Pharmacokinetic and tissue distribution study of eight volatile constituents in rats orally administrated with the essential oil of Artemisiae argyi Folium by GC-MS/MS.

Artemisia argyi is commonly used as a remedy for gynecological and respiratory disease in traditional Chinese medicine. The essential oil is considered as the major active ingredients of A. argyi, mainly composed of eucalyptol, α-thujone, camphor, borneol, bornyl acetate, eugenol, ß-caryophyllene, and caryophyllene oxide, while limited study addresses the in vivo disposition of these volatile ingredients. In present study, a rapid, sensitive and selective GC-MS/MS method has been developed and validated for the quantification of the eight volatile constituents in rat plasma and tissues after orally dosing with the essential oil of Artemisiae Argyi Folium (AAEO) using naphthalene as an internal standard (IS). The analytes were extracted from biosamples by liquid-liquid extraction with hexane/ethyl acetate. The GC separation was achieved on a TG-5SILMS column (30 m × 0.25 mm, 0.25 µm film thickness) and MS detection was performed on selective reaction monitoring (SRM) mode. The assay had a lower limit of quantification (LLOQ) less than 2 ng/ml for the analytes with good linearity (r ≥ 0.9907). Their disposition profile in rat plasma and tissues was characterized after orally giving AAEO, and the data revealed the analytes underwent rapid absorption from GI tract and were mainly transferred to the liver, heart, kidney, lung, and spleen with prompt elimination. The results provided a meaningful basis for guiding the pharmacodynamic study and clinical applications of this herbal medicine.

Pulmonary and systemic toxicity in rats following inhalation exposure of 3-D printer emissions from acrylonitrile butadiene styrene (ABS) filament.

BACKGROUND: Fused filament fabrication 3-D printing with acrylonitrile butadiene styrene (ABS) filament emits ultrafine particulates (UFPs) and volatile organic compounds (VOCs). However, the toxicological implications of the emissions generated during 3-D printing have not been fully elucidated. AIM AND METHODS: The goal of this study was to investigate the in vivo toxicity of ABS-emissions from a commercial desktop 3-D printer. Male Sprague Dawley rats were exposed to a single concentration of ABS-emissions or air for 4 hours/day, 4 days/week for five exposure durations (1, 4, 8, 15, and 30 days). At 24 hours after the last exposure, rats were assessed for pulmonary injury, inflammation, and oxidative stress as well as systemic toxicity. RESULTS AND DISCUSSION: 3-D printing generated particulate with average particle mass concentration of 240 ± 90 µg/m³, with an average geometric mean particle mobility diameter of 85 nm (geometric standard deviation = 1.6). The number of macrophages increased significantly at day 15. In bronchoalveolar lavage, IFN-γ and IL-10 were significantly higher at days 1 and 4, with IL-10 levels reaching a peak at day 15 in ABS-exposed rats. Neither pulmonary oxidative stress responses nor histopathological changes of the lungs and nasal passages were found among the treatments. There was an increase in platelets and monocytes in the circulation at day 15. Several serum biomarkers of hepatic and kidney functions were significantly higher at day 1. CONCLUSIONS: At the current experimental conditions applied, it was concluded that the emissions from ABS filament caused minimal transient pulmonary and systemic toxicity.

Spectral Reflectance Measurement of Evaporating Chemical Films: Initial Results and Application to Skin Permeation.

The present study has 2 aims. First, the method of spectral reflectance was used to measure evaporation rates of thin (∼25-300 µm) films of neat liquid volatile organic chemicals exposed to a well-regulated wind speed u. Gas-phase evaporation mass transfer coefficient (kevap) measurements of 10 chemicals, 9 of which were measured at similar u, are predicted (slope of log-log data = 1.01; intercept = 0.08; R2 = 0.996) by a previously proposed mass transfer correlation. For one chemical, isoamyl alcohol, the dependence of kevap on u0.52 was measured, in support of the predicted exponent value of ½. Second, measured kevap of nicotine was used as an input in analytical models based on diffusion theory to estimate the absorbed fraction (Fabs) of a small dose (5 µL/cm2) applied to human epidermis in vitro. The measured Fabs was 0.062 ± 0.023. Model-estimated values are 0.066 and 0.115. Spectral reflectance is a precise method of measuring kevap of liquid chemicals, and the data are well described by a simple gas-phase mass transfer coefficient. For nicotine under the single exposure condition measured herein, Fabs is well-predicted from a theoretical model that requires knowledge of kevap, maximal dermal flux, and membrane lag time.

