Metabolism and in vitro assessment of the mutagenic activity of urinary extracts from rats after inhalation exposure to 1-methylnaphthalene.

OBJECTIVES: 1-Methylnaphthalene (1-MN) is composed of 2 benzene rings and belongs to polycyclic aromatic hydrocarbons. The metabolism of 1-MN in laboratory animals and bacteria leads to the formation of 1-naphthoic acid (1-NA). MATERIAL AND METHODS: In this study the distribution of 1-NA in lung, liver, spleen, kidney and urinary excretion of 1-NA in rats after single and repeated inhalation exposure to 1-MN vapors were investigated. The activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and cytochrome were measured of the rats. Genotoxic effects were evaluated with the in vitro micronucleus test on V79 hamster fibroblasts. RESULTS: The concentrations of 1-NA in the tissues of rats after single and repeated exposure to 1-MN were dependent on the exposure dose. High levels of 1-NA were found in kidneys of animals after the single and repeated exposure to 1-MN. With an increase of 1-MN dose, an increase in the activity of cytochrome P450 (CYP1A1 and CYP1A2) was observed in the liver of rats. Compared to control animals, significantly higher ALT activity was noted in serum of rats exposed to 1-MN. The micronuclei frequency in V79 cells exposed to 1-MN (in the range of analyzable concentrations; i.e., 5-25 µg/ml) did not differ significantly from the vehicle control, whereas urine extracts from rats exposed to 1-MN induced a significant increase in the frequency of micronuclei compared to urine extracts from the group of control animals. CONCLUSIONS: Metabolism of 1-MN in rats after the inhalation exposure leading to 1-NA was mainly observed during the first day after the end of exposure. It is likely that 1-MN metabolites present in rat urine can induce the increased micronuclei frequency as was shown in V79 cells. Int J Occup Med Environ Health. 2022;35(6):731-46.

Review of data on chemical content in an aerosol resulting from heating a tobacco or a solution used in e-cigarettes and in the smoke generated from the reference cigarettes.

BACKGROUND: The article presents a review of the literature on the chemical composition of smoke generated from a standard cigarette and the aerosol generated after heating tobacco and chemical compounds formed in the aerosol of electronic cigarettes. METHODS: The literature review was carried out on the PubMed online bibliographic database, Google search engine, Google Scholar based on science articles published in recent 20 years. RESULTS: The bibliographic analysis shows that: replacing smoking in the traditional way by heating tobacco modifies significantly the content of chemical substances found in aerosol, the substances found in aerosols generated by e-cigarettes have proven toxic effects, e.g. pro-inflammatory effect on lung epithelial cells (e.g. crotonaldehyde) or a mutagenic effect (e.g. NNK), using e-cigarette aerosol does not rule out a health risk for people, which is not fully recognized at present. CONCLUSIONS: Replacing smoking in the traditional way by heating tobacco modifies significantly the content of chemical substances found in aerosol. Using e-cigarette aerosol does not rule out a health risk for people, because the substances found in aerosols generated by e-cigarettes have proven toxic effects.

Blood plasma levels of biomarkers of liver status and lipid profile among nail technicians occupationally exposed to low-level mixture of volatile organic compounds.

PURPOSE: Nail technicians (NTs) are exposed to a low-level mixture of volatile organic solvents (VOCs), yet the health hazards related to such exposure are unknown. This study thus aimed to compare the blood plasma levels of selected biomarkers related to liver status and lipid profile among occupationally exposed NTs and unexposed controls. Associations between out-of-normal-range levels of such biomarkers and occupational exposure to VOCs mixture have also been investigated. METHODS: The study enrolled 145 female NTs and 152 unexposed controls. Biochemical analyses were performed using spectrophotometric assays and obtained data were analyzed using general linear model and Poisson regression modelling adjusted to multiple confounders. RESULTS: Compared to controls, NTs presented significantly increased plasma activities of ALT (2.04 ± 0.63 ln-U/l vs. 1.25 ± 0.71 ln-U/l; p < 0.0001) and AST (2.73 ± 0.25 ln-U/l vs. 2.08 ± 0.95 ln-U/l; p < 0.0001), and significantly increased plasma levels of TG (4.38 ± 0.53 ln-mg/dl vs. 4.21 ± 0.42 ln-mg/dl; p < 0.05) and TC/HDL ratio (1.18 ± 0.36 vs. 1.02 ± 0.27; p < 0.0005). Plasma levels of HDL were significantly lower among NTs (4.02 ± 0.29 ln-mg/dl vs. 4.21 ± 0.26 ln-mg/dl; p < 0.0001). Moreover, NTs were found to present significantly increased risk of occurrence of clinically relevant plasma HDL levels below 3.91 ln-mg/dl (i.e., 50 mg/dl; RR = 1.58, 95% CI 1.07-2.32, p < 0.05), as well as increased risk of clinically relevant TC/HDL ratio above the normal range limit of 3.5 (RR = 1.68, 95% CI 1.19-2.35, p < 0.005), as compared to unexposed controls. CONCLUSION: Nail technicians are subject to adverse changes in selected plasma biomarkers related to liver functions, some of which may be of clinical relevance.

