Assessment of maximal inspiratory and expiratory pressures in skeletal Class II patients with different growth patterns.

OBJECTIVES: To evaluate maximal inspiratory (MIP) and expiratory (MEP) pressures, which are reflective of respiratory muscle strength, in skeletal Class II patients with different growth patterns (horizontal, average, and vertical) and to correlate those with airway dimension. MATERIALS AND METHODS: Patients with a Class II skeletal base seeking orthodontic treatment were assigned to the following groups: average, horizontal, and vertical growth pattern. The control group (n = 14) comprised patients with a Class I skeletal base and average growth pattern. Airway dimensions were obtained using cone-beam computed tomography scans, and a spirometer with a pressure transducer was used for assessment of MIP and MEP. Routine spirometry for assessment of lung function was also performed. RESULTS: No significant differences were found in maximal inspiratory and expiratory pressures for the study groups in comparison with the control group. Class I patients had significantly greater oropharyngeal and nasopharyngeal airway volumes compared with the study groups. No significant difference in minimal cross-section area of the airway was observed among groups. A weak positive correlation between maximal inspiratory pressure and airway volume was observed. CONCLUSIONS: Although Class I patients displayed significantly greater oropharyngeal and nasopharyngeal airway volumes, there was no significant difference in respiratory muscle strength or airway function between Class II patients with different growth patterns and the Class I control group. The findings underscore the significance of exploring factors beyond craniofacial growth patterns that may contribute to sleep-related breathing disorders.

Exposure limits for indoor volatile substances concerning the general population: The role of population-based differences in sensory irritation of the eyes and airways for assessment factors.

Assessment factors (AFs) are essential in the derivation of occupational exposure limits (OELs) and indoor air quality guidelines. The factors shall accommodate differences in sensitivity between subgroups, i.e., workers, healthy and sick people, and occupational exposure versus life-long exposure for the general population. Derivation of AFs itself is based on empirical knowledge from human and animal exposure studies with immanent uncertainty in the empirical evidence due to knowledge gaps and experimental reliability. Sensory irritation in the eyes and airways constitute about 30-40% of OELs and is an abundant symptom in non-industrial buildings characterizing the indoor air quality and general health. Intraspecies differences between subgroups of the general population should be quantified for the proposal of more 'empirical' based AFs. In this review, we focus on sensitivity differences in sensory irritation about gender, age, health status, and vulnerability in people, based solely on human exposure studies. Females are more sensitive to sensory irritation than males for few volatile substances. Older people appear less sensitive than younger ones. However, impaired defense mechanisms may increase vulnerability in the long term. Empirical evidence of sensory irritation in children is rare and limited to children down to the age of six years. Studies of the nervous system in children compared to adults suggest a higher sensitivity in children; however, some defense mechanisms are more efficient in children than in adults. Usually, exposure studies are performed with healthy subjects. Exposure studies with sick people are not representative due to the deselection of subjects with moderate or severe eye or airway diseases, which likely underestimates the sensitivity of the group of people with diseases. Psychological characterization like personality factors shows that concentrations of volatile substances far below their sensory irritation thresholds may influence the sensitivity, in part biased by odor perception. Thus, the protection of people with extreme personality traits is not feasible by an AF and other mitigation strategies are required. The available empirical evidence comprising age, lifestyle, and health supports an AF of not greater than up to 2 for sensory irritation. Further, general AFs are discouraged for derivation, rather substance-specific derivation of AFs is recommended based on the risk assessment of empirical data, deposition in the airways depending on the substance's water solubility and compensating for knowledge and experimental gaps. Modeling of sensory irritation would be a better 'empirical' starting point for derivation of AFs for children, older, and sick people, as human exposure studies are not possible (due to ethical reasons) or not generalizable (due to self-selection). Dedicated AFs may be derived for environments where dry air, high room temperature, and visually demanding tasks aggravate the eyes or airways than for places in which the workload is balanced, while indoor playgrounds might need other AFs due to physical workload and affected groups of the general population.

The importance of variations in in vitro dosimetry to support risk assessment of inhaled toxicants.

