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Biomedical subjects

J Brodeur

Publications and source records attributed to J Brodeur.

At least 19 recordsLinked to original sources

Geographic biotype and host-associated local adaptation in a polyphagous species, Lambdina fiscellaria (Lepidoptera: Geometridae) feeding on balsam fir on Anticosti Island, Canada.

The debate about mechanisms underlying the evolution of host specialization by herbivorous insects remains open. Natural selection may act locally and lead to different patterns of geographic variation in life history traits of polyphagous herbivores. The hypothesis of genetically-based trade-offs in offspring performance on different hosts has been proposed but this has rarely been demonstrated. Under laboratory conditions, the biological performance of two populations of the hemlock looper Lambdina fiscellaria (Guenée), a highly polyphagous lepidopteran, was compared when reared on three different tree host species: balsam fir, eastern hemlock and sugar maple. One population originated from Anticosti Island, Québec, Canada, where the insect has evolved without having access to two of the three tree species tested, the other being from the mainland where all tree species are present. When reared on balsam fir foliage, which was naturally available to each population, larvae from Anticosti Island underwent four instars compared with five for the mainland population, indicating the existence of geographic biotypes in L. fiscellaria. When reared on the foliage of non-naturally available host trees, larvae from Anticosti Island had a higher incidence of supernumerary instars. This is a unique example where local adaptation to environmental conditions of an insect herbivore is expressed through a differential number of larval instars. Moreover, the Anticosti Island population showed a higher growth related index on the host available to both populations indicating that a fitness trade-off was the evolutionary process underlying the local adaptation of this population on balsam fir.

Abies↗

Behavioral thermoregulation in the migratory locust: a therapy to overcome fungal infection.

We examined under laboratory conditions the thermopreference of the migratory locust, Locusta migratoria migratorioides, following infection by the entomopathogenic fungus Metarhizium anisopliae var. acridum and its influence on mycosis. Infected locusts raised their body temperature more frequently than healthy conspecifics through selection of high temperatures in a heat gradient. Thermoregulation did not, however, alter the frequency of feeding events nor the amount of food eaten by infected L. migratoria. A thermoregulation regime of a minimum of 4 h/day substantially increased survival of inoculated insects (by 85%). However, the therapeutic effect decreased when thermoregulation was delayed following inoculation of the pathogen. Thermoregulation reduced locust mortality but did not completely eliminate the fungus from infected hosts; the fungus grew and killed the insects when thermoregulation was interrupted. We suggest that periodic, short bouts of thermoregulation, when performed from the onset of infection and for an extended period of time, are sufficient to provide a therapeutic effect to infected hosts. Such thermoregulatory capacity of locusts may limit the potential of fungal pathogens as biological control agents under certain ecological conditions.

Adaptation, Physiological↗

Importance of nutrition and host availability on oogenesis and oviposition of Cephalonomia stephanoderis (Hymenoptera: Bethylidae).

A variety of host and non-host meals were tested for their potential in triggering oogenesis and oviposition in females of Cephalonomia stephanoderis Betrem, a synovigenic parasitoid of the coffee berry borer, Hypothenemus hampei (Ferrari). The consumption of non-host meals or meals composed of honey and crushed host eggs or pupae was insufficient to initiate oogenesis. The presence of suitable hosts for oviposition appeared essential for inducing oogenesis and oviposition in this parasitoid. Whereas females may host-feed on all developmental stages of H. hampei, these were not equally suitable in stimulating oogenesis and oviposition. In no-choice tests, oogenesis and oviposition were observed only in females supplied with fully-developed larvae, prepupae and pupae. Direct contact with hosts apparently stimulated egg maturation and egg-laying. Delaying the allocation of energy to egg production until suitable hosts are available for oviposition may be an adaptive attribute of a parasitoid of a concealed and patchily distributed host such as H. hampei.

Animal Nutritional Physiological Phenomena↗

Lack of association between smoking and DNA fragmentation in the spermatozoa of normal men.

