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.

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.

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.

[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.

[Concentration and Distribution of Novel Brominated Flame Retardants in Human Serum from Three Chinese Cities].

Four novel brominated flame retardants (NBFRs), hexabromobenzene (HBB), pentabromotoluen (PBT), pentabromophenyl (PBBz), and tetrabromo-p-xylene (PTBX), were found in human serum samples pooled by donor age (≥ 60, 50-59, 40-49, 30-39, and 20-29 years old) and supplied by Yitong (YT, Jilin Province), Ganzi (GZ, Sichuan Province), and Huaihua (HH, Hunan Province). PBBz, PBT, and HBB were found in each of the pooled samples. The total NBFRs concentration in YT and HH were higher than the concentration found in GZ. The concentrations of total NBFRs, HBB, PBT, and PBBz (except GZ) were elevated in young people. In both YT and HH, the main pollutants were found in the five age groups; however, the main pollutants in GZ were not obvious, and the concentration ratios of four of the NBFRs were basically stable in the five age groups. The distribution of NBFRs in human serum in the three cities showed different trends in the five age groups, which indicated different sources of pollution in different areas. The total concentrations of NBFRs in the industrially developed areas (YT and HH) were higher than that in the less developed areas (GZ).

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)

Volatile Organic Compounds in Blood as Biomarkers of Exposure to JP-8 Jet Fuel Among US Air Force Personnel.

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.

Fatal acute poisoning from massive inhalation of gasoline vapors: case report and comparison with similar cases.

We describe a case of an acute lethal poisoning with hydrocarbons resulting from massive accidental inhalation of gasoline vapors. The victim, a 50-year-old man was found unconscious inside a control room for the transport of unleaded fuel. Complete autopsy was performed and showed evidence of congestion and edema of the lungs. Toxicological investigation was therefore fundamental to confirm exposure to fumes of gasoline. Both venous and arterial blood showed high values of volatiles in particular for benzene (39.0 and 30.4 µg/mL, respectively), toluene (23.7 and 20.4 µg/mL), and xylene isomers (29.8 and 19.3 µg/mL). The relatively low values found in the lungs are consistent with the fact that the subject, during the rescue, underwent orotracheal intubation followed by resuscitation techniques, while the low concentrations for all substances found in urine and kidneys could point to a death that occurred in a very short time after first contact with the fumes of gasoline.

Assessment of occupational exposure to benzene, toluene and xylenes in urban and rural female workers.

OBJECTIVES: This is the first research study to compare among female, non-smoker workers: (a) the exposure to benzene, toluene and xylenes (BTXs) in urban air during work in the street (traffic policewomen, TP) vs. work in vehicles (police drivers, PD); (b) the exposure to BTXs in urban environments (in street and in car) vs. rural environments (roadwomen, RW); (c) the values of blood benzene, urinary trans, trans muconic acid (t,t-MA) and urinary S-phenylmercapturic acid (S-PMA) in urban areas (in street and in car) vs. rural areas. METHODS: Passive personal samplings and data acquired using fixed monitoring stations located in different areas of the city were used to measure environmental and occupational exposure to BTXs during the work shift in 48 TP, 21 PD and 22 RW. In the same study subjects, blood benzene, t,t-MA and S-PMA were measured at the end of each work shift. RESULTS: Personal exposure of urban workers to benzene seemed to be higher than the exposure measured by the fixed monitoring stations. Personal exposure to benzene and toluene was (a) similar among TP and PD and (b) higher among urban workers compared to rural workers. Personal exposure to xylenes was (a) higher in TP than in PD and (b) higher among urban workers compared to rural workers. Blood benzene, t,t-MA and S-PMA levels were similar among TP and PD, although the blood benzene level was significantly higher in urban workers compared to rural workers. In urban workers, airborne benzene and blood benzene levels were significantly correlated. CONCLUSIONS: Benzene is a human carcinogen, and BTXs are potential reproductive toxins at low dose exposures. Biological and environmental monitoring to assess exposure to BTXs represents a preliminary and necessary tool for the implementation of preventive measures for female subjects working in outdoor environments.

