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R Tardif

Publications and source records attributed to R Tardif.

At least 37 records · Page 2Linked to original sources
PubMed1995

Physiologically-based pharmacokinetic modeling of a mixture of toluene and xylene in humans.

A physiologically-based pharmacokinetic (PBPK) model for a mixture of toluene (TOL) and xylene (XYL), developed and validated in the rat, was used to predict the uptake and disposition kinetics of TOL/XYL mixture in humans. This was accomplished by substituting the rat physiological parameters and the blood:air partition coefficient with those of humans, scaling the maximal velocity for hepatic metabolism on the basis of body weight0.75, and keeping all other model parameters species-invariant. The human TOL/XYL mixture PBPK model, developed based on the quantitative biochemical mechanism of interaction elucidated in the rat (i.e., competitive metabolic inhibition), simulated adequately the kinetics of TOL and XYL during combined exposures in humans. The simulations with this PBPK model indicate that an eight hour co-exposure to concentrations that remain within the current threshold limit values of TOL (50 ppm) and XYL (100 ppm) would not result in significant pharmacokinetic interferences, thus implying that data on biological monitoring of worker exposure to these solvents would be unaffected during co-exposures.

Animals↗
PubMed1994

Nervous system dysfunction among workers with long-term exposure to manganese.

Neurological disorders, bearing many similarities to Parkinson's disease, have been associated with environmental and occupational exposure to manganese (Mn). To document early nervous system dysfunction associated with long-term exposure to Mn, a battery of neurofunctional tests was administered to workers employed in Mn alloy production. Study participation was 95% (n = 115). A matched pair design was used; actively working men, with no history of workplace exposure to neurotoxins, were recruited from the region as referents. Matching was done on the variables: age (+/- 3 years), educational level (+/- 2 years), smoking status, and number of children. Stationary environmental sampling indicated that Mn levels varied widely (geometric means: Mn dust, 0.89 mg/m3; respirable Mn, 0.04 mg/m3). The alloy workers had significantly higher levels of whole blood Mn (geometric mean: 1.03 microgram/100 ml vs 0.68 microgram/100 ml); no differences were observed for urinary Mn. Univariate analysis (paired t test, Signed Rank and McNemar) and multivariate analysis of variance (Hotelling-Lawley statistic) revealed that the pairs differed on symptom reporting, emotional state, motor functions, cognitive flexibility, and olfactory perception threshold; verbal fluency, basic mathematics, reading capability, and attentional capacity were similar. These findings are consistent with current knowledge on brain Mn activity and suggest that manifestations of early manganism can be observed in well designed population studies, using sensitive testing methods.

Adult↗
PubMed1994

Ethanol induced modification of m-xylene toxicokinetics in humans.

This study was undertaken to determine whether previous subacute treatment with ethanol could modify the kinetics of m-xylene in humans. A group of six volunteers was exposed twice to either 100 or 400 ppm of m-xylene during two hours (between 0800 and 1000). Ethanol was given orally in the early evening on each of two consecutive days before exposures (total ethanol intake of 137 g). Such ethanol pretreatment affected the kinetics of m-xylene but only at the high exposure (400 ppm). The modifications were: (1) decreased concentration of m-xylene in blood and alveolar air during and after exposure; (2) increased urinary excretion of m-methylhippuric acid at the end of exposure. Ethanol treatment also enhanced the elimination of antipyrine in saliva. Overall, this study showed that the effect of enzyme induction on the metabolism of m-xylene, after ethanol ingestion, depends on the exposure concentration and is not likely to occur as long as the exposure concentrations remain under the current maximum allowable concentration (100 ppm) in the workplace.

Adult↗
PubMed1993

Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat.

