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Volatile organic compounds (VOCs) are the air pollutants emitted from the petrochemical industry known to pose adverse health effects on workers. The database based on the third phase of The Environmental Health Study in the Korean National Industrial Complexes (EHSNIC) in Ulsan conducted from 2018 to 2021 was used. Subjects were divided into the exposed and control group according to the estimated pollution level and distances from the industrial complexes. Ambient benzene, ethylbenzene, and xylene were significantly higher in the exposed group compared to the controls, as well as their metabolites. Risk of chronic disease and atopic dermatitis was higher in the exposed group which was supported by higher serum inflammatory markers and high hazard index of the exposed region. These results can draw attention to people engaged with environmental plans and used as primary data when making policies to reduce pollutant levels around industrial complexes.

Objective: Benzene is widely recognized as a potential carcinogen. Furthermore, the deficiency of specific nutrients may render individuals more vulnerable to cancer. For instance, β-cryptoxanthin, which possesses anti-inflammatory, antioxidant, and anticancer properties, has been identified as one such nutrient. Elevated benzene levels and reduced β-cryptoxanthin levels are reportedly correlated with an augmented susceptibility to cancer. To date, whether these 2 substances are linked with one another in the above correlation is yet to be determined., Method: This study included 1358 participants with data on the serum concentration of β-cryptoxanthin as well as benzene and its derivatives. The data were sourced from the 2003-2004 National Health and Nutrition Examination Survey, a cross-sectional survey of the noninstitutionalized US population. Headspace solid-phase microextraction with gas chromatography and mass spectrometry was used to measure serum benzene and its derivatives, while high-performance liquid chromatography using multiwavelength photodiode-array absorbance detection was employed to quantify serum β-cryptoxanthin., Results: In this study, male and female participants showed average β-cryptoxanthin levels of 9.10 ± 6.35 and 9.92 ± 8.95 ug/dL, respectively ( p  = 0.049). Styrene exhibited the strongest correlation with the change in β-cryptoxanthin concentration (β = -3.30, p for trend <0.001) upon comparing highest-quartile participants with those in the lowest quartile, followed by benzene (β = -2.95, p for trend <0.001), toluene (β = -2.90, p for trend <0.001), and ethylbenzene (β = -1.43, p for trend = 0.09). Subgroup analysis by sex displayed a statistically significant negative correlation of β-cryptoxanthin with benzene, styrene, and toluene in both the unadjusted and multivariate-adjusted models., Conclusions: The sera of noninstitutionalized US individuals exhibit a negative association of β-cryptoxanthin levels with benzene and its derivatives. Styrene demonstrates the strongest link with a substantial decline in serum β-cryptoxanthin levels, followed by benzene, toluene, and ethylbenzene.

Introduction: Exposures to volatile organic compounds and metals have previously been associated with liver diseases including steatohepatitis, although more data are needed. Benzene, toluene, ethylbenzene, xylenes, styrene (BTEXS) and metals were measured in blood samples collected between May 2012-July 2013 from volunteers participating in home visits for the Gulf Long-term Follow-up (GuLF) Study. This cross-sectional analysis evaluates associations of exposure biomarkers with serum liver injury and adipocytokine biomarkers in a sample of 214 men., Methods: Adult nonsmoking men without a history of liver disease or heavy alcohol consumption were included. The serologic disease biomarkers evaluated were the hepatocellular injury biomarker, cytokeratin 18 [whole (CK18 M65) and caspase-cleaved fragment (CK18 M30)]; and adipocytokines. Confounder-adjusted beta coefficients were determined using linear regression models for the overall sample (primary endpoints) and for obesity-classified sub-groups (secondary endpoints). A product interaction term between the exposure of interest and a dichotomized indicator of obesity was included to determine the disease modifying effects of obesity on the biomarker associations., Results: The study sample was 57% white and 51% obese. In the overall sample, lead was positively associated with CK18 M30 (β = 21.7 ± 6.0 (SE), p = 0.0004); IL-1β (β = 32.8 ± 5.2, p < 0.0001); IL-6 (β = 72.8 ± 18.3, p = 0.0001); and IL-8 (β = 140.8 ± 42.2, p = 0.001). Cadmium exposures were associated with increased IL-1β (β = 77.8 ± 26.3, p = 0.003) and IL-8 (β = 419.5 ± 201.2, p = 0.04). There were multiple significant interactions between obesity and exposure to lead, cadmium, benzene and toluene in relation to outcome biomarkers. Among obese participants (n = 108), benzene, lead, and cadmium were each positively associated with CK18 M30, IL-1β, IL-6, and IL-8. In obese subjects, lead was also inversely associated with leptin, and toluene was positively associated with IL-1β., Conclusion: For the overall sample, heavy metal exposures were associated with liver injury (lead only) and/or systemic inflammation (lead and cadmium). Obesity modified the associations between BTEXS and heavy metal exposures on several of the outcome variables. In the obesity subgroup, liver injury was positively associated with lead, cadmium and benzene exposures; systemic inflammation was increased with lead, cadmium, benzene, and toluene exposures; and leptin was inversely associated with lead exposures. The cross-sectional design of this study makes it difficult to determine causality, and all results should be interpreted cautiously. Nonetheless, the potential impact of exposures to lead, cadmium, benzene and toluene in steatohepatitis, an obesity-associated inflammatory liver disease, warrants further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Cave previously received a contract from Lakeside Life Sciences related to the clinical development of the cytokeratin 18 biomarker for alcoholic hepatitis. That contract is not directly related to this work., (Published by Elsevier Ltd.)

Background: Military aircrews' health status is critical to their mission readiness, as they perform physically and cognitively demanding tasks in nontraditional work environments. Research Objectives: Our objective is to develop a broad operational risk assessment framework and demonstrate its applicability to health risks to aircrews because of airborne chemical exposure, considering stressors such as heat and exertion., Methods: Extrapolation of generic exposure standards to military aviation-specific conditions can include computation of risk-relevant internal dosimetry estimates by incorporating changes in breathing patterns and blood flow distribution because of aspects of the in-flight environment. We provide an example of the effects of exertion on peak blood concentrations of 1,2,4-trimethylbenzene computed using a physiologically based pharmacokinetic model., Results: Existing published collections on the effects of flight-related stressors on breathing patterns and blood flow address only a limited number of stressors. Although data exist that can be used to develop operational exposure limits specific to military aircrew activities, efforts to integrate this information in specific chemical assessments have been limited., Conclusions: Efforts to develop operational exposure limits would benefit from guidance on how to make use of existing assessments and expanded databases of the impact of environmental stressors on adult human physiology., (© Association of Military Surgeons of the United States 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

For human risk assessment of toxic chemicals, especially volatile organic compounds (VOCs), the Ministry of the Environment, Government of Japan, has called for the interconversion of inhalation-dose and oral-dose data, two common exposure routes. To address this issue, the present study investigated the time-course changes of ethylbenzene (EB) concentrations in the blood of rats during and after 6-hr inhalation exposure to EB (25, 50, 100, and 200 ppm) and after oral administration of EB by a single oral gavage (25, 50, 100, and 200 mg/kg) of EB. The Area Under the blood concentration-time Curve (AUC) at each blood collection time point (0, 30, 60, 120, 180, 360, 420, 540, and 1440 min, after starting exposure) was determined. The inhalation dose of 25 ppm corresponded closely to the oral administration of 25 mg/kg・bw (r value of 0.859), and the inhalation dose of 200 ppm correlated with the oral administration of 100 mg/kg・bw (r value of 0.948). These results suggest that this comparison using the AUC data at each blood collection time point is valuable for understanding the route- and dose-effects of EB. This study will improve risk assessment of human exposure to EB and other VOCs.

We developed a biomineral-inspired hybrid material composed of CaCO3 and an organic polymer as a column packing material for HPLC. This material combines a hierarchical mesoporous structure and the functionality of the polymer. The surface of monodispersed mesoporous CaCO3 microspheres was modified with poly(maleic acid-alt-1-octadecene) (PMAcO) comprising hydrophobic alkyl chains and anionic carboxylate groups. PMAcO adsorbed onto the surface of CaCO3 through electrostatic interaction between Ca2+ sites and carboxylate groups, resulting in an octadecene coated microsphere interface. These microspheres were applied as a HPLC column and exhibited reversed-phase retention behavior in the separation of alkylbenzenes. This column showed high alkaline mobile phase resistance compared with the conventionally applied ODS column packing material. Quantitative analysis of the basic antidepressants clomipramine and imipramine spiked into whole blood was achieved with an alkaline mobile phase, demonstrating the potential of the biomineral-inspired material as a HPLC stationary phase for practical applications in routine analyses of basic drugs requiring alkaline mobile phases.

