Modeling the impact of heat stress on the toxicokinetics of toluene and acetone.

Many workers can be exposed simultaneously to heat and volatile chemicals. In a controlled human exposure study, it was observed that an increase in ambient temperature was associated with increased blood concentrations for acetone and toluene. Based on the expected changes in physiological parameters that occur with an increase in ambient temperature, we aimed to develop a PBPK model for acetone and toluene that could account for the impact of temperature on the kinetics of these solvents. Changes in temperature-dependent physiological parameters (i.e. blood flows, cardiac output, alveolar ventilation) based on recent measurements in volunteers were introduced in the PBPK models to simulate observed blood concentrations for different temperature exposure conditions. Because initial simulations did not adequately predict solvent kinetics at any temperature, the most sensitive parameter (alveolar ventilation; Qp) was, therefore, optimized on experimental acetone blood concentrations to obtain a relationship with temperature. The new temperature-dependent Qp relationship gave Qp values consistent with the literature and estimated a mean increase of 19% at 30 °C (wet bulb globe temperature) compared to 21 °C. The integration of a new temperature-dependent Qp relationship in the PBPK toluene model yielded adequate simulations of the experimental data for toluene in blood, exhaled air and urine. With further validation with other solvents, the temperature-dependant PBPK model could be a useful tool to better assess the risks of simultaneous exposure to volatile chemicals and heat stress and interpret biomonitoring data in workers as well as in the general population. TRN: NCT02659410, Registration date: January 15, 2016.

Determination of blood:air, urine:air and plasma:air partition coefficients of selected microbial volatile organic compounds.

Partition coefficients (PCs) are essential parameters for understanding the toxicokinetics of chemicals in the human body since they are used in the description of different processes of absorption, distribution, and excretion in physiologically based pharmacokinetic (PBPK) models used in chemical exposure and risk assessment. The goal of this study was to determine urine:air, blood:air and plasma:air partition coefficients (PCs) of microbial volatile organic compounds (mVOCs) previously selected as having high potential as biomarkers of indoor mold exposure. To achieve this goal, the vial-equilibration technique was used, and quantification was performed using headspace gas chromatography tandem mass spectrometry (HS-GC-MS/MS) analysis. Matrix:air PCs of 19 different mVOCs have been successfully determined and their values ranged between 14 and 3586 for urine:air, 78 and 4721 for blood:air and 64 and 5604 for plasma:air PCs. Water:air PCs were also determined, and their values varied between 16 and 2210, showing a good correlation with urine:air PCs for 17 compounds of the selected mVOCs (R2 = 0.97, slope close to unity) indicating that water:air PCs below 103 may be a good surrogate for urine:air PCs. All studied mVOCs have high blood:air PCs (greater than 78) indicating strong pulmonary uptake. Due to their high blood:urine PCs, some mVOCs may be more easily measured in blood than in urine. This work is an important preliminary step toward the use of mVOCs as potential biomarkers of indoor mold exposure. The data obtained in this study will help to determine the most appropriate matrix to use in this biomonitoring approach and will eventually facilitate the development of PBPK models for these chemicals.

CETP inhibitor evacetrapib enters mouse brain tissue.

High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer's disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer's disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer's disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease.

Full-scale multisampling and empirical modeling of DBPs in water and air of indoor pools.

Disinfection by-products (DBPs) are formed in the water in swimming pools due to reactions between disinfectants (chlorine, bromine, ozone) and the organic matter introduced by bathers and supply water. High concentrations of DBPs are also reported in the air of indoor swimming pools. Based on a robust multisampling program, the levels and variations of DBPs in the air (trichloramine [TCAM] and trihalomethanes [THMs]) and water (THM) were assessed, as well as their precursors (total organic carbon, water temperature, pH, free, and total chlorine) and proxies (CO2 and relative humidity) in four indoor chlorinated swimming pools. High-frequency sampling was conducted during one high-attendance day for each pool. This study focused on parameters that are easy to measure in order to develop models for predicting levels of THMs and TCAM in the air. The results showed that the number of bathers had an important impact on the levels of THMs and TCAM, with a two-to-three-fold increase in air chloroform (up to 110 µg/m3) and a two-to-four-fold increase in TCAM (up to 0.52 mg/m3) shortly after pools opened. The results of this study for the first time showed that CO2 and relative humidity can serve as proxies for monitoring variations in airborne THMs and TCAM. Our results highlight the good predictive capacity of the developed models and their potential for use in day-to-day monitoring. This could help optimize and control DBPs formation in the air of indoor swimming pools and reduce contaminant exposure for both pool employees and users.

