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PubMed1990

Assessments of lung toxicity to Acrawax C following acute inhalation exposure.

Acrawax is a trademark for a series of synthetic waxes which are used as flatteners in paint, and lubricants in plastics, and these materials have been routinely regarded as nuisance dusts. Due to a paucity of information regarding the pulmonary toxicity of this material, we investigated the effects of acute inhalation of Acrawax C in rats. CD rats were exposed to aerosols of Acrawax C for 6 hours at 112 mg/m3. Fluids and cells from sham and exposed animals were recovered by bronchoalveolar lavage (BAL) and measured for cellular and biochemical parameters at 0, 24, 48, 172 hrs (8 days), and 1 month postexposure. Pulmonary macrophages (PM) were cultured and studied for in vitro and in vivo phagocytosis, as well as surface morphology. The lungs of additional animals exposed to Acrawax were fixed for assessment by histopathology, and transmission electron microscopy. Our results showed that Acrawax C exposure produced a mild inflammatory response at 24 hours postexposure, but cell differentials were not significantly different from controls at 48 hrs after exposure. BAL levels of lactate dehydrogenase, alkaline phosphatase and protein were slightly different from controls only at 8 days postexposure, and had returned to control values by 1 month of recovery. Acrawax exposure had no adverse effects on either morphology or the phagocytic capacity of pulmonary macrophages recovered from exposed animals. Histopathologic analysis of lung tissue from Acrawax C-exposed rats revealed normal lung architecture. Based on acute studies, our results suggest that the response to inhaled Acrawax C is not substantially different from the response to other nuisance dusts such as carbonyl iron and titanium dioxide.

Administration, Inhalation↗
PubMed1992

Dermal and inhalation exposure to dimethoate.

Dermal and respiratory exposure and plasma acetylcholinesterase (ChE) activity were monitored on six workers spraying tomato crops under plastic houses with dimethoate [O,O-dimethyl S-(N-methylcarbamoylmethyl) phosphorodithoate]. The mean dermal exposure was 914 mg/day and the mean respiratory exposure was 17 mg/day. The maximum dose received by the spraymen was 18.2 mg/day. It was estimated that 84% of the dermal exposure was to the forearms and hands. Of the body areas monitored, the back of the neck received the least rate of exposure. The results also show a reduction in plasma ChE among spraymen. The mean difference was 37.1% less than the preexposure values, which exceeds the limits set by the World Health Organization.

Administration, Inhalation↗
PubMed1986

Assessment of toxicity of o-nitrochlorobenzene in rats following a 4-week inhalation exposure.

o-Nitrochlorobenzene (ONCB) is a chemical intermediate used for the synthesis of various industrial chemicals. To evaluate the subchronic toxicity of this compound, three groups of 15 male and 15 female Sprague-Dawley rats were exposed to ONCB vapor 6 hr/day, 5 days/week for 4 weeks at target concentrations of 10, 30, or 60 mg/m3. A control group of 15 animals/sex was exposed to room air in a separate inhalation chamber. Concentrations of ONCB in the chambers were determined at least three times a day using a uv spectrophotometer. Parameters monitored in this study included observation for signs of toxicity, body weights, ophthalmoscopic exam, hematology, and clinical chemistry. At necropsy, selected organ weights were recorded and over 35 tissues/animal were examined microscopically for all control and high-exposure level animals. No mortality was observed in this study. Mean body weights of all groups were comparable to controls. Animals exposed to the mid and high concentrations of ONCB showed a significant increase in blood methemoglobin and a significant decrease in hemoglobin, hematocrit, and red blood cell counts. Spleen and liver weights (absolute and relative to body weight) were significantly increased for these two groups. Microscopic changes, observed only in the spleen, included increased degree of extramedullary hematopoiesis and hemosiderosis. These data suggest that the toxicity of ONCB is comparable to that of its structural analog, p-nitrochlorobenzene. Thus these two compounds should have similar work-place exposure limits.

Administration, Inhalation↗
PubMed1996

A distributed parameter physiologically-based pharmacokinetic model for dermal and inhalation exposure to volatile organic compounds.