Impact of cigarette smoking on volatile organic compound (VOC) blood levels in the U.S. population: NHANES 2003-2004.

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.

Evaluation of neuropsychological symptoms and exposure to benzene, toluene and xylene among two different furniture worker groups in Izmir.

This study was conducted to determine whether there was any exposure to toluene, xylene and benzene and to assess the health impact of these solvents on workers in furniture enterprises in Karabaglar, Izmir. This cross-sectional study covered furniture enterprises in Karabaglar, Izmir. This study was comprised of an exposed group consisting of workers engaged in painting and varnishing and therefore exposed either directly or indirectly toluene, xylene and benzene in the workplace and the non-exposed group engaged in other aspects of production. While a total of 261 individuals completed questionnaires, 210 workers agreed to provide blood samples. Blood solvents levels were determined using gas chromatograph at Ege University, Intoxication Research and Application Centre. The modified EUROQUEST questionnaire was used to assess neuropsychological symptoms and neurological and general examination were performed. Occupational and exposure history, demographic and work-related information was collected. In this study of workers, blood toluene and benzene levels were found to be significantly higher among those engaged in painting and varnishing compared to those who perform other tasks. The average blood toluene and benzene concentrations among exposed workers were 6.95 times and 1.64 times respectively higher than those in the nonexposed groups. Smokers and participants who worked in excess of 8 hours/day had higher blood toluene and benzene levels. The most frequently work-related health complaints were back pain, allergies and asthma. No differences were found in the average scores in the neuropsychological symptoms questionnaire between exposed and non-exposed groups. Neurological examination of two individuals with these complaints revealed a loss of reflexes. The workers were unaware that they were being exposed to solvents at work. Tobacco smoke is a major source of internal exposure to benzene. Improving working conditions in furniture work places is a priority.

Higher blood concentrations of synthetic musks in women above fifty years than in younger women.

Synthetic musk compounds are widely used as fragrance ingredients in many consumer products. Little is known about their accumulation in humans and especially in older persons. In this study, we determined concentrations of 11 synthetic musks in women above fifty years and compared the results with earlier results from samples of young females. Blood was taken from 53 women above 50 years of age, visiting outpatients of the Department of Angiology at the Hanusch-Krankenhaus in Vienna, Austria. The used analytical methods consist of an extraction and clean-up step and a chromatographic analysis by GC/MS. Tonalide-D3 was used as recovery standard in all samples. Hexachlorobenzene (13)C(6) was used as internal standard. Study participants also completed a questionnaire on the use of cosmetics, about nutrition and other life-style aspects. The two substances which could be detected in higher percentages of the blood plasma samples were galaxolide (89 percent, maximum concentration 6900 ng/L) and musk xylene (62 percent, maximum concentration 190 ng/L). Regression analysis revealed a significant association of galaxolide concentration with frequent use of perfumes, deodorants and shampoos. Frequent use of soaps and fabric softener was associated with higher plasma concentrations of musk xylene. Nutrition habits, skin type, body mass index or surface area were not related to plasma concentration of these musk compounds. From the study group investigated older persons showed higher plasma concentrations. These findings could be due to the higher use of lotions and crèmes on face and hands and a more frequent use of skin care products because older persons reported more frequently dry skin. In addition, physiological aging related changes might be responsible for higher dermal absorption of synthetic musks. These results indicate that more focus on aging tissues is needed.

Tacrolimus hydrate ointment inhibits skin plasma extravasation in rats induced by topical m-xylene but not capsaicin.