Quantification of the Conjugated Forms of Dichlorobisphenol A (3,3'-Cl 2 BPA) in Rat and Human Plasma Using HPLC-MS/MS.

BACKGROUND: Bisphenol A (BPA) is a ubiquitous contaminant that has endocrine-disrupting effects. Chlorinated derivatives of BPA are formed during chlorination of drinking water and have higher endocrine-disrupting activity. Dichlorobisphenol A (Cl 2 BPA) is the most abundant chlorinated BPA derivative found in several human biological matrices. Recent in vitro experiments have shown that Cl 2 BPA is metabolized in sulpho- and glucuro-conjugated compounds. To date, no assay has been developed to quantify the sulfo- and glucuro-conjugates of 3,3'-Cl 2 BPA (3,3'-Cl 2 BPA-S and 3,3'-Cl 2 BPA-G, respectively). METHODS: A high-performance liquid chromatography-tandem mass spectrometry assay for the determination of 3,3'-Cl 2 BPA conjugated forms in plasma samples was developed and validated according to the European Medicines Agency guidelines. Quantification was performed in the multiple reaction monitoring mode for all target analytes using a SCIEX 6500 + tandem mass spectrometer with an electrospray source operating in the negative ionization mode. Chromatographic separation was achieved using a C18 column maintained at 40°C and a binary mobile phase delivered in the gradient mode at a flow rate of 0.35 mL/min. Sample was prepared via simple precipitation using acetonitrile. The assay was validated and applied to rat and human plasma samples. RESULTS: Linearity was demonstrated over the range of 0.006-25 ng/mL for 3,3'-Cl 2 BPA-G and 0.391-100 ng/mL for 3,3'-Cl 2 BPA-S. Intraday and interday bias values were in the 95%-109% range, and the imprecision <9%. Internal standard corrected matrix effects were also investigated. This method enabled quantification of the conjugated forms of 3,3'-Cl 2 BPA in plasma samples. CONCLUSIONS: This is the first report on the development and validation of an analytical method for the quantification of 3,3'-Cl 2 BPA-G and 3,3'-Cl 2 BPA-S in the plasma matrix. This study is also the first report on the in vivo occurrence of these metabolites.

Comparison of sampling collection strategies for assessing airborne trichloramine levels in indoor swimming pools.

Since 1995, Hery's trichloramine sampling procedure has been widely used to determine trichloramine exposure in indoor swimming pools. This method consists of pumping air at a 1 L/min flow rate for 2 h through a Teflon prefilter and two quartz fiber filters. Modified Hery methods have been reported using different sampling pump flow rates and types of prefilters. It is possible that the prefilter type or sample collection pump flow rate influenced the results of these studies. This study is designed to evaluate the effects of different cassette assemblies and sampling flow rates on the levels of measured trichloramine. Laboratory tests were performed using a trichloramine production setup designed for this study. Workplace measurements were carried out at four indoor swimming pools. Different prefiltering strategies were used: no prefilter, glass prefilter or Teflon prefilter in the sampling cassette, and an original separable prefilter cassette is presented in this study. Laboratory tests indicated that at trichloramine concentrations higher than 1 mg/m3, the percentage of trichloramine captured on the first filter could be less than 75%, which demonstrated possible loss of the material during sampling. An investigation of the prefilter effect on the sampling strategy using different cassette assemblies revealed that using a separable cassette assembly prevented overestimations of trichloramine levels. Furthermore, there were no significant differences between trichloramine concentrations measured at flow rates (from 0.5 to 2 L/min) in swimming pools.