Male factor infertility patients can have anomalies in their sperm nuclei, displaying high levels of loosely packaged chromatin and damaged DNA. The primary objectives of this study were to compare the extent of DNA fragmentation in the spermatozoa of healthy light and heavy smokers versus non-smokers, and to investigate its correlation with concentrations of the smoking markers cotinine and cadmium. A secondary objective was to compare the concentrations of blood cadmium and serum cotinine with corresponding concentrations in seminal plasma. Ninety-seven healthy male volunteers were divided into three groups: non-smokers, light and heavy smokers. There was no difference between the three groups with respect to age, number of ejaculations per week, serum testosterone concentration, and parameters of semen analysis. The percentages of DNA fragmentation in spermatozoa were not statistically different in the heavy smokers (12.11%), light smokers (11.66%) and non-smokers (20.41%). Serum and seminal plasma concentrations of cotinine were significantly higher in heavy smokers compared with the other groups (P < 0.0001). Median values for blood cadmium concentration were higher in heavy smokers (4.50 microg/l) than in light smokers (0.20 microg/l) and non-smokers (0.20 microg/l) (P < 0.001). Cadmium concentration in seminal plasma was significantly higher in heavy smokers (0.20 microg/l) than in light smokers (0.10 microg/l) and non-smokers (0. 10 microg/l) (P < 0.05). In summary, our results indicate no association between smoking and DNA fragmentation in the spermatozoa of healthy men.

Adult↗

Lawn parameters influencing abundance and distribution of the hairy chinch bug (Hemiptera: Lygaeidae).

Management of lawns that promotes conditions detrimental to the development of insect pests may represent a valuable environmentally benign turfgrass management strategy. In the cool-humid region of Quebec, Canada, we investigated 45 lawns infested with hairy chinch bug, Blissus leucopterus hirtus Montandon, to identify lawn parameters related to its distribution and abundance. Kentucky bluegrass, creeping bentgrass, and perennial ryegrass, respectively, accounted for 55.8, 19.6, and 9.3% of the grass species. Chinch bug population density was associated positively with abundance of perennial ryegrass, whereas it was marginally negatively related with the abundance of creeping bentgrass. An index of the severity of chinch bug infestation was obtained for each lawn by combining estimates of number of infested patches per lawn, average size of the patches, and chinch bug number per patch. The index was associated positively with abundance of Kentucky bluegrass and perennial ryegrass. There was evidence that abundance of creeping bentgrass was associated negatively with the number of infested patches per lawn, area of the patches, and number of chinch bugs within those patches. The number of infested patches increased, whereas patch area and chinch bug number per patch tended to decrease, when broad-leaf weeds were more abundant on a lawn. No significant relationship was found between thatch thickness and patterns of chinch bug abundance and distribution. These results suggest that management of lawns to respectively increase and decrease abundance of creeping bentgrass and perennial ryegrass could facilitate control of hairy chinch bug populations in cool-humid regions.

Animals↗

Sequential sampling plans for the hairy chinch bug (Hemiptera: Lygaeidae).

Two sequential sampling plans were developed to produce tools to reduce the use of pesticides for the control of the hairy chinch bug, Blissus leucopterus hirtus Montandon, on turfgrass lawns in the cool-humid region of Quebec, Canada. A first plan based on Wald's method was shown to be too conservative in a validation conducted on infested lawns. The second plan developed using Iwao's method yielded good results. The difference between the two plans may have occurred because no common k could be found for the negative binomial functions describing chinch bug distribution on lawns, thereby violating an essential assumption of Wald's approach. Application of the Iwao plan, which is based on visual sampling of 0.1-m2 quadrats, requires approximately 20 min when lawn evaluation is conducted by a single person. Estimation of the occurrence of chinch bug infestations (28% infested lawns in the regions of Montreal and Quebec cities), and results from validation of the Iwao plan on infested lawns, indicate that the error rates alpha and beta of the plan are lower than an upper limit of 0.05 and 0.14, respectively. The adequate precision and practicality of this plan suggest that it could become an essential tool for management of turfgrass lawns in regions where the hairy chinch bug completes less than two generations per growing season.

Animals↗

Ultrastructural and cytochemical characterization of aphid invasion by the hyphomycete verticillium lecanii

Chronological events of the interaction between the hyphomycete Verticillium lecanii and the potato aphid Macrosiphum euphorbiae were investigated by light, scanning, and transmission electron microscopy. The parasitism of M. euphorbiae by V. lecanii appears to involve the following events: (i) adherence of conidia to the host cuticle through a thin mucilagenous matrix; (ii) germination of the conidia and production of mycelium that colonizes the surface of the cuticle; (iii) penetration of germ tubes into the aphid cuticle 24 h after application of the pathogen; (iv) extensive lateral development of hyphae accompanied by pronounced degradation of the cuticular layers by 72 h. Labeling with the WGA/ovomucoid-gold complex showed that penetration and colonization of the cuticle by the fungus resulted from localized enzymatic hydrolysis, likely through the synergistic action of chitinases and mechanical pressure; (v) production of blastospores and massive invasion of aphid internal tissues; (vi) assimilation of nutrients and accumulation of lipids by fungal cells; and (vii) production of conidiophores and release of the fungus from aphid cadavers. These observations bring further insights into the mechanisms by which V. lecanii parasitizes M. euphorbiae. They also provide a basis for comparing the modes of action of V. lecanii against hosts from fungal and animal origins. Copyright 1999 Academic Press.