Background: The chemicals benzene, toluene, ethylbenzene, and xylenes (BTEX) are neuroactive. Exposures often co-occur because they share common sources. We examined neurologic effects of environmental BTEX exposure among U.S. Gulf coast residents taking into account concomitant exposures., Methods: We measured blood concentrations of BTEX in 690 Gulf state residents. Neurologic symptoms were ascertained via telephone interview. We used log-binomial regression to estimate associations between blood BTEX levels and self-reported neurologic symptoms independently for the presence of any neurologic, central (CNS), or peripheral nervous system (PNS) symptoms. We estimated associations in single chemical models mutually adjusted for co-occurring BTEX and used weighted quantile sum regression to model associations between the combined BTEX mixture and neurologic symptoms., Results: Half (49%) of participants reported at least one neurologic symptom. Each BTEX chemical was associated with increased CNS and PNS symptoms in single-chemical models comparing the highest to lowest quartile of exposure. After adjusting for coexposures, benzene was associated with CNS symptoms among all participants (PR = 2.13, 95% CI: 1.27, 3.57) and among nonsmokers (PR = 2.30, 95% CI: 1.35, 3.91). After adjusting for coexposures, associations with toluene were apparent only for reporting multiple PNS symptoms (PR = 2.00, 95% CI: 0.96, 4.16). In mixture analyses, a one-quartile increase in BTEX exposure was associated with neurologic symptoms (OR = 1.47, 95% CI: 1.11, 1.98). The weighted quantile sum index weighted benzene most heavily, which was consistent with single chemical analyses., Conclusions: Increasing blood benzene concentration was associated with increased prevalence of CNS symptoms. In this sample, BTEX-associated neurologic effects are likely driven by exposure to benzene and, to a lesser extent, toluene., (Copyright © 2019. Published by Elsevier Inc.)

Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) recently approved in Korea as a next-generation therapeutics for gastric acid-related diseases. In the present study, we demonstrate a simple bioanalytical liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of tegoprazan and its major metabolite (M1) in dog plasma. The developed method is based on protein precipitation and LC-MS/MS, validated according to the regulatory guidance for bioanalytical method validation. The calibration curves were linear in the concentration range of 50 ng/mL-50 μg/mL and 5 ng/mL-5 μg/mL for tegoprazan and M1, respectively. The inter- and intra-day precisions were evaluated with a coefficient of variation of <15%, and the mean accuracy ranged 92.6%-105%. The method exhibited good sensitivity and specificity. The stability of bench-top (for 8 h), freeze-thaw (3 cycles), and processed-samples (for 24 h at 4 °C) was acceptable. Tegoprazan was stable in dog plasma for 6 weeks at -70 °C. In conclusion, we successfully established a method for the simultaneous quantification of tegoprazan and M1 in dog plasma, and the method was validated for specificity, sensitivity, linearity, matrix effects, recovery, accuracy, precision, and stability. Finally, we show that the method was successfully applied to a pharmacokinetic study in dogs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Few studies have examined the effects of environmental concentrations of benzene, toluene, ethylbenzene, and xylene (BTEX) on the hematologic system of residents near a petrochemical complex. This study evaluated the potential effects of blood BTEX concentrations on the hematologic parameters of residents in a community near a petrochemical complex (contaminated group) and another community free of known petrochemical pollution (control group). Volunteer residents were randomly recruited. Each participant completed a questionnaire and donated blood samples to evaluate blood BTEX concentrations and hematologic parameters. We found the mean concentrations of blood BTEX of the contaminated group were 1.2 to 6.7 times higher than the control group. Multiple hematologic parameters of participants were significantly different between the two study groups. Inverse associations were found for ln-transformed blood benzene concentrations with mean corpuscular hemoglobin concentration (MCHC) (β = - 2.75) and platelet counts (β = -8.18). Several weaker associations were also observed between other compounds and multiple hematologic parameters. Our results suggest that the residents living near petrochemical complexes have higher blood BTEX concentrations. Furthermore, the increased blood BTEX levels in residents are associated with the reduction in RBC counts, hemoglobin concentration, hematocrit, MCHC, and platelet counts. This study provided particularly important information for the health risk assessment of residents living near petrochemical complexes.

Objective: The main purpose of this study was to ascertain whether (or not) exposure to benzene, toluene, xylene and ethylbenzene (BTXE) , under normal working conditions, was associated with any health effects. Methods: From January to December 2014, the workplaces concentrations of BTXE were measured of 71 enterprises in Suzhou Industrial Park. Occupational health examination were investigated on 764 employees who exposed to BTXE, as well as 4409 employees of the corresponding enterprises who unexposed to BTXE, and analyzed the data of the two groups. Results: A total of 6 monitoring sites in 3 enterprises BTXE concentrations excess of the standards, the unexposed group was under the limit of detection. The means of red blood cell count, hemoglobin, hematocrit, intermediate cell count and percentage of intermediate cells were significantly higher in exposed group than in unexposed group ( P <0.05) . Conversely, platelet count was significantly lower in exposed group than in unexposed group ( P <0.05) . The proportion of red blood cell volume, lymphocyte count and percentage of intermediate cells were significantly lower in exposed group than in unexposed group ( P <0.05) . Both means and proportion of glutamic pyruvic transaminase and urea nitrogen were significantly higher in exposed group than in unexposed group ( P <0.05) . The positive rate of protein, urine, urine red blood cell were significantly higher in exposed group than in unexposed group ( P <0.05) . The abnormal rate of electrocardiogram, liver and kidney B scan were significantly higher in exposed group than in unexposed group ( P <0.05) . Multivariate logistic regression analysis revealed that percentage of intermediate cells increased, urea nitrogen increased, urine protein positived, urine red blood cells positived in exposed group the OR values were 1.689, 3.291, 3.163 and 1.743 ( P <0.05) . Conclusion: Occupational exposure to low concentrations of BTXE had a certain impact on the blood system and liver and kidney function of the employees, occupational health surveillance for such people should be strengthened.

Data from National Health and Nutrition Examination Survey were analyzed to evaluate detection rates, trend in and factors affecting the observed levels of 1,4-dichlorobenzene, benzene, ethylbenzene, o-xylene, styrene, toluene, and m/p-xylene among US adolescents and adults over 2005-2012. Over 2005-20102, among adolescents, detection rates declined by more than 50% for benzene, ethylbenzene, and o-xylene, and among adults, detection rates declined by more than 50% for ethylbenzene and o-xylene and by a little less than 50% for benzene. Among adults, adjusted levels of 1, 4-dichlorobenzene, benzene, ethylbenzene, o-xylene, toluene, and m/p-xylene decreased by 13.7%, 17.1%, 20%, 17.7%, 23.2%, and 18.7% respectively for every two-year survey cycle. Among adolescents, percentage decline in the levels of 1, 4-dichlorobenzene, benzene, ethylbenzene, o-xylene, styrene, toluene, and m/p-xylene was 15.2%, 21.4%, 19.3%, 16.1%, 47.8%, and 17.7% respectively for every two year survey period. The ratio of adjusted geometric means for adult smokers as compared to adult nonsmokers was 10.7 for benzene, 3.5 for ethylbenzene, 2.0 for o-xylene, 3.4 for styrene, 3.5 for toluene, and 2.2 for m/p-xylene. Among adolescents, gender did not affect the adjusted levels of any of the seven VOCs, and the order in which adjusted levels for 1, 4-dichlorobenzene by race/ethnicity was observed was: non-Hispanic white (0.038ng/mL)

Background: Studies of workers exposed to benzene at average air concentrations below one part per million suggest that benzene, a known hematotoxin, causes hematopoietic damage even at low exposure levels. However, evidence of such effects outside of occupational settings and for other volatile organic compounds (VOCs) is limited., Objective: To investigate associations between ambient exposures to five VOCs, including benzene, and hematologic parameters among adult residents of the U.S. Gulf Coast., Materials and Methods: Blood concentrations of selected VOCs were measured in a sample of adult participants in the Gulf Long-term Follow-up Study (GuLF STUDY) during 2012 and 2013. Complete blood counts with differentials were also performed on a subset of participants (n=406). We used these data together with detailed questionnaire data to estimate adjusted associations between blood BTEXS (benzene, toluene, ethylbenzene, o-xylene, m/p-xylene, and styrene) concentrations and hematologic parameters using generalized linear models., Results: We observed inverse associations between blood benzene concentrations and hemoglobin concentration and mean corpuscular hemoglobin concentration, and a positive association with red cell distribution width among tobacco smoke-unexposed participants (n=146). Among tobacco smoke-exposed participants (n=247), we observed positive associations between blood VOC concentrations and several hematologic parameters, including increased white blood cell and platelet counts, suggestive of hematopoietic stimulation typically associated with tobacco smoke exposure. Most associations were stronger for benzene than for the other VOCs., Conclusions: Our results suggest that ambient exposure to BTEXS, particularly benzene, may be associated with hematologic effects, including decreased hemoglobin concentration, mean corpuscular hemoglobin concentration, and increased red cell distribution width., (Published by Elsevier Inc.)

