Modeling the impact of heat stress on the toxicokinetics of toluene and acetone.

Many workers can be exposed simultaneously to heat and volatile chemicals. In a controlled human exposure study, it was observed that an increase in ambient temperature was associated with increased blood concentrations for acetone and toluene. Based on the expected changes in physiological parameters that occur with an increase in ambient temperature, we aimed to develop a PBPK model for acetone and toluene that could account for the impact of temperature on the kinetics of these solvents. Changes in temperature-dependent physiological parameters (i.e. blood flows, cardiac output, alveolar ventilation) based on recent measurements in volunteers were introduced in the PBPK models to simulate observed blood concentrations for different temperature exposure conditions. Because initial simulations did not adequately predict solvent kinetics at any temperature, the most sensitive parameter (alveolar ventilation; Qp) was, therefore, optimized on experimental acetone blood concentrations to obtain a relationship with temperature. The new temperature-dependent Qp relationship gave Qp values consistent with the literature and estimated a mean increase of 19% at 30 °C (wet bulb globe temperature) compared to 21 °C. The integration of a new temperature-dependent Qp relationship in the PBPK toluene model yielded adequate simulations of the experimental data for toluene in blood, exhaled air and urine. With further validation with other solvents, the temperature-dependant PBPK model could be a useful tool to better assess the risks of simultaneous exposure to volatile chemicals and heat stress and interpret biomonitoring data in workers as well as in the general population. TRN: NCT02659410, Registration date: January 15, 2016.

Quantification of the Conjugated Forms of Dichlorobisphenol A (3,3'-Cl 2 BPA) in Rat and Human Plasma Using HPLC-MS/MS.

BACKGROUND: Bisphenol A (BPA) is a ubiquitous contaminant that has endocrine-disrupting effects. Chlorinated derivatives of BPA are formed during chlorination of drinking water and have higher endocrine-disrupting activity. Dichlorobisphenol A (Cl 2 BPA) is the most abundant chlorinated BPA derivative found in several human biological matrices. Recent in vitro experiments have shown that Cl 2 BPA is metabolized in sulpho- and glucuro-conjugated compounds. To date, no assay has been developed to quantify the sulfo- and glucuro-conjugates of 3,3'-Cl 2 BPA (3,3'-Cl 2 BPA-S and 3,3'-Cl 2 BPA-G, respectively). METHODS: A high-performance liquid chromatography-tandem mass spectrometry assay for the determination of 3,3'-Cl 2 BPA conjugated forms in plasma samples was developed and validated according to the European Medicines Agency guidelines. Quantification was performed in the multiple reaction monitoring mode for all target analytes using a SCIEX 6500 + tandem mass spectrometer with an electrospray source operating in the negative ionization mode. Chromatographic separation was achieved using a C18 column maintained at 40°C and a binary mobile phase delivered in the gradient mode at a flow rate of 0.35 mL/min. Sample was prepared via simple precipitation using acetonitrile. The assay was validated and applied to rat and human plasma samples. RESULTS: Linearity was demonstrated over the range of 0.006-25 ng/mL for 3,3'-Cl 2 BPA-G and 0.391-100 ng/mL for 3,3'-Cl 2 BPA-S. Intraday and interday bias values were in the 95%-109% range, and the imprecision <9%. Internal standard corrected matrix effects were also investigated. This method enabled quantification of the conjugated forms of 3,3'-Cl 2 BPA in plasma samples. CONCLUSIONS: This is the first report on the development and validation of an analytical method for the quantification of 3,3'-Cl 2 BPA-G and 3,3'-Cl 2 BPA-S in the plasma matrix. This study is also the first report on the in vivo occurrence of these metabolites.

Toxicokinetics of silver element following inhalation of silver nitrate in rats.

