Derivation of internal dose-based thresholds of toxicological concern for occupational inhalation exposure to systemically acting organic chemicals

This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61?×?10^?2 and 9?×?10^?4 mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55?×?10^?1 and 8.5?×?10^?3 mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r² = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework.     

Can a threshold for 11‐nor‐9‐carboxy‐Δ9 ‐tetrahydrocannabinol in hair be derived when its respective concentration in blood serum indicates regular use?

A 100 μg/L or higher concentration of 11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannabinol (THC‐COOH) in blood serum is generally assumed to be associated with regular and/or heavy use of cannabis. At present, determination of the extent of cannabis use by means of the concentration of THC‐COOH in hair has not been assessed. Therefore, we aimed at establishing a threshold for THC‐COOH concentrations in hair to prove frequent consumption by comparing THC‐COOH concentrations in 129 corresponding serum and hair samples, respectively. The concentration of THC‐COOH in the serum was analyzed by gas chromatography–mass spectrometry and in the hair by liquid chromatography–tandem mass spectrometry. Data were statistically evaluated using receiver operating characteristic curves and contingency tables. Our results suggest that a THC‐COOH concentration of ≥4.2 pg/mg in hair was always accompanied by a THC‐COOH concentration of at least 100 μg/L in blood serum. Should this be confirmed by further studies of a larger study population, a hair concentration of 4.2 pg/mg THC‐COOH can be set as a threshold to predict regular and/or heavy consumption of cannabis even if no corresponding blood sample is available for analysis.     

Acute irritant threshold correlates with barrier function,skin hydration and contact hypersensitivity in atopic dermatitis and rosacea

The aim of the study was to disclose interactions between epidermal barrier, skin irritation and sensitization in healthy and diseased skin. Transepidermal water loss (TEWL) and stratum corneum hydration (SCH) were assessed in adult patients with atopic dermatitis (AD), rosacea and healthy controls. A 4‐h patch test with seven concentrations of sodium lauryl sulphate was performed to determine the irritant threshold (IT). Contact sensitization pattern was revealed by patch testing with European baseline series. Subjects with a lower IT had higher TEWL values and lower SCH. Subjects with positive allergic reactions had significantly lower IT. In AD, epidermal barrier deterioration was detected on both volar forearm and nasolabial fold, while in rosacea, impeded skin physiology parameters were observed on the facial skin only, suggesting that barrier impediment is restricted to the face in rosacea, in contrast with AD where the abnormal skin physiology is generalized.     

Response of left ventricular diastolic filling to graded exercise relative to the lactate threshold

Summary During incremental exercise, the left ventricular ejection fraction increases up to the intensity of the anaerobic threshold and tends to level off at higher exercise intensities. Since there is a correlation between the response of peak filling rate and ejection fraction to exercise, this study was conducted to determine whether the response of left ventricular diastolic function is similar to the response of systolic function relative to lactate threshold. Twelve healthy men performed two exercise tests on a cycle ergometer. In the first test, lactate threshold and maximal power output were determined. In the second exercise test, gated radionuclide ventriculography was performed at rest, at the lactate threshold intensity, and at peak exercise to measure ejection fraction and peak filling rate. Ejection fraction increased significantly from rest [mean (SD): 62 (5)%] to lactate threshold [76 (7) %] and did not change significantly from lactate threshold to peak exercise [77 (7)%]. Likewise, peak filling rate (normalized for stroke counts) increased from resting [6.1 (0.9)V _s · s^–1] to lactate threshold [9.4 (1.8)V _s · s^–1] and did not change significantly from lactate threshold to peak exercise [9.6 (2.9)V _s · s^–1]. There was no correlation between the change in peak filling rate and the change in ejection fraction from rest to lactate threshold. Thus, during incremental exercise, left ventricular diastolic function responds qualitatively similar to systolic function.     

Low-Temperature-Processed High-Performance Pentacene OTFTs with Optimal Nd-Ti Oxynitride Mixture as Gate Dielectric

When processed at a low temperature of 200 °C, organic thin-film transistors (OTFTs) with pentacene channel adopting high-k Neodymium-Titanium oxynitride mixtures (NdTiON) with various Ti contents as gate dielectrics are fabricated. The Ti content in the NdTiON is varied by co-sputtering a Ti target at 0 W, 10 W, 20 W and 30 W, respectively, while fixing the sputtering power of an Nd target at 45 W. High-performance OTFT is obtained for the 20 W-sputtered Ti, including a small threshold voltage of −0.71 V and high carrier mobility of 1.70 cm²/V·s. The mobility improvement for the optimal Ti content can be attributed to smoother dielectric surface and resultant larger overlying pentacene grains as reflected by Atomic Force Microscopy measurements. Moreover, this sample with the optimal Ti content shows much higher mobility than its counterpart processed at a higher temperature of 400 °C (0.8 cm²/V·s) because it has a thinner gate-dielectric/gate-electrode interlayer for stronger screening on the remote phonon scattering by the gate electrode. In addition, a high dielectric constant of around 10 is obtained for the NdTiON gate dielectric that contributes to a threshold voltage smaller than 1 V for the pentacene OTFT, implying the high potential of the Nd-Ti oxynitride in future high-performance organic devices.     