Organophosphorus flame retardants, polybromobenzenes, and polybrominated diphenyl ethers (PBDEs) were determined in pooled human serum samples collected in an area in which these chemicals are produced in North China. Tri (2-chloroethyl) phosphate (TCEP) was found at a higher concentration than the other chemicals, and the mean TCEP concentration was 480.4 ng/g lipid. This is the first time TCEP has been detected in human serum from China. The PBDE concentration in serum was found to have decreased between 2007 and 2013. BDE-209 remained the dominant PBDE congener, and its mean concentration was 91.3 ng/g lipid in this study. The polybromobenzene concentrations were relatively low, but pentabromobenzene and pentabromotoluene were found in very many of the samples. The highest TCEP, tris(2-butoxyethyl)phosphate, pentabromobenzene, and pentabromotoluene concentrations were found in samples from young people (<30 y old). This suggests that the risks posed by these alternative flame retardants also need more concerns., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

γ-Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. γ-Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK-0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose-related effects of MK-0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source., (© 2016 American Society for Clinical Pharmacology and Therapeutics.)

Objective: This study aimed to evaluate blood volatile organic compound (VOC) levels as biomarkers of occupational jet propulsion fuel 8 (JP-8) exposure while controlling for smoking., Methods: Among 69 Air Force personnel, post-shift blood samples were analyzed for components of JP-8, including ethylbenzene, toluene, o-xylene, and m/p-xylene, and for the smoking biomarker, 2,5-dimethylfuran. JP-8 exposure was characterized based on self-report and measured work shift levels of total hydrocarbons in personal air. Multivariate regression was used to evaluate the relationship between JP-8 exposure and post-shift blood VOCs while controlling for potential confounding from smoking., Results: Blood VOC concentrations were higher among US Air Force personnel who reported JP-8 exposure and work shift smoking. Breathing zone total hydrocarbons was a significant predictor of VOC blood levels, after controlling for smoking., Conclusions: These findings support the use of blood VOCs as a biomarker of occupational JP-8 exposure.

Objectives: The aim of the study has been to explore hemimellitene distribution in blood, liver, lung and kidney as well as toxicokinetics of its elimination from blood of rats after single and repeated inhalation exposure to this compound. Tissue distribution and excretion with urine of 2-dimethylbenzoic acids (2,3-DMBA and 2,6-DMBA) were also evaluated., Material and Methods: Male outbred IMP:WIST rats were used in the experiment. The animals were exposed to hemimellitene vapors at the nominal concentration of 25 ppm, 100 ppm, and 250 ppm in the dynamic inhalation chambers for 6 h for single exposure purpose and for 4 weeks (6 h/day for 5 day/week) for repeated exposure purposes., Results: Significantly lower concentrations of hemimellitene were detected in the blood and tissues of animals after repeated inhalation exposure of animals to hemimellitene vapors, which points to reduced retention of the chemical in the lungs of the experimental rats. The trend of hemimellitene elimination from the blood depended solely on exposure intensity, irrespective of exposure time, both after single and repeated exposure. As regards the 2 determined hemimellitene metabolites, the major trend of the metabolic transformation involved formation of 2,3-DMBA., Conclusions: The significantly higher urinary 2,3-DMBA concentration after repeated exposure shows that hemimellitene induces enzymatic processes in the rat., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

A method of platinum quantification in whole blood samples after microwave digestion using sector field inductively coupled plasma mass spectrometry has been developed. The following analytical figures of merit have been established: limit of detection 1.1 µg/L for blood samples, dynamic range 3.6-200 µg/L, intra-day precision (relative standard deviation, n = 9) did not exceed 5%. Spiked samples were analyzed for method validation. The method was used for pharmacokinetics studies of a novel anti-cancer drug BP-С1, a complex of cis-configured platinum and benzene-poly-carboxylic acids. Main pharmacokinetic parameters (area under curve, maximum concentration, clearance, half-life times for α- and β-phase) were estimated for two dosage forms of BP-C1 0.05 and 0.125 mass %. Pharmacokinetic curves were assessed for single and course administration. Studies were performed using rabbits (n = 6) as a model. BP-C1 was injected intramuscularly. The study established dose proportionality of the tested dosage forms and suggested clinical dosing schedule: 5 days of injections followed by 2 days' break. Platinum tissue distribution was studied in tissue samples collected 20 days after the last injection. Predominant platinum accumulation was observed in kidneys, liver, and muscles near injection site. 'Slow' phase of platinum excretion kinetics may be related to the muscles at the injection site., (© 2015 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Purpose: Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752., Methods: MK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot., Results: Ten eligible patients were enrolled (median age 8.8 years; range 3.1-19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1-10). Two patients continued on therapy for at least 6 months. The median (range) C(max) of MK-0752 was 88.2 μg/mL (40.6 to 109 μg/mL) and 60.3 μg/mL (59.2 to 91.9 μg/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752., Conclusion: MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.

Traditional Chinese Medicine (TCM) nasal therapy has been utilized to treat numerous diseases for over two millennia. It has many advantages compared with other routes. In this article, headspace-solid phase microextraction-gas chromatography-mass spectrometry and high performance liquid chromatography-atmospheric pressure chemical ionization-ion trap-time of flight-multistage mass spectrometry were applied for the first time to analyze the absorbed constituents in rabbit plasma and cerebrospinal fluid (CSF) after intranasal administration of Asari Radix et Rhizoma (AR). In total, 47 absorbed AR constituents including 14 monoterpenes, 10 phenylpropanoids, four benzene derivatives, two alkanes, nine N-alkylamides and eight lignans were tentatively identified in the rabbit plasma and CSF. Thirty-three absorbed constituents are found to have different bioactivities related to the pharmacological actions of AR through bibliography data retrieval. These indicated that many types of constituents of TCM can be absorbed at the nasal cavity into both rabbit blood and CSF. This is the first study to explore the absorption of AR, and comprehensively analyze the absorbed constituents after intranasal administration of TCM. These findings extend our understanding of the effective substances of AR, and inspire us to make a hypothesis on the mechanism of additive effect of multiple constituents of TCMs, which is very worthy of further investigation.