The present study was undertaken to investigate the mechanism of toxicokinetic interaction between toluene (TOL) and m-xylene (XYL) in vivo in the male Sprague-Dawley rat by physiologically based toxicokinetic (PBTK) modeling. First, the metabolic constants (Vmax and Km) were determined for TOL and XYL individually by conducting a series of closed-chamber inhalation exposures of three rats to starting concentrations of 500 to 4000 ppm. The values of Km (TOL, 0.55 mg/liter; XYL, 0.20 mg/liter) and Vmax (TOL, 4.8 mg/hr/kg; XYL, 8.4 mg/hr/kg) were obtained following best visual fit of PBTK model simulations to experimental data. Then using the same experimental set-up, rats were exposed to three different mixtures of both solvents (500 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 500 ppm XYL). The data from the time course of chamber solvent concentrations were analyzed with a binary chemical mixture PBTK model that had four mechanistic hypotheses of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition) quantitatively defined in the liver compartment. The validity of the various model descriptions was verified with open-chamber inhalation exposure data on toxicokinetics of TOL and XYL. Overall, the results of this combined experimental and modeling approach are consistent with a competitive metabolic inhibition between XYL and TOL in the rat.

Animals↗
PubMed1993

A descriptive and mechanistic study of the interaction between toluene and xylene in humans.

This study was undertaken to characterize the mechanism of toxicokinetic interaction between toluene (TOL) and m-xylene (XYL) in the rat using physiologically-based toxicokinetic (PBTK) modeling approach. First, the metabolic rate constants were determined by conducting closed-chamber inhalation exposures with individual solvents (Vmax: TOL = 4.8, XYL = 8.4 mg/hr/kg; Km: TOL = 0.55, XYL = 0.2 mg/l). Then, using the same experimental set-up, rats were exposed to different binary mixtures of TOL and XYL. PBTK analysis of the data showed competitive inhibition as the plausible mechanism of TOL/XYL interaction. This mechanistic modeling study suggests that the interaction between TOL and XYL is likely to be observed when the exposure concentration exceeds 50 ppm of each solvent.

Animals↗
PubMed1993

Effect of various exposure scenarios on the biological monitoring of organic solvents in alveolar air. I. Toluene and m-xylene.

The present study was undertaken to investigate the influence of different exposure scenarios on the elimination of toluene and m-xylene in alveolar air and other biological fluids in human volunteers. The study was also aimed at establishing the effectiveness of physiologically based toxicokinetic models in predicting the value of biological monitoring data after exposure to toluene and m-xylene. Two adult male and two adult female white volunteers were exposed by inhalation, in a dynamic, controlled-environment exposure chamber, to various concentrations of toluene (21-66 ppm) or m-xylene (25-50 ppm) in order to establish the influence of exposure concentration, duration of exposure, variation of concentration within day, and work load on respective biological exposure indices. The concentrations of unchanged solvents in end-exhaled air and in blood as well as the urinary excretion of hippuric acid and m-methyl-hippuric acid were determined. The results show that doubling the exposure concentration for both solvents led to a proportional increase in the concentrations of unchanged solvents in alveolar air and blood at the end of a 7-h exposure period. Cumulative urinary excretion of the respective metabolites exhibited a nearly proportional increase. Adjustment of exposure concentration to account for a prolongation of the duration of exposure resulted in essentially identical cumulative urinary excretion of the metabolites. Induced within-day variations in the exposure concentration led to corresponding but not proportional changes in alveolar concentration for both solvents, depending on whether or not sampling preceded or followed peak exposure to solvent. At the end of repeated 10-min periods of physical exercise at 50 W, alveolar air concentrations of both solvents were increased by 40%. Experimental data collected during the present study were adequately simulated by physiologically based toxicokinetic modeling. These results suggest that alveolar air solvent concentration is a reliable index of exposure to both toluene and m-xylene under various experimental exposure scenarios. For clinical situations likely to be encountered in the workplace, physiologically based toxicokinetic modeling appears to be a useful tool both for developing strategies of biological monitoring of exposure to volatile organic solvents and for predicting alveolar air concentrations under a given set of exposure conditions.

Adult↗
PubMed1993

Cytogenetic effects of low-level exposure to toluene, xylene, and their mixture on human blood lymphocytes.

