Creatinine and specific gravity normalization in biological monitoring of occupational exposures.

Reference values for the biological monitoring of occupational exposures are generally normalized on the basis of creatinine (CR) concentration or specific gravity (SG) to account for fluctuations in urine dilution. For instance, the American Conference of Governmental Industrial Hygienists (ACGIH(®)) uses a reference value of 1g/L for CR. The comparison of urinary concentrations of biomarkers between studies requires the adjustment of results based on a reference CR and/or SG value, although studies have suggested that age, sex, muscle mass, and time of the day can exert non-negligible influences on CR excretion, while SG appears to be less affected. The objective of this study was to propose reference values for urinary CR and SG based on the results of samples sent for analysis by occupational health practitioners to the laboratory of the Occupational Health and Safety Research Institute of Québec (IRSST). We analyzed a database containing 20,395 urinary sample results collected between 1985 and 2010. Linear mixed-effects models with worker as a random effect were used to estimate the influence of sex and collection period on urinary CR and SG. Median CR concentrations were 25-30% higher in men (1.6 g/L or 14.4 mmol/L) than in women (1.2 g/L or 10.2 mmol/L). Four percent of the samples for men and 12% for women were below the acceptable threshold for CR (4.4 mmol/L). For SG, 5% of samples for men and 12% for women were below the threshold of 1.010. The difference in SG levels between sexes was lower than for CR, with a median of 1.024 for men compared to 1.020 for women. Our results suggest that the normalization of reference values based on a standard CR value of 1 g/L as proposed by the ACGIH is a conservative approach. According to the literature, CR excretion is more influenced by physiological parameters than SG. We therefore suggest that correction based on SG should be favored in future studies involving the proposal of reference values for the biological monitoring of occupational exposures.

Rat pulmonary responses to inhaled nano-TiO2: effect of primary particle size and agglomeration state.

BACKGROUND: The exact role of primary nanoparticle (NP) size and their degree of agglomeration in aerosols on the determination of pulmonary effects is still poorly understood. Smaller NP are thought to have greater biological reactivity, but their level of agglomeration in an aerosol may also have an impact on pulmonary response. The aim of this study was to investigate the role of primary NP size and the agglomeration state in aerosols, using well-characterized TiO2 NP, on their relative pulmonary toxicity, through inflammatory, cytotoxic and oxidative stress effects in Fisher 344 male rats. METHODS: Three different sizes of TiO2 NP, i.e., 5, 10-30 or 50 nm, were inhaled as small (SA) (< 100 nm) or large agglomerates (LA) (> 100 nm) at 20 mg/m³ for 6 hours. RESULTS: Compared to the controls, bronchoalveolar lavage fluids (BALF) showed that LA aerosols induced an acute inflammatory response, characterized by a significant increase in the number of neutrophils, while SA aerosols produced significant oxidative stress damages and cytotoxicity. Data also demonstrate that for an agglomeration state smaller than 100 nm, the 5 nm particles caused a significant increase in cytotoxic effects compared to controls (assessed by an increase in LDH activity), while oxidative damage measured by 8-isoprostane concentration was less when compared to 10-30 and 50 nm particles. In both SA and LA aerosols, the 10-30 nm TiO2 NP size induced the most pronounced pro-inflammatory effects compared to controls. CONCLUSIONS: Overall, this study showed that initial NP size and agglomeration state are key determinants of nano-TiO2 lung inflammatory reaction, cytotoxic and oxidative stress induced effects.

Identification of workers exposed concomitantly to heat stress and chemicals.

In the context of climate change, concomitant exposure to heat stress and chemicals takes on great importance. However, little information is available in this regard. The purpose of this research, therefore, was to develop an approach aimed at identifying worker groups that would be potentially most at risk. The approach comprises 5 consecutive steps: - Establishment of a list of occupations for all industry sectors - Determination of heat stress parameters - Identification of occupations at risk of heat stress - Determination of exposure to chemicals - Identification of occupations potentially most at risk. Overall, 1,010 occupations were selected due to their representativeness of employment sectors in Québec. Using a rating matrix, the risk stemming from exposure to heat stress was judged "critical" or "significant" for 257 occupations. Among these, 136 occupations were identified as showing a high potential of simultaneous exposure to heat stress and chemicals. Lastly, a consultation with thirteen experts made it possible to establish a list of 22 priority occupations, that is, 20 occupations in the metal manufacturing sector, as well as roofers and firefighters. These occupations would merit special attention for an investigation and evaluation of the potential effects on workers' health.