The construction in Constantí (Tarragona County, Catalonia) of the first, and up till now the only hazardous waste incinerator (HWI) in Spain, finished in 1999. In this study, we measured the concentrations of a number of organic substances determined in blood and urine of the HWI workers. Samples of 18 men and 9 women, classified according to their respective workplaces, were collected in 2011, after approximately 12 years of regular operations in the facility. The current results were compared with those of the baseline survey, as well as with the most recent surveys performed in 2008, 2009 and 2010. Plasma analyses were carried out for hexachlorobenzene (HCB), polychlorinated biphenyls (PCBs 28, 52, 101, 138, 153, and 180) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), while the levels of 2,4- and 2,5-dichlorophenol (DCP), 2,4,5- and 2,4,6-trichlorophenol (TCP), pentachlorophenol (PCP) and 1-hydroxypyrene (1-HP) were measured in urine samples. In plasma, the mean concentrations were the following: 10.8μg/kg lipid for HCB; 0.8μg/kg lipid for PCB28; 0.3μg/kg lipid for PCB52; 0.5μg/kg lipid for PCB101; 42.2μg/kg lipid for PCB138; 18.5μg/kg lipid for PCB153, and 51.2μg/kg lipid for PCB180. For PCDD/Fs, the mean concentration was 4.6ng I-TEQ/kg lipid (4.7ng WHO-TEQ/kg lipid). These levels, as well as those found in urine samples, are in agreement with the data of previous surveys performed in the same area. The current results in HWI workers do not show any evident sign of occupational exposure to PCDD/Fs and other organic substances. However, these results must be considered only as an indication of potential exposure, as the study presents notable limitations, such as the reduced number of participants and the lack of data relative to the air concentrations of chemicals. Consequently, general conclusions cannot be derived and the results should not be used as a basis for the implementation of industrial hygiene measures in other HWIs., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Needle trap devices (NTDs) are a relatively new and promising tool for headspace (HS) analysis. In this study, a dynamic HS sampling procedure is evaluated for the determination of volatile organic compounds (VOCs) in whole blood samples. A full factorial design was used to evaluate the influence of the number of cycles and incubation time and it is demonstrated that the controlling factor in the process is the number of cycles. A mathematical model can be used to determine the most appropriate number of cycles required to adsorb a prefixed amount of VOCs present in the HS phase whenever quantitative adsorption is reached in each cycle. Matrix effect is of great importance when complex biological samples, such as blood, are analyzed. The evaluation of the salting out effect showed a significant improvement in the volatilization of VOCs to the HS in this type of matrices. Moreover, a 1:4 (blood:water) dilution is required to obtain quantitative recoveries of the target analytes when external calibration is used. The method developed gives detection limits in the 0.020-0.080μg L(-1) range (0.1-0.4μg L(-1) range for undiluted blood samples) with appropriate repeatability values (RSD<15% at high level and <23% at LOQ level). Figure of merits of the method can be improved by using a smaller phase ratio (i.e., an increase in the blood volume and a decrease in the HS volume), which lead to lower detection limits, better repeatability values and greater sensibility. Twenty-eight blood samples have been evaluated with the proposed method and the results agree with those indicated in other studies. Benzene was the only target compound that gave significant differences between blood levels detected in volunteer non-smokers and smokers., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The impact of cigarette smoking on volatile organic compound (VOC) blood levels is studied using 2003-2004 National Health and Nutrition Examination Survey (NHANES) data. Cigarette smoke exposure is shown to be a predominant source of benzene, toluene, ethylbenzene, xylenes and styrene (BTEXS) measured in blood as determined by (1) differences in central tendency and interquartile VOC blood levels between daily smokers [≥1 cigarette per day (CPD)] and less-than-daily smokers, (2) correlation among BTEXS and the 2,5-dimethylfuran (2,5-DMF) smoking biomarker in the blood of daily smokers, and (3) regression modeling of BTEXS blood levels versus categorized CPD. Smoking status was determined by 2,5-DMF blood level using a cutpoint of 0.014 ng/ml estimated by regression modeling of the weighted data and confirmed with receiver operator curve (ROC) analysis. The BTEXS blood levels among daily smokers were moderately-to-strongly correlated with 2,5-DMF blood levels (correlation coefficient, r, ranging from 0.46 to 0.92). Linear regression of the geometric mean BTEXS blood levels versus categorized CPD showed clear dose-response relationship (correlation of determination, R(2), ranging from 0.81 to 0.98). Furthermore, the pattern of VOCs in blood of smokers is similar to that reported in mainstream cigarette smoke. These results show that cigarette smoking is a primary source of benzene, toluene and styrene and an important source of ethylbenzene and xylene exposure for the U.S. population, as well as the necessity of determining smoking status and factors affecting dose (e.g., CPD, time since last cigarette) in assessments involving BTEXS exposure., (Published by Elsevier Ltd.)

Objective: To determine if non-elite athletes undertaking short duration running exercise adjacent to a busy roadway experience increased blood levels of common pollutant volatile organic compounds (benzene, toluene, ethylbenzene and xylene (BTEX))., Design and Setting: The study was observational in design. Participants (nine males/one female non-elite athletes) ran for 20 min, near a busy roadway along a 100 m defined course at their own pace. Blood levels of BTEX were determined both pre- and post-exercise by SPME-GC-MS. Environmental BTEX levels were determined by passive adsorption samplers., Results: Subjects completed a mean (range) distance of 4.4 (3.4 to 5.2) km over 20 min (4.5 (3.8 to 5.9) min/km pace), with a mean (SD) exercise intensity of 93 (2.3)% HR(max), and mean (SD) ventilation significantly elevated compared with resting levels (86.2 (2.3) vs 8.7 (0.9) l/min; p<0.001). The mean (SD) environmental levels (time weighted average) were determined as 53.1 (4.2), 428 (83), and 80.0 (3.7) microg/m(3) for toluene, ethylbenzene and xylenes, respectively, while benzene was below the detectable limit due to the short exposure period. Significant increases in blood BTEX levels were observed in runners between pre- and postexercise for toluene (mean increase of 1.4 ng/ml; p=0.002), ethylbenzene (0.7 ng/ml; p=0.0003), m/p-xylene (2.0 ng/ml; p=0.004) and o-xylene (1.1 ng/ml; p=0.002), but no change was observed for benzene., Conclusions: Blood BTEX levels are increased during high-intensity exercise such as running undertaken in areas with BTEX pollution, even with a short duration of exercise. This may have health implications for runners who regularly exercise near roadways.

Pyrethroid insecticides are very widely used in agriculture and household due to high effectiveness and low toxicity to humans. We have described a case of a fatal oral intoxication with decis, the insecticide containing pyrethroid (deltamethrin) in a hydrocarbon base. Pyrethroids, including deltamethrin, undergo rapid biotransformation by liver enzymes, which limit their systemic toxicity. Thus, we assume that in the presented case, fatal outcome of poisoning with decis was rather connected with toxic effects of hydrocarbon base (solvent naphtha) than with deltamethrin action. In the described case, detection of aromatic hydrocarbons in blood and lung tissue and their metabolites in urine confirms that these substances were absorbed from gastrointestinal tract to the systemic circulation. Predominant among the clinical outcomes in our patient was profound depression of CNS with apnea, which could be connected with narcotic action of organic solvents. The cardiac arrest was in mechanism of asystolia with prior non-responsive to catecholamines bradycardia and vascular collapse. We connect it with hydrocarbon-induced cardiotoxicity. It is worth remembering that many pyrethroid-containing insecticides are formulated in a hydrocarbon base. Intoxication with such preparations should always be considered not only as poisoning with pyrethroid alone but also as intoxication with hydrocarbons.

Diphenyl diselenide [(PhSe)2], an organoselenium compound, presents pharmacological and toxicological properties in rodents. The aim of this study was to carry out the determination and quantification of (PhSe)2 in plasma after oral administration (p.o.) of this compound (500 mg/kg), dissolved in canola oil, in rats and mice. The second objective was to verify the involvement of different routes of administration ((p.o.), intraperitoneal (i.p.) and subcutaneous (s.c.)) and vehicle solutions (canola oil and dimethyl sulfoxide (DMSO)) in the appearance of seizure episodes and in the plasmatic levels of (PhSe)2 in rats and mice. Analysis of (PhSe)2 in blood samples was performed by gas chromatography/flame ionized detector system (GC/FID). Rat and mouse peak plasma (PhSe)2 levels were 13.13 and 10.11 microg/ml (C(max)), respectively, and occurred at 0.5h (T(max)) post-dosing. The use of different administration routes (p.o., i.p. and s.c.) and vehicle solutions (canola oil or DMSO) in rats and mice indicated that the appearance of seizures and (PhSe)2 plasmatic levels are dependent of administration routes (i.p.>p.o.>s.c.), vehicle solutions (DMSO>canola oil) and animal species (mice>rat).

Purpose: To determine the blood and urine concentrations of a number of metals and organic substances in workers at a hazardous waste incinerator (HWI) in Catalonia, Spain, 8 years after regular operations in the facility. To compare these concentrations with the baseline (1999) levels and with those obtained in previous (2000 and 2005) surveys., Methods: The employees were divided into three groups according to their specific workplaces. Plasma analyses of hexachlorobenzene (HCB), polychlorinated biphenyls (PCBs 28, 52, 101, 138, 153 and 180) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), as well as urinary analyses of 2,4- and 2,5-dichlorophenol (DCP), 2,4,5- and 2,4,6-trichlorophenol (TCP), pentachlorophenol (PCP) and 1-hydroxypyrene (1-HP) were carried out. Blood concentrations of manganese and mercury, and urinary levels of nickel were also determined., Results: For organic compounds in plasma, the comparison of the current levels with those of previous surveys did not show any significant increase for any of the compounds analyzed. In contrast, plasma levels of PCBs 28, 52 and 101 were significantly lower than the respective baseline concentrations, while especially notable was the significant reduction in the levels of PCDD/Fs in plasma of plant workers, which decreased from 26.7 pg I-TEQ/g lipid in the baseline survey to the current 2.5 pg I-TEQ/g lipid., Conclusion: According to the results of the present study, there are no evident signs of occupational exposure to a number of metals and organic substances in the workers of the HWI.