The effects of 1-methylnaphthalene after inhalation exposure on the serum corticosterone levels in rats.

OBJECTIVES: This paper reports on the trend of the stressogenic stimulus caused by a repeated exposure to 1-methylnaphthalene (1-MN) vapors at the nominal concentrations of 0 mg/m3 (the control restrainer), 50 mg/m3 or 200 mg/m3 in the nose-only inhalation system, by analyzing the serum corticosterone (CORT) levels in rats. MATERIAL AND METHODS: Three groups of rats were exposed in restrainers to 1-MN vapors at the nominal concentrations of 0 mg/m3, 50 mg/m3 or 200 mg/m3 for 5 days. One control group of animals spent all the time during the experiment in an individually ventilated plastic cage. The serum CORT concentrations were determined in all 4 groups of the rats. The blood samples drawn from the tail vein were collected every day after termination of the 6-h exposure. On the fifth day, blood samples were collected 15 min, 30 min, 45 min, 1 h, and 3 h after termination of the 6-h exposure. RESULTS: On the fifth day of the study, no statistically significant changes in body weights between all groups of animals were found. After 5 days of the observation, increased food intake in the control groups was noted. Significantly higher CORT concentrations in the rats exposed to 1-MN at 200 mg/m3 and in the animals from the control restrainer were found, comparing to the animals exposed to 1-MN at 50 mg/m3 and the animals from the control cage. CONCLUSIONS: The application of 6-h restraining induced high concentrations of the stress hormone, CORT, in the blood of rats. The short-term exposure of rats to 1-MN non-linearly reduced the restraint stress measured with CORT concentration. Int J Occup Med Environ Health. 2020;33(5):691-9.

The distribution and excretion of 1-Methylnaphthalene in rats exposed to 1-Methylnaphthalene by inhalation.

OBJECTIVES: 1-Methylnaphthalene (1-MN) is a constituent of polycyclic aromatic hydrocarbons, the chemicals that have become ubiquitous in the environment as result of natural and industrial process. This paper reports a study on the distribution and excretion of 1-MN in rats after single and repeated inhalation exposure to 1-MN vapor. MATERIAL AND METHODS: Male Wistar rats were exposed to 1-MN vapor at nominal concentrations of 50 mg/m3 or 200 mg/m3 in the dynamic inhalation chambers (TSE Systems Head Nose Only Exposure) for 6 h (single exposure) or 5 days (6 h/day, repeated exposure). Blood, urine and tissue samples were collected during and after the exposure. Blood, urine and tissue concentrations of 1-MN were estimated by gas chromatography using the headspace technique. RESULTS: The elimination of 1-MN from blood followed an open 2-compartment model. The concentration in rat tissues was dependent on the magnitude and time of exposure. After repeated exposure, the concentration 1-MN in tissue decreased in comparison to single exposure. The elimination of 1-MN with urine after single and repeated exposure to 1-MN occurred mainly in the samples collected during the first day of collection. CONCLUSIONS: 1-Methylnaphthalene was rapidly eliminated from the blood and tissues of animals exposed by inhalation to 1-MN. In repeated exposure, there was probably a significant increase of 1-MN metabolism in rats exposed to low and high 1-MN doses. Under conditions of repeated 1-MN exposure, no significant systemic 1-MN accumulation could be observed. Int J Occup Med Environ Health 2018;31(6):763-770.

