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.

Acetone-assisted co-processing of meloxicam with amino acids for enhanced dissolution rate.

Meloxicam is a widely used non-steroidal anti-inflammatory agent. However, its erratic and poor dissolution delays its onset of action. Dissolution enhancement of such medicine is essential to obtain rapid pain relief. Amino acids showed high potential to enhance the dissolution rate of drugs after co-processing. Accordingly, the objective of this work was to investigate the effect of co-processing of meloxicam with arginine, cysteine, and glycine on its crystalline structure and dissolution rate. Meloxicam was mixed with increasing molar ratios of amino acids before acetone-assisted kneading. The resulting products were examined using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction in addition to monitoring the dissolution behavior. Combined instrumental analysis indicated salt formation with a possibility of further crystalline changes at high concentration of amino acids. Salt formation and crystalline structure modification were associated with a significant increase in the dissolution rate of meloxicam. The study introduced amino acids as potential excipients for enhanced dissolution of meloxicam after wet co-processing.

Modular Acid-Activatable Acetone-Based Ketal-Linked Nanomedicine by Dexamethasone Prodrugs for Enhanced Anti-Rheumatoid Arthritis with Low Side Effects.

Given the physically encapsulated payloads with drug burst release and/or low drug loading, it is critical to initiate an innovative prodrug strategy to optimize the design of modular nanomedicines. Here, we designed modular pH-sensitive acetone-based ketal-linked prodrugs of dexamethasone (AKP-dexs) and formulated them as nanoparticles. We comprehensively studied the relationships between AKP-dex structure and properties, and we selected two types of AKP-dex-loaded nanoparticles for in vivo studies on the basis of their size, drug loading, and colloidal stability. In a collagen-induced arthritis rat model, these AKP-dex-loaded nanoparticles showed higher accumulation in inflamed joints and better therapeutic efficacy than free dexamethasone phosphate with less-severe side effects. AKP-dex-loaded nanoparticles may be useful for treating other inflammatory diseases and thus have great translational potential. Our findings represent an important step toward the development of practical applications for acetone-based ketal-linked prodrugs and are useful in the design of modular nanomedicines.

Ethylone-Related Deaths: Toxicological Findings.

Synthetic cathinones are an emerging class of designer drugs, frequently with deceptive labels and a multitude of analogs to circumvent drug control regulations. Research regarding the pharmacological effects and toxicity of these amphetamine derivatives is scarce, heightening the risk to the public health and safety. The composition of synthetic cathinone products continually changes and laboratories began to notice ethylone-positive products in late 2011. This report presents nine postmortem cases in whom ethylone was identified. Ethylone was isolated using solid-phase extraction and detected by gas chromatography-mass spectrometry. Seven of the cases had measurable concentrations of ethylone in blood, ranging from 38 to 2,572 ng/mL; ethylone was detected in the blood sample of one case with a concentration below the assay limit of quantification (25 ng/mL), and one case did not have detectable ethylone in blood. Besides ethylone, all but one case were also positive for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol; seven cases had other drugs quantified in blood, including ethanol, alprazolam, benzoylecgonine, diphenhydramine, morphine and tramadol. In five cases where ethylone was present at blood concentrations >400 ng/mL, no other drugs excluding ethanol, cannabis metabolite and doxylamine (one case) were found. The assay also tested for mephedrone, methylone and three dimethoxyamphetamine analogs; no case was positive for these analytes. The present report documents postmortem blood concentrations of ethylone, a novel synthetic cathinone, along with other concurrently identified substances. The findings provide valuable information for developing analytical assays and evaluating a toxic concentration range of ethylone.

Ventilation/perfusion ratios measured by multiple inert gas elimination during experimental cardiopulmonary resuscitation.