Toxicokinetics of silver element following inhalation of silver nitrate in rats.

Silver (Ag) and its compounds are priority contaminants, for which toxicological effects are well documented, but their toxicokinetics are not fully documented for a proper risk assessment. While the toxicokinetics of insoluble Ag nanoparticles (Ag NPs) was recently documented, there is a lack of data on the kinetic behavior of the soluble form, such as one of the mostly used silver nitrate (AgNO3) form. This study aimed to better document the toxicokinetics of Ag element following inhalation of soluble AgNO3 for comparison with a previous study on the kinetics of inhaled Ag NPs using a similar experimental design. We exposed male Sprague-Dawley rats to AgNO3 during 6 continuous hours (typical of a daily worker exposure) to determine the kinetic time courses of Ag element in blood, tissues, and excreta over a 14-day period post-exposure. Only a small fraction of Ag was found in lungs following the onset of the 6-h inhalation of AgNO3 (on average (± SD) 0.3 ± 0.1% at the end of the 6-h inhalation). Blood profiles of Ag element showed peak levels right after the end of the 6-h inhalation period and levels decreased rapidly thereafter. Toxicokinetic parameter values calculated from the average blood-concentration profiles showed a mean residence time (MRT) of 135 h and mean half-life (t1/2) of 94 h, with AUC of 2.5 mg/L × h and AUMC of 338 mg/L × h2. In terms of percent of inhaled dose, highest levels of Ag in extrapulmonary organs were found in liver, which represented on average (± SD) 1.6 ± 0.6% of calculated inhaled dose followed by the kidney with 0.1 ± 0.08%. Peak levels in the GI tract (including contents) were found at the end of the 6-h inhalation and represented 20 ± 15.6% of the inhaled dose. The dominant excretion route of Ag was through feces. The time course of Ag element in the GI tract and feces following AgNO3 inhalation is also compatible with an intestinal reabsorption of Ag. When compared to results of Ag NPs of a prior study with the same design, this study showed differences in the kinetics of soluble AgNO3 compared to insoluble Ag NPs, with higher levels in blood, GI tract, and extrapulmonary tissues but lower levels in lungs following AgNO3 exposure.

Temporal and spatial variations in the levels of prominent airborne disinfection by-products at four indoor swimming pools.

Exposure to airborne disinfection by-products, especially trichloramine and trichloromethane, may cause various adverse health effects for the workers and users of indoor swimming pools. This study aims to evaluate the spatial and temporal variations in trichloramine and trichloromethane concentrations within and between swimming pools. Workplace measurements were carried out at four indoor swimming pools in Quebec (Canada) during the cold season. To fully represent daily operating conditions, sampling started 2 hr before the swimming pool opened and continued until 2 hr after closing. To quantify trichloramine and trichloromethane concentrations, 304 air samples have been collected. Temperature, humidity, and CO2 were measured-simultaneously every 2 hr. The results showed that both trichloramine and trichloromethane concentrations varied significantly in time. The observed daily variations in trichloramine and trichloromethane concentrations suggest that the common practice of collecting a single 2-hr air sample does not represent daily pool trichloramine and trichloromethane contamination levels and, consequently, does not represent the true exposure and health risks for workers that are present for a full 8-hr shift. This study recommends a new 8-hr sampling strategy or a full-shift strategy using a cassette with three impregnated filters as a valid and cost-effective solution for comparing time-weighted average (TWA) concentrations to permissible trichloramine exposure limits.

A new headspace solid-phase microextraction coupled with gas chromatography-tandem mass spectrometry method for the simultaneous quantification of 21 microbial volatile organic compounds in urine and blood.