Silver (Ag) and its compounds are priority contaminants, for which toxicological effects are well documented, but their toxicokinetics are not fully documented for a proper risk assessment. While the toxicokinetics of insoluble Ag nanoparticles (Ag NPs) was recently documented, there is a lack of data on the kinetic behavior of the soluble form, such as one of the mostly used silver nitrate (AgNO3) form. This study aimed to better document the toxicokinetics of Ag element following inhalation of soluble AgNO3 for comparison with a previous study on the kinetics of inhaled Ag NPs using a similar experimental design. We exposed male Sprague-Dawley rats to AgNO3 during 6 continuous hours (typical of a daily worker exposure) to determine the kinetic time courses of Ag element in blood, tissues, and excreta over a 14-day period post-exposure. Only a small fraction of Ag was found in lungs following the onset of the 6-h inhalation of AgNO3 (on average (± SD) 0.3 ± 0.1% at the end of the 6-h inhalation). Blood profiles of Ag element showed peak levels right after the end of the 6-h inhalation period and levels decreased rapidly thereafter. Toxicokinetic parameter values calculated from the average blood-concentration profiles showed a mean residence time (MRT) of 135 h and mean half-life (t1/2) of 94 h, with AUC of 2.5 mg/L × h and AUMC of 338 mg/L × h2. In terms of percent of inhaled dose, highest levels of Ag in extrapulmonary organs were found in liver, which represented on average (± SD) 1.6 ± 0.6% of calculated inhaled dose followed by the kidney with 0.1 ± 0.08%. Peak levels in the GI tract (including contents) were found at the end of the 6-h inhalation and represented 20 ± 15.6% of the inhaled dose. The dominant excretion route of Ag was through feces. The time course of Ag element in the GI tract and feces following AgNO3 inhalation is also compatible with an intestinal reabsorption of Ag. When compared to results of Ag NPs of a prior study with the same design, this study showed differences in the kinetics of soluble AgNO3 compared to insoluble Ag NPs, with higher levels in blood, GI tract, and extrapulmonary tissues but lower levels in lungs following AgNO3 exposure.

Full-scale multisampling and empirical modeling of DBPs in water and air of indoor pools.

Disinfection by-products (DBPs) are formed in the water in swimming pools due to reactions between disinfectants (chlorine, bromine, ozone) and the organic matter introduced by bathers and supply water. High concentrations of DBPs are also reported in the air of indoor swimming pools. Based on a robust multisampling program, the levels and variations of DBPs in the air (trichloramine [TCAM] and trihalomethanes [THMs]) and water (THM) were assessed, as well as their precursors (total organic carbon, water temperature, pH, free, and total chlorine) and proxies (CO2 and relative humidity) in four indoor chlorinated swimming pools. High-frequency sampling was conducted during one high-attendance day for each pool. This study focused on parameters that are easy to measure in order to develop models for predicting levels of THMs and TCAM in the air. The results showed that the number of bathers had an important impact on the levels of THMs and TCAM, with a two-to-three-fold increase in air chloroform (up to 110 µg/m3) and a two-to-four-fold increase in TCAM (up to 0.52 mg/m3) shortly after pools opened. The results of this study for the first time showed that CO2 and relative humidity can serve as proxies for monitoring variations in airborne THMs and TCAM. Our results highlight the good predictive capacity of the developed models and their potential for use in day-to-day monitoring. This could help optimize and control DBPs formation in the air of indoor swimming pools and reduce contaminant exposure for both pool employees and users.

Hepatic metabolism of chlorinated derivatives of bisphenol A (ClxBPA) and interspecies differences between rats and humans.

