Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling.

Protein tyrosine phosphatase, nonreceptor type 2 (PTPN2) is mainly expressed in hematopoietic cells, where it negatively regulates growth factor and cytokine signaling. PTPN2 is an important regulator of hematopoiesis and immune/inflammatory responses, as evidenced by loss-of-function mutations of PTPN2 in leukemia and lymphoma and knockout mice studies. Benzene is an environmental chemical that causes hematological malignancies, and its hematotoxicity arises from its bioactivation in the bone marrow to electrophilic metabolites, notably 1,4-benzoquinone, a major hematotoxic benzene metabolite. Although the molecular bases for benzene-induced leukemia are not well-understood, it has been suggested that benzene metabolites alter topoisomerases II function and thereby significantly contribute to leukemogenesis. However, several studies indicate that benzene and its hematotoxic metabolites may also promote the leukemogenic process by reacting with other targets and pathways. Interestingly, alterations of cell-signaling pathways, such as Janus kinase (JAK)/signal transducer and activator of transcription (STAT), have been proposed to contribute to benzene-induced malignant blood diseases. We show here that 1,4-benzoquinone directly impairs PTPN2 activity. Mechanistic and kinetic experiments with purified human PTPN2 indicated that this impairment results from the irreversible formation (kinact = 645 m-1·s-1) of a covalent 1,4-benzoquinone adduct at the catalytic cysteine residue of the enzyme. Accordingly, cell experiments revealed that 1,4-benzoquinone exposure irreversibly inhibits cellular PTPN2 and concomitantly increases tyrosine phosphorylation of STAT1 and expression of STAT1-regulated genes. Our results provide molecular and cellular evidence that 1,4-benzoquinone covalently modifies key signaling enzymes, implicating it in benzene-induced malignant blood diseases.

Assessing human variability in kinetics for exposures to multiple environmental chemicals: a physiologically based pharmacokinetic modeling case study with dichloromethane, benzene, toluene, ethylbenzene, and m-xylene.

The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to "low" (RfC-like) or "high" (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant "low" exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16-24%, vs. 12-15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO's CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For "high" exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11-16% to 2-6%) and TODD (CV= 12-13% to 7-9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.

Validation of Armadillo officinalis Dumèril, 1816 (Crustacea, Isopoda, Oniscidea) as a bioindicator: in vivo study of air benzene exposure.

This study tests the potential for using Armadillo officinalis as a bioindicator of exposure to and activation of benzene metabolic pathways using an in vivo model. A. officinalis specimens collected in a natural reserve were divided into a control and three test groups exposed to 2.00, 5.32 or 9.09 µg/m(3) benzene for 24h. Three independent tests were performed to assess model reproducibility. Animals were dissected to obtain three pooled tissue samples per group: hepatopancreas (HEP), other organs and tissues (OOT), and exoskeleton (EXO). Muconic acid (MA), S-phenylmercapturic acid (S-PMA), two human metabolites of benzene, and changes in mtDNA copy number, a human biomarker of benzene exposure, were determined in each sample; benzene was determined only in EXO. MA was measured by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection, S-PMA by triple quadrupole mass spectrometer liquid chromatography with electro spray ionization (LC-MS-ESI-TQD), mtDNA by real-time quantitative PCR and end-point PCR, and benzene by quadrupole mass spectrometer head-space gas chromatography (HSGC-MS). MA and S-PMA levels rose both in HEP and OOT; EXO exhibited increasing benzene concentrations; and mtDNA copy number rose in HEP but not in OOT samples. Overall, our findings demonstrate that A. officinalis is a sensitive bioindicator of air benzene exposure and show for the first time its ability to reproduce human metabolic dynamics.

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

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

[Interstitial endocrine apparatus of testes of experimental animals in conditions of chromium-benzene intoxication].

With the use of histological, morphometric and statistical methods there was shown a gonadotropic effect of chromium, benzene and also their mixtures in male mice (CBA x C57Bl6) F1. The established structural changes in the testes of exposed animals showed the suppression of their germinative and endocrine functions. The response of Leydig cells in the chromium group expresses a development of the compensatory process in the relation with the destruction of seminiferous epithelium.