A physiologically based pharmacokinetic (PBPK) model was developed for inhaled ethylbenzene (EB) in B6C3F1 mice. The mouse physiological parameters were obtained from the literature, but the blood:air and tissue:air partition coefficients were determined by vial equilibration technique. The maximal velocity for hepatic metabolism (Vmax) obtained from a previously published rat study was increased by a factor of approximately 3 to account for enzyme induction during repeated exposures. The Michaelis affinity constant (Km) for hepatic metabolism of EB, obtained from a previously published rat PBPK modeling study, was kept unchanged during single and repeated exposure scenarios. Hepatic metabolism alone could not adequately describe the clearance of EB from mouse blood. Additional metabolism was assumed to be localized in the lung. The parameters for pulmonary metabolism were obtained by optimization of PBPK model fits to kinetic data collected following exposures to 75-1000 ppm. The PBPK model successfully predicted all available blood and tissue concentration data in mice exposed to 75 or 750 ppm EB. Overall, the results indicate that the rate of EB clearance is markedly higher in B6C3F1 mice than rats or humans and exceeds the hepatic metabolism capacity. Available biochemical evidence is consistent with a significant role for pulmonary metabolism; however, the extent to which the extrahepatic metabolism is localized in the lung is unclear. Overall, the PBPK model developed for the mouse adequately simulated the blood and tissue kinetics of EB by accounting for its high rate of clearance.

Ethylbenzene + toluene are known individually to have ototoxic potential at high exposure levels and with prolonged exposure times generally of 4-16 weeks. Both ethylbenzene + toluene are minor constituents of JP-8 jet fuel; this fuel has recently been determined to promote susceptibility to noise-induced hearing loss. Therefore, the current study evaluates the ototoxic potential of combined exposure to ethylbenzene + toluene exposure in a ratio calculated from the average found in three laboratories. Rats received ethylbenzene + toluene by inhalation and half of them were subjected simultaneously to an octave band of noise (OBN) of 93-95 dB. Another group received only the noise exposure which was designed to produce a small, but permanent auditory impairment while an unexposed control group was also included. In two separate experiments, exposures occurred either repeatedly on 5 successive days for 1 week or for 5 days on 2 successive weeks to 4000 mg/m(3) total hydrocarbons for 6 h based upon initial pilot studies. The concentration of toluene was 400 ppm and the concentration of ethylbenzene was 660 ppm. Impairments in auditory function were assessed using distortion product otoacoustic emissions and compound action potential testing. Following completion of these tests, the organs of Corti were dissected to permit evaluation of hair cell loss. The uptake and elimination of the solvents was assessed by harvesting key organs at two time points following ethylbenzene + toluene exposure from additional rats not used for auditory testing. Similarly, glutathione (GSH) levels were measured in light of suggestions that oxidative stress might result from solvent-noise exposures. Ethylbenzene + toluene exposure by itself at 4000 mg/m(3) for 6 h did not impair cochlear function or yield a loss of hair cells. However, when combined with a 93-dB OBN exposure combined solvent + noise did yield a loss in auditory function and a clear potentiation of outer hair cell death that exceeded the loss produced by noise alone. No evidence was found for a loss in total GSH in lung, liver, or brain as a consequence of ethylbenzene + toluene exposure.

This study characterized the exposure of crude oil process operators to benzene and related aromatics during ordinary activity and investigated whether the operators take up benzene at this level of exposure. We performed the study on a fixed, integrated oil and gas production facility on Norway's continental shelf. The study population included 12 operators and 9 referents. We measured personal exposure to benzene, toluene, ethylbenzene and xylene during three consecutive 12-h work shifts using organic vapour passive dosimeter badges. We sampled blood and urine before departure to the production facility (pre-shift), immediately after the work shift on Day 13 of the work period (post-shift) and immediately before the following work shift (pre-next shift). We also measured the exposure to hydrocarbons during short-term tasks by active sampling using Tenax tubes. The arithmetic mean exposure over the 3 days was 0.042 ppm for benzene (range <0.001-0.69 ppm), 0.05 ppm for toluene, 0.02 ppm for ethylbenzene and 0.03 ppm for xylene. Full-shift personal exposure was significantly higher when the process operators performed flotation work during the shift versus other tasks. Work in the flotation area was associated with short-term (6-15 min) arithmetic mean exposure to benzene of 1.06 ppm (range 0.09-2.33 ppm). The concentrations of benzene in blood and urine did not differ between operators and referents at any time point. When we adjusted for current smoking in regression analysis, benzene exposure was significantly associated with the post-shift concentration of benzene in blood (P = 0.01) and urine (P = 0.03), respectively. Although these operators perform tasks with relatively high short-term exposure to benzene, the full-shift mean exposure is low during ordinary activity. Some evidence indicates benzene uptake within this range of exposure.

We used natural spline (NS) models to investigate nonlinear relationships between levels of benzene metabolites (E,E-muconic acid, S-phenylmercapturic acid, phenol, hydroquinone, and catechol) and benzene exposure among 386 exposed and control workers in Tianjin, China. After adjusting for background levels (estimated from the 60 control subjects with the lowest benzene exposures), expected mean trends of all metabolite levels increased with benzene air concentrations from 0.03 to 88.9 ppm. Molar fractions for phenol, hydroquinone, and E,E-muconic acid changed continuously with increasing air concentrations, suggesting that competing CYP-mediated metabolic pathways favored E,E-muconic acid and hydroquinone below 20 ppm and favored phenol above 20 ppm. Mean trends of dose-specific levels (micromol/L/ppm benzene) of E,E-muconic acid, phenol, hydroquinone, and catechol all decreased with increasing benzene exposure, with an overall 9-fold reduction of total metabolites. Surprisingly, about 90% of the reductions in dose-specific levels occurred below about 3 ppm for each major metabolite. Using generalized linear models with NS-smoothing functions (GLM + NS models), we detected significant effects upon metabolite levels of gender, age, and smoking status. Metabolite levels were about 20% higher in females and decreased between 1% and 2% per year of life. In addition, levels of hydroquinone and catechol were greater in smoking subjects. Overall, our results indicate that benzene metabolism is highly nonlinear with increasing benzene exposure above 0.03 ppm, and that current human toxicokinetic models do not accurately predict benzene metabolism below 3 ppm. Our results also suggest that GLM + NS models are ideal for evaluating nonlinear relationships between environmental exposures and levels of human biomarkers.

This paper presents data from both a human volunteer study looking at exposure to 1,3,5-trimethylbenzene (TMB) and an occupational hygiene study of a printing firm using screen wash containing technical grade TMB. The biomarkers measured were TMB in blood and breath, and urinary dimethylbenzoic acids (DMBAs). The volunteer (N = 4) study showed that TMB was rapidly absorbed into the bloodstream reaching a mean level of 0.85 micromol l(-1) during a 4 h exposure to 25 p.p.m. TMB. There was little decline 1 h post-exposure possibly indicating storage of TMB in adipose tissue. Breath TMB levels peaked within an hour of exposure commencing and averaged 137 nmol l(-1) during exposure. Elimination of TMB in breath was biphasic with an initial half-life of 60 min. Peak excretion of urinary DMBA occurred 4-8 h after the end of exposure and averaged 40 mmol mol(-1) creatinine. Elimination of DMBA in urine was biphasic with half-lives of 13 and 60 h indicating that accumulation of body burden throughout the working week is likely if exposure is repeated. The occupational hygiene study demonstrated an excellent correlation between personal air TMB levels and post-shift urinary DMBA levels (r = 0.997) collected on the third working day. The regression equation from this study indicates that 8 h exposure to 25 p.p.m. TMB would result in a urinary DMBA level of 206 mmol mol(-1) creatinine. All workers showed pre-shift levels of DMBA from exposure to TMB on previous days. Both urinary DMBA and breath TMB levels can be used as biomarkers of TMB exposure. Urine samples should be taken post-shift towards the end of the working week as significant body burden accumulation throughout the working week can be expected. Breath sampling is more suited to task or single-shift monitoring.