During chlorination treatments of drinking water, aqueous bisphenol A (BPA) can react with chlorine to form chlorinated derivatives of BPA (mono, di, tri and tetra-chlorinated derivatives) or ClxBPA. These emerging substances are endocrine disruptors associated with obesity, type II diabetes (TD2M) and myocardial infarction. ClxBPA are present in different human biological matrices but their toxicokinetics remain unknown. The aim of this study was to measure and compare the metabolic kinetics in the liver of four ClxBPA (ClBPA, Cl2BPA, Cl3BPA and Cl4BPA) between compounds and between species (Sprague-Dawley rats vs humans). To estimate their metabolic constants (Vmax, Km, Intrinsic clearance), metabolic assays were performed in hepatocyte suspensions. Assays revealed that metabolic constants of ClxBPA can greatly vary depending on substances and species. While ClBPA and Cl2BPA show similar unbound intrinsic clearances (ClintU) in rat incubation media, values for Cl3BPA and Cl4BPA are very different (3.109 and 0.684 mL/min/106 hepatocytes, respectively). Unlike in rats, human results are quite different as Cl3BPA and Cl4BPA have similar unbound intrinsic clearances, while ClBPA and Cl2BPA diverge (0.350 and 1.363 mL/min/106 hepatocytes, respectively). In both species, Cl2BPA and Cl3BPA have relatively similar clearances, and ClBPA is very different from Cl4BPA. Although we quantified the proportion of sulfo- and glucurono-metabolites, other metabolites may have been formed (e.g., glutathione, disulfate, or oxidative metabolites). This study showed that chlorination had an impact on hepatic intrinsic clearance of ClxBPA in rats and humans and measured values will be valuable for the development of PBPK models for use in exposure assessment.

Kinetic time courses of inhaled silver nanoparticles in rats.

Silver nanoparticles (Ag NPs) are priority substances closely monitored by health and safety agencies. Despite their extensive use, some aspects of their toxicokinetics remain to be documented, in particular following inhalation, the predominant route of exposure in the workplace. A same experimental protocol and exposure conditions were reproduced two times (experiments E1 and E2) to document the kinetic time courses of inhaled Ag NPs. Rats were exposed nose-only to 20 nm Ag NPs during 6 h at a target concentration of 15 mg/m3 (E1: 218,341 ± 85,512 particles/cm3; E2, 154,099 ± 5728 particles/cm3). The generated aerosol showed a uniform size distribution of nanoparticle agglomerates with a geometric mean diameter ± SD of 79.1 ± 1.88 nm in E1 and 92.47 ± 2.19 nm in E2. The time courses of elemental silver in the lungs, blood, tissues and excreta were determined over 14 days following the onset of inhalation. Excretion profiles revealed that feces were the dominant excretion route and represented on average (± SD) 5.1 ± 3.4% (E1) and 3.3 ± 2.5% (E2) of the total inhaled exposure dose. The pulmonary kinetic profile was similar in E1 and E2; the highest percentages of the inhaled dose were observed between the end of the 6-h inhalation up to 6-h following the end of exposure, and reached 1.9 ± 1.2% in E1 and 2.5 ± 1.6% in E2. Ag elements found in the GIT followed the trend observed in lungs, with a peak observed at the end of the 6-h inhalation exposure and representing 6.4 ± 4.9% of inhaled dose, confirming a certain ingestion of Ag NPs from the upper respiratory tract. Analysis of the temporal profile of Ag elements in the liver showed two distinct patterns: (i) progressive increase in values with peak at the end of the 6-h inhalation period followed by a progressive decrease; (ii) second increase in values starting at 72 h post-exposure with maximum levels at 168-h followed by a progressive decrease. The temporal profiles of Ag elements in lymphatic nodes, olfactory bulbs, kidneys and spleen also followed a pattern similar to that of the liver. However, concentrations in blood and extrapulmonary organs were much lower than lung concentrations. Overall, results show that only a small percentage of the inhaled dose reached the lungs-most of the dose likely remained in the upper respiratory tract. The kinetic time courses in the gastrointestinal tract and liver showed that part of the inhaled Ag NPs was ingested; lung, blood and extrapulmonary organ profiles also suggest that a small fraction of inhaled Ag NPs progressively reached the systemic circulation by a direct translocation from the respiratory tract.

Cardiopulmonary parameters and organ blood flows for workers expressed in terms of VO2 for use in physiologically based toxicokinetic modeling.