BACKGROUND: During cardiopulmonary resuscitation (CPR) the ventilation/perfusion distribution (VA /Q) within the lung is difficult to assess. This experimental study examines the capability of multiple inert gas elimination (MIGET) to determine VA /Q under CPR conditions in a pig model. METHODS: Twenty-one anaesthetised pigs were randomised to three fractions of inspired oxygen (1.0, 0.7 or 0.21). VA/ Q by micropore membrane inlet mass spectrometry-derived MIGET was determined at baseline and during CPR following induction of ventricular fibrillation. Haemodynamics, blood gases, ventilation distribution by electrical impedance tomography and return of spontaneous circulation were assessed. Intergroup differences were analysed by non-parametric testing. RESULTS: MIGET measurements were feasible in all animals with an excellent correlation of measured and predicted arterial oxygen partial pressure (R(2) = 0.96, n = 21 for baseline; R(2) = 0.82, n = 21 for CPR). CPR induces a significant shift from normal VA /Q ratios to the high VA /Q range. Electrical impedance tomography indicates a dorsal to ventral shift of the ventilation distribution. Diverging pulmonary shunt fractions induced by the three inspired oxygen levels considerably increased during CPR and were traceable by MIGET, while 100% oxygen most negatively influenced the VA /Q. Return of spontaneous circulation were achieved in 52% of the animals. CONCLUSIONS: VA /Q assessment by MIGET is feasible during CPR and provides a novel tool for experimental purposes. Changes in VA /Q caused by different oxygen fractions are traceable during CPR. Beyond pulmonary perfusion deficits, these data imply an influence of the inspired oxygen level on VA /Q. Higher oxygen levels significantly increase shunt fractions and impair the normal VA /Q ratio.

A quantitative study of the influence of inhaled compounds on their concentrations in exhaled breath.

Throughout the development of breath analysis research, there has been interest in how the concentrations of trace compounds in exhaled breath are related to their concentrations in the ambient inhaled air. In considering this, Phillips introduced the concept of 'alveolar gradient' and judged that the measured exhaled concentrations of volatile organic compounds should be diminished by an amount equal to their concentrations in the inhaled ambient air. The objective of the work described in this paper was to investigate this relationship quantitatively. Thus, experiments have been carried out in which inhaled air was polluted by seven compounds of interest in breath research, as given below, and exhaled breath has been analysed by SIFT-MS as the concentrations of these compounds in the inhaled air were reduced. The interesting result obtained is that all the exogenous compounds are partially retained in the exhaled breath and there are close linear relationships between the exhaled and inhaled air concentrations for all seven compounds. Thus, retention coefficients, a, have been derived for the following compounds: pentane, 0.76 ± 0.09; isoprene, 0.66 ± 0.04; acetone, 0.17 ± 0.03; ammonia, 0.70 ± 0.13, methanol, 0.29 ± 0.02; formaldehyde, 0.06 ± 0.03; deuterated water (HDO), 0.09 ± 0.02. From these data, correction to breath analyses for inhaled concentration can be described by coefficients specific to each compound, which can be close to 1 for hydrocarbons, as applied by Phillips, or around 0.1, meaning that inhaled concentrations of such compounds can essentially be neglected. A further deduction from the experimental data is that under conditions of the inhalation of clean air, the measured exhaled breath concentrations of those compounds should be increased by a factor of 1/(1 - a) to correspond to gaseous equilibrium with the compounds dissolved in the mixed venous blood entering the alveoli. Thus, for isoprene, this is a factor of 3, which we have confirmed experimentally by re-breathing experiments.

Evaluation of occupational exposure: comparison of biological and environmental variabilities using physiologically based toxicokinetic modeling.

PURPOSE: Few studies compare the variabilities that characterize environmental (EM) and biological monitoring (BM) data. Indeed, comparing their respective variabilities can help to identify the best strategy for evaluating occupational exposure. The objective of this study is to quantify the biological variability associated with 18 bio-indicators currently used in work environments. METHOD: Intra-individual (BV(intra)), inter-individual (BV(inter)), and total biological variability (BV(total)) were quantified using validated physiologically based toxicokinetic (PBTK) models coupled with Monte Carlo simulations. Two environmental exposure profiles with different levels of variability were considered (GSD of 1.5 and 2.0). RESULTS: PBTK models coupled with Monte Carlo simulations were successfully used to predict the biological variability of biological exposure indicators. The predicted values follow a lognormal distribution, characterized by GSD ranging from 1.1 to 2.3. Our results show that there is a link between biological variability and the half-life of bio-indicators, since BV(intra) and BV(total) both decrease as the biological indicator half-lives increase. BV(intra) is always lower than the variability in the air concentrations. On an individual basis, this means that the variability associated with the measurement of biological indicators is always lower than the variability characterizing airborne levels of contaminants. For a group of workers, BM is less variable than EM for bio-indicators with half-lives longer than 10-15 h. CONCLUSION: The variability data obtained in the present study can be useful in the development of BM strategies for exposure assessment and can be used to calculate the number of samples required for guiding industrial hygienists or medical doctors in decision-making.