Assessment of the contribution of electron microscopy to nanoparticle characterization sampled with two cascade impactors.

This study assessed the contribution of electron microscopy to the characterization of nanoparticles and compared the degree of variability in sizes observed within each stage when sampled by two cascade impactors: an Electrical Low Pressure Impactor (ELPI) and a Micro-Orifice Uniform Deposit Impactor (MOUDI). A TiO(2) nanoparticle (5 nm) suspension was aerosolized in an inhalation chamber. Nanoparticles sampled by the impactors were collected on aluminum substrates or TEM carbon-coated copper grids using templates, specifically designed in our laboratories, for scanning and transmission electron microscopy (SEM, TEM) analysis, respectively. Nanoparticles were characterized using both SEM and TEM. Three different types of diameters (inner, outer, and circular) were measured by image analysis based on count and volume, for each impactor stage. Electron microscopy, especially TEM, is well suited for the characterization of nanoparticles. The MOUDI, probably because of the rotation of its collection stages, which can minimize the resuspension of particles, gave more stable results and smaller geometric standard deviations per stage. Our data suggest that the best approach to estimate particle size by electron microscopy would rely on geometric means of measured circular diameters. Overall, the most reliable data were provided by the MOUDI and the TEM sampling technique on carbon-coated copper grids for this specific experiment. This study indicates interesting findings related to the assessment of impactors combined with electron microscopy for nanoparticle characterization. For future research, since cascade impactors are extensively used to characterize nano-aerosol exposure scenarios, high-performance field emission scanning electron microscopy (FESEM) should also be considered.

Generating nano-aerosols from TiO2 (5 nm) nanoparticles showing different agglomeration states. Application to toxicological studies.

Agglomeration of nanoparticles (NP) is a key factor in the generation of aerosols from nano-powders and may represent an important parameter to consider in toxicological studies. For this reason, the characterization of NP aerosols (e.g., concentration, size, and structure of agglomerates) is a critical step in the determination of the relationship between exposure and effects. The aim of this study was to generate and characterize aerosols composed of TiO2 (5 nm) NP showing different agglomeration states. Two concentrations were tested: 2 and 7 mg/m³. Stable mass concentrations over 6 hr were successfully generated by a wet method using Collison and Delavan nebulizers that resulted in aerosols composed of smaller agglomerates (<100 nm), while aerosols composed of larger agglomerates (>100 nm) were obtained by dry generation techniques using either a Palas dust feeder or a Fluidized Bed. Particle size distributions in the aerosols were determined by an electrical low pressure impactor. Median number aerodynamic diameters corresponding to the aerosol with smaller and larger agglomerates were 30 and 185 nm, respectively, for the 2 mg/m³ concentration, and 31 and 194 nm for the 7 mg/m³ experiment. Image analysis by transmission electron microscopy showed the presence of compact or agglomerates with void spaces in the different nano-aerosols. These characterized nano-aerosols will be used in further experiments to study the influence of agglomerate size on NP toxicity.

Immunotoxicity of 3 chemical forms of beryllium following inhalation exposure.

The toxicity of 3 chemical forms of beryllium (Be) was compared in this study. A total of 160 mice equally divided into 4 groups were exposed by inhalation (nose only) for 3 consecutive weeks, 5 d/week, 6 h/d. One group was used as control, while the 3 others were exposed to fine particles of Be metal, Be oxide (BeO), or Be aluminum (BeAl). Except for the controls, the target level of exposure was 250 µg/m(3). In all, 35 mice/group were sacrificed 1 week postexposure and another 5 mice 3 weeks postexposure. The BeO group showed the highest lung Be concentration with higher interleukin 12 (IL-12) and interferon-γ (IFN-γ) levels, while the Be group produced the most severe lung inflammation and higher tumor necrosis factor-α (TNF-α) and CD4+ T cells levels. Data suggested that Be and BeO apparently produced more pulmonary toxicity than BeAl. However, this conclusion is not definitive, because of different confounding factors such as particle sizes, specific surface area, and solubility.

Development and validation of analytical methods for ultra-trace beryllium in biological matrices.