Estimates of dermal dose from exposures to toxic chemicals are typically derived using models that assume instantaneous establishment of steady-state dermal mass flux. However, dermal absorption theory indicates that this assumption is invalid for short-term exposures to volatile organic chemicals (VOCs). A generalized distributed parameter physiologically-based pharmacokinetic model (DP-PBPK), which describes unsteady state dermal mass flux via a partial differential equation (Fickian diffusion), has been developed for inhalation and dermal absorption of VOCs. In the present study, the DP-PBPK model has been parameterized for chloroform, and compared with two simpler PBPK models of chloroform. The latter are lumped parameter models, employing ordinary differential equations, that do not account for the dermal absorption time lag associated with the accumulation of permeant chemical in tissue represented by permeability coefficients. All three models were evaluated by comparing simulated post-exposure exhaled breath concentration profiles with measured concentrations following environmental chloroform exposures. The DP-PBPK model predicted a time-lag in the exhaled breath concentration profile, consistent with the experimental data. The DP-PBPK model also predicted significant volatilization of chloroform, for a simulated dermal exposure scenario. The end-exposure dermal dose predicted by the DP-PBPK model is similar to that predicted by the EPA recommended method for short-term exposures, and is significantly greater than the end-exposure dose predicted by the lumped parameter models. However, the net dermal dose predicted by the DP-PBPK model is substantially less than that predicted by the EPA method, due to the post-exposure volatilization predicted by the DP-PBPK model. Moreover, the net dermal dose of chloroform predicted by all three models was nearly the same, even though the lumped parameter models did not predict substantial volatilization.

Absorption↗
PubMed1994

Effects of ethylene on micronucleus formation in the bone marrow of rats and mice following four weeks of inhalation exposure.

Male Fischer 344 rats and male B6C3F1 mice (10/species/group) were exposed to ethylene 6 h/day, 5 days/week, for 4 weeks. The ethylene target concentrations were 0, 40, 1000, and 3000 ppm. An ethylene oxide (EO) control group for each species was exposed under the same conditions at a target concentration of 200 ppm. Bone marrow was collected approximately 24 h after the final exposure. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios were determined and 2000 PCE/animal were scored for the presence of micronuclei. Ethylene did not produce statistically significant, exposure-related increases in the frequency of micronucleated PCE (MNPCE) in the bone marrow of either rats or mice when compared to air-exposed control animals. As expected, EO exposure resulted in significant increases in the frequencies of MNPCE in both species.

Administration, Inhalation↗
PubMed2001

PBPK modeling of canine inhalation exposures to halogenated hydrocarbons.

Human exposure guidelines for halogenated hydrocarbons (halons) and halon replacement chemicals have been established using dose-response data obtained from canine cardiac sensitization studies. In order to provide a tool for decision makers and regulators tasked with setting guidelines for egress from exposure to halon replacement chemicals, a quantitative approach, using a physiologically based pharmacokinetic model, was established that allowed exposures to be assessed in terms of the chemical concentrations in blood during the exposure. This model, which includes a respiratory tract compartment containing a dead-space region, a pulmonary exchange area, and a breath-by-breath description of respiratory tract uptake, allows successful simulation of exhaled breath concentrations of humans during the first minute of exposure to the anesthetics halothane, isoflurane, and desflurane. In the current study, the human model was modified with canine parameters and validated with data obtained from dog studies with halothane, isoflurane, desflurane, and CFC-11. With consideration of appropriate values for ventilation and cardiac output, the model successfully simulated data collected under a variety of exposure scenarios. The canine model can be used for simulating blood concentrations associated with the potential for cardiac sensitization. These target blood concentrations can then be used with the human model for establishing safe human exposure duration. Development of the canine model stresses the need for appropriate data collection for model validation.

Administration, Inhalation↗
PubMed1999

Mutagenicity of 1,3-butadiene at the Hprt locus of T-lymphocytes following inhalation exposures of female mice and rats.

The species specific response to 1,3-butadiene (BD), an important industrial chemical, was investigated by determining the influence of exposure duration and exposure concentration on the mutagenicity of BD in mice and rats and by defining the spectra of mutations in the Hprt gene T-cell mutants from control and BD-exposed mice. Female B6C3F1 mice and F344 rats (4-5 weeks old) were exposed by inhalation to 0, 20, 62.5, or 625 ppm of BD for up to 4 weeks (6 h/day, 5 days/week). Groups of control and exposed animals (n=4-12/group) were necropsied at multiple time points after exposure and the T-cell cloning assay was used to measure Hprt mutant frequencies in lymphocytes isolated from spleen. Mutant clones collected from control and BD-exposed mice were propagated and analyzed by RT-PCR to produce Hprt cDNA for sequencing. In animals necropsied 4 weeks after 2 or 4 weeks of BD exposure (0 or 625 ppm), the rate of accumulation of mutations was greater in mice than in rats. Supra-linear dose-response curves were observed in BD-exposed mice, indicating a higher efficiency of mutant induction at lower concentrations of BD. The mutagenic potency estimates (represented by the differences in the areas under the mutant T-cell 'manifestation' curves of treated vs. control animals) in mice were 11 and 61 following 4 weeks of exposures to 62.5 and 625 ppm of BD, respectively, while mutant frequencies (Mfs) in rats were significantly increased only at 625 ppm BD (mutagenic potency of 7). Molecular analysis of Hprt cDNA from expanded T-cell clones from control and BD-exposed mice demonstrated an increased frequency of mutants in exposed animals that likely contain large deletions in the Hprt gene (P=0.016). These data indicate that both exposure duration and exposure concentration are important in determining the magnitude of mutagenic response to BD, and that mutagenic and carcinogenic properties of BD in mice may be related more to the ability of its metabolites to cause chromosomal deletions than to produce point mutations.