Journal Article↗

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.

Chromatography, Gas↗

Physiologically based pharmacokinetic modeling of a ternary mixture of alkyl benzenes in rats and humans.

The objective of the present study was to develop a physiologically based pharmacokinetic (PBPK) model for a ternary mixture of alkyl benzenes [toluene (TOL), m-xylene (XYL), and ethylbenzene (EBZ)] in rats and humans. The approach involved the development of the mixture PBPK model in the rat and extrapolation to humans by substituting rat physiological parameters and blood:air partition coefficients in the model with those of humans, scaling maximal velocity for metabolism on the basis of body weight0.75 and keeping all other model parameters species-invariant. The development of the PBPK model for the ternary mixture in the rat was accomplished by initially validating or refining the existing PBPK models for TOL, XYL, and EBZ and linking the individual chemical models via the hepatic metabolism term. Accordingly, the Michaelis-Menten equation for each solvent was modified to test four possible mechanisms of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition). The metabolic inhibition constant (Ki) for each binary pair of alkyl benzenes was estimated by fitting the binary chemical PBPK model simulations to previously published data on blood concentrations of TOL, XYL, and EBZ in rats exposed for 4 hr to a binary combination of 100 or 200 ppm of each of these solvents. Competitive metabolic inhibition appeared to be the most plausible mechanism of interaction at relevant exposure concentrations for all binary mixtures of alkyl benzenes in the rat (Ki,TOL-XYL = 0.17; Ki,TOL-EBZ = 0.79; Ki,XYL-TOL = 0.77; Ki,XYL-EBZ = 1.50; Ki,EBZ-TOL = 0.33; Ki,EBZ-XYL = 0.23 mg/L). Incorporating the Ki values obtained with the binary chemical mixtures, the PBPK model for the ternary mixture simulated adequately the time course of the venous blood concentrations of TOL, XYL, and EBZ in rats exposed to a mixture containing 100 ppm each of these solvents. Following the validation of the ternary mixture model in the rat, it was scaled to predict the kinetics of TOL, XYL, and EBZ in blood and alveolar air of human volunteers exposed for 7 hr to a combination of 17, 33, and 33 ppm, respectively, of these solvents. Model simulations and experimental data obtained in humans indicated that exposure to atmospheric concentrations of TOL, XYL, and EBZ that remain within the permissible concentrations for a mixture would not result in biologically significant modifications of their pharmacokinetics. Overall, this study demonstrates the utility of PBPK models in the prediction of the kinetics of components of chemical mixtures, by accounting for mechanisms of binary chemical interactions.

Animals↗

Assessment of the role of glutathione conjugation in the protection afforded by anethol dithiolthione against hexachloro-1,3-butadiene-induced nephrotoxicity.

