMed, RSCI, as well as eLIBRARY.ru portal data for the last 10 years. An assessment of the statistical data and publication activity of the authors was made for the query modeling and ethics in veterinary medicine and medicine.The aim of the study was to analyze modern models and prospects for using new biomodels for experiments in pharmacology and toxicology.Having established protocols is important to ensure consistency between different studies within the same model, ensuring reproducibility and repeatability in experiments.Based on the analysis of literature sources over the past 10 years, it can be concluded that despite the large number of regulatory framework and transgenic laboratory animals with embedded human target genes in their genome, it is not possible to obtain an identity. Probably, the main bias in predictive toxicology will be made on neural networks and computer replacement of existing biomodels. Since, despite their relative accuracy, maintenance and feeding are costly, and the field of using animals in experiments is increasingly criticized and requires new approaches.

Rapid measurement tools or fast identification of bioaerosols

Rapid measurement tools or fast identification of bioaerosols Bioaerosols are complex mixtures of airborne particles of biological origin, many are of inhalable size, but those less than 10 μm are respirable and can penetrate deep into the respiratory system, making them a health concern, argue Professors Frederic Coulon and Corinne Whitby. While causing infectious diseases, such as tuberculosis and COVID-19, bioaerosols are also associated with non-infectious diseases, such as hypersensitivity, allergies, chronic obstructive pulmonary disease (COPD) and asthma, that cause significant mortality and morbidity. There are two major challenges to the fast identification of bioaerosols: 1) bioaerosol sampling and characterisation, 2) lack of evidenced exposure thresholds to inform regulators and health officials. In this article, the researchers look at the opportunities, sampling and characterisation of these bioaerosols.

Heavy metal(loid)s contamination in water and sediments in a mining area in Ecuador: a comprehensive assessment for drinking water quality and human health risk.

Elevated heavy metal(loid)s concentrations in water lower its quality posing a threat to consumers. This study aims to assess the human health risk caused by heavy metal(loid)s in tap water in Santa Rosa city, Ecuador, and the ecological risk of stream water and sediments in the Santa Rosa River. Concentrations of As, Cd, Cr, Cu, Ni, Pb, and Zn were evaluated in tap waters, stream waters, and sediment samples during the rainy and dry seasons. The Metal Index (MI), Geo-accumulation Index (Igeo), Potential Ecological Risk Index (PERI), and the levels of carcinogenic (CR) and non-carcinogenic risk (HQ) were determined. The results revealed severe pollution levels, mainly in Los Gringos and El Panteon streams, both tributaries of the Santa Rosa River, the primary water source for Santa Rosa inhabitants. More than 20% of the surface water samples showed severe contamination (MI > 6), and 90% of the tap water samples presented a MI value between 1 and 4, which indicates slight to moderate pollution. Drinking water displayed high levels of As, with 83% of the tap water samples collected from households in the dry season above the recommended concentration set by the World Health Organization and Ecuadorian legislation. The Igeo-Cd in the sediment samples was significantly high (Igeo > 3), and the PERI showed very high ecological risk (PERI > 600), with Cd as the main pollutant. HQ and CR were above the safe exposure threshold, suggesting that residents are at risk from tap water consumption, with As being the primary concern.

Influence of Asymmetric Agglomerations Effects over the Photothermal Release of Liposome-Encapsulated Nanodiamonds Assisted by Opto-Mechanical Changes

An analysis of optical effects exhibited by blood plasma under healthy/unhealthy conditions, and of the penetrating evolution of nanovehicles conformed by nanodiamonds (NDs) encapsulating liposomes (L) within these biofluids, is presented. Optical ablation of liposome clusters was actuated and controlled by a standard two-wave mixing (λ = 532 nm, τp = 4 ns) laser light method. Radiant time exposure effects (30 min) and threshold laser energy parameters (250 mJ/cm2 numerical; 181 mJ/cm2 experimental) necessary to release NDs were identified and confirmed with similar experiments in the literature. Interactions during the sedimentation process between nanovehicles and the laser beams barrier were considered as the principal thermal damage process to achieve the release and transportation of drugs within these static fluids. The mechanical response during the release of NDs focuses on the temperature propagation, dynamic effects of nanovehicles associated with the diffusion coefficient, and some agglomeration effects. The principal findings of this research concern the threshold temperature (51.85 °C) of liposomes for the release of NDs with respect to that typically quoted in the literature (40–70 °C) for pure liposomes. The assessment of the release of NDs focuses on the numerical magnitude of Quantum Yield. Furthermore, the optical contrast enhancement was associated with NDs size agglomerations and the healthy/unhealthy conditions of fluids. This research aims to be a first proof approximation for delivery and transportation approaches to guide and interpret outcomes when combined with the vectorial nature basis of laser light and further effects once the cargo is retained in the fluids.

