Ginette Truchon

Effects of inhaled nano-TiO2 aerosols showing two distinct agglomeration states on rat lungs

Nano-aerosols composed of large agglomerates (LA) (>100nm) are more likely to promote pulmonary clearance via macrophages phagocytosis. Small agglomerates (SA) (<100nm) seem to escape this first defense mechanism and are more likely to interact directly with biological material. These different mechanisms can influence pulmonary toxicity. This hypothesis was evaluated by comparing the relative pulmonary toxicity induced by aerosolized nano-TiO(2) showing two different agglomeration states: SA (<100nm) and LA (>100nm) at mass concentrations of 2 or 7mg/m(3). Groups of Fisher 344 male rats were nose-only exposed for 6h. The median number aerodynamic diameters were 30 and 185nm at 2mg/m(3), and 31 and 194nm at 7mg/m(3). We found in rats bronchoalveolar lavage fluids (BALF) a significant 2.1-fold increase in the number of neutrophils (p<0.05) in the group exposed to the 7mg/m(3) LA nano-aerosol suggesting a mild inflammatory response. Rats exposed to the 7mg/m(3) SA nano-aerosol showed a 1.8-fold increase in LDH activity and 8-isoprostane concentration in BALF, providing evidence for cytotoxic and oxidative stress effects. Our results indicate that biological responses to nanoparticles (NP) might depend on the dimension and concentration of NP agglomerates.

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.

A weight of evidence approach for the assessment of the ototoxic potential of industrial chemicals

There is accumulating epidemiological evidence that exposure to some solvents, metals, asphyxiants and other substances in humans is associated with an increased risk of acquiring hearing loss. Furthermore, simultaneous and successive exposure to certain chemicals along with noise can increase the susceptibility to noise-induced hearing loss. There are no regulations that require hearing monitoring of workers who are employed at locations in which occupational exposure to potentially ototoxic chemicals occurs in the absence of noise exposure. This project was undertaken to develop a toxicological database allowing the identification of possible ototoxic substances present in the work environment alone or in combination with noise exposure. Critical toxicological data were compiled for chemical substances included in the Quebec occupational health regulation. The data were evaluated only for noise exposure levels that can be encountered in the workplace and for realistic exposure concentrations up to the short-term exposure limit or ceiling value (CV) or 5 times the 8-h time-weighted average occupational exposure limit (TWA OEL) for human data and up to 100 times the 8-h TWA OEL or CV for animal studies. In total, 224 studies (in 150 articles of which 44 evaluated the combined exposure to noise and a chemical) covering 29 substances were evaluated using a weight of evidence approach. For the majority of cases where potential ototoxicity was previously proposed, there is a paucity of toxicological data in the primary literature. Human and animal studies indicate that lead, styrene, toluene and trichloroethylene are ototoxic and ethyl benzene, n-hexane and p-xylene are possibly ototoxic at concentrations that are relevant to the occupational setting. Carbon monoxide appears to exacerbate noise-induced hearing dysfunction. Toluene interacts with noise to induce more severe hearing losses than the noise alone.

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

BackgroundThe 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.MethodsThree 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.ResultsCompared 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.ConclusionsOverall, 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.

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.

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 μmol/L (REST), 4.02 ± 1.52 μmol/L (TWAI 34W), 4.25 ± 1.53 μmol/L (TWAI 38W), 3.73 ± 2.09 μmol/L (TWAI 63W), 3.6 ± 1.34 μmol/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.

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

Abstract 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.

Physiologically Based Modeling of n-Hexane Kinetics in Humans Following Inhalation Exposure at Rest and Under Physical Exertion: Impact on Free 2,5-Hexanedione in Urine and on n-Hexane in Alveolar Air

We used a modified physiologically based pharmacokinetic (PBPK) to describe/predict n-hexane (HEX) alveolar air concentrations and free 2,5-HD urinary concentrations in humans exposed to n-HEX by inhalation during a typical workweek. The effect of an increase in workload intensity on these two exposure indicators was assessed and, using Monte Carlo simulation, the impact of biological variability was investigated. The model predicted HEX alveolar air concentrations at rest of 19.0 ppm (25 ppm exposure) and 38.7 ppm (50 ppm exposure) at the end of the last working day (day 5), while free 2,5-HD urinary concentrations of 3.4 μ mol/L (25 ppm) and 6.3 μ mol/L (50 ppm) were predicted for the same period (last 4.5 hours of Day 5). Monte Carlo simulations showed that the range of values expected to occur in a group of 1000 individuals exposed to 50 ppm of HEX (95% confidence interval) for free 2,5-HD (1.7–14.7 μ mol/L) is much higher compared with alveolar air HEX (33.4–46 ppm). Simulations of exposure at 50 ppm with different workloads predicted that an increase in workload intensity would not greatly affect both indicators studied. However, the alveolar air HEX concentration is more sensitive to modifications of workload intensity and time of sampling, after the end of exposure, compared with 2,5-HD. The PBPK model successfully described the HEX alveolar air concentrations and free 2,5-HD urinary concentrations measured in human volunteers and is the first, to our knowledge, to describe the excretion kinetics of free 2,5-HD in humans over a 5-day period.

Impact of emerging pollutants on pulmonary inflammation in asthmatic rats: ethanol vapors and agglomerated TiO2 nanoparticles

Context: Titanium dioxide nanoparticles (nano-TiO2) and ethanol vapors are air contaminants with increasing importance. The presence of a pathological pulmonary condition, such as asthma, may increase lung susceptibility to such contaminants. Objective: This study aimed to investigate if exposure to inhaled ethanol vapors or nano-TiO2 can modulate the rat pulmonary inflammatory response resulting from an allergic asthmatic reaction. Materials and methods: Brown Norway rats were sensitized (sc) and challenged (15 min inhalation, 14 days later) with chicken egg ovalbumin (OVA). Leukocytes were counted in bronchoalveolar lavages (BAL) performed at 6, 24, 36, 48 and 72 h following the challenge and either after ethanol exposures (3000 ppm, 6 h/day, daily) or at 48 h (peak inflammation) for nano-TiO2 exposures (9.35 mg/m3 aerosol for 6 and 42 h after the OVA challenge). For the nano-TiO2 exposures, plasma and BAL cytokines were measured and lung histological analyzes were performed. Results: Exposure to ethanol did not significantly affect BAL leukocytes after OVA challenge. Exposure to nano-TiO2 significantly decreased BAL leukocytes compared to OVA-challenged controls. Plasma and BAL IL-4, IL-6, and INF-γ levels were also decreased in the nano-TiO2 group. Discussion: While ethanol vapors do not modify the pulmonary inflammation in rats during an asthmatic response, a surprising protective effect for agglomerated nano-TiO2 was observed. A putative mechanistic basis involving a decrease in the Th2 response caused by OVA is proposed. Conclusion: Allergic pulmonary inflammation is not up-regulated by inhalation of the pollutants ethanol and nano-TiO2. On the contrary, nano-TiO2 decreases lung inflammation in asthmatic rats.

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 µm (fine Be or Be‐F) and <10 µm (inhalable Be or Be‐I) on C3H/HeJ mice following 3 weeks of nose‐only inhalation exposure at a target concentration of 250 µg 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 µm for Be‐F and 4.1 ± 0.6 µm 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‐γ expression for both Be particle sizes, particularly for fine particles. Cytokine assays of bronchoalveolar lavage revealed significantly greater levels of IL‐12, TNF‐α and IFN‐γ for mice exposed to fine particles. Our findings suggest that exposure to fine particles may induce more pronounced immunological effects than inhalable particles. Copyright