Clara cells protein, prolactin and transcription factors of protein NF-ĸB and c-Jun/AP-1 levels in rats inhaled to stainless steel welding dust and its soluble form.

OBJECTIVES: Welding processes that generate fumes containing toxic metals, such as hexavalent chromium (Cr(VI)), manganese, and nickel (Ni), have been implicated in lung injury, inflammation, and lung tumor promotion in animal models. Bronchiolar epithelium Clara cells/club cells, coordinate these inflammatory responses. Clara cells secretory protein (CC16) with ant-inflammatory role. MATERIAL AND METHODS: The pulmonary toxicity of welding dust (WD) was assessed for Wistar rats exposed to 60 mg/m3 of respirable-size welding dust (mean diameter 1.17 µm for 1 and 2 weeks (6 h/day, 5 days/week)) or the aerosols of soluble form (SWD) in the nose-only exposure chambers. Additionally the effect of antiinflammatory betaine supplementation was assessed. Clara cells secretory protein, differential cell counts, total protein concentrations and cellular enzyme (lactate dehydrogenase - LDH) activities were determined in bronchoalveolar lavage fluid, and corticosterone and thiobarbituric acid reactive substances (TBARS) and prolactin concentrations were assessed in serum. Histopathology examination of lung, brain, liver, kidney, spleen was done. Additionally slices of brain and lung were exanimated in laser ablation inductively coupled plasma mass spectrometry. RESULTS: Both WD and SWD exposure evoked large bronchiolar infiltration shoved in histopathology examination. In this study, TBARS inversely correlated with a significant decrease of CC16 concentration that occurred after instillation of both WD and SWD indicating decreased anti- inflammatory potential in the lung. In WD exposed rats prolactin correlated with nuclear factor-kappa B (NF-κB), LDH, TBARS and serum levels Cr, Ni and inversely with c-Jun. In SWD exposed rats prolactin correlated with CC16 indicated effect of prolactin on the population of epithelial cells. CONCLUSIONS: In the current study, deleterious effects of repeated inhalation stainless steel welding dust form on club (Clara) cell secretory protein (CC16) were demonstrated. Clara cells secretory protein relation with prolactin in exposed rats to welding dust were shown and explored whether the NF-κB and c-Jun/activator protein 1 related pathway was involved. Int J Occup Med Environ Health 2018;31(5):613-632.

Faster health deterioration among nail technicians occupationally exposed to low levels of volatile organic compounds.

OBJECTIVES: The study has aimed at investigating the subjective assessment of an individual's health status and comparing the prevalence of selected work-related symptoms among nail technicians occupationally exposed to volatile organic compounds (VOCs) to the one among control subjects. Associations between occupational exposure to VOCs and the incidence of adverse health effects were also analyzed. MATERIAL AND METHODS: The study involved 145 female nail technicians and 152 control subjects. Data on the prevalence of adverse health effects was collected using the researcher- made questionnaire and then analyzed by means of survival analysis methods. RESULTS: Only 22% of nail technicians as compared to 45% of control subjects described their current health status as "excellent" or "very good" (odds ratio (OR) = 0.4, 95% confidence interval (CI): 0.2-0.6, p < 0.00005). In general, 61% of nail technicians confirmed to have experienced any out of all symptoms considered in the study since the commencement of the job, which was significantly higher as compared to 17% of control subjects (adjusted OR = 2.8, 95% CI: 2.1-3.7, p < 0.0001). Estimated median length of the employment period free of investigated symptoms was significantly shorter among nail technicians as compared to controls (12 years vs. 33 years, p < 0.0001), consistent with almost 4-times increased hazard of the occurrence of such symptoms among the technicians (hazard ratio (HR) = 3.9, 95% CI: 2.7-5.7, p < 0.0001). Cox proportional hazard regression modeling revealed almost 5-times increased hazard of the occurrence of any symptoms among nail technicians exposed to higher levels of the mixture of VOCs as compared to those exposed to lower levels (HR = 4.9, 95% CI: 1-24.1, p = 0.05). CONCLUSIONS: All outcomes combined together indicate that nail technicians are subject to faster health deterioration, which may be assumed to be caused by occupational exposure to low levels of VOCs. Int J Occup Med Environ Health 2017;30(3):469-483.