Increased levels of IL-17 and autoantibodies following Bisphenol A exposure were associated with activation of PI3K/AKT/mTOR pathway and abnormal autophagy in MRL/lpr mice

Bisphenol A (BPA) is a common environmental endocrine disruptor which mimic the effect of estrogen. The immunotoxicity of BPA has attracted widespread attention in recent years. However, the effects and mechanism of BPA on autoimmune disease were rarely reported. Systemic lupus erythematosus (SLE) is a typical autoimmune disease, and its etiology and mechanism are complex and unclear. Currently, inflammation and the production of autoantibodies are considered to be important pathological mechanisms of SLE, and estrogen contributes to the occurrence and development of SLE. Therefore, in order to explore whether BPA exposure can affect the development of SLE and its possible mechanism, we used MRL/lpr (lupus-prone mice) and C57/BL6 female mice exposed to 0.1 and 0.2 µg/mL BPA for 6 weeks. We discovered that BPA exposure increased the concentration of serum anti-dsDNA antibody and IL-17, and the level of RORγt protein (the transcription factor of Th17 cells). Moreover, there were higher expression of p-PI3K, p-AKT, p-mTOR, ULK, Rubicon, P62, Becline1 and LC3 protein in spleen tissue of BPA exposed MRL/lpr mice compared with the control. However, there were no significant changes in the expression of IL-17, RORγt or mTOR in C57 mice exposed to BPA at the same dose. Our study implied that BPA exposure induced the development of SLE, which might be related to the up-regulation of PI3K/AKT/mTOR signaling pathway and abnormal autophagy. Our study indicated that lupus mice were more susceptible to BPA, and provided a new insight into the mechanism by which BPA exacerbated SLE. Therefore, our study suggested that autoimmune patients and susceptible population should be considered when setting thresholds for environmental BPA exposure.

Trace elements in farmland soils and crops, and probabilistic health risk assessment in areas influenced by mining activity in Ecuador

Consumption of food grown in contaminated soils may be a significant human exposure pathway to pollutants, including toxic elements. This study aimed to investigate the pollution level of trace elements in farmland soil and crops collected in orchards from Ponce Enriquez, one of the Ecuador’s most important gold mining areas. The concentration of arsenic (As), cadmium (Cd), chrome (Cr), copper (Cu), nickel (Ni), lead (Pb), and zinc (Zn) was analyzed in soil and crop samples (celery, chives, corn, herbs, lettuce, turnips, green beans, cassava, and carrots). In addition, a probabilistic human health risk assessment, in terms of hazard quotients (HQ) and cancer risk (CR), was conducted to assess the potential risk related to local crop ingestion. The contents of As, Cr, Cu, and Ni in soils exceeded the Ecuadorian quality guidelines for agricultural soils. The trace elements concentration in local crops was higher than the maximum permissible levels set by the Food and Agriculture Organization of the United Nations (FAO). The HQ and CR of local crop ingestion were several orders higher than the safe exposure threshold, mainly for lettuce, chives, and turnips. Our results revealed that inhabitants of the study area are exposed to developing carcinogenic and non-carcinogenic effects due to long-term food consumption with high trace elements. This study sheds light on the need to assess further the quality of agricultural soils and crops grown in mining areas with signs of contamination to guarantee consumer food safety.

Building a City with Low Noise Pollution: Exploring the Mental Health Effect Thresholds of Spatiotemporal Environmental Noise Exposure and Urban Planning Solution.

