Biomedical subjects

Robert Tardif

Publications and source records attributed to Robert Tardif.

At least 19 recordsLinked to original sources

PubMed2006

Two generation reproduction study of ethylbenzene by inhalation in Crl-CD rats.

BACKGROUND: This study was conducted to evaluate the potential adverse effects of ethylbenzene (EB) on reproductive capability from whole-body inhalation exposure of F0 and F1 parental animals. METHODS: Four groups of Crl:CD(SD)IGS BR rats (30/sex/group for F0 and 25/sex/group for F1) were exposed to 0, 25, 100, and 500 ppm EB for 6 hr/day for at least 70 consecutive days before mating. Inhalation exposure for the F0 and F1 females continued throughout mating, gestation through gestation day (GD) 20, and lactation days (LD) 5-21. On LD 1-4, females received EB in corn oil via oral gavage at dose levels of 26, 90, and 342 mg/kg/day (divided into three equal doses, approximately 2 hr apart), as calculated from a physiologically-based pharmacokinetic (PBPK) model to provide similar maternal blood area-under-concentration (AUC) as provided by inhalation. Pups were weaned on postnatal day (PND) 21 and exposure of the F1 generation started on PND 22. Estimates of internal exposure were determined by measuring EB concentrations in blood collected from F1 dams (4/group) and their culled pups 1 hr after the last gavage dose on PND 4. On PND 22, blood was collected from these same F1 dams and their weanlings for EB analysis 1 hr after a 6-hr inhalation exposure. The remainder of the F2 generation was not directly exposed. RESULTS: EB exposure did not affect survival or clinical observations. Male rats in the 500 ppm group in both generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either generation. Male and female mating and fertility indices, pre-coital intervals, spermatogenic endpoints, ovarian follicle counts, reproductive organ weights, lengths of estrous cycle and gestation, live litter size, pup weights, developmental landmarks, and postnatal survival were unaffected. No adverse exposure-related macroscopic pathology was noted at any level. CONCLUSIONS: Increased liver weights were found in the animals exposed to 500 ppm. F1 maternal whole blood EB concentrations of 0.49, 3.51, or 18.28 mg/L were found 1 hr after administration of a composite oral dose of 26, 90, or 342 mg/kg/day, respectively, but no detectable EB was found in blood samples of their F2 PND 4 culled pups. F1 maternal mean whole blood EB levels 1 hr after a 6-hr inhalation exposure on postpartum day (PPD) 22 was 0.11 mg/L (25 ppm), 0.56 mg/L (100 ppm), and 11 mg/L (500 ppm). For the offspring exposed with their dams on PND 22, F2 pup blood EB concentrations ranged from 0.017-0.039 mg/L (25 ppm), 0.165-0.465 mg/L (100 ppm), and 8.82-15.74 mg/L (500 ppm). Because decreased weight gain in the 500 ppm males was transient and no histopathological changes were associated with the increased liver weights in the 500 ppm male and female groups, these changes were not considered adverse. Therefore, for parental systemic toxicity, 100 ppm was considered a NOEL and 500 ppm a NOAEL in this study. The 500 ppm exposure concentration was considered a NOAEL for F0 and F1 reproductive toxicity and offspring developmental endpoints.

Administration, Oral↗

PubMed2006

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.

Administration, Cutaneous↗

PubMed2006

Biological exposure indicators: quantification of biological variability using toxicokinetic modeling.

Compartmental and physiologically based toxicokinetic modeling coupled with Monte Carlo simulation were used to quantify the impact of biological variability (physiological, biochemical, and anatomic parameters) on the values of a series of bio-indicators of metal and organic industrial chemical exposures. A variability extent index and the main parameters affecting biological indicators were identified. Results show a large diversity in interindividual variability for the different categories of biological indicators examined. Measurement of the unchanged substance in blood, alveolar air, or urine is much less variable than the measurement of metabolites, both in blood and urine. In most cases, the alveolar flow and cardiac output were identified as the prime parameters determining biological variability, thus suggesting the importance of workload intensity on absorbed dose for inhaled chemicals.