GC-MS method for determination and pharmacokinetic study of seven volatile constituents in rat plasma after oral administration of the essential oil of Rhizoma Curcumae.

Rhizoma Curcumae (RC) is perennial herbaceous plant mainly present in China, India and Malaysiabelong, which is belong to the family Zingiberaceae. The rhizomes of RC have been used as a famous traditional Chinese medicine for the treatment of syndrome of blood stasis. A selective, sensitive and accurate gas chromatography-mass spectroscopy (GC-MS) method was developed and validated in this paper for the simultaneous determination and pharmacokinetic study of α-Pinene, 1,8-Cineole, Borneol, ß-Elemene, Curcumol, Germacrone, and Curdione in rat plasma. The GC-MS system was operated under selected ion monitoring (SIM) mode using a DB-5 (30m×0.25mm (ID)×0.25µm (film thickness)) column. Linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability were used to validate the current GC/MS assay. The lowest limit of quantifications (LLOQ) of α-Pinene, 1,8-Cineole, Borneol, ß-Elemene, Curcumol, Germacrone, Curdione were 2.71ng/mL, 7.76ng/mL, 3.37ng/mL, 21.68ng/mL, 40.21ng/mL, 24.84ng/mL and 47.78ng/mL respectively. After oral administration 1.0g/kg of RC rhizomes to the rats, the maximum plasma concentration (Cmax) was 34.72±9.97ng/mL for α-Pinene, 99.86±5.54ng/mL for 1,8-Cineole, 16.10±3.37ng/mL for Borneol, 248.98±86.19ng/mL for ß-Elemene, 673.75±104.15ng/mL for Curcumol, 2353.64±637.83ng/mL for Germacrone and 2420.04±708.51ng/mL for Curdione. The time to reach the maximum plasma concentration (Tmax) was 2.33±0.29h for α-Pinene, 0.67±0.29h for 1,8-Cineole, 1.33±0.58h for Borneol, 1.83±0.76h for ß-Elemene, 0.83±0.29h for Curcumol, 0.89±0.98h for Germacrone and 1.17±0.76h for Curdione. In this study, a validated GC-MS method for simultaneous determination of seven volatile oil compounds in rat plasma after oral administration of the extract of RC rhizomes and research on their pharmacokinetics was validated. The recovery and stability results were satisfactory in this study.

Investigation of faecal volatile organic metabolites as novel diagnostic biomarkers in inflammatory bowel disease.

BACKGROUND: The aetiology of inflammatory bowel disease (IBD) remains poorly understood. Recent evidence suggests an important role of gut microbial dysbiosis in IBD, and this may be associated with changes in faecal volatile organic metabolites (VOMs). AIM: To describe the changes in the faecal VOMs of patients with IBD and establish their diagnostic potential as non-invasive biomarkers. METHODS: Faecal samples were obtained from 117 people with Crohn's disease (CD), 100 with ulcerative colitis (UC), and 109 healthy controls. Faecal VOMs were extracted using solid-phase micro-extraction and analysed by gas chromatography mass spectrometry. Data analysis was carried out using partial least squares-discriminate analysis (PLS-DA) to determine class membership based on distinct metabolomic profiles. RESULTS: The PLS-DA model showed clear separation of active CD from inactive disease and healthy controls (P < 0.001). Heptanal, 1-octen-3-ol, 2-piperidinone and 6-methyl-2-heptanone were up-regulated in the active CD group [variable important in projection (VIP) score 2.8, 2.7, 2.6 and 2.4, respectively], while methanethiol, 3-methyl-phenol, short-chain fatty acids and ester derivatives were found to be less abundant (VIP score of 3.5, 2.6, 1.5 and 1.2, respectively). The PLS-DA model also separated patients with small bowel CD from healthy controls and those with colonic CD from UC (P < 0.001). In contrast, less distinct separation was observed between active UC, inactive UC and healthy controls. CONCLUSIONS: Analysis of faecal volatile organic metabolites can provide an understanding of gut metabolomic changes in IBD. It has the potential to provide a non-invasive means of diagnosing IBD, and can differentiate between UC and CD.