Beryllium (Be) is still not well understood from a toxicological point of view, and studies that involve the determination of different Be compounds species in tissues need to be conducted. In this paper we describe the development and validation of reliable methods for the detection of ultra-trace levels of Be in various biological matrices. Blood and tissues (liver, lung, spleen, and kidney) were used in this study. The samples were digested with a mixture of nitric and perchloric acids for Be and BeAl and an addition of sulfuric acid was made for BeO. The solutions were analyzed by inductively coupled plasma mass spectrometry with (6)Li as internal standard. The detection limits are in the order of 0.02 ng/g for tissue and 0.03 ng/mL for blood, and were compared to existing reference methods. To our knowledge, this is the first study that assesses dissolution of the different Be compounds in biological matrices, while also undergoing a rigorous optimization and complete validation. This method has proven that it is reliable, among the most sensitive available in the literature, and that it can be used in trace toxicological studies for Be.

Urinary levels, tissue concentrations and lung inflammation after nose-only exposure to three different chemical forms of beryllium.

This study aimed to determine the toxicity and toxicokinetic of three Be chemical species A total of 120 mice (four groups of 30) were nose-only exposed. The first group was used as a control while the three others were exposed to 250 microg m(-3) of fine particles of three different Be species (Be metal, Be-F; Be oxide, BeO-F; Be aluminium, BeAl-F). Exposure lasted over three consecutive weeks, five days per week and 6 h per day. Blood and several tissues were collected one week after exposure. Urines were collected before the beginning of exposure, at the end of every week of exposure and one week after exposure. Results showed that urine concentrations were different from one Be species to another and that excretion continued after the end of exposure. Except for BeO-F, where Be urine concentrations were stable during the three weeks of exposure, concentrations of Be-F and BeAl-F reached a peak after the first week. According to particle size, BeO-F obtained the highest theoretical pulmonary deposition rate, which partially led to the highest Be lung concentration. This group also presented the lowest urine concentration but that did not lead to more severe lung inflammation. Moreover, even if BeAl-F obtained the lowest percentage theoretical pulmonary deposition, it showed the highest Be urinary concentration, the lowest Be lung concentration and the lowest lung toxicity. In this specific case, a high Be concentration in urine did not reflect a high exposure or a severe toxic effect.

Beryllium contamination and exposure monitoring in an inhalation laboratory setting.

Beryllium (Be) is used in several forms: pure metal, beryllium oxide, and as an alloy with copper, aluminum, or nickel. Beryllium oxide, beryllium metal, and beryllium alloys are the main forms present in the workplace, with inhalation being the primary route of exposure. Cases of workers with sensitization or chronic beryllium disease challenge the scientific community for a better understanding of Be toxicity. Therefore, a toxicological inhalation study using a murine model was performed in our laboratory in order to identify the toxic effects related to different particle sizes and chemical forms of Be. This article attempts to provide information regarding the relative effectiveness of the environmental monitoring and exposure protection program that was enacted to protect staff (students and researchers) in this controlled animal beryllium inhalation exposure experiment. This includes specific attention to particle migration control through intensive housekeeping and systematic airborne and surface monitoring. Results show that the protective measures applied during this research have been effective. The highest airborne Be concentration in the laboratory was less than one-tenth of the Quebec OEL (occupational exposure limit) of 0.15 microg/m(3). Considering the protection factor of 10(3) of the powered air-purifying respirator used in this research, the average exposure level would be 0.03 x 10(- 4) microg/m(3), which is extremely low. Moreover, with the exception of one value, all average Be concentrations on surfaces were below the Quebec Standard guideline level of 3 microg/100 cm(2) for Be contamination. Finally, all beryllium lymphocyte proliferation tests for the staff were not higher than controls.

Effect of physical exertion on the biological monitoring of exposure to various solvents following exposure by inhalation in human volunteers: III. Styrene.

