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PubMed1990

2-week inhalation study of N-monomethylformamide in rats.

N-Monomethylformamide (MMF) is a chemical intermediate with potential for inhalation exposure in humans. Human exposures to MMF have occurred in cancer chemotherapy but have been limited due to liver damage. To assess the toxicity of MMF, groups of 15 male rats each were exposed by nose-only inhalation, 6 hr/day, 5 days/week, for 2 weeks to either 0 (control), 50, 130, or 400 ppm MMF. Five rats per group were killed following the 10th exposure, five were killed after a 14-day postexposure recovery period, and five rats were used to determine urinary MMF excretion. Parameters investigated were clinical observations and body weights, clinical pathology, and gross and microscopic pathology including organ weights. Liver damage occurred in rats exposed to either 130 or 400 ppm. This was detected both by increases in serum enzyme activity indicative of liver injury and by microscopic changes in the liver. The changes were more severe in the 400-ppm rats and were partially reversible. Other organs were not adversely affected by inhalation of MMF. The amount of MMF excreted in the urine was dependent on the exposure concentration and MMF was present 14 days postexposure at the higher exposure levels. The no-observed-effect level under the conditions of this experiment was 50 ppm.

Administration, Inhalation↗
PubMed1989

Testicular atrophy and loss of nerve growth factor-immunoreactive germ cell line in rats exposed to n-hexane and a protective effect of simultaneous exposure to toluene or xylene.

Testicular and germ cell line morphology in rats were studied 2 weeks, 10 months and 14 months after cessation of a 61-day inhalation exposure to 1000 ppm n-hexane. Androgen biosynthetic capacity of testis, testosterone blood concentration, vas deferens morphology and noradrenaline (NA) concentration, epididymal sperm morphology, and fertility were also studied. Severe testicular atrophy involving the seminiferous tubules with loss of the nerve growth factor (NGF) immunoreactive germ cell line was found. Total loss of the germ cell line was found in a fraction of animals up to 14 months post-exposure, indicating permanent testicular damage. No impairment of androgen synthesis or androgen dependent accessory organs was observed. Simultaneous administration of 1000 ppm n-hexane and 1000 ppm toluene, or 1000 ppm n-hexane and 1000 ppm xylene, did not cause germ cell line alterations or testicular atrophy. Toluene and xylene were thus found to protect from n-hexane induced testicular atrophy.

Animals↗
PubMedDate not supplied

Cancer risk assessment for oral exposure to PAH mixtures.

Cancer risk estimates for oral uptake of polycyclic aromatic hydrocarbons (PAHs) currently are based on risk estimates for benzo[a]pyrene (BAP). The potency of PAH mixtures often is calculated using relative potency values (BAP equivalency factors). We used recent oral carcinogenicity studies with BAP and coal tar mixtures, as well as older studies for a critical reappraisal of the current practice. A literature survey identified several carcinogenicity studies with oral and dermal exposure and lung implantation that allow a direct comparison of the carcinogenic potency of pure BAP and PAH mixtures. Moreover, when the PAH composition of the mixture has been analysed, prediction of the potency of PAH mixtures by BAP equivalency factors could be compared with the observed PAH potency. The analysis indicates that BAP equivalency factors do not describe adequately the potency of PAH mixtures and lead to underestimations of carcinogenic potency in most cases. Evaluation of several studies with various PAH mixtures revealed that the potency ratio between pure BAP and the PAH mixture in the same assay is highly dependent on the exposure pathway and the target organ, therefore potency estimates for PAH mixtures should be derived separately for oral, dermal and inhalative exposure using data from studies with the relevant pathway. A cancer slope factor for oral PAH exposure was derived based on data from a recent feeding study with coal tar mixtures. By using incidence data for all exposure-related tumours, a slope factor for humans of 11.5 (human excess risk per oral lifetime exposure with 1 mg BAP kg(-1)day(-1) in a PAH mixture) was obtained. Our analysis led to the conclusion that the contribution of BAP to the carcinogenic potency of the mixture depends on the exposure pathway and type of cancer observed but is relatively constant for various PAH mixtures from industrial sources. Thus, the derived oral slope factor is recommended to be used for the risk assessment of PAH-contaminated soils.