Air Pollutants, Occupational↗

PubMed2006

Effect of physical exertion on the biological monitoring of exposure of various solvents following exposure by inhalation in human volunteers: I. Toluene.

Physical exertion (work load) has been recognized as one of several factors that can influence the kinetics of xenobiotics within the human body. This study was undertaken to evaluate the impact of physical exertion on two exposure indicators of toluene (TOL) in human volunteers exposed under controlled conditions in an inhalation chamber. A group of four volunteers (one woman, three men) were exposed to TOL (50 ppm) according to the following scenarios involving several periods during which volunteers were asked to perform either aerobic (AERO), muscular (MUSC), or both (AERO/MUSC) types of physical exercise (exercise bicycle, treadmills, pulleys). The target intensities (W) for each exercising period of 30 min--interspaced with 15 min at rest--were the following: REST, 50 W AERO (time-weighted average intensity [TWAI]: 46 watts); 50 W AERO/MUSC (TWAI: 38 watts) and 100 W AERO (TWAI: 71 watts) for 7 hours and 50 W MUSC for 3 hours (TWAI: 29 watts). Alveolar air and urine samples were collected at different time intervals before, during, and after exposure for the measurement of unchanged TOL in expired air (TOL-A) and urinary o-cresol (o-CR). Overall, the results showed that TOL-A measured during and after all scenarios involving physical activities were higher (approximately 1.4-2.0 fold) compared with exposures at rest. All scenarios involving physical exertion also resulted in increased end-of-exposure urinary o-CR (mean +/- SD): 0.9 +/- 0.1 mg/L (REST) vs. 2.0 +/- 0.1 mg/L (TWAI 46 watts). However, exposure at a TWAI of 71 watts did not further increase o-CR excretion (1.7 +/- 0.2 mg/L). This study confirms the significant effect of work load on TOL kinetics and showed that o-CR excretion increased proportionally with work load expressed as TWAI or with the estimated mean pulmonary ventilation during the period of exposure. This study also shows that exposure to TOL (50 ppm) involving a work load of around 50 W (light intensity) or lower is likely to produce urinary o-CR values that clearly exceed the current biological exposure index value for TOL.

Adult↗

PubMed2005

Characterization of the metabolic interaction between trihalomethanes and chloroacetic acids using rat liver microsomes.

The aim of this study was to investigate the in vitro metabolism of trihalomethanes (THMs) in the presence of trichloroacetic acid (TCA), dichloracetic acid (DCA), monochloroacetic acid (MCA), and 4-methylpyrazole (4-MP) using liver microsomes from male Sprague-Dawley rats. Using the vial equilibration technique, initial experiments were carried out with starting concentrations of approximately 40 ppm THMs and 12-22 mM chloroacetic acids. The results indicated a mutual metabolic inhibition between THMs present as binary or quaternary mixtures. Although DCA and MCA had no influence on THMs, TCA produced a marked inhibition of the metabolism of all THMs: chloroform (CHCl3) (55%), bromodichloromethane (BDCM) (34%), dibromochloromethane (DBCM) (30%), and bromoform (TBM) (23%). The presence of 4-MP also reduced THM metabolism, the importance of which decreased in the following order: CHCl3 > BDCM > DBCM = TBM. In further vial equilibration experiments, using 9-140 ppm as starting concentrations of THMs, enzyme kinetic parameters (i.e., Michaelis constant, K(m), and maximum velocity, V(max)) were determined both in the absence and in the presence of TCA (12.2 mM). Results are consistent with a competitive inhibition between TCA and CHCl3, whereas the metabolic inhibition of BDCM and TMB by TCA was non-competitive. As for DBCM, results suggest a more complex pattern of inhibition. These results suggest that CYP2E1 is involved in the metabolism of THMs as well as in the metabolic interaction between THMs and TCA.

Acetates↗

PubMed2005

Quantitative structure-property relationships for interspecies extrapolation of the inhalation pharmacokinetics of organic chemicals.