This study evaluated the impact of different work load intensities on biological indicators of styrene exposure. Four adult Caucasian men, aged 20 to 44 years, were recruited. Groups of 2-4 volunteers were exposed to 20 ppm of styrene in an exposure chamber according to scenarios involving either aerobic, muscular, or both types of physical exercise for 3 or 7 hr. The target intensities for each 30-min exercise period-interspaced with 15 min at rest-were the following: REST, 38 watts AERO (time-weighted average intensity), 34 watts AERO/MUSC, 49 watts AERO/MUSC, and 54 watts AERO for 7 hr and 22 watts MUSC for 3 hr. End-exhaled air samples were collected at 15 time points during and after 7-hr exposures for the determination of styrene concentrations. Urine samples were collected before the start of exposure, after the first 3 hr of exposure, and at the end of exposure for the determination of mandelic acid (MA) and phenylglyoxilic acid (PGA) concentrations. Compared with exposure at rest, styrene in alveolar air increased by a factor up to 1.7, while the sum of urinary MA and PGA increased by a factor ranging from 1.2 to 3.5, depending on the exposure scenario. Concentrations of biological indicators of styrene fluctuated with physical exertion and were correlated with the magnitude of the physical activity and pulmonary ventilation. Despite the physical exertion effect, urinary concentrations of styrene metabolites after a single-day exposure remain below the current biological exposure index value recommended by ACGIH; therefore, no additional health risk is expected. However, results shows that work load intensities must be considered in the interpretation of biological monitoring data and in the evaluation of the health risk associated with styrene exposure.

The effect of workload on biological monitoring of occupational exposure to toluene and n-Hexane: contribution of physiologically based toxicokinetic modeling.

A physiologically based toxicokinetic model was used to examine the impact of work load on the relationship between the airborne concentrations and exposure indicator levels of two industrial solvents, toluene and n-Hexane. The authors simulated occupational exposure (8 hr/day, 5 days/week) at different concentrations, notably 20 ppm and 50 ppm, which are the current threshold limit values recommended by ACGIH for toluene and n-hexane, respectively. Different levels of physical activity, namely, rest, 25 W, and 50 W (for 12 hr followed by 12 hr at rest) were simulated to assess the impact of work load on the recommended biological exposure indices: toluene in blood prior to the last shift of the workweek, urinary o-cresol (a metabolite of toluene) at the end of the shift, and free (nonhydrolyzed) 2,5-hexanedione (a metabolite of n-hexane) at the end of the shift at the end of the workweek. In addition, urinary excretion of unchanged toluene was simulated. The predicted biological concentrations were compared with the results of both experimental studies among human volunteers and field studies among workers. The highest predicted increase with physical exercise was noted for toluene in blood (39 microg/L at 50 W vs. 14 microg/L at rest for 20 ppm, i.e., a 2.8-fold increase). The end-of-shift urinary concentrations of o-cresol and toluene were two times higher at 50 W than at rest (for 20 ppm, 0.65 vs. 0.33 mg/L for o-cresol and 43 vs. 21 microg/L for toluene). Urinary 2,5-hexanedione predicted for 50 ppm was 1.07 mg/L at 50 W and 0.92 mg/L at rest (+16%). The simulations that best describe the concentrations among workers exposed to toluene are those corresponding to 25 W or less. In conclusion, toxicokinetic modeling confirms the significant impact of work load on toluene exposure indicators, whereas only a very slight effect is noted on n-hexane kinetics. These results highlight the necessity of taking work load into account in risk assessment relative to toluene exposure.

Immunological responses in C3H/HeJ mice following nose-only inhalation exposure to different sizes of beryllium metal particles.

Beryllium is used in a wide variety of industries. Chronic beryllium disease is the most common occupational disease among workers following exposure to Be. The objective of this study was to determine the immunologic effects of two different particle sizes of Be metal, <2.5 microm (fine Be or Be-F) and <10 microm (inhalable Be or Be-I) on C3H/HeJ mice following 3 weeks of nose-only inhalation exposure at a target concentration of 250 microg m(-3). Mice were sacrificed either on day 28 or day 42 (Be-F group only) after exposure. The mass median aerodynamic diameter obtained in the inhalation chamber was 1.5 +/- 0.1 microm for Be-F and 4.1 +/- 0.6 microm for Be-I. Results showed peri-bronchial inflammation with early granulomatous changes in exposed mice. The extent of the inflammation appeared more severe for mice sacrificed at day 42. Splenocyte proliferation was higher for mice exposed to fine particles compared with Be-I and control animals. Flow-cytometric analysis indicated a significantly greater expression of CD4(+), CD8(+) and intracellular IFN-gamma expression for both Be particle sizes, particularly for fine particles. Cytokine assays of bronchoalveolar lavage revealed significantly greater levels of IL-12, TNF-alpha and IFN-gamma for mice exposed to fine particles. Our findings suggest that exposure to fine particles may induce more pronounced immunological effects than inhalable particles.