Separating uncertainty and physiological variability in human PBPK modelling: The example of 2-propanol and its metabolite acetone.

Parameter uncertainty and interindividual variability in the predictions of a generic human physiologically based pharmacokinetic (PBPK) model were separated by means of nested Monte Carlo simulations. Separate information on uncertainty and variability can help decision makers to identify whether they should focus on identification of sensitive individuals rather than on additional research to obtain more accurate estimates for particular parameters. In this study, the concentration of acetone in human blood was simulated during and after 4h of exposure to 2-propanol via air. It was shown that the influence of interindividual variability and uncertainty varies over time, from the uptake phase, via a steady-state phase, into the elimination phase. During the uptake phase, interindividual variability played a significant role in the predicted variation of acetone concentrations in blood, with variability up to a factor of 2-3 (90th/10th percentile ratio). After exposure ceased, the parameter uncertainty increased up to a factor of 100 after 16h, whereas variability remained unchanged. Parameter importance analysis indicated that variability in human physiology had the largest influence on predicted acetone concentrations in blood during exposure. Uncertainty in the metabolic rate of acetone was most important after the exposure had ceased and overruled variability.

Wetting ability of an acetone/based etch&rinse adhesive after NaOCl-treatment

Objectives: to evaluate the effect of sodium hypochlorite (NaOCl) treatment on surface dentin roughness (Ra) and contact angle (CA) when using Prime&Bond NT adhesive (PB NT). Study Design: Extracted human third molars were sectioned to expose flat, superficial and deep dentin surfaces. CA and Ra were measured (1) before and (2) after 35% H3PO4 etching, and (3) H3PO4 etching + 5% NaOCl treated for 2 minutes before the application of PB NT. CA was measured by the Axisymmetric Drop Shape Analysis Technique using distilled and deionized water and PB NT. Roughness was evaluated with a profilometer, twelve radial measurements were performed in each treatment surface. Data were analyzed with two-way ANOVA and Newman-Keuls multiple comparison test procedures. Results: CA values decreased after acid etching and even more after NaOCl treatment on deep dentin when water was tested. With resin, there were not differences on CA results after H3PO4 neither after NaOCl treatment, in both dentin surfaces. Etching and NaOCl treatment resulted in surface roughness increase. Conclusions: In spite of the higher roughness after NaOCl treatment on superficial and deep dentin, the use of 5% NaOCl for 2 min after dentin demineralization when PB NT was employed did not improved the wettability of dentin, probably due to nanofiller content and/or hydrogen-bonding interactions with residues of the organic matrix on collagen-depleted dentin (AU)

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone.

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide (NO) have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which may reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways, (ii) the concentrations in the tracheo-bronchial lining fluid, (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, the model illuminates the discrepancies between observed and theoretically predicted blood-breath ratios of acetone during resting conditions, i.e., in steady state. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases and thus is expected to have general relevance for a wider range of blood-borne inert gases. The chief intention of the present modeling study is to provide mechanistic relationships for further investigating the exhalation kinetics of acetone and other water-soluble species. This quantitative approach is a first step towards new guidelines for breath gas analyses of volatile organic compounds, similar to those for nitric oxide.

Chemical-specific adjustment factors for intraspecies variability of acetone toxicokinetics using a probabilistic approach.

Human health risk assessment has begun to depart from the traditional methods by replacement of the default assessment factors by more reasonable, data-driven, so-called chemical-specific adjustment factors (CSAFs). This study illustrates a scheme for deriving CSAFs in the general and occupationally exposed populations by quantifying the intraspecies toxicokinetic variability in surrogate dose using probabilistic methods. Acetone was used as a model substance. The CSAFs were derived by Monte Carlo simulation, combining a physiologically based pharmacokinetic model for acetone, probability distributions of the model parameters from a Bayesian analysis of male volunteer experimental data, and published distributions of physiological and anatomical parameters for females and children. The simulations covered how factors such as age, gender, endogenous acetone production, and fluctuations in workplace air concentration and workload influence peak and average acetone levels in blood, used as surrogate doses. According to the simulations, CSAFs of 2.1, 2.9, and 3.8 are sufficient to cover the differences in surrogate dose at the upper 90th, 95th, and 97.5th percentile, respectively, of the general population. However, higher factors were needed to cover the same percentiles of children. The corresponding CSAFs for the occupationally exposed population were 1.6, 1.8, and 1.9. The methodology presented herein allows for derivation of CSAFs not only for populations as a whole but also for subpopulations of interest. Moreover, various types of experimental data can readily be incorporated in the model.

