Jules Brodeur

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.

Physiological Daily Inhalation Rates for Free-Living Individuals Aged 1 Month to 96 Years, Using Data from Doubly Labeled Water Measurements: A Proposal for Air Quality Criteria, Standard Calculations and Health Risk Assessment

ABSTRACT Reported disappearance rates of oral doses of doubly labeled water (2H2O and H2 18O) in urine, monitored by gas-isotope-ratio mass spectrometry for an aggregate period of over 30,000 days and completed with indirect calorimetry and nutritional balance measurements, have been used to determine physiological daily inhalation rates for 2210 individuals aged 3 weeks to 96 years. Rates in m3/kg-day for healthy normal-weight individuals (n = 1252) were higher by 6 to 21% compared to their overweight/obese counterparts (n = 679). Rates for healthy normal-weight males and females drop by about 66 to 75% within the course of a lifetime. Infants and children between the age of 3 weeks to less than 7 years inhale 1.6 to 4.3 times more air (0.395 ± 0.048 to 0.739 ± 0.071 m3/kg-day, mean ± S.D., n = 581) than adults aged 23 to 96 years (0.172 ± 0.037 to 0.247 ± 0.039 m3/kg-day, n = 388). The 99th percentile rate of 0.725 m3/kg-day based on measurements for boys aged 2.6 to less than 6 months is recommended for air quality criteria and standard calculation for non-carcinogenic compounds pertaining to individuals of any age or gender (normality confirmed using the Shapiro-Wilk test, p ≥ 0.05). This rate is 2.5-fold more protective than the daily inhalation estimate of 0.286 m3/kg-day published by the Federal Register in 1980 (i.e., 20 m3/day for a 70-kg adult). It ensures that very few newborns aged 1 month and younger, less than 1% of infants aged 2.6 to less than 6 months and of course no older individuals up to 96 years of age inhale more toxic chemicals than associated safe doses which are not anticipated to result in any adverse effects in humans, when air concentration reaches the resulting air quality criteria and standard values. This rate is also protective for underweight, overweight, and obese individuals. Finally, as far as newborns are concerned, a rate of 0.956 m3/kg-day based on the 99th percentile estimates is recommended for short-term criteria and standard calculations for toxic chemicals that yield adverse effects over instantaneous to short-term duration.

o-Cresol: A Good Indicator of Exposure to Low Levels of Toluene

This study evaluates the suitability of using urinary excretion of o-cresol (o-CR) as a biological marker of occupational exposure to various concentrations of toluene (TOL). Thirty-eight individuals from three plants involved in the manufacture of paints or inks agreed to participate in the environmental and biological monitoring evaluations, which lasted one to two days. In all, 62 measurements of environmental TOL and urinary o-CR and hippuric acid (HA) levels were made. The eight-hour TOL exposure (time-weighted average [TWA]) ranged from 0 to 111 ppm, depending on plant and job title. TOL exposure was well correlated to post-shift urinary o-CR (r = 0.89) and HA (r = 0.67) levels. At low exposure levels (below 50 ppm), however, o-CR shows a stronger correlation (r = 0.71) than HA (r = 0.24). Based on our results, occupational exposure to 50 ppm of TOL would result in end-of-shift urinary o-CR concentration of 0.72 mumol/mmol creatinine (0.69 mg/L, assuming a urinary creatinine concentration of 1 g/L). This value is of the same order of magnitude as the level proposed by the American Conference of Governmental Industrial Hygienists (ACGIH) in 1998 for exposure to 50 ppm of TOL, namely 0.5 mg/L. Our results suggest that the level of urinary o-CR is a more sensitive index of exposure to low concentrations of TOL than is the urinary concentration of HA.