The use of biomonitoring data in exposure and human health risk assessment: benzene case study.

Abstract A framework of "Common Criteria" (i.e. a series of questions) has been developed to inform the use and evaluation of biomonitoring data in the context of human exposure and risk assessment. The data-rich chemical benzene was selected for use in a case study to assess whether refinement of the Common Criteria framework was necessary, and to gain additional perspective on approaches for integrating biomonitoring data into a risk-based context. The available data for benzene satisfied most of the Common Criteria and allowed for a risk-based evaluation of the benzene biomonitoring data. In general, biomarker (blood benzene, urinary benzene and urinary S-phenylmercapturic acid) central tendency (i.e. mean, median and geometric mean) concentrations for non-smokers are at or below the predicted blood or urine concentrations that would correspond to exposure at the US Environmental Protection Agency reference concentration (30 µg/m(3)), but greater than blood or urine concentrations relating to the air concentration at the 1 × 10(-5) excess cancer risk (2.9 µg/m(3)). Smokers clearly have higher levels of benzene exposure, and biomarker levels of benzene for non-smokers are generally consistent with ambient air monitoring results. While some biomarkers of benzene are specific indicators of exposure, the interpretation of benzene biomonitoring levels in a health-risk context are complicated by issues associated with short half-lives and gaps in knowledge regarding the relationship between the biomarkers and subsequent toxic effects.

Determination of trans,trans-muconic acid in workers' urine through ultra-performance liquid chromatography coupled to tandem mass spectrometry.

A novel method for the biological monitoring of benzene-exposed workers has been developed through ultra-performance liquid chromatography coupled to tandem mass spectrometry. The method uses trans,trans-muconic acid in urine as the benzene-exposure biomarker. The method was developed using a triple quadrupole mass spectrometer with enough sensitivity to facilitate diluting and injecting the urine samples directly, rather than performing a solid-phase extraction procedure as is common in the available protocols. Moreover, compared with a conventional high-pressure liquid chromatography system, the separation power provided by the ultra-performance liquid chromatography system allows a 10-fold reduction in run time. The method was adjusted to a dynamic range of between 198.9 and 4916.7 µg/L to cover the biological exposure index of trans,trans-muconic acid in urine. Also, the method demonstrated intra-day and inter-day precision at 98%, and accuracy within an acceptable range of 101 ± 8%. The method has been used to quantify various types of urine samples, such as workers' urine and inter-laboratory proficiency tests. Depending on the sample, the quantified levels ranged from less than the limit of quantitation to 3836.7 µg/L. No levels exceeding the calibration range were detected in the urine of workers, and the reported concentrations in urine for the proficiency tests were, as expected, based on known values. Moreover, the new method using sample dilution and faster chromatographic run was more effective, facilitating fast communication of results, as needed, to decision-makers.

A tobacco-related carcinogen: assessing the impact of smoking behaviours of cohabitants on benzene exposure in children.

BACKGROUND: Secondhand smoke (SHS) represents a major preventable cause of morbidity for communities, especially for children, who are more susceptible than adults to the adverse effects of passive smoking. SHS contains several carcinogens, including benzene. OBJECTIVE: To investigate the role of household characteristics and the smoking behaviours of cohabitants in predicting SHS-derived benzene exposure levels. Methods In this cross-sectional study, 122 children (aged 5-11 years old) were selected from a school in rural Italy. Characteristics of their home environment and the smoking habits of the children's cohabitants were obtained via questionnaire, and urinary unmodified benzene (u-UB) and cotinine (a specific nicotine metabolite) levels were determined from spot urine samples. RESULTS: Significant differences between SHS-exposed and SHS-unexposed children were found with respect to u-UB levels (median values 359.50 and 92.50 ng/litre, respectively; p<0.001). The excretion of u-UB increased significantly in parallel to increased SHS exposure as follows: unexposed to SHS (median value 92.50 ng/litre)

Benzene absorption in animals and man: an overview.