Administration, Inhalation↗
PubMed1990

Functional, biochemical, and histopathological evidence of airway obstruction in rats following a four-hour acute inhalation exposure to n-butyl isocyanate.

Pulmonary function, arterial blood gases, acid-base status, and bronchoalveolar lavage fluid (BALF) composition were assessed in male Wistar rats after a single 4-h exposure to 0, 7.6, 23.5 or 55.2 mg n-butyl isocyanate (n-BIC)/m3 air. No significant changes other than transient clinical signs were observed in the rats exposed to 7.6 mg/m3 air. Four weeks after exposure the animals of the 55.2 mg/m3 group showed significant effects: those were pronounced histopathological changes of airways and parenchyma, and elevated relative lung weight. The neutrophils, LDH, and protein in BALF were elevated. Quasi-static lung compliance, peak expiratory flow rate, mean mid expiratory flow rate were decreased whereas lung resistance, residual volume, and single breath CO-diffusing capacity were increased. Blood gas measurements revealed an elevation in hemoglobin, pH, arterio-alveolar oxygen difference, and venous admixture. Arterial pO2 and pCO2 were decreased. In animals exposed to 23.5 mg/m3 only marginal effects were detectable.

Acid-Base Equilibrium↗
PubMed1976

Inhalation exposure of animals.

Relative advantages and disadvantages and important design criteria for various exposure methods are presented. Five types of exposures are discussed: whole-body chambers, head-only exposures, nose or mouth-only methods, lung-only exposures, and partial-lung exposures. Design considerations covered include: air cleaning and conditioning; construction materials; losses of exposure materials; evenness of exposure; sampling biases; animal observation and care; noise and vibration control, safe exhausts, chamber loading, reliability, pressure fluctuations; neck seals, masks, animal restraint methods; and animal comfort. Ethical considerations in use of animals in inhalation experiments are also discussed.

Aerosols↗
PubMedDate not supplied

Inhalation exposure to white spirit causes region-dependent alterations in the levels of glial fibrillary acidic protein.

Enhanced expression of glial fibrillary acidic protein (GFAP) is known to be associated with toxicant-induced gliosis, a homotypic response of the central nervous system to neural injury. A variety of neurochemical and neurophysiological effects have been observed in experimental animals exposed to white spirit, but a linkage of such effects to neural damage has not been established. Here we evaluated the regional levels of GFAP to assess potential sites of CNS damage in the rat, following exposure to dearomatized and aromatic white spirit. Samples from rats exposed to dearomatized white spirit were assayed for GFAP levels in the United States and Denmark. The results were remarkably similar between countries. Small region-dependent increases and decreases in GFAP were observed with the cerebellum showing the most consistent effects (increases). In contrast, samples from rats exposed to aromatic white spirit showed large (as much as 150% of control) increases in regional levels of GFAP; again, the cerebellum showed the most consistent effects. The data are indicative of an aromatic white-spirit-induced astrogliosis in several regions of the rat CNS and suggest that chronic exposure to this solvent may be associated with underlying neural damage.

Administration, Inhalation↗
PubMed1983

Effect of inhalation exposure to cadmium oxide on arterial blood pressure, lipid metabolism and tissue cadmium concentration in rats.