In vitro methods provide a key opportunity to model human-relevant exposure scenarios for hazard identification of inhaled toxicants. Compared to in vivo tests, in vitro methods have the advantage of assessing effects of inhaled toxicants caused by differences in dosimetry, e.g., variations in con­centration (exposure intensity), exposure duration, and exposure frequency, in an easier way. Variations in dosimetry can be used to obtain information on adverse effects in human-relevant exposure scenarios that can be used for risk assessment. Based on the published literature of exposure approaches using air-liquid interface models of the respiratory tract, supplemented with additional experimental data from the EU H2020 project "PATROLS" and research funded by the Dutch Ministry of Agriculture, Nature and Food Quality, the advantages and disadvantages of dif­ferent exposure methods and considerations to design an experimental setup are summarized and discussed. As the cell models used are models for the respiratory epithelium, our focus is on the local effects in the airways. In conclusion, in order to generate data from in vitro methods for risk assessment of inhaled toxicants it is recommended that (1) it is considered what information really is needed for hazard or risk assessment; (2) the exposure system that is most suitable for the chemical to be assessed is chosen; (3) a deposited dose that mimics deposition in the human respiratory tract is used, and (4) the post-exposure sampling methodology should be carefully considered and relevant to the testing strategy used.

The impact of airborne pollutants on human health is determined by what pollutant it is, how much we breathe in, for how long and how often. Testing in animals is cumbersome and results may not reflect human health impacts. Advanced cell models of the human lung allow prediction of the health impact of many different exposure scenarios. Here, we compare different models and exposure methods and provide criteria that may assist in designing experiments, interpreting the results, and thus assessing the risks posed by airborne pollutants. We recommend (1) determining what infor­mation is needed to plan the experiment, (2) choosing an exposure method that is suitable for the pollutant of interest, (3) determining the amount of pollutant that interacts with the human lung, to relate this to realistic deposition in the lung, and (4) considering the time between the exposure and measurement of the effect.

Development of Respiratory Tract Organs for ICRP Pediatric Mesh-type Reference Computational Phantoms.

ABSTRACT: As part of the activities of the International Commission on Radiological Protection (ICRP) Task Group 103, the present study developed a new set of respiratory tract organs consisting of the extrathoracic, bronchial, bronchiolar, and alveolar-interstitial regions for newborn, 1-, 5-, 10-, and 15-y-old males and females for use in pediatric mesh-type reference computational phantoms. The developed respiratory tract organs, while preserving the original topologies of those of the pediatric voxel-type reference computational phantoms of ICRP Publication 143, have improved anatomy and detailed structure and also include µm-thick target and source regions prescribed in ICRP Publication 66. The dosimetric impact of the developed respiratory tract organs was investigated by calculating the specific absorbed fraction for internal electron exposures, which were then compared with the ICRP Task Group 96 values. The results showed that except for the alveolar-interstitial region as a source region, the pediatric mesh phantoms showed larger specific absorbed fractions than the Task Group 96 values. The maximum difference was a factor of ~3.5 for the extrathoracic-2 basal cell and surface as target and source regions, respectively. These results reflect the differences in the target masses and geometry caused by the anatomical enhancement of the pediatric mesh phantoms. For the alveolar-interstitial region as a source region, the pediatric mesh phantoms showed larger values for low energy ranges and lower values with increasing energies, owing to the differences in the size and shape of the alveolar-interstitial region.

PM2.5 and its respiratory tract depositions on blood pressure, anxiety, depression and health risk assessment: A mechanistic study based on urinary metabolome.

Effects of fine particulate matter (PM2.5) and regional respiratory tract depositions on blood pressure (BP), anxiety, depression, health risk and the underlying mechanisms need further investigations. A repeated-measures panel investigation among 40 healthy young adults in Hefei, China was performed to explore the acute impacts of PM2.5 exposure and its deposition doses in 3 regions of respiratory tract over diverse lag times on BP, anxiety, depression, health risk, and the potential mechanisms. We collected PM2.5 concentrations, its deposition doses, BP, the Self-Rating Anxiety Scale (SAS) score and the Self-Rating Depression Scale (SDS) score. An untargeted metabolomics approach was used to detect significant urine metabolites, and the health risk assessment model was used to evaluate the non-carcinogenic risks associated with PM2.5. We applied linear mixed-effects models to assess the relationships of PM2.5 with the aforementioned health indicators We further evaluate the non-carcinogenic risks associated with PM2.5. We found deposited PM2.5 dose in the head accounted for a large proportion. PM2.5 and its three depositions exposures at a specific lag day was significantly related to increased BP levels and higher SAS and SDS scores. Metabolomics analysis showed significant alterations in urinary metabolites (i.e., glucoses, lipids and amino acids) after PM2.5 exposure, simultaneously accompanied by activation of the cAMP signaling pathway. Health risk assessment presented that the risk values for the residents in Hefei were greater than the lower limits of non-cancer risk guidelines. This real-world investigation suggested that acute PM2.5 and its depositions exposures may increase health risks by elevating BP, inducing anxiety and depression, and altering urinary metabolomic profile via activating the cAMP signaling pathway. And the further health risk assessment indicated that there are potential non-carcinogenic risks of PM2.5 via the inhalation route in this area.