The objectives of this study were to (i) develop quantitative structure-property relationships (QSPRs) for blood:air partition coefficients (Pb:a), tissue:air partition coefficients (Pt:a), and hepatic clearance (CLh) and (ii) conduct interspecies extrapolations of the pharmacokinetics of low molecular weight volatile organic chemicals (VOCs) by incorporating the above QSPRs within a physiologically based pharmacokinetic (PBPK) modeling framework. Pb:a and Pt:a were predicted using the following algorithm: FnlxPo:a+FwxPw:a+f(b)xFpxPp:a, where Fnl=content of neutral lipid equivalents in biological matrix, Fw=content of water equivalents in biological matrix, Fp=protein content of blood and tissues, Po:a=vegetable oil:air partition coefficient, Pw:a=water:air partition coefficient, f(b)=fraction of total protein involved in the partitioning process, and Pp:a=protein:air partition coefficient. CLh was estimated as follows: Qlx[(CLintxC(P4502E1)xVl)/(Ql+CLintxC(P4502E1)xVl)], where CLint=intrinsic clearance normalized for P450 2E1 content, Ql=blood flow to the liver, C(P4502E1)=hepatic concentration of P450 2E1 in the species of interest, and Vl=volume of liver. QSPRs relating molecular fragments of 46 VOCs and parameters required for estimating Pb:a, Pt:a, and CLh (namely, Po:a, Pw:a, Pp:a, and CLint) were established using a group contribution method (f(i)xCi, where f=frequency of occurrence of the group i in a given molecule and Ci=contribution of the group i to Po:a, Pw:a, Pp:a, or CLint). Values of group contributions were determined by multilinear regression of experimental data. The species specific parameters required for solving the above algorithms were obtained from the literature. These algorithms, once incorporated into a multispecies PBPK modeling framework, enabled extrapolation of the kinetics of chemicals across species. The inhalation pharmacokinetics of dichloromethane and toluene as well as two de novo compounds (1,2,4-trimethyl benzene and ethyl benzene) were extrapolated from rat to human, using the present modeling methodology. This study has demonstrated that it is possible to extrapolate the pharmacokinetic behavior of chemicals from rats to humans on the basis of QSPRs and species specific physiological information.

Administration, Inhalation↗

PubMed2004

Childhood urine mercury excretion: dental amalgam and fish consumption as exposure factors.

The authors investigated the effect of amalgam fillings and fish consumption on urine mercury level (UHg), in children aged 4-8 years old inclusive. Using a sample of 60 children, we found that children with amalgam fillings had significantly higher UHg levels than children without amalgams (geometric mean=1.412microg Hg/g versus 0.436 microg Hg/g, respectively, P = 0.0001). Subjects with reported higher fish consumption also had significantly higher UHgs (P = 0.004). Univariate analyses provide evidence of an association between elevated UHg level and young age (P = 0.009), short height (P = 0.024), and low weight (P = 0.049) in children with amalgam chewing surfaces. We also found a negative correlation between urine mercury and age (-0.378), height (-0.418), and weight (-0.391). A multiple logistic regression model shows that the presence of amalgam fillings leads to increased odds of high UHg in children (OR=47.18), even after adjusting for high fish consumption (OR=8.66) and height (OR=11.36).

Age Factors↗

PubMed2004

Exhaled ethanol and acetaldehyde in human subjects exposed to low levels of ethanol.