Risk assessment of volatile organic compounds benzene, toluene, ethylbenzene, and xylene (BTEX) in consumer products.

Exposure and risk assessment was performed by evaluating levels of volatile organic compounds (VOC) benzene, toluene, ethylbenzene, and xylene (BTEX) in 207 consumer products. The products were categorized into 30 different items, consisting of products of different brands. Samples were analyzed for BTEX by headspace-gas chromatography/mass spectrometry (headspace-GC/MS) with limit of detection (LOD) of 1 ppm. BTEX were detected in 59 consumer products from 18 item types. Benzene was detected in whiteout (ranging from not detected [ND] to 3170 ppm), glue (1486 ppm), oil-based ballpoint pens (47 ppm), and permanent (marking) pens (2 ppm). Toluene was detected in a leather cleaning product (6071 ppm), glue (5078 ppm), whiteout (1130 ppm), self-adhesive wallpaper (15-1012 ppm), shoe polish (806 ppm), permanent pen (609 ppm), wig adhesive (372 ppm), tapes (2-360 ppm), oil-based ballpoint pen (201 ppm), duplex wallpaper (12-52 ppm), shoes (27 ppm), and air freshener (13 ppm). High levels of ethylbenzene were detected in permanent pen (ND-345,065 ppm), shoe polish (ND-277,928 ppm), leather cleaner (42,223 ppm), whiteout (ND-2,770 ppm), and glue (ND-792 ppm). Xylene was detected in permanent pen (ND-285,132 ppm), shoe polish (ND-87,298 ppm), leather cleaner (12,266 ppm), glue (ND-3,124 ppm), and whiteout (ND-1,400 ppm). Exposure assessment showed that the exposure to ethylbenzene from permanent pens ranged from 0 to 3.11 mg/kg/d (men) and 0 to 3.75 mg/kg/d (women), while for xylene, the exposure ranges were 0-2.57 mg/kg/d and 0-3.1 mg/kg/d in men and women, respectively. The exposure of women to benzene from whiteout ranged from 0 to 0.00059 mg/kg/d. Hazard index (HI), defined as a ratio of exposure to reference dose (RfD), for ethylbenzene was 31.1 (3.11 mg/kg/d/0.1 mg/kg/d) and for xylene (2.57 mg/kg/d/0.2 mg/kg/d) was 12.85, exceeding 1 for both compounds. Cancer risk for benzene was calculated to be 3.2 × 10(-5) based on (0.00059 mg/kg/d × 0.055 mg/kg-d(-1), cancer potency factor), assuming that 100% of detected levels in some products such as permanent pens and whiteouts were exposed in a worst-case scenario. These data suggest that exposure to VOC via some consumer products exceeded the safe limits and needs to be reduced.

Clinical breath analysis: discriminating between human endogenous compounds and exogenous (environmental) chemical confounders.

Volatile organic compounds (VOCs) in exhaled breath originate from current or previous environmental exposures (exogenous compounds) and internal metabolic (anabolic and catabolic) production (endogenous compounds). The origins of certain VOCs in breath presumed to be endogenous have been proposed to be useful as preclinical biomarkers of various undiagnosed diseases including lung cancer, breast cancer, and cardio-pulmonary disease. The usual approach is to develop difference algorithms comparing VOC profiles from nominally healthy controls to cohorts of patients presenting with a documented disease, and then to apply the resulting rules to breath profiles of subjects with unknown disease status. This approach to diagnosis has a progression of sophistication; at the most rudimentary level, all measurable VOCs are included in the model. The next level corrects exhaled VOC concentrations for current inspired air concentrations. At the highest level, VOCs exhibiting discriminatory value also require a plausible biochemical pathway for their production before inclusion. Although these approaches have all shown some level of success, there is concern that pattern recognition is prone to error from environmental contamination and between-subject variance. In this paper, we explore the underlying assumptions for the interpretation and assignment of endogenous compounds with probative value for assessing changes. Specifically, we investigate the influence of previous exposures, elimination mechanisms and partitioning of exogenous compounds as confounders of true endogenous compounds. We provide specific examples based on a simple classical pharmacokinetic approach to identify potential misinterpretations of breath data and propose some remedies.