The arterial blood pressure, lipid content in serum and some organs, cadmium level in blood, aorta wall, lung and liver have been examined in rats repeatedly exposed to cadmium oxide fume 5 hours daily, 5 days a week, during 6 months. The blood pressure in rats exposed to cadmium oxide at concentration 0.02 mg Cd/m3 and 0.16 mg Cd/m3 was not changed, but it was slightly lowered at concentration 1.0 mg Cd/m3, which has been found lethal for rats. The concentration of total cholesterol, phospholipids and cholesterol esters in serum of female rats exposed at concentration of 0.16 mg Cd/m3 for 3 months was decreased, but was not affected after 6 months of exposure. The content of cholesterol and triglycerides in aorta wall, heart and liver was unchanged, although the content of cholesterol was decreased in adrenals of rats exposed for 3 months at concentration of 0.16 mg Cd/m3. Inhalation of cadmium oxide brought about the marked increase of Cd content in lung and kidney of rats exposed at all concentrations an increase of Cd blood level in rats exposed at concentrations of 0.16 mg Cd/m3 and 1.0 mg Cd/m3 and no increase of Cd content in aorta wall.

Air Pollutants↗
PubMed2000

Formation of DNA adducts and induction of mutagenic effects in rats following 4 weeks inhalation exposure to ethylene oxide as a basis for cancer risk assessment.

Ethylene oxide (EO) is mutagenic in various in vitro and in vivo test systems and carcinogenic in rodents. EO forms different adducts upon reaction with DNA, N7-(2-hydroxyethyl)guanine (N7-HEG) being the main adduct. The major objectives of this study were: (a) to determine the formation and persistence of N7-HEG adducts in liver DNA of adult male rats exposed to 0, 50, 100 and 200 ppm by inhalation (4 weeks, 5 days/week, 6 h/day) and (b) to assess dose-response relationships for Hprt gene mutations and various types of chromosomal changes in splenic lymphocytes.N7-HEG adducts were measured 5, 21, 35 and 49 days after cessation of exposure. By extrapolation, the mean concentrations of N7-HEG immediately after cessation of exposure ('day 0') to 50, 100 and 200 ppm were calculated as 310, 558 and 1202 adducts/10(8) nucleotides, respectively, while the mean concentration in control rats was 2.6 adducts/10(8) nucleotides. At 49 days, N7-HEG values had returned close to background levels. The mean levels of N-(2-hydroxyethylvaline) adducts in haemoglobin were also determined and amounted 61.7, 114 and 247 nmol/g globin, respectively. Statistically significant linear relationships were found between mean N7-HEG levels ('day 0') and Hprt mutant frequencies at expression times 21/22 and 49/50 days and between mean N7-HEG ('day 0') and sister-chromatid exchanges (SCEs) or high frequency cells (HFC) measured 5 days post-exposure. At day 21 post-exposure, SCEs and HFCs in-part persisted and were significantly correlated with persistent N7-HEG adducts. No statistically significant dose effect relationships were observed for induction of micronuclei, nor for chromosome breaks or translocations. In conclusion, this study indicates that following sub-chronic exposure, EO is only weakly mutagenic in adult rats. Using the data of this study to predict cancer risk in man resulting from low level EO exposures in conjunction with other published data, i.e., those on (a) genotoxic effects of EO in humans and rats, (b) DNA binding of other carcinogens, (c) natural background DNA binding and (d) genotoxic potency of low energy transfer (LET) radiation, it is not expected that long term occupational exposure to airborne concentrations of EO at or below 1 ppm EO produces an unacceptable increased risk in man.

Administration, Inhalation↗
PubMed1997

Evaluation of the metabolism and hepatotoxicity of styrene in F344 rats, B6C3F1 mice, and CD-1 mice following single and repeated inhalation exposures.

Styrene is used for the manufacture of plastics and polymers. The metabolism and hepatotoxicity (mice only) of styrene was compared in male B6C3F1 mice, CD-1 mice, and F344 rats to evaluate biochemical mechanisms of toxicity. Rats and mice were exposed to 250 ppm styrene for 6 h/day for 1 to 5 days, and liver (mice only) and blood were collected following each day of exposure. Mortality and increased serum alanine aminotransferase (ALT) activity were observed in mice but not in rats. Hepatotoxicity in B6C3F1 mice was characterized by severe centrilobular congestion after one exposure followed by acute centrilobular necrosis. Hepatotoxicity was delayed by 1 day in CD-1 mice, and the increase in ALT and degree of necrosis was less than observed for B6C3F1 mice. Following exposure to unlabeled styrene for 0, 2, or 4 days, rats and mice were exposed to [7-14C]-styrene (60 microCi/mmol) for 6 h. Urine, feces, and expired air were collected for up to 48 h. Most styrene-derived radioactivity was excreted in urine. The time-course of urinary excretion indicates that rats and CD-1 mice eliminated radioactivity at a faster rate than B6C3F1 mice following a single 250 ppm exposure, consistent with a greater extent of liver injury for B6C3F1 mice. The elimination rate following 3 or 5 days of exposure was similar for rats and both mouse strains. Following three exposures, the total radioactivity eliminated in excreta was elevated over that measured for one exposure for both mouse strains. An increased excretion of metabolites on multiple exposure is consistent with the absence of ongoing acute necrosis following 4 to 5 daily exposures. These data indicate that an induction in styrene metabolism occurs after multiple exposures, resulting in an increased uptake and/or clearance for styrene.