With the increased use of ethanol-blend gasoline as an alternative to gasoline, there is a demand for new data to assess the potential health risk of ethanol exposure. Currently, there is very limited information from the scientific database on the adverse effects of inhaled low doses of ethanol (ETOH). The aim of this study was to determine the concentration of ETOH and acetaldehyde (ACTDH), a toxic metabolite of ETOH, in the alveolar air (AA) of subjects exposed to low ETOH vapor concentrations by inhalation. Five healthy adults (2 women, 3 men), nonsmoking, 25-55 yr of age, were exposed for 6 consecutive hours to 25, 100, or 1000 ppm ETOH and were asked to provide AA samples at various intervals during and after each exposure session, for ETOH and ACTDH measurements. Results showed that the concentrations of ACTDH and ETOH in AA measured after 2 h of exposure at 25 ppm were 0.06 ppm and 7.5 ppm, respectively. Overall, there was a significant correlation between ETOH exposure and ETOH (R(2) =.92, p <.001) and ACTDH (R(2) =.99, p <.001) in AA. The ratios between ACTDH and ETOH in AA after 4 h of exposure to 25.9 ppm, 101.7 ppm, and 990.8 ppm ETOH were 0.005, 0.008, and 0.006, respectively. In conclusion, this study showed that inhalation of ETOH at low concentrations resulted in measurable levels of ACTDH in AA and suggests that ACTDH may be used, with good toxicological relevance, as an indicator of exposure to low levels of ETOH in air.

Acetaldehyde↗

PubMed2004

Performance of small evacuated canisters equipped with a novel flow controller for the collection of personal air samples.

Small evacuated canisters have become more common in industrial hygiene personal sampling in recent years. The smaller canisters necessitate a low flow rate to ensure a full-shift air sample can be collected. Evaluation of small evacuated canisters compared to sorbent sampling methods is essential to ensure that the canisters accurately monitor airborne contamination. This data, in a controlled environment, will provide practitioners with valuable reference information when considering air-sampling campaigns. Six 300-mL evacuated canisters were used to collect 6-hour breathing zone samples of styrene on volunteers in a large exposure chamber. The canisters were specially designed with a capillary flow controller developed at McGill University in the mid-1990s. Based on the geometry of the capillary the airflow into the canisters was controlled to a low flow rate, approximately 0.3 mL/min. This low sampling flow rate allowed for the use of small-volume canisters as personal samplers to collect styrene vapors. Charcoal tubes and diffusive badges were simultaneously used to collect side-by-side samples for comparison. In addition, an online gas chromatograph (GC) documented the concentration in the chamber throughout the duration of the exposure. The three methods did not disclose any significant statistical difference when compared to the online GC values and to each other. In addition, linear regression analysis between the charcoal tubes and the canisters resulted in a correlation (R(2) > 0.95). An evaluation of the bias and precision (overall uncertainty) of the capillary-canister method, charcoal tubes, and diffusive badges found them to be within criteria established by European Committee for Standardization 482. The results indicate that the capillary-canister sampling device can be an acceptable alternative to sorbent samplers as a personal sampler providing reliable results that are representative of exposures.

Adsorption↗

PubMed2003

Evaluation of the influence of chloroacetic acids on the pharmacokinetics of trihalomethanes in the rat.

Chloroacetic acids (monochloroacetic acid [MCA], dichloroacetic acid [DCA], and trichloroacetic acid [TCA]) and trihalomethanes (THMs: chloroform [CHCl(3)], bromodichloromethane [BDCM], dibromochloromethane [DBCM], and bromoform [TBM]) are common by-products of the chlorination of drinking water. The purpose of this study was to evaluate the influence of chloroacetic acids on the pharmacokinetics of trihalomethanes in the male Sprague-Dawley rat. In the first series of studies, groups of 5 animals were given, by intravenous injections, a single dose of 0.125 mmol/kg of one of the four THMs. Additional groups received a binary mixture containing 0.125 mmol/kg of a THM plus 0.125 mmol/kg of a chloroacetic acid. The venous blood concentrations of unchanged THMs were measured by headspace gas chromatography from 5 min to 6 h postadministration. The areas under the blood concentration versus time curves (AUCs) of CHCl(3), BDCM, and DBCM were increased by a factor of 3.5, 1.6, and 2, respectively, by coadministration of TCA. DCA coadministration resulted in an increase in the AUC of DBCM (x2.5) and TBM (x1.3), whereas MCA modified the Cmax (x1.5) and AUC (x1.8) of BDCM and the AUC of DBCM (x2.5). In the second series of experiments, animals received either a single dose of 0.03125 mmol/kg of one of the four THMs, a mixture containing 0.03125 mmol/kg of each of the four THMs (total dose = 0.125 mmol/kg), or a mixture containing 0.03125 mmol/kg of each of the four THMs plus 0.125 mmol/kg of either TCA or DCA. Results indicated that the AUCs of CHCl(3), BDCM, DBCM, and TBM were increased during coadministration compared to single administrations (+2.5-fold). Combined administration of the four THMs with TCA, and not DCA, resulted in an increase of the AUCs of THMs (CHCl(3): x11.7; BDCM, DBCM, and TBM: x3.9) and an increase in the Cmax of CHCl(3) (x1.9). Overall, these results indicate that, at the dose levels tested in this study, TCA alters the blood concentration profiles of THMs.