Tacrolimus ointment is used to treat various chronic inflammatory skin diseases. However, the effect of this ointment on acute neurogenic inflammation in the skin remains to be fully elucidated. Topical capsaicin and m-xylene produce tachykinin release from sensory nerves in the skin, resulting in skin plasma leakage. We investigated the effect of tacrolimus ointment (0.1%) on skin microvascular leakage induced by topical capsaicin (10 mM) and m-xylene (neat), and intracutaneous compound 48/80 (c48/80) (10 microg/ml, 50 microl/site) in two groups of rats pretreated with excessive capsaicin or its vehicle. The amount of leaked Evans blue dye reflected skin plasma leakage. Capsaicin, m-xylene or c48/80 was applied to the shaved abdomens of rats 8 h after topical application of tacrolimus ointment or its base. Desensitization with capsaicin reduced the skin response to capsaicin and m-xylene by 100% and 65%, respectively, but not to c48/80. Tacrolimus ointment significantly inhibited the skin response induced by m-xylene and c48/80, regardless of pretreatment with capsaicin. However, topical tacrolimus did not influence the skin response induced by capsaicin. We also evaluated whether topical capsaicin and m-xylene, and intracutaneous c48/80 cause mast cell degranulation in skin treated with tacrolimus. Mast cell degranulation was microscopically assessed. Topical tacrolimus only significantly suppressed degranulation induced by m-xylene and c48/80. Our data shows that tacrolimus ointment partially inhibits plasma leakage and mast cell degranulation in rat skin induced by m-xylene and c48/80 but not capsaicin, suggesting that the inhibitory effect is not associated with a reduction in neurogenic-mediated mechanisms.

[DNA damage assessment and biological monitoring of occupational exposure to organic solvents, 2006]. / Evaluación del daño en el ADN y vigilancia biológica de la exposición laboral a solventes orgánicos, 2006.

INTRODUCTION: Exposure to solvents is one of the highest potential risks for millions of workers in the world; they can generate substantial environmental pollution leading to outbreaks of public health problems. OBJECTIVE: Blood levels were determined for metabolites of benzene, toluene and xylene, and polymorphisms for enzymes CYP2E1, GSTM1, GSTT1 were characterized. Damage to DNA was assessed by the comet assay for exposure to organic solvents. MATERIALS AND METHODS: A cross-sectional study was undertaken in 90 employees from 5 different companies. A survey form was administered; blood was sampled to detect the genetic polymorphisms and to apply the comet assay (single cell gel electrophoresis) to detect DNA fragmentation. The concentrations of phenol, ortho and meta methylhippuric acids were measured in urine. Statistical analyses explored the possible associations. RESULTS: The percentage of workers directly exposed to solvents was 34.4%. In this group, the evidence indicated concentrations higher than the permitted limits: 3.3% for phenol, 6.6% for hippuric acid, 3.3% for ortho-methylhippuric acid and 36.7% for metamethylhippuric acid. In the Comet assay, the length of the comets tail was greater than average (19.5 ìm) in exposed subjects, and the percentage of cells with mild damage (19.0%) (p=0.0007) was higher. The percentage of exposed individuals with absent genotypes for enzymes GSTT1 and GSTM1 was 46.7% and 56.8% respectively. CONCLUSION: Exposure biomarkers have become fundamental tools for the evaluation of risk associated with exposure to toxic agents.

[Oral intoxication with xylene--a case report]. / Doustne zatrucie ksylenem--opis przypadku.

UNLABELLED: A case of a suicidal oral exposure to xylene has been described. A 33 year-old female ingested 300-500 ml of xylene 2.5 hours before admission to the hospital. Hypotonia, metabolic acidosis, diarrhea and moderate, transient dysphagia were observed. Concentrations of xylene, toluene and ethylbenzene in blood at admission were 11.7; 2.9 and 0.18 mg/l respectively and 1.1; 0.33 and 0 mg/l after 24 hours after therapy. CONCLUSIONS: The course of acute xylene intoxication in the described case was relatively uneventful despite high blood concentration of xylene. Further study is necessary to establish the potentially lethal blood concentration of xylene.

An unusual case of drug-facilitated sexual assault using aromatic solvents.