The present study was undertaken to investigate, both in vitro and in vivo, the genotoxic potential of short-term low-level exposure to toluene, xylene, and their mixture, for which information is limited at the present time. Five adult healthy white men were exposed for 7 consecutive hours per day over 3 consecutive days to 50 ppm toluene and 40 ppm xylene either alone or in combination in a controlled exposure chamber. Such an exposure was repeated three times at intervals of 2 weeks. Blood samples were taken before and after the termination of such exposure. Three different cytogenetic end-points were evaluated using peripheral blood lymphocytes: number of sister chromatid exchanges (SCEs), cell cycle delay, and cell mortality. No significant effects on SCEs, cell cycle delay, and cell mortality were observed following such exposure to toluene or xylene or their mixture. Similarly, exposure of human blood lymphocytes in vitro to either toluene (0-2.5 mM) or xylene (0-2 mM) or their mixture for 72 h did not result in any significant cytogenetic effects at lower concentrations, while at higher concentrations, only cell mortality was found to be significantly affected. Thus our present study indicates that simultaneous exposure to low levels (within the admissible limits) of toluene, xylene, or their mixture for a short period does not pose any potential mutagenic threat to humans.

Adult↗
PubMed1992

Influence of various mixtures of inhaled toluene and xylene on the biological monitoring of exposure to these solvents in rats.

The present study was undertaken to describe the influence of simultaneous exposure by inhalation to toluene and xylene on some aspects of their respective metabolic disposition. Adult male rats were exposed acutely (5 h) to 75, 150, and 225 ppm of toluene or xylene and to various mixtures of these solvents: toluene (75 ppm) and xylene (225 ppm), toluene (150 ppm) and xylene (150 ppm), toluene (225 ppm) and xylene (75 ppm). Compared with single exposure, simultaneous exposure resulted in lower amounts of excreted hippuric acid (20-30%) and methylhippuric acids (4-40%) in urine over a period of 24 h, even though significant differences were seen only with the toluene (150 ppm) and xylene (150 ppm) combination. In addition, increased concentrations of solvents in blood (toluene, 230%; xylene, 500%) and in brain (toluene, 230%; xylene, 320%) were found during the immediate post-exposure period. Simultaneous exposure also enhanced the pulmonary elimination of both solvents (toluene, 190-240%; xylene, 340-650%). Influence of repeated simultaneous exposure (9 days) was investigated for the toluene (150 ppm) and xylene (150 ppm) combination and the results compared with those of repeated exposure to each solvent administered singly. Under these conditions, repeated simultaneous exposure decreased the excretion of urinary metabolites, but only after the first exposure. On the other hand, simultaneous exposure resulted in significantly higher concentrations of toluene (210%) and xylene (240%) in blood throughout the entire 9-day exposure period. These results strongly suggest mutual metabolic interactions (inhibition) between toluene and xylene that affect the metabolic disposition of both solvents and ultimately the biological monitoring of data of exposure to a combination of solvents in rats.

Administration, Inhalation↗
PubMed1991

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

Studies 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 4 h (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 micrograms/100 ml; B-xylene, 67.6 vs 77.8 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Influence of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid, on the urinary elimination of mercapturic acids of ethylene oxide, dibromoethane, and acrylonitrile: a dose-effect study.

Metabolic disposition of ethylene oxide, dibromoethane, and acrylonitrile in rats after acute exposure was studied by examining the relationship between dose and urinary metabolites, and by establishing the influence of a glutathione precursor, L-2-oxothiazolidine-4-carboxylic acid (OTCA), on the above relationship. Respective urinary metabolites, hydroxyethylmercapturic acid, cyanoethylmercapturic acid, thiocyanate, and ethylene glycol, were quantified to estimate the extent to which each compound was metabolized. The animals were given either ethylene oxide (0.34, 0.68, or 1.36 mmol/kg), dibromoethane (0.2, 0.4, or 0.6 mmol/kg), or acrylonitrile (0.10, 0.38, or 0.76 mmol/kg). Urine samples were collected at 24 h. The metabolic biotransformation of all three chemicals to their respective mercapturic acids was strongly indicative of saturable metabolism. Administration of OCTA (4-5 mmol/kg) enhanced gluthathione availability and increased excretion of urinary mercapturic acids at the higher doses of the chemicals. This study indicates that OTCA increases the capacity for detoxification via the glutathione pathway thereby partially correcting the nonlinearity between the administered dose of ethylene oxide, dibromoethane, and acrylonitrile and the amount of certain urinary metabolites.