The time-dependent health and biochemical effects in rats exposed to stainless steel welding dust and its soluble form.

Welding processes that generate fumes containing toxic metals, such as hexavalent chromium (Cr(VI)), manganese (Mn), and nickel (Ni), have been implicated in lung injury, inflammation, and lung tumor promotion in animal models. The principal objective of this study was to determine the dynamics of toxic effects of inhalation exposure to morphologically rated welding dust from stainless steel welding and its soluble form in TSE System with a dynamic airflow. We assessed the pulmonary toxicity of welding dust in Wistar rats exposed to 60.0 mg/m3 of respirable-size welding dust (mean diameter 1.17 µm) for 2 weeks (6 h/day, 5 days/week); the aerosols were generated in the nose-only exposure chambers (NOEC). An additional aim included the study of the effect of betaine supplementation on oxidative deterioration in rat lung during 2 weeks of exposure to welding dust or water-soluble dust form. The animals were divided into eight groups (n = 8 per group): control, dust, betaine, betaine + dust, soluble-form dust, soluble-form dust + betaine, saline and saline + betaine groups. Rats were euthanized 1 or 2 weeks after the last exposure for assessment of pulmonary toxicity. Differential cell counts, total protein concentrations and cellular enzyme (lactate dehydrogenase-LDH) activities were determined in bronchoalveolar lavage (BAL) fluid, and corticosterone and thiobarbituric acid reactive substances (TBARS) concentrations were assessed in serum. The increase in polymorphonuclear (PMN) leukocytes in BAL fluid (a cytological index of inflammatory responses of the lung) is believed to reflect pulmonary toxicity of heavy metals. Biomarkers of toxicity assessed in bronchoalveolar fluids indicate that the level of the toxic effect depends mainly on the solubility of studied metal compounds; biomarkers that showed treatment effects included: total cell, neutrophil and lymphocyte counts, total protein concentrations, and cellular enzyme (lactate dehydrogenase) activity. Betaine supplementation at 250 mg/kg/day in all study rats groups attenuated stress indices, and corticosterone and TBARS serum levels, and simultaneously stimulated increase of polymorphonuclear cells in BALF of rats. The study confirmed deleterious effect of transitory metals and particles during experimental inhalation exposure to welding dusts, evidenced in the lungs and brain by increased levels of total protein, higher cellular influx, rise of LDH in BALF, elevated TBARS and increased corticosterone in serum of rats. Our result confirm also the hypothesis about the effect of the welding dusts on the oxidative stress responsible for disturbed systemic homeostasis and impairment of calcium regulation.

Does the Low-level occupational exposure to volatile organic compounds alter the seasonal variation of selected markers of oxidative stress? A case-control study in nail technicians.

BACKGROUND: In this study we tested whether the seasonal variations in levels of selected biomarkers of oxidative stress in female nail technicians occupationally exposed to low levels of volatile organic compounds (VOCs) differ significantly from those observed among healthy unexposed controls. Airborne levels of selected VOCs in nail salons were also analyzed and tested for associations with seasonal variations of the levels of biomarkers among nail technicians. METHODS: The study enrolled 145 female nail technicians and 145 healthy unexposed female controls. The airborne VOCs and levels of biomarkers were assessed by GC-MS chromatography and absorption/fluorescence spectrophotometry, respectively. RESULTS: Plasma levels of thiobarbituric acid reactive species, ceruloplasmin, the activity of glutathione peroxidase (GPx1) and the SOD1/GPx1 activity ratio presented significant differences between the so-called "hot" and "cold" seasons in the case of nail technicians as well as in unexposed controls (p < <0.0001 for all four biomarkers). The pattern of these variations among nail technicians was found to be significantly different compared to that of the control subjects (p < <0.0001). Although such differences might intuitively be attributed to occupational exposure of nail technicians to VOCs, which was found to be higher during the "cold" season compared to the "hot" one, our study provided only limited evidence in favor of the hypothesis, that the different pattern of seasonal variations of biomarkers among nail technicians might have resulted from seasonal fluctuations in their occupational exposure to VOCs. CONCLUSION: Further investigation is thus needed in order to elucidate the effect of low-level occupational exposure to VOCs on seasonal variations of biomarkers of oxidative stress.