Bayesian population analysis of a washin-washout physiologically based pharmacokinetic model for acetone.

The aim of this study was to derive improved estimates of population variability and uncertainty of physiologically based pharmacokinetic (PBPK) model parameters, especially of those related to the washin-washout behavior of polar volatile substances. This was done by optimizing a previously published washin-washout PBPK model for acetone in a Bayesian framework using Markov chain Monte Carlo simulation. The sensitivity of the model parameters was investigated by creating four different prior sets, where the uncertainty surrounding the population variability of the physiological model parameters was given values corresponding to coefficients of variation of 1%, 25%, 50%, and 100%, respectively. The PBPK model was calibrated to toxicokinetic data from 2 previous studies where 18 volunteers were exposed to 250-550 ppm of acetone at various levels of workload. The updated PBPK model provided a good description of the concentrations in arterial, venous, and exhaled air. The precision of most of the model parameter estimates was improved. New information was particularly gained on the population distribution of the parameters governing the washin-washout effect. The results presented herein provide a good starting point to estimate the target dose of acetone in the working and general populations for risk assessment purposes.

Transdermal resorption of an ethanol- and 2-propanol-containing skin disinfectant.

BACKGROUND AND AIMS: Ethanol- or 2-propanol-containing disinfectant agents are widely used in medical practice, particularly in the surgical environment. It was the primary objective of this phase I study to comparatively investigate the transdermal resorption of ethanol and 2-propanol within 1 h after dermal application of the two agents as single preparations and a commercial product containing both alcohols in combination, respectively. The secondary objective was to examine whether a mutual influence of the two alcohols in combination exists. MATERIALS AND METHODS: Following the double-blind, randomized, three-times cross-over design for this clinical trial, 20 ml of three different alcohol-containing disinfectants were applied on a 200-cm(2) gauze swab on skin areas, identical in size and location, of 14 healthy volunteers for 10 min to investigate the absorption rate of ethanol and 2-propanol with special focus on the question whether the two alcohols might influence each other's absorption rate when being applied in combination. RESULTS: No clinically relevant enhancement of dermal absorption, with respect to ethanol and 2-propanol, could be observed within 1 h after application, neither when used as single preparations, nor in combination. CONCLUSION: Therefore, the use of ethanol- and 2-propanol-containing disinfectants in the medical environment can be considered as safe.

Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling.

Chlordecone (CD) and mirex (M) differ by a single carbonyl group in CD in place of two chlorines in M. Although both compounds are lipophilic, their tissue distributions differ markedly: CD concentrations are highest in liver; M concentrations are highest in fat. We used tissue time course data in rats from our laboratory for CD and M and literature data from monkeys to develop PBPK models to study differences in liver and fat partitioning. The PK model for M had partitioning in tissue without specific hepatic binding. The CD model had partitioning similar to M, and also included liver binding: the maximal binding (B(max)) and binding affinity constant (Kd) required to describe the rat data were 370 nmol/g liver and 100 nM, respectively. To see if other ketones with electron withdrawing constituents at the alpha carbon were also preferentially distributed to liver, we developed a PBPK description for tissue distribution of hexafluoroacetone (HFA). Compared to acetone, HFA is known to be preferentially sequestered in liver and more slowly excreted unchanged from the body. Acetone is more equally distributed to tissues. HFA distribution was evaluated with a PBPK model that included hepatic binding. B(max) and Kd were 1.58 micromol/g liver and 301 microM. In summary, liver sequestration of CD and HFA most likely represents relatively high-affinity but reversible binding of activated carbonyls in these compounds (activated by the presence of electron withdrawing substituents on the alpha-carbons) with glutathione and glutathione transferases, that are present at much higher concentrations in liver than in other tissues. Strong, but reversible hemithioketal formation with active sulfhydryls may also be associated with the toxic responses to CD and HFA.

A human physiological model describing acetone kinetics in blood and breath during various levels of physical exercise.