Effect of physical exertion on the biological monitoring of exposure to various solvents following exposure by inhalation in human volunteers: II. n-Hexane.

This study evaluated the impact of physical exertion on two n-hexane (HEX) exposure indicators in human volunteers exposed under controlled conditions in an inhalation chamber. A group of four volunteers (two women, two men) were exposed to HEX (50 ppm; 176 mg/m(3)) according to several scenarios involving several periods when volunteers performed either aerobic (AERO), muscular (MUSC), or both AERO/MUSC types of exercise. The target intensities for 30-min exercise periods separated by 15-min rest periods were the following: REST, 50W AERO [time-weighted average intensity including resting period (TWAI): 38W], 50W AERO/MUSC (TWAI: 34W), 100W AERO/MUSC (TWAI: 63W), and 100W AERO (TWAI: 71W) for 7 hr (two 3-hr exposure periods separated by 1 hr without exposure) and 50W MUSC for 3 hr (TWAI: 31W). Alveolar air and urine samples were collected at different time intervals before, during, and after exposure to measure unchanged HEX in expired air (HEX-A) and urinary 2,5-hexanedione (2,5-HD). HEX-A levels during exposures involving AERO activities (TWAI: 38W and 71W) were significantly enhanced (approximately +14%) compared with exposure at rest. MUSC or AERO/MUSC exercises were also associated with higher HEX-A levels but only at some sampling times. In contrast, end-of-exposure (7 hr) urinary 2,5-HD (mean +/- SD) was not modified by physical exertion: 4.14 +/- 1.51 micromol/L (REST), 4.02 +/- 1.52 micromol/L (TWAI 34W), 4.25 +/- 1.53 micromol/L (TWAI 38W), 3.73 +/- 2.09 micromol/L (TWAI 63W), 3.6 +/- 1.34 micromol/L (TWAI 71W) even though a downward trend was observed. Overall, this study showed that HEX kinetics is practically insensitive to moderate variations in workload intensity; only HEX-A levels increased slightly, and urinary 2,5-HD levels remained unchanged despite the fact that all types of physical exercise increased the pulmonary ventilation rate.

A web tool for the identification of potential interactive effects of chemical mixtures.

This project was undertaken to develop a toxicological database allowing the identification of possible additive or other interactive effects of mixtures present in the work environment. In the first phase of the project, whose findings have already been published, critical toxicological data were compiled for each of the 695 chemical substances in the Quebec Occupational Health Regulation, allowing the prediction of potential additivity among components of a mixture. In the second phase of this project, the types of interactions for mixtures most likely to be found in workplaces and for which primary literature data are available were specified. The toxicological data were evaluated only for realistic exposure concentrations up to the short-term exposure limit or ceiling value or five times the 8-hr time-weighted average (TWA) permissible exposure limit (PEL) for human data and up to 100 times the 8-hr TWA PEL or ceiling value for animal studies. In total, 675 studies were evaluated covering 209 binary mixtures of substances. For the majority of cases where potential additivity was identified in Phase 1, there is a lack of toxicological data in the primary literature. In these cases, the results of the first phase will be useful as the default hypothesis. The resulting database integrates the results from both phases of the project. A web-based computer tool allows the user to determine whether there is potential additivity or interaction among components of a mixture.

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.

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.

Database for the toxicological evaluation of mixtures in occupational atmospheres.

Workers are regularly simultaneously exposed to multiple chemical substances. As in the ACGIH (American Conference of Governmental Industrial Hygienists) approach, the Québec Regulation prescribes that when two or more hazardous substances are present in workplaces and have similar effects on the same organs of the human body, their effects should be considered additive, unless established otherwise. This project was undertaken to develop a user-friendly toxicological database aid in identification of possible interactive effects of mixtures present in the work environment. In the first phase of the project, standard general literature references were used to compile critical data, such as target organs, effects on the target organs, mechanisms of action, and toxicokinetic characteristics of each of the 668 chemical substances appearing in the regulation. Each substance was assigned to one or more of 32 classes of biological effects retained by a group of toxicologists. The resulting database allows the user to find if there is potential additivity among components of a mixture.

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.

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.