Area under the blood concentration-time curve (AUC) of ethylbenzene concentration in rats: relationship to inhalation and oral administration route-dose.

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.

Blood BTEX levels and neurologic symptoms in Gulf states residents.

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.

[Study on the health effects of occupational exposure to low concentrations of benzene].

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.

Associations between blood BTEXS concentrations and hematologic parameters among adult residents of the U.S. Gulf States.

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.

Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study.

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.

Identification of absorbed constituents in the rabbit plasma and cerebrospinal fluid after intranasal administration of Asari Radix et Rhizoma by HS-SPME-GC-MS and HPLC-APCI-IT-TOF-MSn.

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.

Negative Association of Serum ß-Cryptoxanthin With Benzene and Its Derivatives.

OBJECTIVE: Benzene is widely recognized as a potential carcinogen. Furthermore, the deficiency of specific nutrients may render individuals more vulnerable to cancer. For instance, ß-cryptoxanthin, which possesses anti-inflammatory, antioxidant, and anticancer properties, has been identified as one such nutrient. Elevated benzene levels and reduced ß-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 ß-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 ß-cryptoxanthin. RESULTS: In this study, male and female participants showed average ß-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 ß-cryptoxanthin concentration (ß = -3.30, p for trend <0.001) upon comparing highest-quartile participants with those in the lowest quartile, followed by benzene (ß = -2.95, p for trend <0.001), toluene (ß = -2.90, p for trend <0.001), and ethylbenzene (ß = -1.43, p for trend = 0.09). Subgroup analysis by sex displayed a statistically significant negative correlation of ß-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 ß-cryptoxanthin levels with benzene and its derivatives. Styrene demonstrates the strongest link with a substantial decline in serum ß-cryptoxanthin levels, followed by benzene, toluene, and ethylbenzene.

Volatile organic compounds in runners near a roadway: increased blood levels after short-duration exercise.

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.

Considerations for Development of Exposure Limits for Chemicals Encountered During Aircraft Operation.

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.

Blood BTEXS and heavy metal levels are associated with liver injury and systemic inflammation in Gulf states residents.

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 (ß = 21.7 ± 6.0 (SE), p = 0.0004); IL-1ß (ß = 32.8 ± 5.2, p < 0.0001); IL-6 (ß = 72.8 ± 18.3, p = 0.0001); and IL-8 (ß = 140.8 ± 42.2, p = 0.001). Cadmium exposures were associated with increased IL-1ß (ß = 77.8 ± 26.3, p = 0.003) and IL-8 (ß = 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-1ß, IL-6, and IL-8. In obese subjects, lead was also inversely associated with leptin, and toluene was positively associated with IL-1ß. 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.

Levels of metals and organic substances in workers at a hazardous waste incinerator: a follow-up study.

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.

Simultaneous quantification of tegoprazan and its major metabolite M1 in dog plasma using liquid chromatography-tandem mass spectrometry.

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.

The hematologic effects of BTEX exposure among elderly residents in Nanjing: a cross-sectional study.

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) (ß = - 2.75) and platelet counts (ß = -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.

A biomimetic hybrid material consisting of CaCO3 mesoporous microspheres and an alternating copolymer for reversed-phase HPLC.

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.

Promotion of noise-induced cochlear injury by toluene and ethylbenzene in the rat.

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.

Physiologically based modeling of the inhalation pharmacokinetics of ethylbenzene in B6C3F1 mice.

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.

Concentrations of organophosphorus, polybromobenzene, and polybrominated diphenyl ether flame retardants in human serum, and relationships between concentrations and donor ages.

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.

Detection rates, trends in and factors affecting observed levels of selected volatile organic compounds in blood among US adolescents and adults.

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)

Modeling human metabolism of benzene following occupational and environmental exposures.

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.