Minute ventilation rates (VE), alveolar ventilation rates (VA), cardiac outputs (Q), liver blood flow (LBF) and kidneys blood flows (KBF) for physiologically based toxicokinetic modeling and occupational health risk assessment in active workers have apparently not been determined. Minute energy expenditure rates (E) and oxygen consumption rates (VO2) in workers during exertions and their aggregate daytime activities are obtained by using open-circuit wearable devices for indirect calorimetry measurements and the doubly labeled water method respectively. Hundreds of E (in kcal/min) and VO2 (in L of O2/min) were previously reported for workers. The oxygen uptake factors of 0.2059 ± 0.0019 and 0.2057 ± 0.0018 L of O2/kcal during postprandial and fasting phases respectively enabled conversion of E into VO2. Equations determined in this study based upon more than 25 000 published measurements enable the calculation of 15 parameters in the same worker only by using the VO2 reflecting workload. These parameters, notably VE, VA, VE/VO2 VA/Q, Q, LBF and KBF were found to be interrelated. Altering one of these changes the order of magnitude of the others. Q, LBF and KBF decrease when supine adults at rest switch to an upright position. This effect of gravity diminished when VO2 increased. The fall in LBF and KBF during exertion might enhance muscle blood flow as reported previously. Taken together these equations and data may improve the accuracy of physiologically based toxicokinetic modeling as well as occupational health assessment studies in active workers exposed to xenobiotics.List of main abbreviations: AVOD: arterioveinous oxygen content difference.BMI: body mass index (in kg/m2).BSA: body surface area (in m2).BTPS: body temperature and saturated with water vapor.Bw: body weight (in kg).E: minute energy expenditure rate (in kcal/min).FGE: organ blood flow factor for the gravitational effect on blood circulation.H: oxygen uptake factor, volume of oxygen (at STPD) consumed to produce 1 kcal of energy expended.KBF: kidneys blood flow (in ml/min).LBF: liver blood flow (in ml/min).PBF: liver or kidneys blood flows expressed in terms of percentages (in %) of Qsup C values: namely PBF = (LBF or KBF/Qsup C) x 100.Q: cardiac output (in L/min or ml/min).Qsup C: cardiac output for the cohort of males or females in supination (in ml/min).STPD: standard temperature and pressure, dry air.sup: values measured when adults are in the supine position.up: values measured when adults are in the upright position.VDphys: physiological dead space at BTPS (in L).VT: tidal volume at BTPS (in L).VA: alveolar ventilation rate at BTPS (in L/min).VA/Q: ventilation-perfusion ratio (unitless).VE: minute ventilation rate at BTPS (in L/min).VO2: oxygen consumption rate (i.e. the oxygen uptake) at STPD (in L/min).VQ: ventilatory equivalent for VO2 (VE at BTPS /VO2 at STPD).

Temporal and spatial variations in the levels of prominent airborne disinfection by-products at four indoor swimming pools.

Exposure to airborne disinfection by-products, especially trichloramine and trichloromethane, may cause various adverse health effects for the workers and users of indoor swimming pools. This study aims to evaluate the spatial and temporal variations in trichloramine and trichloromethane concentrations within and between swimming pools. Workplace measurements were carried out at four indoor swimming pools in Quebec (Canada) during the cold season. To fully represent daily operating conditions, sampling started 2 hr before the swimming pool opened and continued until 2 hr after closing. To quantify trichloramine and trichloromethane concentrations, 304 air samples have been collected. Temperature, humidity, and CO2 were measured-simultaneously every 2 hr. The results showed that both trichloramine and trichloromethane concentrations varied significantly in time. The observed daily variations in trichloramine and trichloromethane concentrations suggest that the common practice of collecting a single 2-hr air sample does not represent daily pool trichloramine and trichloromethane contamination levels and, consequently, does not represent the true exposure and health risks for workers that are present for a full 8-hr shift. This study recommends a new 8-hr sampling strategy or a full-shift strategy using a cassette with three impregnated filters as a valid and cost-effective solution for comparing time-weighted average (TWA) concentrations to permissible trichloramine exposure limits.

Cardiopulmonary values and organ blood flows before and during heat stress: data in nine subjects at rest in the upright position.

Physiological changes associated with thermoregulation can influence the kinetics of chemicals in the human body such as alveolar ventilation (VA) and redistribution of blood flow to organs. In this study, the influence of heat stress on various physiological parameters was evaluated in nine male volunteers during sessions of exposure to wet-bulb globe temperatures (WBGT) of 21, 25, and 30 °C for 4 h. Skin and core temperatures and more than 20 cardiopulmonary parameters were measured. Liver, kidneys, brain, skin, and muscles blood flows were also determined based on published measurements. Results show that most subjects (eight out of nine) have been affected by the inhalation of hot and dry air at the WBGT of 30 °C. High respiratory rates, superficial tidal volumes, and low VA values were notably observed. The skin blood flow increased by 2.16-fold, whereas the renal blood flow and liver blood flow decreased by about by 11% and 18%, respectively. A complete set of key cardiopulmonary parameters in healthy male adults before and during heat stress was generated for use in physiologically based pharmacokinetic modeling. A toxicokinetic studies are ongoing to evaluate the impact of heat stress on the absorption, biotransformation and excretion rates of volatile xenobiotics.

Estimation of toluene exposure in air from BMA (S-benzylmercapturic acid) urinary measures using a reverse dosimetry approach based on physiologically pharmacokinetic modeling.

This study aimed to use a reverse dosimetry PBPK modeling approach to estimate toluene atmospheric exposure from urinary measurements of S-benzylmercapturic acid (BMA) in a small group of individuals and to evaluate the uncertainty associated to urinary spot-sampling compared to 24-h collected urine samples. Each exposure assessment technique was developed namely to estimate toluene air exposure from BMA measurements in 24-h urine samples (24-h-BMA) and from distributions of daily urinary BMA spot measurements (DUBSM). Model physiological parameters were described based upon age, weight, size and sex. Monte Carlo simulations with the PBPK model allowed converting DUBSM distribution (and 24-h-BMA) into toluene air levels. For the approach relying on DUBSM distribution, the ratio between the 95% probability of predicted toluene concentration and its 50% probability in each individual varied between 1.2 and 1.4, while that based on 24-h-BMA varied between 1.0 and 1.1. This suggests more variability in estimated exposure from spot measurements. Thus, estimating toluene exposure based on DUBSM distribution generated about 20% more uncertainty. Toluene levels estimated (0.0078-0.0138 ppm) are well below Health Canada's maximum chronic air guidelines. PBPK modeling and reverse dosimetry may be combined to interpret urinary metabolites data of VOCs and assess related uncertainties.

Repeat induced abortion and adverse childhood experiences in Aquitaine, France: a cross-sectional survey.

OBJECTIVE: The aim of the study was to analyse the relationship between adverse childhood experiences (ACEs) and repeat induced abortion, with regard to the potential effects of social deprivation and intimate partner violence. METHODS: An observational cross-sectional survey was conducted across each of the 25 abortion centres in Aquitaine, France, from 15 June to 15 September 2009. The sample comprised 806 women >18 years who had requested an induced abortion. Data were collected through a self-reported anonymous questionnaire on ACEs and experience of previous abortion. The main outcome measure was the percentage of repeat induced abortions. RESULTS: Among the participants, 473 (58.7%) were having their first induced abortion and 333 (41.3%) had already had a previous induced abortion. The abortion rank (first, second, third or more) was inversely related to the proportion of women with no ACE exposure (28%, 20% and 9%, respectively) and positively related to the proportion of women with a high ACE exposure (17%, 27% and 32%, respectively). Compared with women with no ACE exposure who were having a first induced abortion, in those with high ACE exposure, the odds of a third or more request for abortion was high: adjusted odds ratio 7.73 (95% confidence interval 3.56, 16.77). CONCLUSION: We found a strong graded link between the extent of ACE exposure and the occurrence of repeat induced abortion.

Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

BACKGROUND: Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown. OBJECTIVE: To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families. METHODS: Medical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype. RESULTS: We report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure. CONCLUSION: We propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.

Impact of pesticide coexposure: an experimental study with binary mixtures of lambda-cyhalothrin (LCT) and captan and its impact on the toxicokinetics of LCT biomarkers of exposure.

This study aimed at gaining more insights into the impact of pesticide coexposure on the toxicokinetics of biomarkers of exposure. This was done by conducting an in vivo experimental case-study with binary mixtures of lambda-cyhalothrin (LCT) and captan and by assessing its impact on the kinetic profiles of LCT biomarkers of exposure. Groups of male Sprague-Dawley rats were exposed orally by gavage to LCT alone (2.5 or 12.5 mg/kg bw) or to a binary mixture of LCT and captan (2.5/2.5 or 2.5/12.5 or 12.5/12.5 mg/kg bw). In order to establish the temporal profiles of the main metabolites of LCT, serial blood samples were taken, and excreta (urine and feces) were collected at predetermined intervals up to 48 h post-dosing. Major LCT metabolites were quantified in these matrices: 3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic (CFMP), 3-phenoxybenzoic acid (3-PBA), 4-hydroxy-3-phenoxybenzoic acid (4-OH3PBA). There was no clear effect of coexposure at the low LCT dose on the kinetics of CFMP and 3-PBA metabolites, based on the combined assessment of temporal profiles of these metabolites in plasma, urine and feces; however, plasma levels of 3-PBA were diminished in the coexposed high-dose groups. A significant effect of coexposure on the urinary excretion of 4-OH3PBA was also observed while fecal excretion was not affected. The temporal profiles of metabolites in plasma and in excreta were further influenced by the LCT dose. In addition, the study revealed kinetic differences between metabolites with a faster elimination of 3-PBA and 4-OH3BPA compared to CFMP. These results suggest that the pyrethroid metabolites CFMP and 3-PBA, mostly measured in biomonitoring studies, remain useful as biomarkers of exposure in mixtures, when pesticide exposure levels are below the reference values. However, the trend of coexposure effect observed in the benzyl metabolite pathway (in particular 4-OH3BPA) prompts further investigation.

An assessment of the impact of multi-route co-exposures on human variability in toxicokinetics: A case study with binary and quaternary mixtures of volatile drinking water contaminants.

This study aimed to assess the impact of multi-route co-exposures to chemicals on interindividual variability in toxicokinetics. Probabilistic physiologically based pharmacokinetic multi-route interaction models were developed for adults and four younger subpopulations. Drinking water-mediated multi-route exposures were simulated for benzene alone or in co-exposure with toluene, ethylbenzene and m-xylene, for trichloroethylene or vinyl chloride (VC), alone and in mixture. These simulations were performed for "low" and "high" exposure scenarios, involving respectively the US EPA's short-term drinking water health advisories, and 10 times these advisory values. Distributions of relevant internal dose metrics for benzene, trichloroethylene and VC were obtained using Monte Carlo simulations. Intergroup variability indexes (VI) were computed for the "low" (VIL ) and "high" (VIH ) exposure scenarios, as the ratio between the 95th percentile in each subpopulation over the median in adults. Thus, for benzene, parent compound's area under the curve-based VIL for single exposures vs. co-exposures correspondingly varied between 1.7 (teenagers) and 2.8 (infants) vs. 1.9 and 3.1 respectively. VIH varied between 2.5 and 3.5 vs. 2.9 and 4.1. Inversely, VIL and VIH for the amount of benzene metabolized via CYP2E1 pathway decreased in co-exposure compared to single exposure. For VC and trichloroethylene, similar results were obtained for the "high" exposure, but "low" co-exposures did not impact the toxicokinetics of individual substances. In conclusion, multi-route co-exposures can have an impact on the toxicokinetics of individual substances, but to an extent, that does not seem to challenge the default values attributed to the factors deemed at reflecting interindividual or child/adult differences in toxicokinetics.

Predictions of bisphenol A hepatic clearance in the isolated perfused rat liver (IPRL): impact of albumin binding and of co-administration with naproxen.

1. This study aimed (i) to characterise hepatic clearance (CL) of bisphenol A (BPA) and naproxen (NAP) administered alone or in binary mixtures to highlight the influence of a binding to albumin (ALB) using an isolated perfused rat liver (IPRL) system; and (ii) to compare results of prediction algorithms with measured clearance rates. 2. The IPRL system and liver microsomes were used to determine the metabolic constants of BPA and NAP either in the presence or absence of ALB. In this study, the IPRL was used as proxy for the in vivo situation. Accordingly, diverse in vitro-to-in vivo and in vivo-to-in vivo extrapolations (IVIVEs) were made to predict CL of BPA determined in situ/in vivo with ALB from metabolic data determined without ALB by using different binding correction methods (i.e., direct and conventional scaling as well as a novel scaling considering an ALB-facilitated uptake mechanism). 3. The addition of ALB significantly influenced the liver kinetics of BPA and NAP either administered alone or in binary mixtures, which was reflected in the Michaelis-Menten constants. Analysis of concomitant exposures of BPA and NAP gave a fully competitive inhibition. Furthermore, the IVIVE method based on the ALB-facilitated uptake mechanism provided the most accurate predictions of CLin vivo as compared with the other IVIVE methods when the impact of ALB is considered. 4. Our findings support the notion that high binding to ALB reduces the biotransformation of BPA and NAP when administered alone or in mixtures in the IPRL system. However, the free drug concentration in liver in vivo is probably higher than expected since the IVIVE method based on a potential ALB-facilitated uptake mechanism is the most robust prediction method. Overall, this study should improve the physiologically-based pharmacokinetic (PBPK) modelling of chemical-drug interactions.

Reverse dosimetry modeling of toluene exposure concentrations based on biomonitoring levels from the Canadian health measures survey.

Biomonitoring might provide useful estimates of population exposure to environmental chemicals. However, data uncertainties stemming from interindividual variability are common in large population biomonitoring surveys. Physiologically based pharmacokinetic (PBPK) models might be used to account for age- and gender-related variability in internal dose. The objective of this study was to reconstruct air concentrations consistent with blood toluene measures reported in the third Canadian Health Measures Survey using reverse dosimetry PBPK modeling techniques. Population distributions of model's physiological parameters were described based upon age, weight, and size for four subpopulations (12-19, 20-39, 40-59, and 60-79 years old). Monte Carlo simulations applied to PBPK modeling allowed converting the distributions of venous blood measures of toluene obtained from CHMS into related air levels. Based upon blood levels observed at the 50th, 90th and 95th percentiles, corresponding air toluene concentrations were estimated for teenagers aged 12-19 years as being, respectively, 0.009, 0.04 and 0.06 ppm. Similarly, values were computed for adults aged 20-39 years (0.007, 0.036, and 0.06 ppm), 40-59 years (0.007, 0.036 and 0.06 ppm) and 60-79 years (0.006, 0.022 and 0.04 ppm). These estimations are well below Health Canada's maximum recommended chronic air guidelines for toluene. In conclusion, PBPK modeling and reverse dosimetry may be combined to help interpret biomonitoring data for chemical exposure in large population surveys and estimate the associated toxicological health risk.

Assessment of air and water contamination by disinfection by-products at 41 indoor swimming pools.

This study was aimed at assessing the profiles (occurrence and speciation) of disinfection by-product (DBP) contamination in air and water of a group of 41 public indoor swimming pools in Québec (Canada). The contaminants measured in the water included the traditional DBPs [i.e., four trihalomethanes (THMs), six haloacetic acids (HAAs)] but also several emergent DBPs [i.e., halonitriles, halonitromethanes, haloketones and nitrosodimethylamine (NDMA)]. Those measured in the air comprised THMs and chloramines (CAMs). Overall, extremely variable DBP levels were found from one pool to another (both quantitatively and in terms of speciation). For instance, in water, among the four THMs, chloroform was usually the most abundant compound (37.9±25.7µg/L). Nevertheless, the sum of the three other brominated THMs represented more than 25% of total THMs at almost half the facilities visited (19 cases). In 13 of them, the levels of brominated THMs (66±24.2µg/L) even greatly outweighed the levels of chloroform (15.2±6.31µg/L). Much higher levels of HAAs (294.8±157.6µg/L) were observed, with a consistent preponderance of brominated HAAs in the swimming pools with more brominated THMs. NDMA levels which were measured in a subset of 8 pools ranged between 2.8ng/L and 105ng/L. With respect to air, chloroform was still the most abundant THM globally (119.4±74.2µg/m(3)) but significant levels of brominated THMs were also observed in various cases, particularly in the previously evoked group of 13 swimming pools with preponderant levels of brominated THMs in water. CAM levels (0.23±0.15mg/m(3)) varied highly, ranging from not detected to 0.56mg/m(3). Overall, the levels were generally relatively high compared to current guidelines or reference values from several countries, and they point to a relatively atypical presence of brominated compounds, and to significant levels of emergent DBPs for which health risk is less documented.

Evaluation and modeling of the impact of coexposures to VOC mixtures on urinary biomarkers.

CONTEXT: Urinary biomarkers are widely used among biomonitoring studies because of their ease of collection and nonintrusiveness. Chloroform and TEX (i.e., toluene, ethylbenzene, and m-xylene) are chemicals that are often found together because of common use. Although interactions occurring among TEX are well-known, no information exists on possible kinetic interactions between these chemicals and chloroform at the level of parent compound or urinary biomarkers. OBJECTIVE: The objective of this study was therefore to study the possible interactions between these compounds in human volunteers with special emphasis on the potential impact on urinary biomarkers. MATERIALS AND METHODS: Five male volunteers were exposed by inhalation for 6 h to single, binary, and quaternary mixtures that included chloroform. Exhaled air and blood samples were collected and analyzed for parent compound concentrations. Urinary biomarkers (o-cresol, mandelic, and m-methylhippuric acids) were quantified in urine samples. Published PBPK model for chloroform was used, and a Vmax of 3.4 mg/h/kg was optimized to provide a better fit with blood data. Adapted PBPK models from our previous study were used for parent compounds and urinary biomarkers for TEX. RESULTS: Binary exposures with chloroform resulted in no significant interactions. Experimental data for quaternary mixture exposures were well predicted by PBPK models using published description of competitive inhibition among TEX components. However, no significant interactions were observed at levels used in this study. CONCLUSION: PBPK models for urinary biomarkers proved to be a good tool in quantifying exposure to VOC.

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.

In vivo effects of naproxen, salicylic acid, and valproic acid on the pharmacokinetics of trichloroethylene and metabolites in rats.

It was recently demonstrated that some drugs modulate in vitro metabolism of trichloroethylene (TCE) in humans and rats. The objective was to assess in vivo interactions between TCE and three drugs: naproxen (NA), valproic acid (VA), and salicylic acid (SA). Animals were exposed to TCE by inhalation (50 ppm for 6 h) and administered a bolus dose of drug by gavage, equivalent to 10-fold greater than the recommended daily dose. Samples of blood, urine, and collected tissues were analyzed by headspace gas chromatography coupled to an electron capture detector for TCE and metabolites (trichloroethanol [TCOH] and trichloroacetate [TCA]) levels. Coexposure to NA and TCE significantly increased (up to 50%) total and free TCOH (TCOHtotal and TCOHfree, respectively) in blood. This modulation may be explained by an inhibition of glucuronidation. VA significantly elevated TCE levels in blood (up to 50%) with a marked effect on TCOHtotal excretion in urine but not in blood. In contrast, SA produced an increase in TCOHtotal levels in blood at 30, 60, and 90 min and urine after coexposure. Data confirm in vitro observations that NA, VA, and SA affect in vivo TCE kinetics. Future efforts need to be directed to evaluate whether populations chronically medicated with the considered drugs display greater health risks related to TCE exposure.