Effect of various exposure scenarios on the biological monitoring of organic solvents in alveolar air. II: 1,1,1-trichloroethane and trichloroethylene

The purpose of the present study was to investigate the influence of different exposure scenarios on the elimination of trichloroethylene (TRI) and 1,1,1-trichloroethane (1,1,1-TRI) in alveolar air and other biological fluids in human volunteers. In addition, it was sought to establish an interactive process between experimental data gathering and simulation modeling in an attempt to predict the influence of the different scenarios of exposure to TRI and 1,1,1-TRI on their respective biological monitoring indices and thus to establish the flexibility and validity of simulation models. Two adult male and two adult female Caucasian volunteers were exposed by inhalation, in a dynamic controlled exposure chamber, to various concentrations of TRI (12.5–25 ppm) or 1,1,1-TRI (87.5–175 ppm) in order to establish the influence of exposure concentration, duration of exposure, variation of concentration within day, and work load on biological exposure indices. The concentrations of unchanged solvents in end-exhaled air and in blood as well as the urinary excretion of trichloroethanol (TCE) and trichloroacetic acid (TCA) 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; this proportionality was still observable in 1,1,1-TRI expired air samples 16 h after the end of the third exposure day. In the case of urinary excretion of TCE and TCA, the proportionality between excretion and exposure concentration was not as good. It was once again observed that the slow excretion of both metabolites leads to progressive cumulation and that their urinary determination is subject to considerable interindividual variations. After adjustment (lowering) of the exposure concentration to account for a prolongation of the duration of exposure (from 8 to 12 h) it was observed that the concentrations of TRI or 1,1,1-TRI towards the end of both exposure periods are more a reflection of the actual exposure concentration than of the exposure duration. Despite important interindividual variations, these adjusted and nonadjusted exposures led to almost identical average total urinary excretion (over 24 h) of TCE and TCA after exposure to 1,1,1-TRI, as was also the case for TCE but not for TCA after exposure to TRI. Induced within-day variations in the exposure concentration led to corresponding but not proportional changes in alveolar air concentrations for both solvents. After exposure to peak concentrations there was a lag period before alveolar air concentrations returned to prepeak levels. At the end of repeated 10-min periods of physical exercise at 50 W, alveolar air concentrations of TRI were increased by 50% while those of 1,1,1-TRI increased by only 12%. After optimization of the physiologically based toxicokinetic model parameters with experimental data collected during the first exposure scenario, results pertaining to the three other scenarios were adequately simulated by the optimized models. Overall, the results of the present study suggest that alveolar air solvent concentration is a reliable index of exposure to both TRI and 1,1,1-TRI under various experimental exposure scenarios. These results also suggest that urinary excretion of TCE and TCA must be interpreted with caution when assessing exposure to either solvents. For exposure 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.

Physiological Daily Inhalation Rates for Free-Living Individuals Aged 2.6 Months to 96 Years Based on Doubly Labeled Water Measurements: Comparison with Time-Activity-Ventilation and Metabolic Energy Conversion Estimates

ABSTRACT In the first part of this article, a critical review of traditional approaches used to estimate daily inhalation rates as a function of age for health risk assessment purposes shows that such rates are not totally reliable due to various biases introduced by both quantitative and qualitative deficiencies regarding certain input parameters. In the second part, the magnitude of under- and overestimations of published inhalation rates derived from each approach is described by a comparison with new sets of physiological daily inhalation rates and distribution percentile values based on total daily energy expenditures (TDEEs) measured by the doubly labeled water (DLW) method. TDEEs are derived from the analysis of deuterium (2H) and heavy oxygen-18 (18O) in urine samples by gas-isotope-ratio mass spectrometry during an aggregate period of over 20,000 days for unrestrained free-living normal-weight individuals aged 2.6 months to 96 years (n = 1252). Regarding physiological values based on DLW measurements, opposite tendencies have been observed between two sets of estimates using time-activity patterns both biased by conservative input data assumptions during sleep and light activities: most estimates based on the time-activity-ventilation approach are overestimated, whereas most of those using metabolic equivalent approach are underestimated. Erroneous food intakes have clearly lead to underestimated rates when used in daily food-energy intake (EFD) and Parameter A approaches. With the latter approach, overestimated basal metabolic rates (BMRs) used in EFD/BMR ratios contribute to the underestimation of inhalation values. Few mean daily inhalation rates and Monte Carlo simulation percentiles based on traditional approaches (57 out of 253) are close to physiological values within a gap of ± 5% or less. Aggregate errors in all estimates (in m3/day and m3/kg-day) vary from -52 to +126%. The most accurate daily inhalation rates are those based on DLW measurements with an error of about ± 5%, as calculated in previous studies for free-living males and females aged 1 month to 96 years and pregnant and lactating adolescents and women aged 11 to 55 years during real-life situations in their normal surroundings.