Benzene is a widespread, naturally occurring substance of environmental concern as systemic exposure in humans is proven to be carcinogenic. Dermal exposure is a common and significant route of systemic entry and percutaneous absorption is critical in exposure risk assessment. This article reviews the scientific principles, methodologies, and research behind the multiple steps of the percutaneous absorption of benzene in animals and man and the application of this information to optimize exposure risk assessments. A focus on occupational exposures to benzene is made with an exploration of the limitations of current preventative measures and hazard assessments. Finally, recommendations for future research to fill existing knowledge gaps are made.

Biomonitoring Equivalents for benzene.

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews available health based risk assessments and exposure guidance values for benzene from the United States Environmental Protection Agency (US EPA), Texas Commission on Environmental Quality (TCEQ), California's Office of Environmental Health Hazard Assessment (OEHHA) and the Agency for Toxic Substances and Disease Registry (ATSDR) to derive BE values for benzene in blood and urine. No BE values were derived for any of the numerous benzene metabolites or hemoglobin and albumin adducts. Using existing physiologically based pharmacokinetic (PBPK) models, government risk assessment values were translated into corresponding benzene levels in blood assuming chronic steady-state exposures. BEs for benzene in urine were derived using measured correlations between benzene in urine with benzene in blood. The BE values for benzene in blood range from 0.04 to 1.29 µg/L, depending upon the underlying non-cancer risk assessment used in deriving the BE. Sources of uncertainty relating to both the basis for the BE values and their use in evaluation of biomonitoring data, including the transience of the biomarkers relative to exposure frequency, are discussed. The BE values derived here can be used as screening tools for evaluation of population biomonitoring data for benzene in the context of the existing risk assessment and can assist in prioritization of the potential need for additional risk assessment efforts for benzene relative to other chemicals.

Pilot study of aromatic hydrocarbon adsorption characteristics of disposable filtering facepiece respirators that contain activated carbon.

Disposable filtering facepiece respirators (FFRs) used by health care workers are not designed to reduce the inhalation of volatile organic compounds (VOCs). Smoke-generating surgical procedures release VOCs and have been associated with the following complaints: foul smell, headaches, nausea, irritated throat and lungs, and asthma. Organic vapor FFRs that contain activated carbon are used by industrial workers to provide odor relief. These respirators remove irritating odors but are not marketed as respirators that provide respiratory protection against a gas or vapor. This study investigated the aromatic hydrocarbon adsorption capabilities of nuisance organic vapor (OV) FFRs. Three OV FFR models were tested to determine the 10% breakthrough time of three aromatic hydrocarbons at ambient room temperature and relative humidity. All respirator models were exposed to each vapor separately in three duplicate tests (n = 27). The respirator was sealed with silicone to an AVON-ISI headform that was placed in a chamber and exposed to VOC-laden air (20 ppm, 37 L/min). Periodically, gas samples were directed to an SRI gas chromatograph (Model 8610C) for analysis. All respirators performed similarly. The average 10% breakthrough values for all tests were at least 64 min, 96 min, and 110 min for benzene, toluene, and xylene, respectively. Respirators were tested with challenge concentrations at nuisance levels (20 ppm) and did not exceed 10% breakthrough values for at least 61 min. While the results of this pilot study hold promise, there is a need for further investigation and validation to determine the effectiveness of nuisance FFRs in mitigating organic vapors such as benzene, toluene, and xylene.

Association between environmental exposure to benzene and oxidative damage to nucleic acids in children.