Mold growth can cause the development of several metabolites including microbial volatile organic compounds (mVOCs). These latter may be considered as potential biomarkers of fungal presence and have been detected in human biological matrices such as urine and blood. Exposure to molds and their metabolites (e.g., mVOCs, mycotoxins) in occupational settings, is responsible for several health effects. Thus, this exposure cannot be neglected and must be evaluated. Herein, a method has been developed to quantify 21 mVOCs in urine and human blood by headspace solid phase micro-extraction (HS-SPME) coupled with gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS). The parameters influencing the extraction process, such as the type of fiber, the incubation and extraction time and temperature and the desorption time, have been optimized to ensure better mVOCs extraction. The developed method showed good linearity over the concentration range of the compounds (R2 ˃ 0.995) for all the mVOCs in all the matrices. The low limits of detection (LOD) ranging from 0.7 to 417 ng/L in urine and from 1 to 507 ng/L in blood, make the developed methods sensitive and effective for biomonitoring of exposure at low levels. Recoveries, at low and high concentrations, were between 87% and 120% in urine and between 83% and 118% in blood. The repeatability and the intermediate precision in terms of coefficients of variation (CV%) was lower than 13% and 8.58% respectively for all compounds in all matrices. These values show satisfactory accuracy and precision of the developed method. Thus, this practical, simple, and sensitive method is well suited for the simultaneous quantification of target mVOCs.

Hepatic metabolism of chlorinated derivatives of bisphenol A (ClxBPA) and interspecies differences between rats and humans.

During chlorination treatments of drinking water, aqueous bisphenol A (BPA) can react with chlorine to form chlorinated derivatives of BPA (mono, di, tri and tetra-chlorinated derivatives) or ClxBPA. These emerging substances are endocrine disruptors associated with obesity, type II diabetes (TD2M) and myocardial infarction. ClxBPA are present in different human biological matrices but their toxicokinetics remain unknown. The aim of this study was to measure and compare the metabolic kinetics in the liver of four ClxBPA (ClBPA, Cl2BPA, Cl3BPA and Cl4BPA) between compounds and between species (Sprague-Dawley rats vs humans). To estimate their metabolic constants (Vmax, Km, Intrinsic clearance), metabolic assays were performed in hepatocyte suspensions. Assays revealed that metabolic constants of ClxBPA can greatly vary depending on substances and species. While ClBPA and Cl2BPA show similar unbound intrinsic clearances (ClintU) in rat incubation media, values for Cl3BPA and Cl4BPA are very different (3.109 and 0.684 mL/min/106 hepatocytes, respectively). Unlike in rats, human results are quite different as Cl3BPA and Cl4BPA have similar unbound intrinsic clearances, while ClBPA and Cl2BPA diverge (0.350 and 1.363 mL/min/106 hepatocytes, respectively). In both species, Cl2BPA and Cl3BPA have relatively similar clearances, and ClBPA is very different from Cl4BPA. Although we quantified the proportion of sulfo- and glucurono-metabolites, other metabolites may have been formed (e.g., glutathione, disulfate, or oxidative metabolites). This study showed that chlorination had an impact on hepatic intrinsic clearance of ClxBPA in rats and humans and measured values will be valuable for the development of PBPK models for use in exposure assessment.

Cardiopulmonary parameters and organ blood flows for workers expressed in terms of VO2 for use in physiologically based toxicokinetic modeling.