Widespread exposure to benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS) and the potential for this exposure to cause health effects drives the need to develop improved methods for measuring exposure. In this work, we demonstrate our latest assay for quantifying BTEXS in blood and characterize sources of both positive and negative biases. This method involves blood sample collection using common techniques followed by static headspace sampling using solid-phase microextraction and gas chromatography/mass spectrometry analysis. We found that the greatest and unexpected source of positive bias was from contamination of butyl rubber materials used in sample preparation consumables such as Vacutainer stoppers, syringe plungers, and sample vial septa. Conversely, the primary cause of negative bias observed was from the diffusion loss of BTEXS from blood during transfer into sample vials. By minimizing or eliminating these and other sources of bias, we improved method accuracy and precision to within 10% while maintaining low-picogram per milliliter detection. Furthermore, upon comparison of these results with those from other laboratories, we observe substantially lower blood BTEXS levels reported to date for nonoccupationally exposed nonsmokers. A relatively unbiased method, as such, will help elucidate any potential associations between adverse health effects and human exposure to low levels of BTEXS.

Background: This study was conducted to evaluate the potential adverse effects of ethylbenzene (EB) on reproductive capability from whole-body inhalation exposure of F0 and F1 parental animals., Methods: Four groups of Crl:CD(SD)IGS BR rats (30/sex/group for F0 and 25/sex/group for F1) were exposed to 0, 25, 100, and 500 ppm EB for 6 hr/day for at least 70 consecutive days before mating. Inhalation exposure for the F0 and F1 females continued throughout mating, gestation through gestation day (GD) 20, and lactation days (LD) 5-21. On LD 1-4, females received EB in corn oil via oral gavage at dose levels of 26, 90, and 342 mg/kg/day (divided into three equal doses, approximately 2 hr apart), as calculated from a physiologically-based pharmacokinetic (PBPK) model to provide similar maternal blood area-under-concentration (AUC) as provided by inhalation. Pups were weaned on postnatal day (PND) 21 and exposure of the F1 generation started on PND 22. Estimates of internal exposure were determined by measuring EB concentrations in blood collected from F1 dams (4/group) and their culled pups 1 hr after the last gavage dose on PND 4. On PND 22, blood was collected from these same F1 dams and their weanlings for EB analysis 1 hr after a 6-hr inhalation exposure. The remainder of the F2 generation was not directly exposed., Results: EB exposure did not affect survival or clinical observations. Male rats in the 500 ppm group in both generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either generation. Male and female mating and fertility indices, pre-coital intervals, spermatogenic endpoints, ovarian follicle counts, reproductive organ weights, lengths of estrous cycle and gestation, live litter size, pup weights, developmental landmarks, and postnatal survival were unaffected. No adverse exposure-related macroscopic pathology was noted at any level., Conclusions: Increased liver weights were found in the animals exposed to 500 ppm. F1 maternal whole blood EB concentrations of 0.49, 3.51, or 18.28 mg/L were found 1 hr after administration of a composite oral dose of 26, 90, or 342 mg/kg/day, respectively, but no detectable EB was found in blood samples of their F2 PND 4 culled pups. F1 maternal mean whole blood EB levels 1 hr after a 6-hr inhalation exposure on postpartum day (PPD) 22 was 0.11 mg/L (25 ppm), 0.56 mg/L (100 ppm), and 11 mg/L (500 ppm). For the offspring exposed with their dams on PND 22, F2 pup blood EB concentrations ranged from 0.017-0.039 mg/L (25 ppm), 0.165-0.465 mg/L (100 ppm), and 8.82-15.74 mg/L (500 ppm). Because decreased weight gain in the 500 ppm males was transient and no histopathological changes were associated with the increased liver weights in the 500 ppm male and female groups, these changes were not considered adverse. Therefore, for parental systemic toxicity, 100 ppm was considered a NOEL and 500 ppm a NOAEL in this study. The 500 ppm exposure concentration was considered a NOAEL for F0 and F1 reproductive toxicity and offspring developmental endpoints.

The objective of the present study was to characterize the inhalation pharmacokinetics of ethylbenzene (EB) in male and female B6C3F1 mice following single and repeated exposures. Initially, groups of 28 male and female mice were exposed for 4 h to 75, 200, 500, or 1000 ppm in order to determine potential non-linearity in the kinetics of EB. Then, groups of male and female mice were exposed for 6 h to 75 ppm and 750 ppm (corresponding to the NTP exposures) for 1 or 7 consecutive days, to evaluate whether EB kinetics was altered during repeated exposures, The maximal blood concentration (Cmax; mean+/-SD, n=4) observed in female mice at the end of a 4-h exposure to 75, 200, 500, and 1000 ppm was 0.53+/-0.18, 2.26+/-0.38, 19.17+/-2.74, and 82.36+/-16.66 mg/L, respectively. The areas under the concentration vs. time curve (AUCs) following 4-h exposure to 75, 200, 500, and 1000 ppm were 88.5, 414.0, 3612.2, and 19,104.1 mg/L/min, respectively, in female mice, and 116.7, 425.7, 3148.3, and 16,039.1 mg/L/min in male mice. The comparison of Cmax and the kinetic profile of EB in mice exposed to 75 ppm suggests that they are similar between 1-day and 7-day exposures. However, at 750 ppm, the rate of EB elimination would appear to be greater after repeated exposures than single exposure, the pattern being evident in both male and female mice. Overall, the single and repeated exposure pharmacokinetic data collected in the present study suggest that EB kinetics is saturable at exposure concentrations exceeding 500 ppm (and therefore at 750 ppm used in the NTP mouse cancer bioassay) but is in the linear range at the lower concentration used in the bioassay (75 ppm). These data suggest that consideration of the nature and magnitude of non-linear kinetics and induction of metabolism during repeated exposures is essential for the conduct of a scientifically sound analysis of EB cancer dose-response data collected in B6C3F1 mice.

Under OSHA and American Conference of Governmental Industrial Hygienists (ACGIH) guidelines, the mixture formula (unity calculation) provides a method for evaluating exposures to mixtures of chemicals that cause similar toxicities. According to the formula, if exposures are reduced in proportion to the number of chemicals and their respective exposure limits, the overall exposure is acceptable. This approach assumes that responses are additive, which is not the case when pharmacokinetic interactions occur. To determine the validity of the additivity assumption, we performed unity calculations for a variety of exposures to toluene, ethylbenzene, and/or xylene using the concentration of each chemical in blood in the calculation instead of the inhaled concentration. The blood concentrations were predicted using a validated physiologically based pharmacokinetic (PBPK) model to allow exploration of a variety of exposure scenarios. In addition, the Occupational Safety and Health Administration and ACGIH occupational exposure limits were largely based on studies of humans or animals that were resting during exposure. The PBPK model was also used to determine the increased concentration of chemicals in the blood when employees were exercising or performing manual work. At rest, a modest overexposure occurs due to pharmacokinetic interactions when exposure is equal to levels where a unity calculation is 1.0 based on threshold limit values (TLVs). Under work load, however, internal exposure was 87%higher than provided by the TLVs. When exposures were controlled by a unity calculation based on permissible exposure limits (PELs), internal exposure was 2.9 and 4.6 times the exposures at the TLVs at rest and workload, respectively. If exposure was equal to PELs outright, internal exposure was 12.5 and 16 times the exposure at the TLVs at rest and workload, respectively. These analyses indicate the importance of (1) selecting appropriate exposure limits, (2) performing unity calculations, and (3) considering the effect of work load on internal doses, and they illustrate the utility of PBPK modeling in occupational health risk assessment.

Physiologically based pharmacokinetic (PBPK) models have often been used to describe the absorption, distribution, metabolism, and excretion of chemicals in animals but have been limited to single chemicals and simple mixtures due to the numerous parameters required in the models. To overcome the barrier to modeling more complex mixtures, we used a chemical lumping approach, used in the past in chemical engineering but not in pharmacokinetic modeling, in a rat PBPK model for gasoline hydrocarbons. Our previous gasoline model consisted of five individual components (benzene, toluene, ethylbenzene, xylene, and hexane) and a lumped chemical that included all remaining components of whole gasoline. Despite being comprised of hundreds of components, the lumped component could be described using a single set of chemical parameters that depended on the blend of gasoline. In the present study, we extend this approach to evaporative fractions of gasoline. The PBPK model described the pharmacokinetics of all of the volatility-weighted fractions of gasoline when differences in partitioning and metabolism between fractions were taken into account. Adjusting the ventilation rate parameter to account for respiratory depression at high exposures also allowed a much improved description of the data. At high exposure levels, gasoline components competitively inhibit each other's metabolism, and the model successfully accounted for binary interactions of this type, including between the lumped component and the five other chemicals. The model serves as a first example of how the engineering concept of chemical lumping can be used in pharmacokinetics.