This report documents a case of drug-facilitated sexual assault (DFSA) under the influence of solvents. The victim was a 13-year-old female. Upon contact with law enforcement, she was still confused and could hardly explain the facts. She told authorities that she had been kidnapped 4 h previously when two individuals with covered faces put a cloth soaked in a solvent over her mouth. She spent a few hours in a room, during which she lost consciousness. The girl awakened semi-nude in the street with memory loss. No alcohol was present in the subject's body; no odor of alcohol was detected on the subject's breath. No lesions were observed during a gynecological exam. A blood sample was taken with the intent to investigate the use of chloroform or similar anesthetics. Toxicological analysis of the victim's blood revealed the presence of 7.6 mg/L of benzene, 24.8 mg/L of toluene, and 0.6 mg/L of xylene (mixture of isomers). As for other analytical findings, diazepam (0.02 mg/L) was also found. The aromatic solvents involved in this case were detected using gas chromatography with flame-ionization detection (GC-FID) and confirmed using GC-mass spectrometry (MS) in full scan mode after liquid-liquid extraction of the whole blood sample. Quantitation of the aromatic solvents was carried out using GC-FID. Diazepam was detected using GC with nitrogen-phosphorus detection (NPD) and confirmed using GC-MS with full scan mode after solid-phase extraction of the whole blood sample using Bond-Elut Certify columns. Quantitation of diazepam was carried out using GC-NPD. No other drugs, including ethanol, were detected. Recoveries for benzene, toluene, and xylene (mixture of isomers) in whole blood at 5 mg/L were 89.2%, 90.8%, and 93.4%, respectively. Intraday precisions were 5.3%, 5.0%, and 4.9%, respectively, and interday precisions were 12.1%, 11.6%, and 11.5%, respectively. The limits of detection (LOD) and quantitation (LOQ) were 30 and 100 microg/L, respectively. The linearity of the blood calibration curves was excellent with r(2) values of > 0.999 (range 0.1-10 mg/L). Recovery for diazepam in whole blood at 0.5 mg/L was 88.2% with intraday and interday precisions of 2.0% and 10.8%, respectively. The LOD and LOQ were 6 and 20 microg/L, respectively. The linearity of the blood calibration curve was excellent with r(2) values of > 0.999 (range 0.1-2 mg/L). We want to alert other toxicologists about new or unexpected products that should be taken into account when the surreptitious use of substances in DFSA is suspected.

An improved approach for accurate quantitation of benzene, toluene, ethylbenzene, xylene, and styrene in blood.

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.

Simultaneous congener-specific determination of selected organochlorine compounds and nitro musks in human whole blood samples by solid-phase extraction and capillary gas chromatography with electron capture detection.

Chlororganic compounds like pesticides or polychlorinated biphenyls (PCB) and nitro musks are environmental contaminants, which remain public health concerns because of their persistence in humans and their toxicological properties. Many of these substances are associated with endocrine dysfunction or with carcinogenicity. Therefore, a simple method using solid-phase extraction followed by capillary gas chromatography with electron capture detection for the simultaneous determination of both organochlorines and nitro musks in human whole blood samples has been developed. Recovery rates of 13 PCB congeners and of 7 pesticides ranged from 67.5% to 100.4% and from 81.1% to 110.5%, respectively. Recoveries of the 5 nitro musks were consistent and ranged from 90.2% to 98.8%. The accuracy for organochlorines and nitro musks varied from 6.3% to 8.6%. Method detection limits ranged from 0.02 microg/L to 0.11 microg/L for the organochlorines and from 0.04 microg/L to 0.08 microg/L for the nitro musks. The method has a high sensitivity with a low detection limit even in slightly contaminated human blood samples. The time and technical effort is small, so the method is feasible for epidemiological studies with regard to the impact of organochlorines and nitro musks on certain diseases.

Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling.

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.

Development of a physiologically based pharmacokinetic model for volatile fractions of gasoline using chemical lumping analysis.

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.