Administration, Inhalation↗
PubMed1996

[Respiratory and cardiovascular effects of acetylcholine provocation after inhalation exposure to various occupational pollutants--studies in the rabbit].

Airway hyperresponsiveness, manifested by increased flow resistance and resulting drop in oxygen partial pressure when conducting provocation tests, is considered an early sign of a developing obstructive airway disease, an example of which is a professionally conditioned asthma. We conducted a detailed study exploring the interrelation between the respiratory mechanical parameters and the partial pressures of oxygen and carbon dioxide (PaO2, PaCO2). Reproducibility tests for the studied cardiovascular, ventilatory and respiratory mechanical parameters at rest and under various conditions of stress (external stenoses, inhalation of hypercapnic and hypoxic gas mixtures, infusion of an acetylcholine solution) showed good reproducibility of the measured data with variation coefficients < 10%. In blood gas analyses we also found comparable variation coefficients. Four groups of experimental animals were exposed for different periods of time to various working place substances (coolants, ammonium peroxodisulfate, hair bleaches [blondizing agents], isocyanates). After the exposure we checked on the bronchial sensitivity to aerosols of 0.2% and 2% acetylcholine solutions. Concomitant with an increased response of dynamic elastance, we found an increased drop in oxygen partial pressure and an almost constant carbon dioxide partial pressure, dependent on the working place substance used and on its concentration. In untreated controls the inhalation of acetylcholine resulted in bronchoconstriction and drop in oxygen partial pressure only on provocation with 2% acetylcholine. However, in the groups exposed to coolants and ammonium peroxodisulfate there was a significant drop in oxygen partial pressure already on provocation with 0.2% acetylcholine, as well as a noticeable bronchial respiratory response. The drop in oxygen partial pressure increases further after provocation with 2% acetylcholine, whereas the oxygen partial pressure dropped to a maximum of one-third of its original level by more than 10%. Placing the drop in oxygen partial pressure provoked by acetylcholine in relation to the increase in dynamic elastance, this can be well expressed by a logarithmic formula (y = -6.2. In (x) + 0.72, r = 0.96) that does not change significantly after exposure to working place substances (y = -7.0. In (x) + 3.33, r = 0.93). The close correlation of both parameters suggests that study of the oxygen partial pressures to determine the airway hyperresponsiveness should be considered important, since a marked drop in oxygen partial pressure is seen even if obstructive respiratory response is only slightly increased (slight increase in dynamic elastance). The reason for the behaviour of the blood gases is probably an increased ventilation-perfusion imbalance due to inhomogenous peripheral bronchial reactions. In the hyperresponsive animals the reactions were merely enhanced without demonstrating any differences.

Acetylcholine↗
PubMed1991

Four-week inhalation exposures of rats to aerosols of three lubricant base oils.

Sprague-Dawley rats were exposed to aerosols of one of three base stocks used to formulate lubricating oils. These stocks were a solvent-refined oil (SRO), a hydrotreated and acid-washed white oil (WTO) and a severely hydrotreated and hydrocracked oil (HBO). Exposures were for 6 h per day, 5 days per week for ca. 4 weeks. There were four groups of rats for each study (10 per sex per group). Aerosol concentrations were ca. 0, 50, 210 and 1000 mg m-3 for each material; the mass median aerodynamic diameter was ca. 1 microns. Following the last exposure, all animals were sacrificed and necropsied. Samples were taken for serum chemistry, hematology, sperm morphology, weights of seven organs and histopathology on at least nine organs. Body weights and clinical signs were not affected by exposures. The only treatment-related changes were in the lung and associated lymph nodes. Both the wet weight of the lung and the dry/wet weight ratio increased in a concentration-related manner. Associated with the increased weight were accumulations of foamy alveolar macrophages, particularly in alveoli close to alveolar ducts. Mild infiltration by neutrophils was observed with WTO and SRO; thickened alveolar walls were noted with the highest concentration of HBO. These mild responses to exposures at very high concentrations indicate a low degree of toxicity for these aerosols.

Administration, Inhalation↗