Benzothiazole toxicity assessment in support of synthetic turf field human health risk assessment.

Synthetic turf fields cushioned with crumb rubber may be a source of chemical exposure to those playing on the fields. Benzothiazole (BZT) may volatilize from crumb rubber and result in inhalation exposure. Benzothiazole has been the primary rubber-related chemical found in synthetic turf studies. However, risks associated with BZT have not been thoroughly assessed, primarily because of gaps in the database. This assessment provides toxicity information for a human health risk assessment involving BZT detected at five fields in Connecticut. BZT exerts acute toxicity and is a respiratory irritant and dermal sensitizer. In a genetic toxicity assay BZT was positive in Salmonella in the presence of metabolic activation. BZT metabolism involves ring-opening and formation of aromatic hydroxylamines, metabolites with mutagenic and carcinogenic potential. A structural analogue 2-mercaptobenzothiazole (2-MBZT) was more widely tested and so is used as a surrogate for some endpoints. 2-MBZT is a rodent carcinogen with rubber industry data supporting an association with human bladder cancer. The following BZT toxicity values were derived: (1) acute air target of 110 µg/m(3) based upon a BZT RD(50) study in mice relative to results for formaldehyde; (2) a chronic noncancer target of 18 µg/m(3) based upon the no-observed-adverse-effect level (NOAEL) in a subchronic dietary study in rats, dose route extrapolation, and uncertainty factors that combine to 1000; (3) a cancer unit risk of 1.8E-07/µg-m(3) based upon a published oral slope factor for 2-MBZT and dose-route extrapolation. While there are numerous uncertainties in the BZT toxicology database, this assessment enables BZT to be quantitatively assessed in risk assessments involving synthetic turf fields. However, this is only a screening-level assessment, and research that better defines BZT potency is needed.

Chemical-specific screening criteria for interpretation of biomonitoring data for volatile organic compounds (VOCs)--application of steady-state PBPK model solutions.

The National Health and Nutrition Examination Survey (NHANES) generates population-representative biomonitoring data for many chemicals including volatile organic compounds (VOCs) in blood. However, no health or risk-based screening values are available to evaluate these data from a health safety perspective or to use in prioritizing among chemicals for possible risk management actions. We gathered existing risk assessment-based chronic exposure reference values such as reference doses (RfDs), reference concentrations (RfCs), tolerable daily intakes (TDIs), cancer slope factors, etc. and key pharmacokinetic model parameters for 47 VOCs. Using steady-state solutions to a generic physiologically-based pharmacokinetic (PBPK) model structure, we estimated chemical-specific steady-state venous blood concentrations across chemicals associated with unit oral and inhalation exposure rates and with chronic exposure at the identified exposure reference values. The geometric means of the slopes relating modeled steady-state blood concentrations to steady-state exposure to a unit oral dose or unit inhalation concentration among 38 compounds with available pharmacokinetic parameters were 12.0 microg/L per mg/kg-d (geometric standard deviation [GSD] of 3.2) and 3.2 microg/L per mg/m(3) (GSD=1.7), respectively. Chemical-specific blood concentration screening values based on non-cancer reference values for both oral and inhalation exposure range from 0.0005 to 100 microg/L; blood concentrations associated with cancer risk-specific doses at the 1E-05 risk level ranged from 5E-06 to 6E-02 microg/L. The distribution of modeled steady-state blood concentrations associated with unit exposure levels across VOCs may provide a basis for estimating blood concentration screening values for VOCs that lack chemical-specific pharmacokinetic data. The screening blood concentrations presented here provide a tool for risk assessment-based evaluation of population biomonitoring data for VOCs and are most appropriately applied to central tendency estimates for such datasets.