Acetates↗

PubMed2003

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.

Animals↗

PubMed2003

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.

Adult↗

PubMed2003

Neuromotor effects of acute ethanol inhalation exposure in humans: a preliminary study.

Ethanol (ETOH) is added to unleaded gasoline to decrease environmental levels of carbon monoxide from automobiles emissions. Therefore, addition of ETOH in reformulated fuel will most likely increase and the involuntarily human exposure to this chemical will also increase. This preliminary study was undertaken to evaluate the possible neuromotor effects resulting from acute ETOH exposure by inhalation in humans. Five healthy non-smoking adult males, with no history of alcohol abuse, were exposed by inhalation, in a dynamic, controlled-environment exposure chamber, to various concentrations of ETOH (0, 250, 500 and 1,000 ppm in air) for six hours. Reaction time, body sway, hand tremor and rapid alternating movements were measured before and after each exposure session by using the CATSYS 7.0 system and a diadochokinesimeter. The concentrations of ETOH in blood and in alveolar air were also measured. ETOH was not detected in blood nor in alveolar air when volunteers were exposed to 250 and 500 ppm, but at the end of exposure to 1,000 ppm, blood and alveolar air concentrations were 0.443 mg/100ml and 253.1 ppm, respectively. The neuromotor tests did not show conclusively significant differences between the exposed and non-exposed conditions. In conclusion, this study suggests that acute exposure to ethanol at 1,000 ppm or lower or to concentrations that could be encountered upon refueling is not likely to cause any significant neuromotor alterations in healthy males.

Adult↗

PubMed2002

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.

Biomarkers↗

PubMed2002

Impact of human variability on the biological monitoring of exposure to toluene, phenol, lead, and mercury: II. Compartmental based toxicokinetic modelling.

In order to quantify the effect of human variability on a wide range of biological exposure indicators (EIs), a general compartmental model was developed and tested on several chemicals. The model consists of four compartments. In a first step, it was applied to four chemicals: toluene (TOL), phenol (Ph), lead (Pb), and mercury (Hg). Individuals were to be exposed 8 h a day, 5 days a week. Physiological parameter values were set to consider a physical workload of 50 W 12 h/day and at rest for the remaining 12 h. Monte Carlo simulations were carried out using realistic distributions of physiological and metabolic parameters. The variability extent index (VEI) and the main parameters of influence were determined for each of the EIs. The results were in agreement with literature data. The present compartmental model provides a fair description of the toxicokinetic (TK) variability of very different chemicals. It will, therefore, further be applied to investigate the variability of a wide range of biological indicators.

Environmental Monitoring↗

PubMed2002

Metabolism and toxicity of trichloroethylene in epididymis and testis.