Minute ventilation rates (VE), alveolar ventilation rates (VA), cardiac outputs (Q), liver blood flow (LBF) and kidneys blood flows (KBF) for physiologically based toxicokinetic modeling and occupational health risk assessment in active workers have apparently not been determined. Minute energy expenditure rates (E) and oxygen consumption rates (VO2) in workers during exertions and their aggregate daytime activities are obtained by using open-circuit wearable devices for indirect calorimetry measurements and the doubly labeled water method respectively. Hundreds of E (in kcal/min) and VO2 (in L of O2/min) were previously reported for workers. The oxygen uptake factors of 0.2059 ± 0.0019 and 0.2057 ± 0.0018 L of O2/kcal during postprandial and fasting phases respectively enabled conversion of E into VO2. Equations determined in this study based upon more than 25 000 published measurements enable the calculation of 15 parameters in the same worker only by using the VO2 reflecting workload. These parameters, notably VE, VA, VE/VO2 VA/Q, Q, LBF and KBF were found to be interrelated. Altering one of these changes the order of magnitude of the others. Q, LBF and KBF decrease when supine adults at rest switch to an upright position. This effect of gravity diminished when VO2 increased. The fall in LBF and KBF during exertion might enhance muscle blood flow as reported previously. Taken together these equations and data may improve the accuracy of physiologically based toxicokinetic modeling as well as occupational health assessment studies in active workers exposed to xenobiotics.List of main abbreviations: AVOD: arterioveinous oxygen content difference.BMI: body mass index (in kg/m2).BSA: body surface area (in m2).BTPS: body temperature and saturated with water vapor.Bw: body weight (in kg).E: minute energy expenditure rate (in kcal/min).FGE: organ blood flow factor for the gravitational effect on blood circulation.H: oxygen uptake factor, volume of oxygen (at STPD) consumed to produce 1 kcal of energy expended.KBF: kidneys blood flow (in ml/min).LBF: liver blood flow (in ml/min).PBF: liver or kidneys blood flows expressed in terms of percentages (in %) of Qsup C values: namely PBF = (LBF or KBF/Qsup C) x 100.Q: cardiac output (in L/min or ml/min).Qsup C: cardiac output for the cohort of males or females in supination (in ml/min).STPD: standard temperature and pressure, dry air.sup: values measured when adults are in the supine position.up: values measured when adults are in the upright position.VDphys: physiological dead space at BTPS (in L).VT: tidal volume at BTPS (in L).VA: alveolar ventilation rate at BTPS (in L/min).VA/Q: ventilation-perfusion ratio (unitless).VE: minute ventilation rate at BTPS (in L/min).VO2: oxygen consumption rate (i.e. the oxygen uptake) at STPD (in L/min).VQ: ventilatory equivalent for VO2 (VE at BTPS /VO2 at STPD).

Kinetic time courses of inhaled silver nanoparticles in rats.

Silver nanoparticles (Ag NPs) are priority substances closely monitored by health and safety agencies. Despite their extensive use, some aspects of their toxicokinetics remain to be documented, in particular following inhalation, the predominant route of exposure in the workplace. A same experimental protocol and exposure conditions were reproduced two times (experiments E1 and E2) to document the kinetic time courses of inhaled Ag NPs. Rats were exposed nose-only to 20 nm Ag NPs during 6 h at a target concentration of 15 mg/m3 (E1: 218,341 ± 85,512 particles/cm3; E2, 154,099 ± 5728 particles/cm3). The generated aerosol showed a uniform size distribution of nanoparticle agglomerates with a geometric mean diameter ± SD of 79.1 ± 1.88 nm in E1 and 92.47 ± 2.19 nm in E2. The time courses of elemental silver in the lungs, blood, tissues and excreta were determined over 14 days following the onset of inhalation. Excretion profiles revealed that feces were the dominant excretion route and represented on average (± SD) 5.1 ± 3.4% (E1) and 3.3 ± 2.5% (E2) of the total inhaled exposure dose. The pulmonary kinetic profile was similar in E1 and E2; the highest percentages of the inhaled dose were observed between the end of the 6-h inhalation up to 6-h following the end of exposure, and reached 1.9 ± 1.2% in E1 and 2.5 ± 1.6% in E2. Ag elements found in the GIT followed the trend observed in lungs, with a peak observed at the end of the 6-h inhalation exposure and representing 6.4 ± 4.9% of inhaled dose, confirming a certain ingestion of Ag NPs from the upper respiratory tract. Analysis of the temporal profile of Ag elements in the liver showed two distinct patterns: (i) progressive increase in values with peak at the end of the 6-h inhalation period followed by a progressive decrease; (ii) second increase in values starting at 72 h post-exposure with maximum levels at 168-h followed by a progressive decrease. The temporal profiles of Ag elements in lymphatic nodes, olfactory bulbs, kidneys and spleen also followed a pattern similar to that of the liver. However, concentrations in blood and extrapulmonary organs were much lower than lung concentrations. Overall, results show that only a small percentage of the inhaled dose reached the lungs-most of the dose likely remained in the upper respiratory tract. The kinetic time courses in the gastrointestinal tract and liver showed that part of the inhaled Ag NPs was ingested; lung, blood and extrapulmonary organ profiles also suggest that a small fraction of inhaled Ag NPs progressively reached the systemic circulation by a direct translocation from the respiratory tract.