Administration of anethol dithiolthione (ADT) to rodents can afford protection against some chemically induced toxicities. The aim of the present study was to assess the effects of ADT on hexachloro-1,3-butadiene (HCBD)-induced nephrotoxicity in the rat and to determine the mechanism of its action. Renal integrity was evaluated by measuring urinary excretion of glucose, protein, and gamma-glutamyl transpeptidase and by histological evaluation. A 3-day pretreatment with ADT (300 mg/kg/day) protected against the toxicity of various doses of HCBD (ranging from 15.6 to 62.5 mg/kg). The pretreatment increased (1.4-fold) the nonprotein sulfhydryl content (NPSH) of the liver. However, it did not modify the biliary excretion of radiolabeled materials in [14C]HCBD- treated (20 mg/kg) rats, nor that of the bioactivated HCBD metabolite, S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-glutathione (PCBG). Moreover, ADT pretreatment protected rats against the nephrotoxicity induced by PCBG (20 mg/kg) itself. The extent of covalent binding to kidney proteins of [14C]HCBD-derived metabolites was not modified by pretreatment with ADT. Incubation of rat kidney cortical slices in a medium containing 0.1 mM of the nephrotoxic glutathione (PCBG) or cysteine (PCBC, S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine) conjugates of HCBD for 30 min resulted in a 75% reduction in the slice/medium ratio of p-aminohipurate (PAH) compared to that seen in controls. When the cortical slices were incubated with ADT (30 min, 0.2 mM) prior to incubation with the nephrotoxic conjugates, the reduction was only 33%. Neither the in vitro nor the in vivo treatments did modify the activity of renal cytosolic beta-lyase; however, the latter treatment caused an increase in NPSH content. A 15-min incubation of kidney cortical slices with glutathione (10 mM) resulted in a 5-fold increase of NPSH, but failed to prevent the reduction in PAH uptake caused by PCBG and PCBC. Altogether, the in vivo and renal slice data suggest that ADT protects rats against HCBD-induced nephrotoxicity by a mechanism that does not involve the modulation of HCBD conjugation with liver GSH, nor the modulation of the kidney NPSH level and beta-lyase activity. The mechanism of protection conferred to rats by an ADT pretreatment against HCBD-induced nephrotoxicity appears to take place in the kidney at a step beyond the generation of ultimate toxic metabolites derived from PCBC.

Anethole Trithione↗

Comparison of the influence of binary mixtures versus a ternary mixture of inhaled aromatic hydrocarbons on their blood kinetics in the rat.

The objective of the present study was to compare the influence of various binary mixtures containing ethylbenzene (EBZ), toluene (TOL) or xylene (XYL) administered by inhalation, with the influence exerted by a ternary mixture, on the kinetics of these solvents in blood. Groups of four rats were exposed for 4 h to TOL, XYL and EBZ, singly or in combination. The concentration of TOL, XYL and EBZ in blood was measured at various times (5, 30, 60, 90 and 120 min) following the end of exposure and the areas under the blood concentration curves (AUC) were calculated. Results showed that exposures to binary and ternary mixtures resulted in significantly higher (P < 0.05) blood concentrations of unchanged solvents as a result of metabolic interaction between these solvents. When the comparison was based on individual solvents, there was no difference between effect exerted by the ternary mixture and the binary mixtures, except for one. However, a comparison based on the total concentration of unchanged solvents disclosed that exposure to the ternary mixture resulted in greater interactive effects (3.17-fold increase) than exposures to binary mixtures (1.97-fold increase), whereas four out of six binary mixtures produced higher total levels of unchanged solvents in blood compared to the ternary mixture. This study shows that the greater risk of toxicity often thought to be associated with exposures to complex mixtures should not only be related to the magnitude of interactive effects among components (i.e., degree of mutual metabolic interaction) resulting from combined exposures, but also should take into account, as is universally recognized, the internal total dose of toxic chemicals in target organs/tissues.

Administration, Inhalation↗

Gas chromatographic determination of urinary o-cresol for the monitoring of toluene exposure.

A sensitive and reproducible gas chromatographic procedure for the quantitative determination of urinary o-cresol is described. The first step involves acid hydrolysis (2N HCl, 100 degrees C, 10 min), which yields unconjugated o-cresol. After extraction (methylene chloride, pH 2), the organic layer is concentrated by evaporation and samples are analyzed by gas chromatography-flame ionization detection with a DB-5 column (30 m x 0.25 mm, 0.25 microns). Initial oven temperature is set at 30 degrees C for 12 min and the increased 2 degrees C/min to 93 decrees C. 3,4-Dimethylphenol is used as the internal standard. The detection limit of the method is 0.36 mumol/L (1 microL injection). Additional validation data were obtained by analysis of urine samples collected from volunteers exposed to various concentrations of toluene: 10, 20, 30, 50, and 100 ppm over 7 h. Urinary o-cresol concentrations (0-3, 3-7, 7-24, and 0-24 h) were highly correlated with toluene exposure.

Chromatography, Gas↗

Estimation of risk of developing bladder cancer among workers exposed to coal tar pitch volatiles in the primary aluminum industry.