Administration, Oral↗
PubMed1990

Effects of ozone, hexachlorobenzene, and bis(tri-n-butyltin)oxide on natural killer activity in the rat lung.

The respiratory tract is a major route of exposure to noxious agents as well as pathogens such as viruses. Natural killer (NK) activity is an important first line of defense to virally infected cells as well as certain neoplasms; therefore, testing the effects of exposure to toxic compounds on this activity is important in understanding the immunotoxic potential of the compound. Lymphoid cell suspensions, obtained after enzymatic dispersion of rat lungs and purification over nylon wool columns, showed in vitro natural killer activity toward YAC lymphoma cells. Validation of the test with well-known NK activity stimulators such as Bacillus Calmette-Guérin (BCG), interleukin-2 (IL-2), interferon (IFN), and inhibitors like anti-asialo-GM1 (ganglio-n-tetrasylceramide) antibody confirmed the reliability of the test as an assay for detecting NK activity in rat lungs. Using this assay, we studied the effects of exposure to ozone (O3), hexachlorobenzene (HCB), and bis(tri-n-butyltin)oxide (TBTO) on NK activity in rat lung. Inhalation exposure to O3 for 7 days at 0.4 and 0.8 mg/m3 resulted in stimulation, and exposure at 1.6 mg O3/m3 resulted in suppression of NK activity. Oral exposure to HCB in concentrations of 150 and 450 mg/kg food for 6 weeks suppressed NK activity in rat lungs in a dose-related manner. This was also true for 6 weeks of oral exposure of rats to 20 and 80 mg TBTO/kg food, but to a lesser extent. In summary, we have developed and validated a method to measure the effects of (toxic) substances on NK activity in rat lung.

Animals↗
PubMed1990

Assessment of risk from exposure to acrylonitrile: the general approach used by a consultant.

The concern from low-level exposure to acrylonitrile is primarily due to its potential for carcinogenicity. Several epidemiology studies provide suggestive evidence for an association of lung cancer in workers exposed to acrylonitrile; however, smoking may be a contributing factor and therefore the role of acrylonitrile as a causative factor is unclear. Seven animal bioassays, using three routes of exposure and two strains of rats, have provided consistent results. Tumors were induced in all studies, with the primary sites of tumor induction being the brain, ear canal, gastrointestinal tract and mammary glands. The linearized multistage model was used for extrapolation purposes. The risk based on brain tumors (astrocytomas) and stomach tumors following oral exposures ranged from 1 x 10(-1) to 4 x 10(-1)mg-1kg-1day-1. The risk of inhalation exposure is somewhat less, (2-3) x 10(-2). Support for carcinogenic potential is obtained from mutagenicity studies. Acrylonitrile has been found to be mutagenic and also binds with DNA. It has been speculated that acrylonitrile is metabolized to 2-cyanoethylene oxide, which is the proximate carcinogen.

Acrylonitrile↗
PubMed1998

Immunomodulation by nitrite inhalants may predispose abusers to AIDS and Kaposi's sarcoma.

Epidemiological studies indicating that nitrite inhalant abuse is a co-factor in HIV infection and in Kaposi's sarcoma are supported by recent experimental studies, described in this review. Inhalation exposure to the nitrites produce a nonspecific cytotoxicity, depleting many cells of the immune system. Apparently distinct from this cytotoxicity, inhalation of the nitrites impairs a variety of immune mechanisms, affecting both humoral and cell-mediated immunity. In addition, the inhalant-increased macrophage production of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), can directly stimulate HIV replication and can also stimulate the growth of Kaposi's sarcoma cells. Thus, nitrite inhalants may impair immune resistance to infection and actively promote viral replication and tumor growth.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

The Acute Exposure Guideline Level (AEGL) program: applications of physiologically based pharmacokinetic modeling.