Acetylcysteine↗
PubMed1988

Distribution of cholesterol in milk fat fractions.

Milk fat was fractionated into liquid (m.p. congruent to 12 degrees C), intermediate (m.p. congruent to 21 degrees C) and solid (m.p. congruent to 39 degrees C) fractions by three different processes--melt crystallization, short-path distillation and supercritical CO2 extraction--and the cholesterol content of these fractions determined. Cholesterol was enriched in the liquid fractions from all three processes, in particular about 80% of the cholesterol being found in the liquid fraction obtained by short-path distillation. The basis of migration of cholesterol into various milk fat fractions was explained by its affinity to various triglycerides (melt crystallization) and by vapour pressure and molecular weight (short-path distillation). It was more complex in the supercritical CO2 extraction process; the interplay of cholesterol affinity toward CO2 and its molar volume, and its vapour pressure enhancement under applied pressure play a role.

Animals↗
PubMed1988

Determination of specific urinary thioethers derived from acrylonitrile and ethylene oxide.

A simple analytical method has been developed for the determination of specific urinary thioethers. Mercapturic acids present in urine are first de-acetylated enzymatically or by acid hydrolysis. Cysteine conjugates thus formed are reacted with o-phthalaldehyde and mercaptoethanol, yielding fluorescent derivatives, which are further separated by high-performance liquid chromatography (HPLC) in a reverse-phase system. The method is applicable to the determination of the following thioethers: 2-hydroxyethylmercapturic acid (N-acetyl-S-2-hydroxyethyl-L-cysteine; HMA), carboxymethylmercapturic acid (N-acetyl-S-carboxymethyl-L-cysteine; CAMA) and 2-cyanoethylmercapturic acid (N-acetyl-S-2-cyanoethyl-L-cysteine; CYMA), and the corresponding cysteine conjugates, S-2-hydroxyethyl-L-cysteine (HCYS), S-2-carboxymethyl-L-cysteine (CACYS) and S-2-cyanoethyl-L-cysteine (CYCYS). The excretion pattern of these thioethers in rats exposed to acrylonitrile and various rodents exposed to ethylene oxide is reported. Thioether excretion can be dependent on species and route of administration. The analytical procedure may prove to be applicable to the biological monitoring in humans of exposure to acrylonitrile, ethylene oxide, vinyl chloride, 1,2-dibromoethane and 1,2-dichloroethane.

Acetylcysteine↗
PubMed1987

Species differences in the urinary disposition of some metabolites of ethylene oxide.

Some aspects of the qualitative and quantitative urinary disposition of some metabolites of ethylene oxide in three rodent species, mouse, rat, and rabbit, were examined by determining urinary N-acetyl-S-(2-hydroxyethyl)-L-cysteine, S-(2-hydroxyethyl)-L-cysteine, S-carboxymethyl-L-cysteine, and ethylene glycol after ethylene oxide exposure by iv and inhalation routes. The animals were given ethylene oxide at 20 and 60 mg/kg, and urine samples were collected at 6 and 24 hr. Important differences were observed between the three species in the urinary metabolic disposition of ethylene oxide. Mice excreted significant quantities of N-acetyl-S-(2-hydroxyethyl)-L-cysteine, S-(2-hydroxyethyl)-L-cysteine, S-carboxymethyl-L-cysteine, and ethylene glycol (8.3, 5.8, 1.9, and 3.3% of the lower dose, respectively, in 24 hr), whereas in rats only N-acetyl-S-(2-hydroxyethyl)-L-cysteine (31%) and ethylene glycol (6%) were apparent. In contrast, the rabbits were found to excrete only ethylene glycol (2%). This study further reveals species-related differences in the urinary excretion of N-acetyl-S-(2-hydroxyethyl)-L-cysteine and ethylene glycol during the two collection periods. The observed differences between the three species in the metabolic disposition of ethylene oxide were found to be qualitatively independent of the route of exposure, i.e., inhalation at 200 ppm or iv. These results suggest that care should be exercised when using an animal species as a model for human disposition of ethylene oxide.