The widespread occupational exposure to trichloroethylene (TCE) led us to test the hypothesis that TCE causes toxicity in the male reproductive system. We also investigated mechanisms mediating the potential cytotoxic response. Mice were exposed to TCE (1000 ppm) by inhalation for 6 h/day for 5 days/week for a total of 19 days. Exposure after the first week was interspersed by a "weekend." To estimate internal exposure, we measured the TCE metabolites, trichloroacetic acid (TCA) and trichloroethanol (TCOH), in urine at Days 4, 9, 14, and 19. Urinary excretion of TCOH was significantly higher than TCA; levels of TCOH and TCA significantly increased by the second and third week, respectively. Cytochrome P450 2E1 (CYP2E1), an enzyme involved in TCE metabolism, was localized in the epididymal epithelium and testicular Leydig cells, and was found at higher levels in the former than the latter. Immunoblotting confirmed that CYP2E1 protein was present in greater amounts in epididymis than in testis. p-Nitrophenol hydroxylation, a CYP2E1 catalytic activity, was also higher in the epididymis than in the testis. Chloral, a major TCE metabolite, was generated in microsomal incubations at significantly higher levels in epididymis than in testis. Antibody inhibition of CYP2E1 reduced chloral formation, which was more pronounced in epididymis than in testis. After 4 weeks of TCE exposure, damage to the epididymis was manifested as sloughing of epithelial cells. These results indicated that TCE is metabolized in the male reproductive tract, leading to adverse effects that are more severe in the epididymis than in the testis.

Administration, Inhalation↗

PubMed2002

Cancer risk associated with household exposure to chloroform.

Chloroform (CHCl3) the trihalomethane most prevalent in drinking water, is a proven animal carcinogen and a suspected human carcinogen. Consequently, standards have been issued by health authorities to limit its concentration in drinking water. These limits are based solely on ingestion, without taking into account inhalation and skin contact. Exposure to CHCl3 was assessed for 18 men (age: mean 38 years; range 23-51) following a 10-min shower in their respective residences located in the Quebec City region (Canada). CHCl3 concentration was measured in alveolar air samples collected before, immediately after, and 15 min and 30 min following the shower. Indoor air and water concentrations were determined concomitantly. Mean CHCl3 concentrations in the air of the shower stall and in water were respectively 147 microg/m3 (SD = 56.2 microg/m3) and 20.1 microg/L (SD = 9.0 microg/L). Water concentrations were comparable to those documented in a large proportion of distribution networks in Canada. The mean increase in alveolar air CHCl3 concentration (deltaCHCIALV) at the end of the shower was 33 microg/m3 (SD = 14.7 microg/m3). A multiple-regression analysis revealed that deltaCHCl3ALV values were only associated with chloroform concentration in air of the shower stall. DeltaCHCl3ALV were described using a physiologically based pharmacokinetic (PBPK) model. This model was then used to estimate concentrations of CHCl3 metabolites bound to liver and kidney macromolecules following a shower, and also according to exposure scenarios that integrate drinking-water ingestion and air inhalation. The concentration predicted in the liver following a worst-case exposure scenario was 0.41 microg CHCl3 equivalents/kg of tissue, some 6,000 times lower than the lowest concentration that did not increase the incidence of hepatic tumors in laboratory animals. Data indicate that for this range of exposure the safety margin appears therefore considerable with respect to the potential carcinogenic effect of household exposure to CHCl3.

Adult↗

PubMed2002

Physiological modeling and extrapolation of pharmacokinetic interactions from binary to more complex chemical mixtures.

The available data on binary interactions are yet to be considered within the context of mixture risk assessment because of our inability to predict the effect of a third or a fourth chemical in the mixture on the interacting binary pairs. Physiologically based pharmacokinetic (PBPK) models represent a potentially useful framework for predicting the consequences of interactions in mixtures of increasing complexity. This article highlights the conceptual basis and validity of PBPK models for extrapolating the occurrence and magnitude of interactions from binary to more complex chemical mixtures. The methodology involves the development of PBPK models for all mixture components and interconnecting them at the level of the tissue where the interaction is occurring. Once all component models are interconnected at the binary level, the PBPK framework simulates the kinetics of all mixture components, accounting for the interactions occurring at various levels in more complex mixtures. This aspect was validated by comparing the simulations of a binary interaction-based PBPK model with experimental data on the inhalation kinetics of m-xylene, toluene, ethyl benzene, dichloromethane, and benzene in mixtures of varying composition and complexity. The ability to predict the kinetics of chemicals in complex mixtures by accounting for binary interactions alone within a PBPK model is a significant step toward the development of interaction-based risk assessment for chemical mixtures.

Animals↗