To confirm the relationship between exposure to coal tar pitch volatiles and bladder cancer among primary aluminum production workers, we carried out a case-control study among blue-collar workers who had worked more than 1 year between 1950-1979 in a major plant using mostly the Soderberg process in the Province of Québec. Cases of bladder cancer (ICD code 188) diagnosed between 1970-1979 (n = 69) were mostly included in a previously reported study. To these were added cases diagnosed between 1980-1988 (n = 69). Each case was matched to three controls on date of birth, date of hiring, and length of service at the company. Smoking habits were assessed from the medical records at the company. Benzene-soluble matter (BSM) and benzo(a)pyrene (BaP) were used as indicators of environmental exposure to coal tar pitch volatiles in the workplace. The estimated risk for current smokers was 2.63 (95% C.I. 1.29-5.37). Estimates of risk by occupational exposure were adjusted for smoking. Men who had worked in the Soderberg potrooms were at higher risk of developing the disease, the risk increasing with the time spent in these departments. Similarly, a strong association between risk and cumulative exposure to BSM or to BaP was observed. The risks associated with cumulative exposure to BSM (mg/m3-years) and to BaP (microgram/m3-years) were described with mathematical models. Using a linear model (1 + bx) and lagging 10 years before the diagnosis, BaP cumulative exposure was a better indicator of risk than BSM cumulative exposure. The risk for each year of exposure to BaP at a concentration of 1 microgram/m3 increased by 1.7% (0.8%-3.2%). Using the same model for BSM, a worker exposed to the current threshold limit value of 0.2 mg/m3 for 40 years will sustain a risk of 2.22 (1.56-3.48). Comparison of risks according to different periods of diagnosis (1970-1979 vs. 1980-1988) did not reveal any significant temporal changes on risk estimates.

Air Pollutants, Occupational↗

Modeling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzofurans in mammalians, including humans. I. Nonlinear distribution of PCDD/PCDF body burden between liver and adipose tissues.

Mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans, globally called PCDXs, are ubiquitously present in the environment. They accumulate in the human organism, especially through uptake from food. In view of their long residence time in the body and their potential adverse health effects for humans, it is therefore important to develop toxicokinetic models capable of predicting their distribution in human tissues. In the present study a physiologically based model which describes the distribution kinetics of PCDXs in various mammalian species is proposed. The approach is both theoretical and empirical. First, a plausible and general dynamical model that takes into account intercellular diffusion, PCDX-receptor and PCDX-protein binding, and PCDX-dependent enzyme induction in the liver is developed. Simplified formulas are proposed to predict the functional dependencies fh(Cb) and f(at)(Cb), which establish the fractions of the total PCDX body burden contained in liver and adipose tissues as a function of overall body concentration at any one moment. These formulas have fewer free parameters that can be determined for various species with the use of already available data. Model simulations are in agreement with published data on the distribution kinetics of PCDXs in rodents and monkeys and clinical data in humans. In rodents and monkeys as well as in humans, the respective relations fh(Cb) and f(at)(Cb) follow a similar nonlinear pattern. These varying distribution functions constitute the basis for a generalized toxicokinetic model of absorption and disposition described in a companion article (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Appl. Pharmacol. 131, 267-276).

Adipose Tissue↗

Modeling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzofurans in mammalians, including humans. II. Kinetics of absorption and disposition of PCDDs/PCDFs.

In the present study, a physiologically based model which describes the absorption and disposition kinetics of PCDDs/PCDFs (globally called PCDXs) in mammalian species, including humans, is developed. The model integrates the distribution model developed in the first article of this series, which described the fractional distribution of total PCDXs between liver and adipose tissues as a function of overall body concentration (G. Carrier, R. C. Brunet, and J. Brodeur, 1995, Toxicol. Appl. Pharmacol. 131, 253-266). In particular it is shown that the liver fraction of the total body burden decreases as overall body concentration decreases. Since elimination is principally through the liver, this leads to lower global elimination rates and longer half-lives of PCDXs. Absorption and disposition kinetics of PCDXs are captured using nonlinear differential equations with anatomically and biochemically relevant input parameters which are readily available. These are solved to predict the fate of PCDXs in liver, adipose tissues, and the body as a whole, as a function of time. Model simulations are in agreement with published data on absorption and disposition kinetics of these substances in rats and in humans. The kinetic profiles are similar for rats and humans, but the varying half-lives differ considerably in both species: weeks with rats, years with humans. For a given body burden, the adipose tissue concentrations vary in an inversely proportional manner to the mass of the adipose tissues; this observation has considerable relevance for interpretation of clinical data for humans. The interest of the proposed model rests upon the fact that it is generalized and broadly applicable: it allows the study of the kinetics of PCDXs for any pattern of exposure from background to highly toxic levels, taking into account variations in time of anatomical and biochemical parameters.

Absorption↗

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.

Adult↗

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↗