The primary aim of the Acute Exposure Guideline Level (AEGL) program is to develop scientifically credible limits for once-in-a-lifetime or rare acute inhalation exposures to high-priority, hazardous chemicals. The program was developed because of the need of communities for information on hazardous chemicals to assist in emergency planning, notification, and response, as well as the training of emergency response personnel. AEGLs are applicable to the general population, including children, the elderly, and other potentially susceptible subpopulations. AEGLs are the airborne concentrations of chemicals above which a person could experience notable discomfort or irritation (AEGL-1); serious, long-lasting health effects (AEGL-2); and life-threatening effects or death (AEGL-3). AEGLs are determined for five exposure periods (10 and 30 min and 1, 4, and 8 h). Physiologically based pharmacokinetic (PBPK) models can be very useful in the interspecies and time scaling often required here. PBPK models are used for the current article to predict AEGLs for trichlorethylene (TCE), based on the time course of TCE in the blood and/or brain of rats and humans. These AEGLs are compared to values obtained by standard time-scaling methods. Comprehensive toxicity assessment documents for each chemical under consideration are prepared by the National Advisory Committee for AEGLs, a panel comprised of representatives of federal, state, and local governmental agencies, as well as industry and private-sector organizations. The documents are developed according to National Research Council (NRC) guidelines and must be reviewed by the NRC Subcommittee on Acute Exposure Guideline Levels before becoming final. AEGLs for 18 chemicals have been published, and it is anticipated that 40 to 50 chemicals will be evaluated annually.

Air Pollutants↗
PubMed2005

Evaluation of employee exposure to organic tin compounds used as stabilizers at PVC processing facilities.

Organic tin compounds are primary substances used as heat stabilizers by the polyvinyl chloride (PVC) industry. The use of these compounds in the PVC industry is generally well controlled, usually by automated processes. This study was conducted to provide an overview of worker exposure to organic tin compounds at PVC processing facilities and to verify that these exposures are below the threshold limit value (TLV((R))) set by the American Conference of Governmental Industrial Hygienists for organic tin. The basis of the TLV indicates the principal concern is to minimize adverse effects on immune function and the central nervous system from airborne exposure to organic tin. The TLV has a skin designation based on the potential for percutaneous absorption; the TLVs for inhalation exposures are based on the presumption that there is no concurrent exposure via the skin and oral ingestion routes. Personal exposure monitoring was conducted following the National Institute for Occupational Safety and Health (NIOSH) 5504 sampling method and a modified version of the NIOSH analytical method. The results were reported as"total tin."The data indicated no average exposure levels for individual tasks exceeded the organic tin TLV, and 96%of results the samples were less than 20%of the TLV. Only 1 sample of 102 exceeded the TLV, and the individual was wearing appropriate respiratory protection. Subsequent investigation indicated the highest exposures occurred while the operators were conducting tasks that included manual handling of the organic tin compounds. These data suggest manual operations may have a greater potential for organic tin exposure.

Environmental Monitoring↗
PubMed2006

Gasoline exhaust emissions induce vascular remodeling pathways involved in atherosclerosis.

Epidemiological evidence indicates that environmental air pollutants are positively associated with the development of chronic vascular disease; however, the mechanisms involved have not been fully elucidated. In the present study we examined molecular pathways associated with chronic vascular disease in atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) mice, including markers of vascular remodeling and oxidative stress, in response to exposure to the ubiquitous environmental pollutant, gasoline engine emissions. ApoE(-/-) mice, on a high-fat diet, were exposed by inhalation to either filtered air; 8, 40, or 60 mug/m(3) particulate matter whole exhaust; or filtered exhaust with gases matching the 60-mug/m(3) concentration, for 7 weeks. Aortas and plasma were collected and assayed for changes in histochemical markers, real-time reverse transcriptase-polymerase chain reaction, and indicators of oxidative damage. Inhalational exposure to gasoline engine emissions resulted in increased aortic mRNA expression of matrix metalloproteinase-3 (MMP-3), MMP-7, and MMP-9, tissue inhibitor of metalloproteinases-2, endothelin-1 and heme oxygenase-1 in ApoE(-/-) mice; increased aortic MMP-9 protein levels were confirmed through immunohistochemistry. Elevated reactive oxygen species were also observed in arteries from exposed animals, despite absence of plasma markers. Similar findings were also observed in the aortas of ApoE(-/-) mice exposed to particle-filtered atmosphere, implicating the gaseous components of the whole exhaust in mediating the expression of markers associated with the vasculopathy. These findings demonstrate that exposure to gasoline engine emissions results in the transcriptional upregulation of factors associated with vascular remodeling, as well as increased markers of vascular oxidative stress, which may contribute to the progression of atherosclerosis and reduced stability of vulnerable plaques.