Volatile organic compounds (VOCs) in indoor air and tap water samples in residences of pregnant women living in an area of unconventional natural gas operations: Findings from the EXPERIVA study.

BACKGROUND: Northeastern British Columbia (Canada) is an area of unconventional natural gas (UNG) exploitation by hydraulic fracturing, which can release several contaminants, including volatile organic compounds (VOCs). To evaluate gestational exposure to contaminants in this region, we undertook the Exposures in the Peace River Valley (EXPERIVA) study. OBJECTIVES: We aimed to: 1) measure VOCs in residential indoor air and tap water from EXPERIVA participants; 2) compare concentrations with those in the general population and explore differences related to sociodemographic and housing characteristics; and 3) determine associations between VOC concentrations and density/proximity to UNG wells. METHODS: Eighty-five pregnant women participated. Passive air samplers were analyzed for 47 VOCs, and tap water samples were analyzed for 44 VOCs. VOC concentrations were compared with those from the Canadian Health Measure Survey (CHMS). We assessed the association between different metrics of well density/proximity and indoor air and tap water VOC concentrations using multiple linear regression. RESULTS: 40 VOCs were detected in >50% of air samples, whereas only 4 VOCs were detected in >50% of water samples. We observed indoor air concentrations >95th percentile of CHMS in 10-60% of samples for several compounds (acetone, 2-methyl-2-propanol, chloroform, 1,4-dioxane, hexanal, m/p-xylene, o-xylene, styrene, decamethylcyclopentasiloxane, dodecane and decanal). Indoor air levels of chloroform and tap water levels of total trihalomethanes were higher in Indigenous participants compared to non-Indigenous participants. Indoor air levels of chloroform and acetone, and tap water levels of total trihalomethanes were positively associated with UNG wells density/proximity metrics. Indoor air BTEX (benzene, toluene, ethylbenzene, xylenes) levels were positively correlated with some well density/proximity metrics. CONCLUSION: Our results suggest higher exposure to certain VOCs in pregnant women living in an area of intense unconventional natural gas exploitation compared with the general Canadian population, and that well density/proximity is associated with increased exposure to certain VOCs.

Impact of heat on biological concentrations of toluene and acetone resulting from exposure by inhalation: A pilot study.

Climatic conditions raise new concerns about the potential impact of heat on the absorption and kinetics of certain chemicals. The impact of 3 temperatures (21, 25 and 30 °C WBGT) on the toxicokinetics of toluene and acetone was therefore evaluated in five human subjects during controlled exposures in an inhalation chamber. Biological samples were collected and analyzed by GC-MS/MS. Increases between 4 and 85 % were observed for solvents concentrations in blood (30 vs 21 °C) while decreases in urine samples for acetone and o-cresol were measured at the end of the exposure period (4 h). Mean blood concentrations at 4 h are well correlated with temperature. Results suggest an increased absorption and/or a decreased elimination of volatile chemicals in the presence of heat. Higher increases of blood chemical concentrations were observed in heavier individuals. Further studies should include physiologically based toxicokinetic models to help in better understanding the mechanisms involved and their respective contribution.

Cardiopulmonary values and organ blood flows before and during heat stress: data in nine subjects at rest in the upright position.