OBJECTIVES: To evaluate the association between environmental exposure to benzene and oxidative damage to nucleic acids in children, also considering the role of Environmental Tobacco Smoke (ETS). METHODS: 396 children living in central Italy were recruited in districts with different urbanization and air pollution. All biomarkers were determined in spot urine samples by mass spectrometric techniques to assess exposure [benzene (U-Benz), and its metabolites (t,t-muconic and S-phenylmercapturic acids, t,t-MA and S-PMA, respectively), cotinine] and nucleic acid oxidation [8-oxo-7, 8-dibydro-2'-deoxyguanosine (8-oxodGuo), 8-oxo-7, 8-dihydroguanosine (8-oxoGuo), and 8-oxo-7, 8-dihydroguanine (8-oxoGua)]. RESULTS: Biomarkers of exposure and nucleic acid oxidation increased with urbanization and were correlated with each other (r > 0.18, p < 0.005). In a multiple linear regression model, benzene exposure, assessed by S-PMA and t,t-MA, was associated (p < 0.0001) with both 8-oxodGuo (R2 = 0.392) and 8-oxoGuo (R2 = 0.193) in all areas of residence, with similar slopes. CONCLUSIONS: (i) Biomarkers of exposure to benzene increased as a function of environmental air pollution and urbanization level; (ii) U-Benz clearly distinguished both exposure to ETS and areas of residence, whereas benzene metabolites were associated only with the latter; (iii) the variance of 8-oxodGuo and 8-oxoGuo was accounted for by environmental benzene exposure, thus suggesting that benzene is a good tracer of other components of complex mixtures of pollutants causing oxidative damage to nucleic acids.

Biological monitoring of low-level exposure to benzene.

INTRODUCTION: Conflicting opinions exist about the reliability of biomarkers of low-level exposure to benzene. We compared the ability of the urinary excretion of trans,trans-muconic acid (t,t-MA), s-phenilmercapturic acid (s-PAMA) and urinary benzene (U-Benz) to detect low level occupational and environmental exposure to benzene. METHODS: We monitored airborne benzene by personal air sampling, and U-Benz, s-PMAI, t,t-MA and cotinine (U-Cotinine) in spot urine samples, collected at 8 am and 8 pm, in 32 oil refinery workers and 65 subjects, randomly selected among the general population of urban and suburban Cagliari, Italy. Information on personal characteristics, diet and events during the sampling day was acquired through in person interviews. RESULTS: The median concentration of airborne benzene was 25.2 microg/m3 in oil refinery workers, and 8.5 microg/m3 in the general population subgroup. U-Benz in morning and evening samples was significantly more elevated among oil refinery workers than the general population subgroup (p = 0.012, and p = 7.4 x 10(-7), respectively) and among current smokers compared to non-smokers (p = 5.2 x 10(-8), and p = 5.2 x 10(-5) respectively). Benzene biomarkers and their readings in the two sampling phases were well correlated to each other. The Spearman's correlation coefficient with airborne benzene was significant for U-Benz in the evening sample, while no correlation was seen with t,t-MA and s-PMA readings in either samplings. The two benzene metabolites were frequently below limit of detection (LOD), particularly among the general population study subjects (17-9% and 39%, for t,t-MA and s-PMA respectively). Morning U-Cotinine excretion showed a good correlation with U-Benz in the morning and in the evening sampling (p < 0.001), and with s-PMA in the evening sample (p < 0.001), but not with t,t-MA in either samplings. t,t-MA in the evening sample was the only biomarker showing a moderate inverse correlation with BMI (p < 0.05). The multiple regression analysis adjusting by BMI and number of cigarettes smoked during the day confirmed the results of the univariate analysis. DISCUSSION: Our results suggest that unmetabolized U-Benz would allow a more reliable biomonitoring of low-level exposure to benzene than s-PMA and t,t-MA.

The impact of saturable metabolism on exposure-response relations in 2 studies of benzene-induced leukemia.

Enzymatic saturation of metabolic pathways is one factor that potentially contributes to the nonlinear exposure-response relations that are frequently reported in occupational epidemiologic studies. The authors propose an approach to explore the contribution of saturable metabolism to previously reported exposure-response relations by integrating predictive models of relevant biomarkers of exposure into the epidemiologic analysis. The approach is demonstrated with 2 studies of leukemia in benzene-exposed workers, one conducted in the Australian petroleum industry (1981-1999) and one conducted in a US rubber hydrochloride production factory in Ohio (1940-1996). The studies differed greatly in their magnitudes and durations of exposure. Substitution of biomarker levels for external estimates of benzene exposure reduced the fold difference of the log relative risk of leukemia per unit of cumulative exposure between the 2 studies by 11%-44%. Nevertheless, a considerable difference in the log relative risk per unit of cumulative exposure remained between the 2 studies, suggesting that exposure misclassification, differences in study design, and potential confounding factors also contributed to the heterogeneity in risk estimates.