Hemimellitene (1,2,3-trimethylbenzene) in the liver, lung, kidney, and blood, and dimethylbenzoic acid isomers in the liver, lung, kidney and urine of rats after single and repeated inhalation exposure to hemimellitene.

OBJECTIVES: The aim of the study has been to explore hemimellitene distribution in blood, liver, lung and kidney as well as toxicokinetics of its elimination from blood of rats after single and repeated inhalation exposure to this compound. Tissue distribution and excretion with urine of 2-dimethylbenzoic acids (2,3-DMBA and 2,6-DMBA) were also evaluated. MATERIAL AND METHODS: Male outbred IMP:WIST rats were used in the experiment. The animals were exposed to hemimellitene vapors at the nominal concentration of 25 ppm, 100 ppm, and 250 ppm in the dynamic inhalation chambers for 6 h for single exposure purpose and for 4 weeks (6 h/day for 5 day/week) for repeated exposure purposes. RESULTS: Significantly lower concentrations of hemimellitene were detected in the blood and tissues of animals after repeated inhalation exposure of animals to hemimellitene vapors, which points to reduced retention of the chemical in the lungs of the experimental rats. The trend of hemimellitene elimination from the blood depended solely on exposure intensity, irrespective of exposure time, both after single and repeated exposure. As regards the 2 determined hemimellitene metabolites, the major trend of the metabolic transformation involved formation of 2,3-DMBA. CONCLUSIONS: The significantly higher urinary 2,3-DMBA concentration after repeated exposure shows that hemimellitene induces enzymatic processes in the rat.

Dysregulation of markers of oxidative stress and DNA damage among nail technicians despite low exposure to volatile organic compounds.

OBJECTIVE: The study aimed to compare levels of selected biomarkers of oxidative stress and DNA damage and their correlation with occupational exposure to volatile organic compounds (VOC) among female nail technicians and a group of unexposed volunteers. METHODS: A panel of biomarkers of oxidative stress and DNA damage was assayed among 145 female nail technicians and 152 healthy female volunteers. Occupational exposure of nail technicians to VOC was assessed analyzing the VOC content in nail salon air samples. RESULTS: The level of occupational exposure of nail technicians to VOC was below the respective threshold limit values with combined airborne exposure to a mixture of VOC, reaching only 3.3% (range 0.2-33.3%) of the threshold limit. Despite that, nail technicians presented increased activity of glutathione peroxidase 1 (GPx1), plasma ceruloplasmin, and the GPx1/superoxide dismutase 1 ratio (P<0.0001). The levels of plasma thiobarbituric acid-reactive species and DNA strand breakage in blood leukocytes were not significantly different. In contrast, total and oxidatively-generated DNA damage were significantly decreased among nail technicians compared to controls (P<0.0001). The individual's current tobacco smoking and alcohol consumption status did not modulate the observed changes. Significant correlations between selected biomarkers of oxidative stress, DNA damage, and airborne levels of VOC (eg, ethanol) were found. CONCLUSIONS: The levels of biomarkers of oxidative stress and DNA damage among nail technicians seem to be dysregulated despite the low level of occupational exposure to VOC. Although the outcomes are not fully conclusive, our findings point to possible causation related to prolonged low-level occupational exposure to VOC.

Effect of inhaled toluene diisocyanate on local immune response based on murine model for occupational asthma.

Highly reactive, low-molecular-weight diisocyanates (DIC) are the most commonly identified cause of occupational asthma (OA). Animal/clinical studies of DIC asthma have been more limited compared with atopic asthma, and an understanding of DIC pathogenesis is less clear. The aim of this study was to investigate in a mouse model, toluene diisocyanate (TDI, as 2,4-TDI isomer)-induced inflammatory reactions/cytokine profile changes in the lungs and accompanying changes in lymph node lymphocyte sub-populations. The study used female BALB/cJ/Han/IMP mice that were exposed first intra-nasally and then in an inhalation chamber to TDI or air. After the final exposure, bronchoalveolar lavage fluid (BALF) was collected and changes induced in inflammatory cell composition, levels of key cytokines (i.e. IL-4, TNFα, IFNγ), and lymphocyte sub-population profiles within auricular lymph nodes, were evaluated. Total number of cells in the BALF of treated mice was significantly higher than in control mice BALF. There was also a significant increase in BALF neutrophil and eosinophil levels with TDI mice compared to in controls; lymphocyte and macrophage numbers did not significantly differ. A significant increase in BALF levels of TNFα and IFNγ was also noted in mice exposed to TDI relative to levels in controls. BALF IL-4 levels were also increased, but the change from control was not significant. Lastly, the levels/percentages of CD3(+)CD4(+) (T-helper [TH]) lymphocytes significantly increased in the lymph nodes of TDI-exposed groups while those of the CD3(+)CD8(+) cells decreased as compared to in control mice. These studies, the first to assess TDI-induced changes in levels of three key cytokines in BALF in conjunction with changes in local lymph nodes following first an intra-nasal and then a general inhalation exposure to a low-level of TDI, confirm that TDI inhalation induces a pathology manifested by airway inflammation, TH cell-derived cytokine production, and shifts in lymph node lymphocytes sub-populations toward increases in TH cells.