Air Pollutants↗
PubMed1975

Preliminary studies on the toxicity and metabolism of palladium and platinum.

Preliminary data are given on the LD50 of PdCl2 following different routes of exposure and on the LD50 of PtCl4 following intravenous exposure. The retention, tissue distribution, and excretion of 103Pd and 191Pt in rats was determined following oral, intravenous, intratracheal, and inhalation exposure. The highest retention for both 103Pd and 191Pt was obtained following intravenous dosing, and the lowest retention occurred after oral dosing. Following a single oral dose, almost all of the 103Pd and 191Pt was excreted in the feces due to nonabsorption, whereas after intravenous dosing, similar quantities were excreted in both the urine and feces. Tissues containing the highest concentrations of these metals were the kidney, spleen and liver. Following intravenous dosing of pregnant rats, a small amount of 103Pd and 191Pt was found in the fetuses.

Administration, Oral↗
PubMedDate not supplied

Malignancy of proliferative pulmonary lesions in the Syrian hamster following inhalation of 239PuO2.

The malignancy of pulmonary lesions induced by inhaled 239PuO2 in the Syrian hamster was tested by transplantation in the hamster cheek pouch. Serving as negative and positive controls, 42 female hamsters were given either 0.9% sodium chloride (NaCl), ferric oxide suspended in NaCl (Fe2O3), or benzo(a)pyrene + Fe2O3 suspended in NaCl (BP), by intratracheal instillation. One hundred female hamsters were given a single, nose-only inhalation exposure to high-fired 239PuO2 (initial lung burden, 2.4 kBq). At intervals from 160 to 425 days after Pu inhalation or instillation, ten 1-mm3 tissue cubes were removed from the lung of each hamster and transplanted into the cheek pouch of male hamsters, for a total of 1320 transplantations. None of the lung transplants from hamsters receiving 239PuO2, NaCl, or Fe2O3 grew in recipient cheek pouches, but 14% of transplants from BP hamsters grew rapidly in the cheek pouch. Lung carcinomas were histologically identified only in BP hamsters and BP transplants. It was concluded that proliferative pulmonary lesions induced by a-irradiation of the lung of hamsters were not malignant, and that the malignancy of lung lesions in the hamster induced by ionizing radiation should be evaluated by transplantation.

Adenocarcinoma↗
PubMedDate not supplied

Covalent binding of benzo(a)pyrene in perfused rat lung following systemic and intratracheal administration.

Covalent binding of benzo(a)pyrene to DNA, RNA, and protein of perfused rat lung after intratracheal administration of the substrate was about 50% of that obtained by direct addition of the substrate into the perfusate. Systemic availability of benzo(a)pyrene by absorption from the intratracheal sites was found to be 25%. During single pass perfusion of rat lung as well as in the combined liver-lung recirculating perfusion system, covalent binding after intratracheal exposure to benzo(a)pyrene was reduced to 50-75%. These experiments point out the relative importance of systemic versus inhalation exposure to benzo(a)pyrene in the development of lesions on the lung macromolecules. The elimination capacity of the perfused lung was found to be relatively high as compared to the liver. At constant benzo(a)pyrene infusion by a single pass medium, clearance values of the 5,6-benzoflavone-induced lung with 7.8 ml/min reach almost half of those of a 5,6-benzoflavone-induced liver (15.9 ml/min). The extraction ratios in lung both during bolus administration in the recirculating system and during constant infusion in the nonrecirculating system are 0.25 and 0.29, respectively, and thus amount to half of those measured in the liver (0.45 and 0.53, respectively). Though the liver is able to exert a protective effect against covalent binding of benzo(a)pyrene in the lung, this protection is not complete, and significant amounts of benzo(a)pyrene are expected to escape metabolic transformation by the liver representing a risk for the lung from the circulatory site in addition to that from the respiratory site.