Dermal absorption of benzene in occupational settings: estimating flux and applications for risk assessment.

There is growing emphasis in the United States and Europe regarding the quantification of dermal exposures to chemical mixtures and other substances. In this paper, we determine the dermal flux of benzene in neat form, in organic solvents, and in aqueous solutions based on a critical review and analysis of the published literature, and discuss appropriate applications for using benzene dermal absorption data in occupational risk assessment. As part of this effort, we synthesize and analyze data for 77 experimental results taken from 16 studies of benzene skin absorption. We also assess the chemical activity of benzene in simple hydrocarbon solvent mixtures using a thermodynamic modeling software tool. Based on the collective human in vivo, human in vitro, and animal in vitro data sets, we find that the steady-state dermal flux for neat benzene (and benzene-saturated aqueous solutions) ranges from 0.2 to 0.4 mg/(cm²·h). Observed outlier values for some of the animal in vivo data sets are possibly due to the use of test species that have more permeable skin than humans or study conditions that resulted in damage to the skin barrier. Because relatively few dermal absorption studies have been conducted on benzene-containing organic solvents, and available test results may be influenced by study design or vehicle effects, it is not possible to use these data to quantify the dermal flux of benzene for other types of solvent mixtures. However, depending on the application, we describe several potential approaches that can be used to derive a rough approximation of the steady-state benzene dermal flux for these mixtures. Important limitations with respect to quantifying and evaluating the significance of dermal exposures to benzene in occupational settings include a lack of data on (1) factors that affect the dermal uptake of benzene, (2) the dermal flux of benzene for different organic solvent mixtures, (3) meaningful metrics for evaluating the dermal uptake of benzene, (4) steady-state versus non-steady-state dermal flux values for benzene, (5) the effect of skin damage on the dermal flux of benzene, (6) standardized test methods for estimating the dermal flux of benzene, and (7) robust estimates of the evaporation rate of benzene from different liquid vehicles.

Assessing the impact of the duration and intensity of inhalation exposure on the magnitude of the variability of internal dose metrics in children and adults.

The objective of this study was to assess the impact of the exposure duration and intensity on the human kinetic adjustment factor (HKAF). A physiologically based pharmacokinetic model was used to compute target dose metrics (i.e. maximum blood concentration (C(max)) and amount metabolized/L liver/24 h (Amet)) in adults, neonates (0-30 days), toddlers (1-3 years), and pregnant women following inhalation exposure to benzene, styrene, 1,1,1-trichloroethane and 1,4-dioxane. Exposure scenarios simulated involved various concentrations based on the chemical's reference concentration (low) and six of U.S. EPA's Acute Exposure Guideline Levels (AEGLs) (high), for durations of 10 min, 60 min, 8 h, and 24 h, as well as at steady-state. Distributions for body weight (BW), height (H), and hepatic CYP2E1 content were obtained from the literature or from P3M software, whereas blood flows and tissue volumes were calculated from BW and H. The HKAF was computed based on distributions of dose metrics obtained by Monte Carlo simulations [95th percentile in each subpopulation/median in adults]. At low levels of exposure, ranges of C(max)-based HKAF were 1-6.8 depending on the chemical, with 1,4-dioxane exhibiting the greatest values. At high levels of exposure, this range was 1.1-5.2, with styrene exhibiting the greatest value. Neonates were always the most sensitive subpopulation based on C(max), and pregnant women were most sensitive based on Amet in the majority of the cases (1.3-2.1). These results have shown that the chemical-specific HKAF varies as a function of exposure duration and intensity of inhalation exposures, and sometimes exceeds the default value used in risk assessments.

A quantitative method for estimating dermal benzene absorption from benzene-containing hydrocarbon liquids.