Urban noise pollution and health hazards have become serious social problems and challenges. Noise prevention and control is the most cost-effective health strategy. However, in urban planning and noise control, reliable evidence is still lacking on individual spatiotemporal environmental noise exposure and its mental health effects. This study used real-time noise exposure data and GPS trackers from 142 volunteers aged 18 to 60 years in Guangzhou, and further analyzed the differences in environmental noise exposure and its mental health impact thresholds under individual spatiotemporal behavior. The results showed that the noise exposure of residents under daily activities has obvious differences in time, space and place. Regarding the threshold relationship between noise exposure and mental health, noise exposure at night, work, personal affairs, travel and sleep activities, as well as at home and work had a threshold effect on residents' mental health. Noise thresholds were 60 dB, 60 dB, and about 34 dB at night, during work or at a workplace, and while sleeping, respectively. The optimal sound environment for personal affairs, traveling, and at home was around 50 dB, 55-70 dB, and 45 dB, respectively. The environmental noise exposure assessment and mental health impact threshold analysis based on the spatial and temporal activities of individuals will provide important reference for government management departments in planning and policy formulation.

The Degradation Product of Ramipril Is Potentially Carcinogenic, Genotoxic and Mutagenic

(1) Background: The aim of this study was to identify the degradation product of ramipril (RAM) formed under dry air and to verify its potential modes of carcinogenicity. We intended to check whether its formation and presence in final dosage forms could pose a cancer risk to humans who are treated with RAM due to cardiological indications. The carcinogenicity of this compound was evaluated with respect to two mechanisms: a potential direct DNA-damage and indirect toxicity, secondary to forming mutagenic N-nitroso metabolites. (2) Methods: Firstly, a forced ageing test under dry air was conducted for pure RAM in order to induce its degradation. The validated HPLC system was used to describe the kinetic order of this reaction. The emerging degradation impurity was identified by HPLC-MS. In the second stage, the cancer risk of the identified RAM degradant was predicted using a structure-based assessment by in silico QSAR model, employing three endpoints: carcinogenicity, genotoxicity and mutagenicity. In the third stage, the obtained QSAR results were experimentally verified. To verify genotoxicity prediction, in vitro micronucleus assay was employed. It enabled us to assess the potential direct DNA-damaging properties of RAM degradant at high concentrations (as screening series) and at concentrations usually observed in human blood (to mimic the clinical scenario). To verify the QSAR mutagenicity prediction, an in vitro Ames test was carried out. It was designed so as to detect two mechanisms of mutagenicity: a direct one (for pure degradant) and an indirect one (via N-nitroso-metabolites formation). N-nitroso-metabolites for mutagenicity assessment were obtained using NAP test. (3) Results: The kinetic mechanism of RAM degradation was first-order, the degradation rate constant was k = 1.396 ± 0.133 × 10−5 s−1 (T = 373 K), thus the formation of impurity was rapid. Energy of activation was 174.12 ± 46.2 kJ/mol, entropy was positive, thus reaction was bimolecular and favored; enthalpy was 171.65 ± 48.7 kJ/mol, thus reaction was endothermic. Only one degradation impurity was formed, and it was identified as RAM diketopiperazine derivative (DKP). QSAR simulation predicted that DKP could be carcinogenic and genotoxic, but this result had only moderate reliability. DKP was also predicted to be non-mutagenic and this prediction was strong (endpoint score 0.2). The confirmatory micronucleus experiment for genotoxicity prediction suggested that DKP was cytotoxic and it could be also aneugenic at a high concentration (0.22 mg/mL), evidenced by a three-fold increase in micronuclei relative to the control (11.86:33.33%, p = 0.0184). At physiologic concentrations, its cytotoxicity and genotoxicity did not occur. This means that the genotoxicity of DKP was limited by a threshold mechanism. In the mutagenicity in vitro assessment, pure DKP was not mutagenic, but its nitrosation product induced base substitutions mutations in test bacteria TA100 following metabolic activation at a concentration of 4.5 mg/mL, confirming its mutagenicity. (4) Conclusions: RAM rapidly cyclizes to diketopiperazine derivative under dry air. This impurity resides in drugs administered to patients. DKP is potentially aneugenic and cytotoxic at high concentrations, yet at concentrations typically occurring in human blood, this effect is unlikely. The exposure of patients to high concentrations of DKP, exceeding the typical blood level and standard RAM dosing, could lead to cancer development, thus the safe threshold for human exposure to DKP must be verified in follow-up in vivo experiments. Based on our results, it is impossible to establish the maximum safe dose of pure DKP to humans. Furthermore, DKP itself is not mutagenic, but it is liable to the formation of mutagenic nitroso-metabolites in vivo. Nitroso-derivatives of DKP are in vitro mutagens and their real-life impact on humans must be further evaluated in in vivo studies. Until this is carried out, RAM should not be formulated by manufacturers using dry procedures to minimize DKP formation and reduce risk of human carcinogenesis, since DKP could cause cancer via two independent mechanisms: direct genotoxicity when the exposure over standard RAM dosing occurs, and indirect mutagenicity via in vivo N-nitrosamine formation.