Physiologically based toxicokinetic (PBTK) modeling of human experimental data suggests difficulties to simultaneously describe the time courses of inhaled polar solvents in blood and breath, especially if exposures occur during physical exercise. We attribute this to the washin-washout effect in the airways. The aim was to develop a PBTK-model that explains the behavior of acetone in blood and exhaled air at different levels of physical exercise. The model includes exchange of inhaled solvent vapor with the blood flow via the mucosa and separate compartments to describe working and resting muscles. The developed model was contrasted to a traditional PBTK-model where the conducting airways were regarded as an inert tube. Our model predictions agrees well with experimentally observed acetone levels in both arterial blood and end- and mixed-exhaled air from 26 inhalation experiments conducted with 18 human volunteers at 0, 50, 100 and 150 W workload. In contrast, the inert-tube model was unable to describe the data. The developed model is to our knowledge the first which explains the toxicokinetics of acetone at such various levels of physical exercise. It may be useful in breath monitoring and to obtain more accurate estimates of absorbed dose during inhalation of polar volatiles.

Synthesis and evaluation of inhaled [11C]butane and intravenously injected [11C]acetone as potential radiotracers for studying inhalant abuse.

The phenomenon of inhalant abuse is a growing problem in the US and many countries around the world. Yet, relatively little is known about the pharmacokinetic properties of inhalants that underlie their abuse potential. While the synthesis of 11C-labeled toluene, acetone and butane has been proposed in the literature, none of these compounds has been developed as radiotracers for PET studies. In the present report we extend our previous studies with [11C]toluene to include [11C]acetone and [11C]butane with the goal of comparing the pharmacokinetic profiles of these three volatile abused substances. Both [11C]toluene and [11C]acetone were administered intravenously and [11C]butane was administered via inhalation to anesthesized baboons. Rapid and efficient uptake of radiolabeled toluene and acetone into the brain was followed by fast clearance in the case of toluene and slower kinetics in the case of acetone. [11C]Butane was detected in the blood and brain following inhalation, but the levels of radioactivity in both tissues dropped to half of the maximal values over the period of less than a minute. To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled acetone and butane in nonhuman primates. These data provide insight into the pharmacokinetic features possibly associated with the abuse liability of toluene, acetone and butane.

Dermal uptake of chloroform and haloketones during bathing.

Dermal contact with some organic disinfection by-products (DBPs) such as trihalomethanes in chlorinated drinking water has been established to be an important exposure route. We evaluated dermal absorption of two haloketones (1,1-dichloropropanone and 1,1,1-trichloropropanone) and chloroform while bathing, by collecting and analyzing time profiles of expired breath samples of six human subjects during and following a 30-min bath. The DBP concentrations in breath increased towards a maximum concentration during bathing. The maximum haloketone breath concentration during dermal exposure ranged from 0.1 to 0.9 microg / m(3), which was approximately two orders of magnitude lower than the maximum chloroform breath concentration during exposure. Based on a one-compartment model, the in vivo permeability of chloroform, 1,1-dichloropropanone, and 1,1,1-trichloropropanone were approximated to be 0.015, 7.5 x 10(- 4), and 4.5 x 10(- 4) cm / h, respectively. Thus, haloketones are much less permeable across human skin under normal bathing conditions than is chloroform. These findings will be useful for future assessment of total human exposure and consequent health risk of these DBPs.

Framework for evaluation of physiologically-based pharmacokinetic models for use in safety or risk assessment.

Proposed applications of increasingly sophisticated biologically-based computational models, such as physiologically-based pharmacokinetic models, raise the issue of how to evaluate whether the models are adequate for proposed uses, including safety or risk assessment. A six-step process for model evaluation is described. It relies on multidisciplinary expertise to address the biological, toxicological, mathematical, statistical, and risk assessment aspects of the modeling and its application. The first step is to have a clear definition of the purpose(s) of the model in the particular assessment; this provides critical perspectives on all subsequent steps. The second step is to evaluate the biological characterization described by the model structure based on the intended uses of the model and available information on the compound being modeled or related compounds. The next two steps review the mathematical equations used to describe the biology and their implementation in an appropriate computer program. At this point, the values selected for the model parameters (i.e., model calibration) must be evaluated. Thus, the fifth step is a combination of evaluating the model parameterization and calibration against data and evaluating the uncertainty in the model outputs. The final step is to evaluate specialized analyses that were done using the model, such as modeling of population distributions of parameters leading to population estimates for model outcomes or inclusion of early pharmacodynamic events. The process also helps to define the kinds of documentation that would be needed for a model to facilitate its evaluation and implementation.