Toxic effect in the lungs of rats after inhalation exposure to benzalkonium chloride.

BACKGROUND: Benzalkonium chloride (BAC) is a quaternary ammonium compound (QAC) toxic to microorganisms. Inhalation is one of the major possible routes of human exposure to BAC. MATERIALS AND METHODS: Experiments were performed on female Wistar rats. The rats were exposed to aerosol of BAC water solution at the target concentration of 0 (control group) and 35 mg/m(3) for 5 days (6 h/day) and, after a 2-week interval, the animals were challenged (day 21) with BAC aerosol at the target concentration of 0 (control group) and 35 mg/m3 for 6 h. RESULTS: Compared to the controls, the animals exposed to BAC aerosol were characterized by lower food intake and their body weight was significantly smaller. As regards BAC-exposed group, a significant increase was noted in relative lung mass, total protein concentration, and MIP-2 in BALF both directly after the termination of the exposure and 18 h afterwards. Significantly higher IL-6 and IgE concentrations in BALF and a decrease in the CC16 concentration in BALF were found in the exposed group immediately after the exposure. The leukocyte count in BALF was significantly higher in the animals exposed to BAC aerosol compared to the controls. In the lungs of rats exposed to BAC the following effects were observed: minimal perivascular, interstitial edema, focal aggregates of alveolar macrophages, interstitial mononuclear cell infiltrations, thickened alveolar septa and marginal lipoproteinosis. CONCLUSION: Inhalation of BAC induced a strong inflammatory response and a damage to the blood-air barrier. Reduced concentrations of CC16, which is an immunosuppressive and anti-inflammatory protein, in combination with increased IgE concentrations in BALF may be indicative of the immuno-inflammatory response in the animals exposed to BAC aerosol by inhalation. Histopathological examinations of tissue samples from the BAC-exposed rats revealed a number of pathological changes found only in the lungs.

Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment.

BACKGROUND: Organophosphates are cholinesterase (ChE) inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours) rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP) poisoning symptomatology. In rodents, corticosterone (CORT) is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentration (the CORT response) and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET) [2-methyl-1,2-di(pyridin-3-yl)propan-1-one] blocks CORT synthesis by inhibiting steroid 11ß-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP) [2-chloro-1-(2,4-dichlorophenyl) ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. MATERIAL AND METHODS: The purpose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. CONCLUSION: The following was observed in the MET-treated rats: i) no rise in plasma CORT concentration after the CVP administration, ii) a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

Comparison of neurobehavioral and biochemical effects in rats exposed to dusts from copper smelter plant at different locations.