Physiological changes associated with thermoregulation can influence the kinetics of chemicals in the human body such as alveolar ventilation (VA) and redistribution of blood flow to organs. In this study, the influence of heat stress on various physiological parameters was evaluated in nine male volunteers during sessions of exposure to wet-bulb globe temperatures (WBGT) of 21, 25, and 30 °C for 4 h. Skin and core temperatures and more than 20 cardiopulmonary parameters were measured. Liver, kidneys, brain, skin, and muscles blood flows were also determined based on published measurements. Results show that most subjects (eight out of nine) have been affected by the inhalation of hot and dry air at the WBGT of 30 °C. High respiratory rates, superficial tidal volumes, and low VA values were notably observed. The skin blood flow increased by 2.16-fold, whereas the renal blood flow and liver blood flow decreased by about by 11% and 18%, respectively. A complete set of key cardiopulmonary parameters in healthy male adults before and during heat stress was generated for use in physiologically based pharmacokinetic modeling. A toxicokinetic studies are ongoing to evaluate the impact of heat stress on the absorption, biotransformation and excretion rates of volatile xenobiotics.

A New Guidance for the Prediction of Hepatic Clearance in the Early Drug Discovery and Development from the in Vitro-to-in Vivo Extrapolation Method and an Approach for Exploring Whether an Albumin-Mediated Hepatic Uptake Phenomenon Could be Present Under in Vivo Conditions.

The in vitro-to-in vivo extrapolation (IVIVE) methods for predicting the hepatic clearance (CL) of drugs based on microsomal or hepatocyte data have certainly advanced; however, there is still place for improving the extrapolations from in vitro assays containing no plasma proteins. Accordingly, there is a discussion on whether the free drug hypothesis or an albumin (ALB)-mediated hepatic uptake phenomenon is the best scaling method. Therefore, the objectives of this study were to guide the prediction of CL and to diagnose which scaling method between the free drug hypothesis and ALB-mediated uptake could be more accurate; this, irrespective of the mechanism(s) governing CL if the drugs can get to the hepatocyte membrane. The analysis of several datasets demonstrated that almost all values of CL in vivo fall within the two calculated values of CL use as boundaries from: 1) the free drug hypothesis, and 2) ALB-mediated uptake. The average value from these two CL boundaries predicted the CL in vivo with an incredible accuracy. Validating these boundaries in preclinical species prior going to human as well as considering the fractional binding in plasma increased the accuracy. Overall, this study is another step towards guiding the CL prediction in drug discovery and development.

A novel solution of using mixed reality in bowel and oral and maxillofacial surgical telepresence: 3D mean value cloning algorithm.

BACKGROUND AND AIM: Most of the mixed reality models used in the surgical telepresence are suffering from the discrepancies in the boundary area and spatial-temporal inconsistency due to the illumination variation in the video frames. The aim behind this work is to propose a new solution that helps produce the composite video by merging the augmented video of the surgery site and virtual hand of the remote expertise surgeon. The purpose of the proposed solution is to decrease the processing time and enhance the accuracy of merged video by decreasing the overlay and visualization error and removing occlusion and artefacts. METHODOLOGY: The proposed system enhanced mean-value cloning algorithm that helps to maintain the spatial-temporal consistency of the final composite video. The enhanced algorithm includes the three-dimensional mean-value coordinates and improvised mean-value interpolant in the image cloning process, which helps to reduce the sawtooth, smudging and discolouration artefacts around the blending region. RESULTS: The accuracy in terms of overlay error of the proposed solution is improved from 1.01 to 0.80 mm, whereas the accuracy in terms of visualization error is improved from 98.8% to 99.4%. The processing time is reduced to 0.173 s from 0.211 s. The processing time and the accuracy of the proposed solution are enhanced as compared to the state-of-art solution. CONCLUSION: Our solution helps make the object of interest consistent with the light intensity of the target image by adding the space distance that helps maintain the spatial consistency in the final merged video.

Estimation of toluene exposure in air from BMA (S-benzylmercapturic acid) urinary measures using a reverse dosimetry approach based on physiologically pharmacokinetic modeling.