Animals↗
PubMed2006

The utility of the guppy (Poecilia reticulata) and medaka (Oryzias latipes) in evaluation of chemicals for carcinogenicity.

There has been considerable interest in the use of small fish models for detecting potential environmental carcinogens. In this study, both guppies (Poecilia reticulata) and medaka (Oryzias latipes) were exposed in the aquaria water to three known rodent carcinogens for up to 16 months. Nitromethane, which caused mammary gland tumors by inhalation exposure in female rats, harderian gland and lung tumors in male and female mice, and liver tumors in female mice by inhalation, failed to increase tumors in either guppies or medaka. Propanediol, which when given in the feed was a multisite carcinogen in both sexes of rats and mice, caused increased liver tumors in male guppies and male medaka. There was reduced survival in female guppies and no increased tumors in female medaka. 1,2,3-Trichloropropane, which when administered by oral gavage was a multisite carcinogen in both sexes of rats and mice, caused an increased incidence of tumors in the liver of both male and female guppies and medaka and in the gallbladder of male and female medaka. The results of this study demonstrate that for these three chemicals, under these specific exposure conditions, the fish appear less sensitive and have a narrower spectrum of tissues affected than rodents. These results suggest that fish models are of limited utility in screening unknown chemicals for potential carcinogenicity.

Animals↗
PubMed2000

Effect of inhaled residual oil fly ash on the electrocardiogram of dogs.

Epidemiology studies have found associations between increases in air pollutants and increases in morbidity and mortality from cardiovascular disease. The 1995 finding by Godleski et al. at Harvard that inhalation exposures of dogs to high concentrations of residual oil fly ash (ROFA) caused changes in the ST segment and T waves in the electrocardiogram (ECG) suggested a potential mechanism, and also suggested that inhaled metals might contribute to the effect. We conducted the present study to establish a baseline correspondence to the Godleski et al. findings in preparation for studies of the cardiac effects of specific particle-borne metals. The ROFA used in this study consisted of 45% carbon and 15.5% transition metals by mass. In vitro assays using cultured A549 cells and rat alveolar macrophages demonstrated that the ROFA was biologically active but was not highly cytotoxic. Four 10.5-yr-old beagles were exposed by oral inhalation to 3 mg/m3 of aerosolized ROFA for 3 h/day on 3 consecutive days. During the exposures, ECGs were continuously recorded from leads I, II, III, and V4. ECG data were also collected during three control exposures to clean air, during one of which changes were induced using drugs as a positive control. The ROFA exposures caused no consistent changes in the amplitude of the ST segment, the form or amplitude of the T wave, or arrhythmias. The data suggested a slight slowing of heart rate during exposure. Whether the difference between the present and previous findings resulted from differences in the composition of the two batches of ROFA or differences in methodology could not be determined by the study. This study did not address the cardiac effects of ROFA in subjects having preexisting cardiac susceptibility factors, nor was it a rigorous evaluation of effects on the frequency distribution of heart rate. Our results indicate that healthy dogs can inhale high concentrations of ROFA without changes in cardiac electrophysiology, which are detectable by clinical evaluations.

Administration, Inhalation↗
PubMed1982

Production of low molecular weight cadmium-binding proteins in rabbit lung following exposure to cadmium chloride.

Low molecular weight cadmium-binding proteins were studed in lung tissue from rabbits exposed to aerosols of CdCl2. Lungs obtained from animals exposed by inhalation to aerosols of 800 or 1600 micrograms/m3 CdCl2 for 2-hr periods/day, every other day for a 5-day period, were found to contain at least three low molecular weight cadmium-binding proteins, two of which were similar electrophoretically and spectrally to rabbit liver metallothionein. The third protein(s), which accounted for the majority of the cadmium in the soluble fraction of the tissue, did not bind to an anionic exchange gel and did not appear to be a polymerized form of metallothionein. Translocation studies of lung cadmium suggest a long half-life for cadmium in lung tissue following inhalation exposure, due perhaps to the high affinity of cadmium for specific lung cadmium-binding proteins. A small but significant redistribution of lung cadmium did occur to both kidney and liver tissue with time.