Mixed exposure to metals (including arsenic and lead) associated with the neurological and respiratory effects constitute one of the major health problems of copper smelting. Chemical composition of the dust, and the expected health effect of inhalation can be very diverse at different parts of the smelter plant. The aims of this study were to compare lung responses and behavioral effects in female Wistar rats after instillation of dust collected from different production processes at the same smelter department. Dusts collected at two different locations of furnace hall were sifted through 25-µm-mesh sieve. Obtained dust fractions, P-25(I) collected near stove, rich in heavy metals and arsenic, and P-25(II) collected near anode residue storage site, rich in aluminium, were instilled to rats. At 1, 7 and 30 days after dusts instillation, lung injury and inflammation were measured by analyzing sings of lung permeability in the bronchoalveolar lavage fluid (BALF), cell differentiation in BALF sediment and lung morphology. The behavioral studies were done 30 days after exposure. Results of biochemical tests showed a strong pro-inflammatory effect of P-25(I) fractions. Mostly characteristic effects after instillation of P-25(I) samples were 10× increased protein leakages in BALF. Both P-25(I) and P-25(II) fractions caused a reduction of Clara-cell 16 protein concentration (CC16) in BALF and activation of serum butyrylcholinesterase (BChE) at all time points. The morphological studies after exposure to P-25(I) fractions showed multi-focal infiltrations in the alveoli. The behavioral results, especially P-25(II) group rats (in open filed, passive avoidance and hot plate tests), indicated adverse effects in the nervous system, which may be related to changes in the dopaminergic and cholinergic pathway. The symptoms were noted in the form of persistent neurobehavioral changes which might be associated with the content of neurotoxic metals. e.g. Al, Mn and/or As. Decrease of CC16 concentration that occurred immediately after instillation of both dust samples, point out impaired anti-inflammatory potential, resulted in early harmful effect not only to the respiratory tract but also to the whole body, including the nervous system.

Fertility and developmental toxicity studies of diethylene glycol monobutyl ether (DGBE) in rats.

OBJECTIVES: The solvent, dimethylene glycol monobutyl ether (DGBE), is a component of latex paints, inks; it is used as a degreasing agent, industrial detergent. The aim of the study was evaluating the effects of DGBE administered by gavage on the estrous cycle and given with drinking water on fertility in rats and early development of their progeny. MATERIALS AND METHODS: Female rats were exposed to DGBE by gavage during 8 weeks at 250, 500 or 1000 mg/kg/day. Vaginal smears were collected during the exposure and 4 weeks after its cessation. Fertility studies were performed in male and female animals exposed to in drinking water. Males were exposed for 10 weeks and then mated with females exposed before mating, during pregnancy and lactation. Young animals were observed during 3 weeks after birth. RESULTS: DGBE does not cause disturbances of the menstrual cycle in females. Parameters used to assess the general toxicity indicate that males receiving DGBE in drinking water are more sensitive to this compound than females: significantly greater, dose-dependent relative spleen weight, significant decrease in hematological parameters from 8% to 15% depending on the dose, were observed. Clinical chemistry parameters (HDL-cholesterol, BUN) and some markers of oxidative stress differ between the exposed groups and the control one, but without adverse health effect. The microscopic examination of internal organs did not reveal morphological changes in male and female rats. CONCLUSION: The results of our study on the impact of exposure to DGBE on fertility in rats indicate that the substance administered for 9-10 weeks to females and males at a limit dose of 1000 mg/kg did not impair fertility or viability of their offspring during the first three weeks of life.

Immunological determinants in a murine model of toluene diisocyanate-induced asthma.

OBJECTIVES: Diisocyanates (DIC) are highly reactive, low-molecular-weight chemicals which are the leading cause of occupational asthma (OA). The aim of the study was to analyze certain aspects of the pathogenesis of allergic inflammation in the airways induced by toluene diisocyanate (TDI) in an experimental model in mice. MATERIALS AND METHODS: The experiment was carried out on 50 female BALB/cJ/Han/IMP mice, which were exposed by inhalation (intranasal and in the inhalation chamber) to toluene diisocyanate (2,4-TDI). After the experiment, the bronchoalveolar lavage fluid (BALF) was collected from the animals, and the composition of the induced inflammatory cells, and the concentrations of certain cytokines (IL-4, IL-5, TNF-α) were evaluated. RESULTS: The total number of cells in BALF of the examined group of mice was significantly higher compared to the control mice. There was also a significant increase in neutrophils and eosinophils in the study group compared to the controls. The number of lymphocytes and macrophages did not differ significantly between the two groups. A statistically significant increase in the level of TNF-α was shown to occur in the group exposed to toluene diisocyanate in comparison to the control group. The concentration of IL-4 increased in the study group, compared to the control one, but the differences did not reach the level of significance, p > 0.05. Such difference was not observed for IL-5. CONCLUSIONS: We developed a murine model of TDI-induced asthma which caused the influx of inflammatory cells like eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF) in the TDI-treated mice. The increase of the concentration of some proinflammatory cytokines (TNF-α, IL-4) in BALF from the exposed mice was also observed.