Convergence of human brain mapping tools: neuronavigated TMS parameters and fMRI activity in the hand motor area

Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) are well-established tools for investigating the human motor system in-vivo. We here studied the relationship between movement-related fMRI signal changes in the primary motor cortex (M1) and electrophysiological properties of the hand motor area assessed with neuronavigated TMS in 17 healthy subjects. The voxel showing the highest task-related BOLD response in the left hand motor area during right hand movements was identified for each individual subject. This fMRI peak voxel in M1 served as spatial target for coil positioning during neuronavigated TMS. We performed correlation analyses between TMS parameters, BOLD signal estimates and effective connectivity parameters of M1 assessed with dynamic causal modeling (DCM). The results showed a negative correlation between the movement-related BOLD signal in left M1 and resting as well as active motor threshold (MT) obtained for left M1. The DCM analysis revealed that higher excitability of left M1 was associated with a stronger coupling between left supplementary motor area (SMA) and M1. Furthermore, BOLD activity in left M1 correlated with ipsilateral silent period (ISP), i.e. the stronger the task-related BOLD response in left M1, the higher interhemispheric inhibition effects targeting right M1. DCM analyses revealed a positive correlation between the coupling of left SMA with left M1 and the duration of ISP. The data show that TMS parameters assessed for the hand area of M1 do not only reflect the intrinsic properties at the stimulation site but also interactions with remote areas in the human motor system.     

The lowest VE/VCO2 ratio best identifies chronic thromboembolic pulmonary hypertension

Introduction

The natural history of acute pulmonary embolism (PE) under treatment is about a gradual resolution of the thrombi, and uncommonly, the development of chronic thromboembolic pulmonary hypertension (CTEPH). We hypothesized that ventilatory efficiency parameters during cardiopulmonary exercise testing (CPET) may be able to monitor the process and predict CTEPH.

Methods

15 patients rehabilitated from acute PE (total resolution of thrombi), 44 patients with chronic PE (with residual thrombi), 66 patients with CTEPH, and 36 sedentary healthy controls performed incremental CPET.

Results

The lowest VE/VCO₂ was higher in CTEPH patients than that in chronic PE and rehabilitated patients (43.4 L/min vs 29.9 L/min vs 27.1 L/min, p < 0.005). The VE/VCO₂ slope (48.4 L/min/L/min vs 29.9 L/min/L/min vs 28.0 L/min/L/min, p < 0.005) and oxygen uptake efficiency plateau (OUEP) (37.1 L/min vs 27.0 L/min vs 25.2 L/min, p < 0.005) had the similar changes. In logistic regression analysis, the lowest VE/VCO₂ ≥ 34.35 L/min was the best predictor of CTEPH (OR 159.0, 95% CI 36.0-702.3, p < 0.001). The lowest VE/VCO₂ was higher in chronic PE patients compared with the controls (29.9 L/min vs 26.5 L/min, p < 0.05), but there was no difference between the rehabilitated patients and the controls. In multiple linear regression analysis, the percentage of vascular obstruction by ventilation-perfusion lung scanning (PVO) was the most significant independent predictor for indices of ventilatory efficiency in chronic PE and rehabilitated patients.

Conclusions

CTEPH is associated with weakened ventilatory efficiency. The lowest VE/VCO2 ratio has the best capability to predict CTEPH. Ventilatory inefficiency improves along with recovery of acute PE.     

Reduced cortical arousability to nocturnal apneic episodes in patients with wake-up ischemic stroke

Study objectivesSleep breathing disorders (SBD) have been linked to wake-up stroke (WUS). Respiratory arousals have an important role in responding to danger during sleep, yet currently no studies have investigated respiratory arousability in WUS. In this study, we used a clinical tool to predict low respiratory arousal threshold (ArTH), and then compared respiratory arousability in patients with WUS and non-WUS.MethodsWe enrolled 119 patients with acute ischemic stroke and assigned them into WUS (n = 34) and non-WUS (n = 85) groups. All participants underwent polysomnography (PSG) during the acute phase of stroke. The respiratory ArTH predictive tool assigns one point for each of the following: apnea-hypopnea index (AHI) < 30/h, nadir oxygen saturation (SaO₂) > 82.5%, and fraction of hypopneas > 58.3%. An ArTH score ≥2 represents low respiratory ArTH.ResultsOur results reconfirmed the association between moderate-to-severe sleep apnea syndrome and WUS (OR 2.879, 95% CI 1.17–7.089, p = 0.021). Significantly fewer participants with obstructive sleep apnea (AHI ≥ 5/h) had low respiratory ArTH in the WUS group than in the non-WUS group (34.8% vs. 68.1%, respectively, p = 0.008). High respiratory ArTH was independently associated with WUS (OR 5.556, 95% CI 1.959–15.761, p = 0.001).ConclusionsThe correlation between SBD and WUS suggests that sleep apnea might induce acute physiological changes that trigger the onset of stroke. We show that reduced respiratory arousability is associated with WUS, and hypothesize that reduced cortical capability to generate respiratory arousal may have a role in triggering stroke during sleep.