Administration, Inhalation↗
PubMed1987

Urinary excretion of mercapturic acids and thiocyanate in rats exposed to acrylonitrile: influence of dose and route of administration.

Adult male Sprague-Dawley rats were exposed acutely to acrylonitrile (ACN) according to 1 of 3 different routes of administration: inhalation (6 h), i.v., or i.p. Urinary metabolites measured 24 h after administration were 2-cyanoethylmercapturic acid (CMA), 2-hydroxyethylmercapturic acid (HMA) and thiocyanate (TCN). In all 3 series of experiments, the relationship between excretion of total urinary metabolites and the degree of exposure was reasonably linear. However, there was a marked influence of the route of administration on the pattern of metabolic excretion. For example, after i.p. and i.v. injection CMA was the most important metabolite while after inhalation it was TCN. Our results also indicate an important effect of the dose on the pattern of excretion for all types of administration.

Acetylcysteine↗
PubMed1986

Urinary N-acetyl-S-2-hydroxyethyl-L-cysteine in rats as biological indicator of ethylene oxide exposure.

There is no simple method known for the biological monitoring of ethylene oxide exposure. N-Acetyl-S-2-hydroxyethyl-L-cysteine (2-hydroxyethylmercapturic acid) excretion was evaluated as a potential indicator of exposure to this gas. Groups of Sprague-Dawley rats were given iv doses of 1, 10, or 100 mg/kg of ethylene oxide dissolved in water. Urines were collected after 12 and 24 hr. In another experiment groups of Sprague-Dawley rats were exposed by inhalation to concentrations of 1, 5, 10, 25, 50, and 200 ppm of ethylene oxide during a 6-hr period and 24-hr urines were collected subsequently. 2-Hydroxyethylmercapturic acid was analyzed in rat urine after enzymatic deacetylation into S-2-hydroxyethyl-L-cysteine, formation of a fluorescent derivative, and separation from other amino acid derivatives by high performance liquid chromatography. No S-2-hydroxyethyl-L-cysteine was observed in any sample when analysis proceeded without the deacetylation step. 2-Hydroxyethylmercapturic acid, however, was present in the urine of all exposed groups. Doses of 1 and 10 mg/kg were excreted at a fairly constant percentage of the dose, ca. 30% from 0 to 12 hr and 5% from 12 to 24 hr, while at 100 mg/kg the equivalent percentages were 16 and 5%, indicating a possible saturation of glutathione conjugation in the first 12 hr. In inhalation experiments, the amount of 2-hydroxyethylmercapturic acid excreted in 24 hr varied linearly with exposure concentration, averaging 0.27 mumol/ppm. The consistency of the excretion of this metabolite over a wide dose span points to 2-hydroxyethylmercapturic acid as a potential biological indicator of exposure to ethylene oxide.

Acetylcysteine↗
PubMed1975

Fluorometric determination of delta-aminolaevulinate dehydratase activity in human erythrocytes as an index to lead exposure.

We describe a fluorometric method for determining delta-aminolaevulinate dehydratase (EC 4.2.1.24) activity in human erythrocytes and compare it with the existing colorimetric method. Incubation conditions are identical. In the proposed method, the porphobilinogen formed during incubation is converted to a stable and highly fluorescent uroporphyrin by heating for 20 min at 93 degrees C in an acidic medium in the presence of air. The correlation between results by the two methods was good (r = 0.89). We found a good negative correlation between the activity of the enzyme and the concentration of circulating lead with both methods (r = -0.61 for present method and -0.59 for colorimetric method) for groups of persons subjected to various degrees of lead exposure. Our method is more sensitive and accurate, requires less sample, and the fluorescence is more stable than is the color in the colorimetric method.

Colorimetry↗