The epidemiology of upper respiratory tract disorders in a population of insured Swedish dogs (2011-2014), and its association to brachycephaly.

Upper respiratory tract (URT) disorders are common in dogs but neither general nor breed-related epidemiological data are widely reported. This study´s aims were to describe the epidemiology of URT disorders in a Swedish population of dogs and to investigate whether brachycephalic breeds were overrepresented among high-risk breeds. A cohort of dogs insured by Agria Djurförsäkring in Sweden (2011-2014) was used to calculate overall and breed-specific incidence rate (IR), age at first URT diagnosis and relative risk (RR) for URT disorders. For breeds with high RR for URT disorders, co-morbidities throughout the dog's insurance period and age at death were investigated. The cohort included approximately 450,000 dogs. URT disorders had an overall IR of 50.56 (95% CI; 49.14-52.01) per 10,000 dog years at risk. Among 327 breeds, the English bulldog, Japanese chin, Pomeranian, Norwich terrier and pug had highest RR of URT disorders. Eight of 13 breeds with high RR for URT disorders were brachycephalic. The median age at first URT diagnosis was 6.00 years (interquartile range 2.59-9.78). French bulldogs with URT diagnoses had a significantly shorter life span (median = 3.61 years) than other breeds with URT diagnosis (median = 7.81 years). Dogs with high risk for URT disorders had more co-morbidities than average.

Simultaneous assessment of central nervous and respiratory systems using jacketed telemetry in socially-housed rats: Application of the "3Rs" principles in core battery safety pharmacology studies.

Central nervous (CNS) and respiratory systems are routinely investigated in safety pharmacology core battery studies. For small molecules, the assessment of both vital organ systems is frequently done in rats in two distinct studies. With the advent of a miniaturized technology of jacketed external telemetry for rats (DECRO system), the simultaneous assessment of modified Irwin's or functional observational battery (FOB) test and respiratory (Resp) studies has become possible within a single study. Therefore, the objectives of this study were to perform the FOB and the Resp studies simultaneously in pair-housed rats fitted with jacketed telemetry, and to assess the feasibility and the outcome of this combination in control, baclofen, caffeine, and clonidine treated groups, i.e., with three agents having both respiratory and CNS effects. Our results provided evidence that performing both Resp and FOB assessment simultaneously in the same rat was feasible and the outcome was successful. The expected CNS and respiratory effects of the 3 reference compounds were accurately captured in each assay confirming the results' relevance. In addition, heart rate and activity level were recorded as additional parameters making this design as an enhanced approach for nonclinical safety assessment in rats. This work provides clear evidence that the "3Rs" principles can be effectively applied in core battery safety pharmacology studies while remaining in compliance with worldwide regulatory guidelines. Both reduction in animal use and refinements in procedures are demonstrated with this model.

The toxicity assessment of neorudin in cynomolgus monkeys.

In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively. The changes of respiratory frequency, respiratory intensity, blood pressure and electrocardiogram before and after administration were recorded. In acute toxicity test, six cynomolgus monkeys were intravenously received EH at a single dose of 171, 257, 385, 578, 867 and 1300 mg/kg respectively. The vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of the animals were determined before administration and on the 7th and 14th day after administration. As the results showed that there were no significant abnormal changes in respiratory frequency, respiratory intensity, blood pressure or electrocardiogram in cynomolgus monkeys after receiving EH at 3 mg/kg and 30 mg/kg, and there was no statistical difference between the treated groups and normal saline group. In the acute toxicity test, no significant abnormalities were observed in vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of six cynomolgus monkeys at day 7 and 14 after EH administration. Furthermore, autopsies of all cynomolgus monkeys showed no abnormalities. The results of toxicokinetics showed that AUClast of the drug increased in proportion to the EH dose in the range of 171-578 mg/kg, and increased in over proportion to the EH dose in the range of 578-1300 mg/kg. The variation of Cmax was basically consistent with AUClast. In a sum, A single intravenous injection of 3 and 30 mg/kg of EH did not affect the circulatory system and respiratory system in cynomolgus monkeys and the maximum tolerated dose of EH in cynomolgus monkey is over 1300 mg/kg (equivalent to 619-1300 times of the proposed clinical equivalent dose).