4-Week inhalation toxicity of 2-methylnaphthalene in experimental animals.

OBJECTIVES: This paper presents toxic effects of 2-MN in laboratory animals under conditions of 4-week inhalation exposure to 2-methylnaphthalene (2-MN) vapors. MATERIALS AND METHODS: Male Wistar rats were exposed to 2-MN vapors at a nominal concentration of 0, 2, 10 or 50 mg/m(3) in dynamic inhalation chambers for 4 weeks (6 h/day, 5 days/week). After 4 weeks of inhalation exposure the animals were necropsied. Blood samples were collected and selected organs were weighted and prepared for histological examinations. RESULTS: The effects of the increased levels of exposure to 2-MN experienced by the experimental rats were as follows: a) increasing γ-glutamylotransferase activity, b) stimulation of the hematopoietic system, c) lower cholesterol concentrations, d) higher number of goblet cells in lobar bronchi, e) hyperplasia of hepatic bile ducts. CONCLUSION: Four-week exposure of the animals to 2-MN at 2 mg/m(3) proved to be the no-observed-adverse-effect-level (NOAEL), while 10 mg/m(3) appeared to represent the lowest-observed-adverse-effect-level (LOAEL).

Neuroendocrine and behavioral response to amphetamine challenge after exposure to an organophosphorus pesticide.

OBJECTIVES: Exposure to various stressors is known to result in sensitization to psychostimulants, a state related to the psychostimulant dependence and addiction. It has been shown in some studies that the rise in corticosterone (CORT) concentration is indispensable for both the induction and the expression of behavioral sensitization. Therefore, it might be suspected that behavioral hyposensitivity to amphetamine (AMPH) is somehow related to a reduced CORT response to the psychostimulant subsequent to the chlorphenvinphos (CVP) intoxication. MATERIALS AND METHODS: The male adult Wistar rats received single i.p. injections of CVP at the doses 0.5, 1.0 or 3.0 mg/kg b.w., or pure corn oil. CORT concentration was determined in samples of blood drawn from the tail vein before and then 30, 60, 180 min and 24 h after injection. The other rats were divided into two groups and tested, three weeks after the CVP injection for the effect of AMPH (0.5 mg/kg b.w. i.p.) on the serum CORT concentration. In addition, behavioral sensitivity to AMPH was assessed by measuring locomotor activity of the animals in an open-field. RESULTS: 1) The stressor property of CVP was confirmed. The injection resulted in up to tenfold increase in the serum CORT concentration. The magnitude and duration of this response were dose-related. 2) Three weeks after the CVP exposure, the CORT response to AMPH was significantly increased. 3) The behavioral response to the psychostimulant, i.e. augmented locomotion, was significantly reduced compared to the control. CONCLUSIONS: The results confirm that CVP exposure causes behavioral hyposensitivity to AMPH. This effect, however, could not be ascribed to a diminished CORT response.

Assessment of neurobehavioral and biochemical effects in rats exposed to copper smelter dusts.

Female Wistar rats were instilled per os by gavage with different copper dust samples: P-25 obtained by passing the test material through a 25 µmsieve, and P-0.1 containing soluble matter and ultra-fine, non-soluble<100 nm particulate matter (PM) fraction. The control group received sterile saline. The effects were studied at day 1, 7, and 30 post-exposure, focusing on bronchoalveolar lavage fluid (BALF) analysis (including biochemistry, cell morphology, cell viability, and Clara cell 16 protein concentration) and pathomorphology of lung. Results of biochemical tests showed a strong pro-inflammatory effect of both particulate fractions. The morphological studies after exposure to P-25 and P-0.1 fractions showed multi-focal infiltrations in the alveoli. Changes in behavioral (radial maze and passive avoidance tests) have shown that memory in groups exposed to dust was impaired. Our findings indicate that both samples of dust from Copper Smelter cause greater and lesser intensity (P-25 > P-0.1) of the symptoms of acute inflammatory reaction immediately 24 h after instillation to rats. Exposure results in dropping CC16 protein level in serum of rats. After one month, previous acute inflammation was resolved and transformed in persistent low-grade inflammation. The low-grade inflammation resulted in induction of neurobehavioral effects probably by changes in "cholinergic anti-inflammatory pathway" in which acetylcholine modulates neurotransmission.