Inhalation bioaccessibility of inhaled triazole fungicides and health risk assessment during spraying.

Ambient air pollution caused by pesticide drift has received great attention. To accurately evaluate the health risk of inhaled pesticides, bioaccessibility should be considered. However, methods to reliably assess pesticide residues remain limited, hindering the precise estimation of exposure assessment. We aimed to optimize an in vitro method for the inhalation bioaccessibility (IBA) measurement of triazole fungicides and to incorporate this into inhalation exposure assessment during pesticide spraying. The IBA of triazole fungicides increased logarithmically with extraction duration, plateauing after 6h. The frequency of agitation displayed a similar pattern, whereas the ratio of solid to liquid between 1/1500 and 1/250 was considerably negatively associated. The predicted values (35.9-53.5%) for IBA based on optimized methodological parameters determined using a response surface methodology showed an acceptable deviation from experimental values (30.7-50.8%), suggesting feasibility for in vitro IBA measurement. Incorporating IBA into calculations of inhalation exposure amount (IE) yielded a value of 8.5 × 10-7 -2.1 × 10-5 mg kg-1 day-1 , a 50-68% reduction compared to IE based on total amount. Additionally, the safety exposure threshold was determined for triazole fungicides using benchmark dose modelling of data from lung A549 cell proliferation toxicity assays, and in this context, margin of exposure (MOE) values were calculated to be within an acceptable level. This in vitro method supplements bioaccessibility evaluation based on pesticide inhalation exposure, along with the risk to human health. © 2023 Society of Chemical Industry.

The impact of occupational exposure to crystalline silica dust on respiratory function (airway obstruction and FEF25-75) in the French general population

IntroductionAlthough several studies have studied the relationship between occupational exposure to crystalline silica dust and respiratory mortality, few have examined the relationship with impairments in respiratory function and the exposure threshold triggering spirometric monitoring in exposed workers. The objective of the present study was to evaluate the impact of exposure to crystalline silica dust on respiratory function. MethodsWe included 1428 male participants (aged 40 to 65) recruited from the French general population, at random from electoral rolls, in the cross-sectional ELISABET study and for whom data on forced expiratory flow-volume curve indices z-scores (calculated using the Global Lung Function Initiative 2012 equations) and exposure (via a questionnaire) were available. A cumulative exposure index (CEI) for crystalline silica dust (CEIsilica, expressed in mg.m−3.year) was calculated using the Matgéné occupational exposure matrix. Results293 of the 1428 participants (20.52%) reported exposure to silica dust. We found that the adjusted z-scores for the forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) ratio decreased significantly as CEIsilica increased. After adjustment, the adjusted z-scores for FEV1/FVC (β: −0.426 (95% confidence interval (CI): −0.792, −0.060) per 1 mg m−3.year increment) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75) (β: −0.552 (95% CI: −0.947, −0.157)) were significantly lower in the participants with CEIsilica ≥1 mg m−3.year than in non-exposed participants. The likelihoods of having airway obstruction (odds ratio (OR): 3.056 (95% CI: 1.107, 7.626)) or having an impaired FEF25-75 (OR: 4.305 (95% CI: 1.393, 11.79)) were also significantly higher in participants with CEIsilica ≥1 mg m−3.year. ConclusionOur results emphasize the importance of spirometry-based monitoring in workers exposed to more than 1 mg m−3.year of crystalline silica dust, in order to identify small airway obstruction or airway obstruction as early as possible.