An update on the biological effects of quantum dots: From environmental fate to risk assessment based on multiple biological models.

Quantum dots (QDs) are zero-dimension nanomaterials with excellent physical and chemical properties, which have been widely used in environmental science and biomedicine. Therefore, QDs are potential to cause toxicity to the environment and enter organisms through migration and bioenrichment effects. This review aims to provide a comprehensive and systematic analysis on the adverse effects of QDs in different organisms based on recently available data. Following PRISMA guidelines, this study searched PubMed database according to the pre-set keywords, and included 206 studies according to the inclusion and elimination criteria. CiteSpace software was firstly used to analyze the keywords of included literatures, search for breaking points of former studies, and summarize the classification, characterization and dosage of QDs. The environment fate of QDs in the ecosystems were then analyzed, followed with comprehensively summarized toxicity outcomes at individual, system, cell, subcellular and molecular levels. After migration and degradation in the environment, aquatic plants, bacteria, fungi as well as invertebrates and vertebrates have been found to be suffered from toxic effects caused by QDs. Aside from systemic effects, toxicity of intrinsic QDs targeting to specific organs, including respiratory system, cardiovascular system, hepatorenal system, nervous system and immune system were confirmed in multiple animal models. Moreover, QDs could be taken up by cells and disturb the organelles, which resulted in cellular inflammation and cell death, including autophagy, apoptosis, necrosis, pyroptosis and ferroptosis. Recently, several innovative technologies, like organoids have been applied in the risk assessment of QDs to promote the surgical interventions of preventing QDs' toxicity. This review not only aimed at updating the research progress on the biological effects of QDs from environmental fate to risk assessment, but also overcame the limitations of available reviews on basic toxicity of nanomaterials by interdisciplinarity and provided new insights for better applications of QDs.

Role of high-sensitivity C-reactive protein (hs-CRP) in assessment of asthma control in children.

INTRODUCTION: Data are scarce on hs-CRP as a biomarker for airway inflammation in pediatric asthma. We aimed to examine correlation between hs-CRP and asthma control levels. METHODS: Children with physician-diagnosed asthma, ages 6-15 years, were enrolled. GINA-2016 criteria were used to assess the level of asthma control. The relationships between serum hs-CRP and each of asthma control measures (asthma control criteria, spirometry, impulse oscillometry, eosinophil counts and fractional exhaled nitric oxide (FeNO) were assessed. RESULTS: 150 asthmatic children were enrolled; 52 (35%) had well controlled asthma, 76 (51%), and 22 (14%) children had partly controlled and uncontrolled asthma, respectively. Median (IQR) values of hs-CRP were 0.47 (0.1, 1.67) mg/L in well controlled, 0.30 (0.1, 1.83) mg/L in partly controlled, and 2.74 (0.55, 3.74) mg/L in uncontrolled asthma (p = 0.029). Using receiver operator characteristic (ROC) curve analysis, area under the curve for hs-CRP (mg/L) to discriminate between uncontrolled and (controlled + partly controlled) asthma was 0.67 (95% CI 0.55, 0.80) and a cutoff 1.1 mg/L of serum hs-CRP level had a sensitivity of 68.1% with specificity of 67.97%. In two groups of hs-CRP (<3 mg/L) and hs-CRP (≥3 mg/L), high hs-CRP group had higher proportion of uncontrolled asthmatic children (p = 0.03). CONCLUSION: We observed higher serum hs-CRP values in children with uncontrolled asthma, suggesting its potential role as a biomarker of asthma control.

Economic loss due to treatment of bovine respiratory disease in Japanese Black calves arriving at a backgrounding operation in Miyazaki.

The present study assessed the economic loss due to treatment of bovine respiratory disease (BRD) in Japanese Black calves that were introduced to a backgrounding operation from the age of 3 to 4 months until the age of 10 months. The data collected from a backgrounding operation in Miyazaki, Japan included the records of 2,690 animals entering the farm from 2013 to 2018. The treatment duration was defined as the number of days from the beginning to end of treatment. The cost of treatment was defined as the total cost of treatment during the treatment duration. The average incidence of BRD was 54.6%, and the relative frequency of calves that had BRD once, twice, and three or more times until they left the farm was 64.4%, 26.8%, and 8.8%, respectively (total recorded diagnoses of BRD: 2,494). Among the 2,494 recorded diagnoses, the average and median duration of treatment of BRD was 5.9 days and 3.0 days, respectively. The average and median cost of treatment was 7,767 and 5,600 Japanese yen, respectively. A prolonged duration of treatment and high cost of treatment were associated with BRD relapse, steers, and early stage of production (P<0.05). At the studied farm, the total cost of treatment during the 6-year study period was 19,658,988 yen, and the annual cost was approximately 3 million yen. In summary, the present study showed that BRD had a large economic impact in this backgrounding operation.

Non invasive jacketed telemetry in socially-housed rats for a combined assessment of respiratory system, electrocardiogram and activity using the DECRO system.

Respiratory and cardiovascular systems are among the vital organ systems that should be studied in safety pharmacology core battery test. Non-invasive jacketed external telemetry technology that enables concomitant monitoring of both systems has been available and used widely for non-rodent species. Recently, the DECRO system, a miniaturized technology system in line with the "3Rs" principles, has been developed to provide a similar approach in rats. However, data to evaluate this system in socially-housed rats is lacking. Therefore, the objectives of this study were to determine the tolerability and the material integrity of this novel solution in pair-housed rats in two conditions: i) in a single session of 22 h simulating a stand-alone safety pharmacology study design, and ii) in three repeated sessions of 22 h each, simulating the inclusion of safety pharmacology endpoints in a 1-month toxicology study. In both conditions, the GABAB receptor agonist baclofen was used as a reference compound inducing cardiorespiratory changes. Our results provided evidence that this novel solution was well tolerated, the material was resistant to deterioration and that it allowed the accurate recording, in a non-invasive manner, of cardiorespiratory parameters and activity level in freely moving, pair-housed rats in the above two conditions. In addition, the expected respiratory depressant effects of baclofen were recorded. These results pave the way for considering this novel solution as an enhanced approach for nonclinical safety assessment in rats.

Application of a new approach method (NAM) for inhalation risk assessment.

The US Environmental Protection Agency (USEPA) and other regulatory authorities have been working to utilize in vitro studies with human cells and in silico modelling to reduce the use of vertebrate animals for evaluating chemical risk. Using the Source-to-Outcome framework, a novel mathematical procedure was developed to estimate the human equivalent concentration (HEC) for inhalation risk assessment based upon the relevant aerosol characterization, respiratory dosimetry modelling, and endpoints derived from an in vitro assay using human respiratory epithelial tissue. The procedure used the retained doses at the various areas of the inhalation tract estimated from a computational fluid-particle dynamics (CFPD) model coupled with a simple clearance model. The effect of exposure was derived from an in vitro assay. The magnitude of exposure and the particle size distributions (PSDs) of the external aerosol droplets were obtained from Unit Exposure values published by the USEPA and published monitoring studies, respectively. The Source-to-Outcome approach incorporates external and internal exposure metrics with the toxicity pathway. The information was then integrated to conduct a risk assessment for agricultural operators exposed to products containing chlorothalonil (CTN), a broad-spectrum fungicide. The HECs for three different PSDs considered in this work ranged from 0.043 to 0.112 mg-CTN/L for nasal and oral breathing. These were compared with the estimated average daily exposure concentration for six representative application scenarios. The resulting margins of exposure (MOEs) ranged from 230 to 70,000 depending on the application scenario. This New Assessment Method (NAM) that combined human in silico and human in vitro methods, eliminated the typical uncertainties associated with extrapolation from rodent studies, with their associated interspecies toxicokinetics and toxicodynamics differences. The intraspecies toxicodynamics and toxicokinetics, are still relevant and may need to be used in an inhalation risk assessment. The NAM presented in this work is not chemical-specific and may be applied to conduct an inhalation risk assessment for workers as well as bystanders who could be exposed to aerosol particles of any cytotoxic respiratory irritant.