This study examines a method for estimating the dermal absorption of benzene contained in hydrocarbon liquids that contact the skin. This method applies to crude oil, gasoline, organic solvents, penetrants, and oils. The flux of benzene through occluded skin as a function of the percent vol/vol benzene in the liquid is derived by fitting a curve to experimental data; the function is supralinear at benzene concentrations < or = 5% vol/vol. When a liquid other than pure benzene is on nonoccluded skin, benzene may preferentially evaporate from the liquid, which thereby decreases the benzene flux. We present a time-averaging method here for estimating the reduced dermal flux during evaporation. Example calculations are presented for benzene at 2% vol/vol in gasoline, and for benzene at 0.1% vol/vol in a less volatile liquid. We also discuss other factors affecting dermal absorption.

Effects of inhaled combined Benzene, Toluene, Ethylbenzene, and Xylenes (BTEX): Toward an environmental exposure model.

Combined environmental exposures to the volatile organic compounds (VOCs) Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) pose clear risks to public health. Research into these risks is under-studied even as BTEX levels in the atmosphere are predicted to rise. This review focuses on the available literature using single- and combined-BTEX component inhaled solvent exposures in animal models, necessarily also drawing on findings from models of inhalant abuse and occupational exposures. Health effects of these exposures are discussed for multiple organ systems, but with particular attention on neurobehavioral outcomes such as locomotor activity, impulsivity, learning, and psychopharmacological responses. It is clear that animal models have significant differences in the concentrations, durations and patterns of exposure. Experimental evidence of the deleterious health and neurobehavioral consequences of exposures to the individual components of BTEX were found, but these effects were typically assessed using concentrations and exposure patterns not characteristic of environmental exposure. Future studies with animal models designed appropriately to explore combined BTEX will be necessary and advantageous to discovering health outcomes and more subtle neurobehavioral impacts of long-term environmental exposures.

Transplacental benzene exposure increases tumor incidence in mouse offspring: possible role of fetal benzene metabolism.

Childhood cancer is the leading cause of disease-related death in children aged 1-14 years in Canada and the USA and it has been hypothesized that transplacental exposure to environmental carcinogens such as benzene may contribute to the etiology of these cancers. Our objectives were to determine if transplacental benzene exposure increased tumor incidence in mouse offspring and assess fetal benzene metabolism capability. Pregnant CD-1 and C57Bl/6N mice were given intraperitoneal injections of corn oil, 200 mg/kg, or 400 mg/kg benzene on gestational days 8, 10, 12 and 14. A significant increase in tumor incidence was observed in CD-1, but not C57BL/6N, 1-year-old offspring exposed transplacentally to 200 mg/kg benzene. Hepatic and hematopoietic tumors were predominantly observed in male and female CD-1 offspring, respectively. Female CD-1 offspring exposed transplacentally to 200 mg/kg benzene had significantly suppressed bone marrow CD11b(+) cells 1 year after birth, correlating with reduced colony-forming unit granulocyte/macrophage numbers in 2-day-old pups. CD-1 and C57Bl/6N maternal blood benzene levels and fetal liver benzene, t, t-muconic acid, hydroquinone and catechol levels were analyzed by gas chromatography/mass spectrometry. Significant strain-, gender- and dose-related differences were observed. Male CD-1 fetuses had high hydroquinone levels, whereas females had high catechol levels after maternal exposure to 200 mg/kg benzene. This is the first demonstration that transplacental benzene exposure can induce hepatic and hematopoietic tumors in mice, which may be dependent on fetal benzene metabolism capability.

A multicompartment liver-based pharmacokinetic model for benzene and its metabolites in mice.

Benzene is a highly flammable, colorless liquid. Ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. After uptake into the body, benzene undergoes a series of metabolic transformations to multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites. This model takes into account the zonal distribution of enzymes and metabolism in the liver rather than treating the liver as one homogeneous compartment, and considers metabolism in tissues other than the liver. Analysis was done to examine the existence and uniqueness of solutions of the system. We then formulated an inverse problem to obtain estimates for the unknown parameters; data from multiple laboratories and experiments were used. Despite the sources of variability, the model simulations matched the data reasonably well in most cases. Our study shows that the multicompartment metabolism model does improve predictions over the previous model (Cole et al. in J. Toxicol. Environ. Health, 439-465, 2001) and that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry.