Robert Tardif

Development of Physiologically Based Toxicokinetic Models for Improving the Human Indoor Exposure Assessment to Water Contaminants: Trichloroethylene and Trihalomethanes

Generally, ingestion is the only route of exposure that is considered in the risk assessment of drinking water contaminants. However, it is well known that a number of these contaminants are volatile and lipophilic and therefore highly susceptible to being absorbed through other routes, mainly inhalation and dermal. The objective of this study was to develop physiologically based human toxicokinetic (PBTK) models for trihalomethanes (THM) and trichloroethylene (TCE) that will facilitate (1) the estimation of internal exposure to these chemicals for various multimedia indoor exposure scenarios, and (2) consideration of the impact of biological variability in the estimation of internal doses. Five PBTK models describing absorption through ingestion, inhalation and skin were developed for these contaminants. Their concentrations in ambient air were estimated from their respective tap water concentrations and their physicochemical characteristics. Algebraic descriptions of the physiological parameters, varying as a function of age, gender and diverse anthropometric parameters, allow the prediction of the influence of interindividual variations on absorbed dose and internal dosimetry. Simulations for various scenarios were done for a typical human (i.e., 70 kg, 1.7 m) as well as for humans of both genders varying in age from 1 to 90 years. Simulations show that ingestion contributes to less than 50% of the total absorbed dose or metabolized dose for all chemicals. This contribution to internal dosimetry, such as maximal venous blood concentrations (Cmax) and the area under the venous blood concentration time curve (AUC), decreases markedly (e.g., as low as 0.9% of Cmax for bromodichloromethane). The importance of this contribution varies mainly as a function of shower duration. Moreover, model simulations indicate that multimedia exposure is more elevated in children than adults (i.e., up to 200% of the adult internal dose). The models developed in this study allow characterization of the influence of the different routes of exposure and an improved estimation of the realistic multimedia exposure to volatile organic chemicals present in drinking water. Hence, such models will greatly improve health risk assessment for these chemicals.

Effect of simultaneous exposure to toluene and xylene on their respective biological exposure indices in humans

SummaryStudies that specifically address the influence of controlled human exposure to a combination of solvents on the biological monitoring of exposure are limited in number. The present study was undertaken to investigate whether simultaneous exposure of human volunteers to toluene and xylene could modify the respective metabolic disposition of these solvents. Five adult Caucasian men were exposed for 7 consecutive h/day over 3 consecutive days to 50 ppm toluene and 40 ppm xylene either separately or in combination in a dynamic, controlled exposure chamber (low-level exposure). The experiment was repeated three times at intervals of 2 weeks. In another experiment, three subjects were exposed to 95 ppm toluene and 80 ppm xylene or a combination of both for 4h (high-level exposure). The concentration of unchanged solvents in blood (B) and in end-exhaled air (EA) as well as the urinary excretion of hippuric acid (HA) and methylhippuric acids (MHAs) were determined. Simultaneous exposure to the lowest level of solvents did not alter the concentration of unchanged solvents in blood or in exhaled air (average of 3-weekly means; single vs mixed exposure at 6.5 h exposure): B-toluene, 77.1 vs 78.1 μg/100 ml; B-xylene, 67.6 vs 77.8 μg/100 ml; EA-toluene, 9.9 vs 9.5 ppm; EA-xylene, 5.3 vs 4.8 ppm. Similarly, mixed exposure did not modify the excretion of urinary metabolites during the 3- to 7-h exposure period: HA, 1.11 vs 1.11 g/g creatinine; MHAs, 0.9 vs 0.87 g/g creatinine. However, simultaneous exposure to higher levels did affect the concentration of unchanged solvents in blood and in exhaled air as measured at 3.5 h exposure (mean value for three subjects ± SD): B-toluene, 135.7 ± 26.7 vs 215.7 ± 34.9 μg/100 ml; B-xylene, 114 ± 19 vs 127.6 ± 22.1 μg/100 ml; EA-toluene, 16.6 ± 0.4 vs 20.5 ± 2.8 ppm; EA-xylene, 9.9 ± 0.6 vs 12.3 ± 1.2 ppm. Such effects were accompanied by a significant delay in the urinary excretion of HA but not of MHAs. These data suggest that there is a threshold level below which metabolic interaction between toluene and xylene is not likely to occur in humans.

Database for Physiologically Based Pharmacokinetic (PBPK) Modeling: Physiological Data for Healthy and Health-Impaired Elderly

Physiologically based pharmacokinetic (PBPK) models have increasingly been employed in chemical health risk assessments. By incorporating individual variability conferred by genetic polymorphisms, health conditions, and physiological changes during development and aging, PBPK models are ideal for predicting chemical disposition in various subpopulations of interest. In order to improve the parameterization of PBPK models for healthy and health-impaired elderly (herein defined as those aged 65 yr and older), physiological parameter values were obtained from the peer-reviewed literature, evaluated, and entered into a Microsoft ACCESS database. Database records include values for key age-specific model inputs such as ventilation rates, organ volumes and blood flows, glomerular filtration rates, and other clearance-related processes. In total, 528 publications were screened for relevant data, resulting in the inclusion of 155 publications comprising 1051 data records for healthy elderly adults and 115 data records for elderly with conditions such as diabetes, chronic obstructive pulmonary disease (COPD), obesity, heart disease, and renal disease. There are no consistent trends across parameters or their associated variance with age; the gross variance in body weight decreased with advancing age, whereas there was no change in variance for brain weight. The database contains some information to inform ethnic and gender differences in parameters; however, the majority of the published data pertain to Asian (mostly Japanese) and Caucasian males. As expected, the number of records tends to decrease with advancing age. In addition to a general lack of data for parameters in the elderly with various health conditions, there is also a dearth of information on blood and tissue composition in all elderly groups. Importantly, there are relatively few records for alveolar ventilation rate; therefore, the relationship between this parameter and cardiac output (usually assumed to be 1:1) in the elderly is not well informed by the database. Despite these limitations, the database represents a potentially useful resource for parameterizing PBPK models for the elderly to facilitate the prediction of dose metrics in older populations for application in risk assessment.

Quantitative structure-property relationships for physiologically based pharmacokinetic modeling of volatile organic chemicals in rats.

The objective of present study was to develop quantitative structure-property relationships (QSPRs) for the chemical-specific input parameters of rat physiologically based pharmacokinetic (PBPK) models (i.e., blood:air partition coefficient (P(b)), liver:air partition coefficient (P(l)), muscle:air partition coefficient (P(m)), fat:air partition coefficient (P(f)), and hepatic clearance (CL(h))), for simulating the inhalation pharmacokinetics of volatile organic chemicals (VOCs). The literature data on P(b), P(l), P(f), and P(m) for 46 low-molecular-weight VOCs as well as CL(h) for 25 such VOCs primarily metabolized by CYP2E1 (alkanes, haloalkanes, haloethylenes, and aromatic hydrocarbons) were analysed to develop QSPRs. The QSPRs developed in this study were essentially multilinear additive models, which imply that each fragment in the molecular structure has an additive and constant contribution to partition coefficients and hepatic clearance. Most of the values in the calibration set could be reproduced adequately with the QSPR approach, which involved the calculation of the sum of the frequency of occurrence of fragments (CH(3), CH(2), CH, C, C=C, H, Cl, Br, F, benzene ring, and H in benzene ring structure) times the fragment-specific contributions determined in this study. The QSPRs for P(b), P(l), P(m), P(f), and CL(h) were then included within a PBPK model, which only required the specification of the frequency of occurrence of fragments in a molecule along with exposure concentration and duration as input for conducting pharmacokinetic simulations. This QSPR-PBPK model framework facilitated the prediction of the inhalation pharmacokinetics of four VOCs present in the calibration dataset (toluene, dichloromethane, trichloroethylene, and 1,1,1-trichloroethane) and four VOCs that were not part of the calibration set (1,2,4-trimethyl benzene, ethyl benzene, 1,3-dichloropropene, and 2,2-dichloro-1,1,1-trifluoroethane) but that could be described using the molecular fragments investigated in the present study. The QSPRs developed in this study should be potentially useful for providing a first-cut evaluation of the inhalation pharmacokinetics of VOCs prior to experimentation, as long as the number and nature of the fragments do not exceed the ones in the calibration dataset used in this study.

Evaluation of the health risk associated with exposure to chloroform in indoor swimming pools.

The exposure of swimmers to chloroform (CHCl5) was investigated in indoor swimming pools of the Quebec City region along with the associated carcinogenic risk. Six training sessions involving 52 competition swimmers (11 to 20 yr old) were conducted in 3 different pools, while 12 adult leisure swimmers attended 5 sessions, each held in a different pool. For each session, water and ambient air CHCl3 concentrations were measured and CHCl3 levels in alveolar air samples (CHCl3ALV) collected from swimmers prior to entering the swimming pool premises and after 15, 35, and 60 min of swimming. Mean water concentrations varied from 18 µg/L to 80 µg/L, while those in air ranged from 78 µg/m3 to 329 µg/m3. Multiple linear regression analyses revealed that CHCl3ALV values in competition swimmers were strongly correlated to ambient air and water levels, and to a lesser degree to the intensity of training. Only ambient air concentration was positively correlated to CHCl3ALV in the leisure group. Concentrations of CHCl3 metabo lites bound to hepatic and renal macromolecules, estimated using a physiologically based pharmacokinetic (PBPK) model, were 1.6 and 1.9 times higher for the competition swimmers than for the leisure swimmers, respectively. The highest hepatic concentration predicted in competition swimmers, 0.22 µg CHCl equivalents/kg of tissue, was at least 10,000 times lower than the smallest no observed3effect level for liver tumors in animals. Data indicate that the safety margin is therefore very large, for competitive swimmers as well as for leisure swimmers.The exposure of swimmers to chloroform (CHCl3) was investigated in indoor swimming pools of the Quebec City region along with the associated carcinogenic risk. Six training sessions involving 52 competition swimmers (11 to 20 yr old) were conducted in 3 different pools, while 12 adult leisure swimmers attended 5 sessions, each held in a different pool. For each session, water and ambient air CHCl3 concentrations were measured and CHCl3 levels in alveolar air samples (CHCl3 ALV) collected from swimmers prior to entering the swimming pool premises and after 15, 35, and 60 min of swimming. Mean water concentrations varied from 18 microg/L to 80 microg/L, while those in air ranged from 78 microg/m3 to 329 microg/m3. Multiple linear regression analyses revealed that CHCl3 ALV values in competition swimmers were strongly correlated to ambient air and water levels, and to a lesser degree to the intensity of training. Only ambient air concentration was positively correlated to CHCl3 ALV in the leisure group. Concentrations of CHCl3 metabolites bound to hepatic and renal macromolecules, estimated using a physiologically based pharmacokinetic (PBPK) model, were 1.6 and 1.9 times higher for the competition swimmers than for the leisure swimmers, respectively. The highest hepatic concentration predicted in competition swimmers, 0.22 microg CHCl3 equivalents/kg of tissue, was at least 10,000 times lower than the smallest no observed effect level for liver tumors in animals. Data indicate that the safety margin is therefore very large, for competitive swimmers as well as for leisure swimmers.

Effects of inhaled nano-TiO2 aerosols showing two distinct agglomeration states on rat lungs

Nano-aerosols composed of large agglomerates (LA) (>100nm) are more likely to promote pulmonary clearance via macrophages phagocytosis. Small agglomerates (SA) (<100nm) seem to escape this first defense mechanism and are more likely to interact directly with biological material. These different mechanisms can influence pulmonary toxicity. This hypothesis was evaluated by comparing the relative pulmonary toxicity induced by aerosolized nano-TiO(2) showing two different agglomeration states: SA (<100nm) and LA (>100nm) at mass concentrations of 2 or 7mg/m(3). Groups of Fisher 344 male rats were nose-only exposed for 6h. The median number aerodynamic diameters were 30 and 185nm at 2mg/m(3), and 31 and 194nm at 7mg/m(3). We found in rats bronchoalveolar lavage fluids (BALF) a significant 2.1-fold increase in the number of neutrophils (p<0.05) in the group exposed to the 7mg/m(3) LA nano-aerosol suggesting a mild inflammatory response. Rats exposed to the 7mg/m(3) SA nano-aerosol showed a 1.8-fold increase in LDH activity and 8-isoprostane concentration in BALF, providing evidence for cytotoxic and oxidative stress effects. Our results indicate that biological responses to nanoparticles (NP) might depend on the dimension and concentration of NP agglomerates.

Impact of human variability on the biological monitoring of exposure to toluene: I. Physiologically based toxicokinetic modelling.

Using an approach involving physiologically based toxicokinetic (PBTK) modelling and Monte Carlo simulation (MCS), we investigated the impact of the biological variability affecting the parameters (e.g. physiological, physicochemical, biochemical) which determine toluene (TOL) kinetics on two exposure indicators (EIs): urinary excretion of o-cresol (o-CR), measured at the end of an 8 h exposure at 50 ppm, and unchanged TOL in blood (B-TOL) sampled prior to the last shift of a 5 day workweek. Population variance was described by assuming normal, or lognormal, distribution of parameter values and assigning to each one+/-2 S.D. (or+/-2 G.S.D.). PBTK-MCS (n=1000) resulted in a geometric mean (G.M.) of 0.635 mmol/mol creatinine for urinary o-CR, upper and lower limits (95%) ranging from 0.23 to 1.75, whereas, the GM for B-TOL was 120.6 microg/l (95% limits: 64.5-225.7). Overall, the results showed that this approach facilitates the prediction of the range of BEI values that could be anticipated to occur in a group of workers exposed to a chemical.

Variability of chlorination by-product occurrence in water of indoor and outdoor swimming pools

Swimming is one of the most popular aquatic activities. Just like natural water, public pool water may contain microbiological and chemical contaminants. The purpose of this study was to study the presence of chemical contaminants in swimming pools, in particular the presence of disinfection by-products (DBPs) such as trihalomethanes (THMs), haloacetic acids (HAAs) and inorganic chloramines (CAMi). Fifty-four outdoor and indoor swimming pools were investigated over a period of one year (monthly or bi-weekly sampling, according to the type of pool) for the occurrence of DBPs. The results showed that DBP levels in swimming pools were greater than DBP levels found in drinking water, especially for HAAs. Measured concentrations of THMs (97.9 vs 63.7 μg/L in average) and HAAs (807.6 vs 412.9 μg/L in average) were higher in outdoor pools, whereas measured concentrations of CAMi (0.1 vs 0.8 mg/L in average) were higher in indoor pools. Moreover, outdoor pools with heated water contained more DBPs than unheated pools. Finally, there was significant variability in tTHM, HAA9 and CAMi levels in pools supplied by the same municipal drinking water network, suggesting that individual pool characteristics (number of swimmers) and management strategies play a major role in DBP formation.

Maternal exposure to drinking-water chlorination by-products and small-for-gestational-age neonates.

Background: There is concern about possible effects of disinfection by-products on reproductive outcomes. The purpose of this study was to evaluate the association between maternal exposure to chlorination by-products and the risk of delivering a small for-gestational-age (SGA) neonate. Methods: We conducted a population-based case-control study in the Québec City (Canada) area. Term newborn cases with birth weights <10th percentile (n = 571) were compared with 1925 term controls with birth weights ≥10th percentile. Concentrations of trihalomethanes and haloacetic acids in the water-distribution systems of participants were monitored during the study period, and a phone interview on maternal habits was completed within 3 months after childbirth. We estimated chlorination by-products ingestion during the last trimester of pregnancy and trihalomethanes doses resulting from inhalation and dermal exposure. We evaluated associations between chlorination by-products in utero exposure and SGA by means of unconditional logistic regression with control of potential confounders. Results: When total trihalomethanes and the 5 regulated haloacetic acids concentrations were divided into quartiles, no clear dose-response relationship was found with SGA. However, increased risk was observed when haloacetic concentrations were above the fourth quartile and when either trihalomethanes or haloacetic acids concentrations were above current water standards (adjusted OR= 1.5 [95% confidence interval = 1.1–1.9] and 1.4 [1.1–1.9], respectively). Inhalation and dermal absorption of trihalomethanes did not contribute to this risk, but a monotonic dose-response was found with haloacetic acids ingestion. Conclusion: Oral exposure to high levels of chlorination by-products in drinking water could be a risk factor for term SGA.

Identification of trichloroethylene and its metabolites in human seminal fluid of workers exposed to trichloroethylene.

We have investigated the potential of the male reproductive tract to accumulate trichloroethylene (TCE) and its metabolites, including chloral, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA). Human seminal fluid and urine samples from eight mechanics diagnosed with clinical infertility and exposed to TCE occupationally were analyzed. In in vivo experimental studies, TCE and its metabolites were determined in epididymis and testis of mice exposed to TCE (1000 ppm) by inhalation for 1 to 4 weeks. In other studies, incubations of monkey epididymal microsomes were performed in the presence of TCE and NADPH. Our results showed that seminal fluid from all eight subjects contained TCE, chloral, and TCOH. DCA was present in samples from two subjects, and only one contained TCA. TCA and/or TCOH were also identified in urine samples from only two subjects. TCE, chloral, and TCOH were detected in murine epididymis after inhalation exposure with TCE for 1 to 4 weeks. Levels of TCE and chloral were similar throughout the entire exposure period. TCOH levels were similar at 1 and 2 weeks but increased significantly after 4 weeks of TCE exposure. Chloral was identified in microsomal incubations with TCE in monkey epididymis. CYP2E1, a P450 that metabolizes TCE, was localized in human and monkey epididymal epithelium and testicular Leydig cells. These results indicated that TCE is metabolized in the reproductive tract of the mouse and monkey. Furthermore, TCE and its metabolites accumulated in seminal fluid, and suggested associations between production of TCE metabolites, reproductive toxicity, and impaired fertility.