This study aimed to use a reverse dosimetry PBPK modeling approach to estimate toluene atmospheric exposure from urinary measurements of S-benzylmercapturic acid (BMA) in a small group of individuals and to evaluate the uncertainty associated to urinary spot-sampling compared to 24-h collected urine samples. Each exposure assessment technique was developed namely to estimate toluene air exposure from BMA measurements in 24-h urine samples (24-h-BMA) and from distributions of daily urinary BMA spot measurements (DUBSM). Model physiological parameters were described based upon age, weight, size and sex. Monte Carlo simulations with the PBPK model allowed converting DUBSM distribution (and 24-h-BMA) into toluene air levels. For the approach relying on DUBSM distribution, the ratio between the 95% probability of predicted toluene concentration and its 50% probability in each individual varied between 1.2 and 1.4, while that based on 24-h-BMA varied between 1.0 and 1.1. This suggests more variability in estimated exposure from spot measurements. Thus, estimating toluene exposure based on DUBSM distribution generated about 20% more uncertainty. Toluene levels estimated (0.0078-0.0138 ppm) are well below Health Canada's maximum chronic air guidelines. PBPK modeling and reverse dosimetry may be combined to interpret urinary metabolites data of VOCs and assess related uncertainties.

Repeat induced abortion and adverse childhood experiences in Aquitaine, France: a cross-sectional survey.

OBJECTIVE: The aim of the study was to analyse the relationship between adverse childhood experiences (ACEs) and repeat induced abortion, with regard to the potential effects of social deprivation and intimate partner violence. METHODS: An observational cross-sectional survey was conducted across each of the 25 abortion centres in Aquitaine, France, from 15 June to 15 September 2009. The sample comprised 806 women >18 years who had requested an induced abortion. Data were collected through a self-reported anonymous questionnaire on ACEs and experience of previous abortion. The main outcome measure was the percentage of repeat induced abortions. RESULTS: Among the participants, 473 (58.7%) were having their first induced abortion and 333 (41.3%) had already had a previous induced abortion. The abortion rank (first, second, third or more) was inversely related to the proportion of women with no ACE exposure (28%, 20% and 9%, respectively) and positively related to the proportion of women with a high ACE exposure (17%, 27% and 32%, respectively). Compared with women with no ACE exposure who were having a first induced abortion, in those with high ACE exposure, the odds of a third or more request for abortion was high: adjusted odds ratio 7.73 (95% confidence interval 3.56, 16.77). CONCLUSION: We found a strong graded link between the extent of ACE exposure and the occurrence of repeat induced abortion.

Comparative Assessment of Extrapolation Methods Based on the Conventional Free Drug Hypothesis and Plasma Protein-Mediated Hepatic Uptake Theory for the Hepatic Clearance Predictions of Two Drugs Extensively Bound to Both the Albumin And Alpha-1-Acid Glycoprotein.

Bteich and coworkers recently demonstrated in a companion manuscript (J Pharm Sci 109: https://doi.org/10.1016/j.xphs.2020.07.003) that a protein-mediated hepatic uptake have occurred in an isolated perfused rat liver (IPRL) model for two drugs (Perampanel; PER and Fluoxetine; FLU) that bind extensively to the albumin (ALB) and alpha-1-acid glycoprotein (AGP). However, to our knowledge, there is no quantitative model available to predict the impact of a plasma protein-mediated hepatic uptake on the extent of hepatic clearance (CLh) for a drug binding extensively to these two proteins. Therefore, the main objective was to predict the corresponding CLh, which is an extension of the companion manuscript. The method consisted of extrapolating the intrinsic clearance from the unbound fraction measured in the perfusate or the unbound fraction extrapolated to the surface of the hepatocyte membrane by adapting an existing model of protein-mediated hepatic uptake (i.e., the fup-adjusted model) to include a binding ratio between the ALB and AGP. This new approach showed a relevant improvement compared to the free drug hypothesis particularly for FLU that showed the highest degree of ALB-mediated uptake. Overall, this study is a first step towards the development of predictive methods of CLh by considering the binding to ALB and AGP.