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.

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

SummaryThis 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.

Influence of long-chain free fatty acids on the binding of warfarin to bovine serum albumin☆

Abstract The effects of the concentration of long-chain free fatty acids and bovine serum albumin on the binding characteristics of warfarin with albumin have been studied by adsorption and fluorescence spectroscopy using the method of ultrafiltration. The binding affinity of warfarin is higher in a concentrated than in a dilute albumin solution. In a dilute solution of serum albumin (55 μM or less), the binding constant of the warfarin-albumin complex is increased in the presence of 100 μM (or less) of either lauric or oleic acid or a mixture of these two acids, but higher concentrations of the fatty acids decrease such binding. A mixture of saturated and unsaturated fatty acids shows the same effects as those by either fatty acid. Simultaneous measurements of the fluorescence peak intensity and polarization of fluorescence of warfarin bound to albumin in a dilute solution indicate that low and high concentrations of free fatty acids induce different conformational states of the same warfarin-binding sites on the albumin molecule. Such a dualistic behavior of free fatty acids could be best interpreted in terms of allosteric interactions involving heterotropic effects. On the other hand, in a concentrated solution of serum albumin, the binding constant of warfarin is decreased in the presence of both low and high concentrations of free fatty acids. Such a decrease in warfarin binding with concentrated albumin in the presence of free fatty acids is not due simply to a displacement of warfarin by free fatty acids from the warfarin-binding sites, but also could result simultaneously from a further conformational change of warfarin-binding sites caused by the interaction of warfarin and free fatty acids (a negative heterotropic effect).

Influence of removal from occupational lead exposure on blood and saliva lead concentrations

Samples of total blood and unstimulated mixed saliva were obtained from 5 male workers occupationally exposed to lead at various time intervals after removal from their work environment. Initial blood lead concentrations were elevated in all workers and then slowly decreased upon removal. Lead concentrations in saliva fell much more abruptly than those in blood, the saliva half-lives being estimated at 5-7 days. Temporary return to work in 2 workers resulted in relatively marked increases of salivary lead concentrations. These results suggest that salivary lead is closely related to recent lead exposure.

Correlation between acetone-potentiated CCl4-induced liver injury and blood concentrations after inhalation or oral administration.

In studies of acetone-potentiated liver injury induced by haloalkanes, acetone is usually given by gavage, whereas industrial exposure to acetone normally occurs by inhalation. It was of interest to verify if the route of administration influences the potentiation. Male Sprague-Dawley rats were exposed for 4 hr to acetone vapors or treated orally with acetone; the minimal effective dose (MED) levels for potentiating CCl4-induced liver injury were estimated to be 2500 ppm and 0.25 ml/kg, respectively. Groups were treated with acetone using 0.4, 1, 2, 4, or 6 times the MED. Half of each group was killed at various time intervals after treatment for blood acetone measurements by gas chromatography; the other half was challenged with CCl4 (0.1 ml/kg, ip) 18 hr after acetone, and killed 24 hr later. Plasma alanine aminotransferase (ALT) activity and bilirubin concentrations were measured. Inhalation and oral administration of acetone both potentiated CCl4 toxicity. Rats exposed repetitively to acetone vapors (10 daily exposures) and subsequently challenged with CCl4 exhibited liver toxicity that was not significantly different from that of rats subjected to a single exposure. Correlations between ALT activities and maximal blood acetone concentrations were found to be linear (positive) and significant for both routes. For a given blood acetone concentration, however, toxicity was least severe following acetone exposure by inhalation. When the concept of threshold concentrations was applied to the data, the severity of the toxic response was dependent on the blood acetone concentration above the threshold, irrespective of the route of administration.