Background: Multiple chemical sensitivity (MCS), although poorly understood, is associated with considerable morbidity., Aim: To investigate potential biological mechanisms underlying MCS in a case-control study., Methods: Two hundred and twenty-three MCS cases and 194 controls (urban females, aged 30-64 years) fulfilled reproducible eligibility criteria with discriminant validity. Routine laboratory results and serum levels of volatile organic compounds (VOCs) were compared. Dose-response relationships, a criterion for causality, were examined linking exposures to likelihood of case status., Results: Routine laboratory investigations revealed clinically unimportant case-control differences in means. Confounder-adjusted odds ratios (OR) showed MCS was negatively associated with lymphocyte count and total plasma homocysteine, positively associated with mean cell haemoglobin concentration, alanine aminotransferase and serum vitamin B6, and not associated with thyroid stimulating hormone, folate or serum vitamin B12. More cases than controls had detectable serum chloroform (P = 0.001) with the OR for detectability 2.78 (95% confidence interval = 1.73-4.48, P < 0.001). Chloroform levels were higher in cases. However, cases had significantly lower means of detectable serum levels of ethylbenzene, m&p-xylene, 3-methylpentane and hexane, and means of all serum levels of 1,3,5- and 1,2,3-trimethylbenzene, 2- and 3-methylpentane, and m&p-xylene., Conclusions: Our findings are inconsistent with proposals that MCS is associated with vitamin deficiency or thyroid dysfunction, but the association of lower lymphocyte counts with an increased likelihood of MCS is consistent with theories of immune dysfunction in MCS. Whether avoidance of exposures or different metabolic pathways in cases explain the observed lower VOC levels or the higher chloroform levels should be investigated.

The determination of volatile organic compounds in blood by headspace gas chromatography is one of the central and long-established analytical techniques in occupational medical biomonitoring. Nevertheless, the relatively low success rate in intercomparison programs shows that the headspace technique is insufficiently standardized. A critical stage of the analytical procedure seems to be the preparation of calibration standards in biological matrices. As part of an extensive interlaboratory comparison by the Analyses of Hazardous Substances in Biological Materials working group of the DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, three typical procedures were compared with one another using typical aromatic solvents as an example. The best correlations between the participating laboratories and the best results for the analyses of samples from interlaboratory comparisons were obtained when highly concentrated stock solutions of the aromatic compounds in ethanol were first diluted with physiological saline and then used for spiking horse blood in headspace vials. This procedure can be easily standardized and is therefore recommended by the Analyses of Hazardous Substances in Biological Materials working group for the preparation of headspace calibration standards for aromatic compounds.

Objective: To assess the extent of exposure for Volatile Organic Compounds (VOCs) among nonoccupationally exposed commuters in Mexico City., Material and Methods: Blood concentrations of benzene, toluene, ethylbenzene, m-/p-xylene, o-xylene and methyl tert-butyl ether were determined on samples collected from participants after the morning commute., Results: Median blood concentrations of benzene (0.11 microg/l), ethylbenzene (0.081 microg/l), m-/p-xylene (0.32 microg/l) and toluene (0.56 microg/l) in the Mexico City participants were all approximately two times higher than in a nonsmoking subset of the Third National Health and Nutrition Examination Survey population of the United States. On the other hand, median VOC blood levels were similar to medians observed in other studies involving commuters in specific U.S. cities, despite the fact that only half the Mexico City study participants commuted by personal vehicles compared with all U.S. commuters., Conclusions: These results reflect the extent of the air pollution problem in Mexico City. The surrounding topography exacerbates the problems caused by heavy vehicular traffic, poor emission-control devices on older vehicles, and poor maintenance practices. Elevated levels of gasoline components in the blood of nonoccupationally exposed commuters emphasize the need for regulatory initiatives and mass-transit options to reduce hydrocarbon emissions and thus reduce the risk for nonoccupational exposure for the residents of Mexico City.

In order to study the monitoring index of individual exposure dose of volatile organic compounds (VOCs) in environment, the thermal desorption capillary gas chromatographic (TD-GC) analysis was used to examine the VOCs level in air and the expired breath of female workers. Headspace solid phase micro-extraction gas chromatography (SPME-GC) was applied to determine the blood concentration of VOCs in female workers. The results from epidemiological study showed clearly that concentration of 10 subtypes of VOCs in blood, environmental air and expired breath from exposure group were higher than those from control group. The findings from the study suggested that the blood concentration of VOCs was sensitive and specific and this index might be one of good indexes in assessment of individual exposure dose of VOCs.

Organochalcogens are important intermediates and useful reagents in organic synthesis, which can increase human exposure risk to these chemicals in the workplace. As well, there are a number of reported cases of acute toxicity following organochalcogen ingestion of vitamins and dietary supplements. Since, the erythrocytic delta-ALA-D activity could be an important indicator of toxicity this report investigated the organochalcogens effects on blood delta-ALA-D in vitro. To investigate a possible involvement of cysteinyl groups in the inhibitory actions of diphenyl diselenide, diphenyl ditelluride and Ebselen (4-100 micro M), the effects of thiol reducing agents (0-3 mM) or zinc chloride (0-2 mM) were examined. Diphenyl ditelluride, diphenyl diselenide and Ebselen inhibited in a concentration-dependent manner delta-ALA-D activity from human erythrocytes. Ebselen was lesser delta-ALA-D inhibitor than (PhSe)(2) and (PhTe)(2), whereas the diorganoyldichalcogenides displayed similar inhibitory potency towards delta-ALA-D. Dithiothreitol, a hydrophobic SH-reducing agent, was able to reactivate and to protect inhibited delta-ALA-D. The pre-incubation of blood with the inhibitors changed considerably the reversing potency of thiols. From these findings we suggest that organochalcogens inactivate in vitro human erythrocyte delta-ALA-D by an interaction with the sulfhydryl group essential of the enzyme activity.

This study was conducted to validate biomarkers for early detection of benzene exposure and effect in 2 phases. The main purpose of phase 1 was to determine whether these biomarkers could reliably detect differences between workers with high exposure levels and unexposed subjects, which is the minimal screening criterion for a biomarker assay. Phase 2 of the study mainly focused on evaluating the exposure-response relation, confounding factors, and sensitivities of biomarkers for low benzene exposures. The Chinese occupational population studied had a broad range of benzene exposures. On the day of biological sample collection, exposures ranged from 0.06 to 122 ppm with a median exposure of 3.2 ppm. The median of the 4-week mean benzene exposures was 3.8 ppm, and the median lifetime cumulative exposure was 51.1 ppm-years. Compared with benzene levels in collected samples, toluene levels were relatively high, with a median of 12.6 ppm (mean, 26.3 ppm), but xylene levels were low, with a median of 0.30 ppm (mean, 0.40 ppm). The biomarkers evaluated were urinary metabolites S-phenylmercapturic acid (S-PMA*), trans,trans-muconic acid (t,t-MA), hydroquinone (HQ), catechol (CAT), and phenol; albumin adducts of benzene oxide and 1,4-benzoquinone (BO-Alb and 1,4-BQ-Alb, respectively) in blood; blood cell counts; and chromosomal aberrations. Blood cell counts in this population, including red blood cells (RBCs), white blood cells (WBCs), and neutrophils, decreased significantly with increased exposures but remained in normal ranges. Chromosomal aberration data showed significant increases of chromatid breaks and total chromosomal aberrations in exposed subjects compared with unexposed subjects. Among the urinary metabolites, the levels of S-PMA and t,t-MA were significantly elevated after benzene exposures. Both markers showed significant exposure-response trends even over the exposure range from 0 to 1 ppm. However, HQ, CAT, and phenol showed significant increases only for benzene exposure levels above 5 ppm. Multiple regression analyses of these urinary metabolites on benzene exposure indicated that toluene exposure, smoking status, and cotinine levels had no significant effects on urinary metabolite levels. A time-course study estimated the half-lives of S-PMA, t,t-MA, HQ, CAT, and phenol to be 12.8, 13.7, 12.7, 15.0, and 16.3 hours, respectively. Both BO-Alb and 1,4-BQ-Alb showed strong exposure-response associations with benzene. Regression analyses showed that after adjustment for potential confounding by smoking, there was still a strong association between benzene exposure and these markers. Furthermore, the analyses for correlations among biomarkers revealed that the urinary metabolites correlated substantially with each other. The albumin adducts also correlated well with the urinary biomarkers, especially with S-PMA. BO-Alb and 1,4-BQ adducts also correlated well with each other (r = 0.74). For benzene exposure monitoring, both S-PMA and t,t-MA were judged to be good and sensitive markers, which detected benzene exposures at around 0.1 ppm and 1 ppm, respectively. But S-PMA was clearly superior to t,t-MA as a biomarker for low levels of benzene exposure.