Aerosols↗
PubMed2000

An observational study on neurobehavioural effects of acute oxydemeton-methyl (insecticide and acaricide) exposure in rats.

Oxydemeton-methyl, an organophosphate insecticide and acaricide produced decrease in the exploratory behaviour and prolongation of barbitone sodium-induced hypnosis after intermittent aerosol spray inhalational exposure for 1 h in rats compared to the saline control group. Further, CD50 +/- S.E.M. value for pentylenetetrazole (PTZ) and CI50 +/- S.E.M. value for electroshock (i.e. the dose of PTZ and intensity of electroshock producing positive seizure response in 50% of rats) were significantly decreased by acute exposure to oxydemeton-methyl compared to that of saline control group. The study has established the central nervous system depressant effect and proconvulsant potential of oxydemeton-methyl which is widely used by the agricultural workers in the form of field spray.

Animals↗
PubMed1996

The role of atopy in grain dust-induced airway disease.

To determine whether atopy influences the physiologic or inflammatory response to grain dust, we compared spirometric measures of airflow and bronchoalveolar lavage (BAL) measures of lower respiratory tract inflammation between demographically similar nonatopic (n = 10) and atopic (n = 10) study subjects after each of two inhalation exposures: Hanks' balanced salt solution (HBSS) and corn dust extract (CDE; 0.4 microgram of endotoxin/kg body weight). Subjects were healthy nonsmokers with similar baseline pulmonary function, without bronchial hyperreactivity, and had not participated in agriculture. Atopic subjects had two or more positive skin responses to 10 common environmental allergens. Both groups developed significant airflow obstruction and lower airway inflammation after CDE inhalation. Importantly, the magnitude of the post-CDE exposure airflow decrements, BAL cellularity, and BAL concentration of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, and IL-8 did not significantly differ between atopics and nonatopics. The concentrations of histamine and eosinophils in the BAL fluid were unaffected by CDE inhalation and did not significantly differ between atopics and nonatopics. Atopic status does not appear to be a significant determinant of airflow obstruction or lower airway inflammation following CDE inhalation. Our findings suggest that atopy may play, at most, a minor role in the development of grain dust-induced airway disease.

Adult↗
PubMed1980

Experimental approaches for exposure to sized glass fibers.

A number of studies have shown that glass fibers induce both malignant mesothelioma and fibrosis in rats and that these reactions may be primarily a function of the physical properties of the fiber. However, these studies were carried out with fibers having broad size distributions and used methods of administration which bear little resemblance to the way man is exposed. To better characterize the health effects of glass fibers, techniques have been developed to expose rats to glass fibers of defined sizes by intratracheal instillation of aqueous suspensions and by "nose only" inhalation exposure, and to determine the deposition, translocation, and ultimate fate of these fibers in the rat. The fibers have known size distributions with geometric mean diameters of 1.5 micrometers (sigma g = 1.1) and lengths of either 5 micrometers (sigma g = 1.49) or 60 micrometers (sigma g = 3.76). The fibers have been activated with neutron irradiation. Of the several resulting radionuclides, 65Zn appeared to be the most suitable for long-term clearance studies by use of in vivo whole body radioassay techniques. A fluidized bed aerosol generator has been developed to expose rats by "nose only" inhalation to approximately 500 fibers/cm3. The generator and exposure system permits reuse of fibers which pass through the exposure chamber and produces no significant alteration of the fiber size distribution. Rats were exposed by intratracheal instillations to 20 mg of the longer fibers and to equal numbers (2 mg) and equal mass (20 mg) of the shorter fibers. Through approximately 19 weeks little difference was observed in the whole rat clearance rate of long versus short fibers in the initial exposure group. Histopathology, however, showed differences at this time with the short fibers apparently successfully phagocytized by alveolar macrophages and cleared to the lymph nodes, while the long fibers were not.

Aerosols↗