Male Wistar rats were exposed to pseudocumene vapors at nominal concentration of 25, 100 or 250 ppm in the dynamic inhalation chambers for 6 h or 4 weeks (6 h/day; 5 days/week). Following the inhalation exposure, pseudocumene concentrations were estimated in the brain, liver and lung homogenates, as well as in the brain (brainstem, hippocampus, temporal cortex, cerebellum) and blood (arterial, venous) structures. To estimate pseudocumene concentrations in biological material gas chromatography using the headspace technique was applied. The elimination of pseudocumene from venous blood after repeated inhalation exposures followed an open two-compartment model. Venous blood concentration was about twice as high as that in arterial blood. In tissues, the highest values were found in the liver after single exposure to pseudocumene vapor at concentrations of 100 and 250 ppm. There were no statistically significant differences in pseudocumene concentrations between the brain, lungs or arterial blood. In the brain structures of the animals exposed to pseudocumene vapors, significantly higher concentration of psedocumene was found in the brainstem.

A method for the determination of benzene, toluene, ethylbenzene and xylene in blood and urine of people not occupationally exposed to solvents is described. The headspace technique combined with gas chromatography with a mass spectrometer detector is used. The sensitivity of recent mass spectrometers is good enough to furnish reliable results also in biological samples collected from the general population. No treatment for concentrating solvents present in the blood or urine is necessary. The main features of the method are easy preparation of biological samples, small volumes (7 ml), good repeatability and linearity in the range of interest. The limits of detection in blood were 16, 43, 22 and 52 ng/l for benzene, toluene, ethylbenzene and m-xylene respectively. Slightly greater sensitivity was found for urine samples. The results obtained in biological samples from 25 woodworkers not occupationally exposed to BTEX (15 non-smokers and 10 smokers) are comparable to those obtained by other investigators., (Copyright 2002 Elsevier Science B.V.)

The present study was designed to compare the ototoxic effects of volatile ethyl benzene in guinea pigs and rats. Rats showed deteriorated auditory thresholds in the mid-frequency range, based on electrocochleography, after 550-ppm ethyl benzene (8 h/day, 5 days). Outer hair cell (OHC) loss was found in the corresponding cochlear regions. In contrast, guinea pigs showed no threshold shifts and no OHC loss after exposure to much higher ethyl benzene levels (2500 ppm, 6 h/day, 5 days). Subsequently, a limited study (four rats and four guinea pigs) was performed in an attempt to understand these differences in susceptibility. Ethyl benzene concentration in blood was determined in both species after exposure to 500-ppm ethyl benzene (8 h/day, 3 days). At the end of the first day, blood of the rats contained 23.2+/-0.8-microg/ml ethyl benzene, whereas the concentration in guinea pig blood was 2.8+/-0.1 microg/ml. After 3 days, the concentration in both species decreased with respect to the first day, but the ethyl benzene concentration in rat blood was still 4.3 times higher than that in guinea pig blood. Thus, the difference in susceptibility between the species may be related to the ethyl benzene concentration in blood.

In a previous study, it was shown that the neurotoxic compound 1,2-diethylbenzene (1,2-DEB) is mainly hydroxylated in the alkyl chain to give 1-(2'-ethylphenyl)ethanol (1,2-EPE) and excreted in urine of rats as two glucuronide compounds (GA1 and GA2). Some findings have suggested that the two enantiomers of 1,2-EPE are formed in vivo. In the present study, a chiral high-performance liquid chromatography method was developed to separate the two enantiomers of 1,2-EPE from a synthesized racemic mixture. Absolute configuration of both enantiomers was determined after esterification with (R)-(+)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid and analysis of their (1)H NMR spectra in CCl(4) added with Eu (fod)(3). The two main urinary metabolites, GA1 and GA2, from [(14)C]1,2-DEB-treated Sprague-Dawley rats (80 mg/kg, i.p.) were identified, after hydrolysis with beta-glucuronidase from Escherichia coli, as (R) and (S) glucuronide conjugates of 1,2-EPE, respectively. In vitro hydroxylation of 1,2-DEB and glucuroconjugation of 1,2-EPE were under stereoselective control in S9 fraction or microsomes from male Sprague-Dawley rat liver. The V(max) and K(m) constants for (R)1,2-EPE enantiomer formation determined in S9 fraction were greater than those for the (S) enantiomer. In the plasma of bile duct-cannulated rats, the ratio was 1.2 +/- 0.02 over the 1- to 4-h period after oral administration of [(14)C]1,2-DEB (100 mg/kg). In contrast, the glucuroconjugation rate of (S)1,2-DEB enantiomer was 4 times that of (R)1,2-EPE glucuroconjugation. A similar ratio of (R) to (S)1,2-EPE glucuronide conjugates was obtained in the plasma of bile duct-cannulated rats.

The interference of some substances with the gas chromatography-flame ionization detection and gas chromatography-Fourier transform infrared detection of toluene and ethylbenzene in volatile substance abuse poses problems. A gas chromatography-mass spectrometry (GC-MS) method that will overcome such interference has been developed for the detection of toluene and/or ethylbenzene in the headspace of preparations and products containing these substances and in the headspace of blood samples in the cases of volatile substance abuse. The method is based on converting toluene to benzoic acid via the formation of benzotrichloride. The latter compound was obtained upon the reaction of toluene with chlorine gas under direct sunlight conditions. In the presence of water, benzotrichloride was converted to benzoic acid. Ethylbenzene was converted to benzoic acid and two phenylethanols via the formation of side chain chloro-substituted phenylethanes followed by reaction with water. The chloro-substituted phenylethanes were obtained by the reaction of ethylbenzene with chlorine under direct sunlight conditions. The benzoic acid resulting from toluene and/or ethylbenzene and the two phenylethanols resulting from ethylbenzene were detected by GC-MS as their trimethylsilyl (TMS) derivatives. For the method to be viable for the detection of volatile substance abuse, the chlorination reactions were effected in the gaseous state.

The results of standardized 8 h lasting exposures of n = 18 volunteers to ethylbenzene (EthBz) at levels of 25 and 100% of the maximum allowable concentrations at the workplace (MAK) value of 100 ppm as well as the results of field studies are considered to evaluate a biological tolerance (BAT) value for EthBz. On the basis of the relationship between the external and internal exposure a BAT value of 1.5 mg/l has been set for the EthBz concentration in blood as the most sensitive and specific parameter of exposure to this aromatic hydrocarbon. The interpretation of EthBz blood values has to take into account the short half-life of t1/2 = 0.5 +/- 0.08 h in the first hour after the end of exposure in which this aromatic hydrocarbon is eliminated from the blood. The additional determination of the EthBz metabolites mandelic acid (MA) and phenylglyoxylic acid (PGA), respectively, excreted in post shift urine as well as in urine samples at the beginning of the next shift shows good correlations with the external exposure. The biological half-life of MA was calculated to t1/2 = 5.3 +/- 1.1 h. Because the time of sampling can vary the relationship between the levels of MA to PGA the total concentration of the excreted metabolites depends less on this influence and is therefore better suited for monitoring exposed persons. On the basis of the standardized experiments a BAT value has been proposed of 2 g MA plus PGA corrected per gram creatinine. Both BAT values are adjusted to data which result from earlier standardized exposures during 30 min to EthBz under physical activity of 50 watt on a bicycle ergometer.

The headspace solid-phase microextraction (HS-SPME) is a novel extraction technique and has been developed rapidly. It is a fast, simple, solventless and sensitive method for sampling, separating, extracting, injecting and analyzing volatile organic compounds. This paper presents the research work in detecting volatile organic compounds(including ten compounds) in blood. The extraction fiber is made by fused-silica fiber with 100 microns polydimethylsiloxane (PDMS). The extraction time of the method was 10 min. The thermal desorption time was 1 min. It was found that the optimized location of the extraction fiber in the injector of GC was to put the whole needle in the injector. The precision of the method was determined to be less 5% relative standard deviation (RSD). The linear range of the detection was rather wide. The lowest detectin limits (LODs) were all < or = 5 ng/ml.