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PubMed1996

Bases for secondary standards for residual radionuclides in soil and some recommendations for cost-effective operational implementation.

The future use of land contaminated with radionuclides depends upon scientifically defensible bases for setting limits for radionuclides in soil. The purpose of this work is to develop such bases for establishing "posting criteria" to protect nonradiological workers at the Nevada Test Site and to provide a rationale for cost-effective measurements to readily determine the boundary conditions. The analysis begins with a mandated limit on total effective dose equivalent (1 mSv y(-1)) via all pathways. The possible pathways of exposure are external gamma exposure, inhalation of resuspended material, and incidental soil ingestion. These pathways are evaluated for each radionuclide of interest on the Nevada Test Site, and the results are used to define for each radionuclide the deposition-density limits for each pathway of exposure. The minimum deposition-density limits are noted to occur via the external gamma-exposure pathway for most radionuclides; exceptions are incidental soil ingestion for 90Sr/90Y and inhalation for 238Pu, 239,240Pu, and 241Am. The limiting values of deposition density or average concentration in soil are then determined appropriately by combining all pathways. Procedures are developed for dealing with mixtures of many radionuclides and to apply the principles developed so that even a simple measurement of external gamma-exposure rate may be used to define the boundary conditions in the field, provided that the relative abundance of the radionuclide mixture is known and that the defining level of exposure rate is sufficiently above background.

Cost-Benefit Analysis↗
PubMed2003

Approaches to induce and elicit respiratory allergy: impact of route and intensity of exposure.

Although a number of test protocols have been developed to predict respiratory allergenic potential, none of these are widely applied or fully accepted. However, given the serious health problems caused by respiratory allergy and the ever-increasing stream of new chemicals into workplaces, early identification of chemical respiratory allergens is important. Inhalation exposure as well as skin application have been used in predictive tests to induce respiratory tract sensitisation. While there are good indications in laboratory animals and humans that skin exposure can act as a route for respiratory tract sensitisation and vice versa, less is known about the effect of the route on the type of allergy evoked and on dose-response relationships. Although, the responses were in general more vigorous after dermal sensitisation than after inhalation sensitisation, the nature of the immune responses seemed to be qualitatively comparable. As to the intensity of exposure, dose or concentration-response relationships have been observed both during respiratory sensitisation and challenge, suggesting that assessment of safe exposure levels is feasible. Finally, a correct distinction between respiratory allergens and non-sensitising airway irritants is needed for effective risk assessment and management.

Administration, Cutaneous↗
PubMed1994

Acute toluene exposure decreases extracellular gamma-aminobutyric acid in the globus pallidus but not in striatum: a microdialysis study in awake, freely moving rats.

Intracerebral brain microdialysis was performed in awake, freely moving rats to study the effect of acute inhalation exposure of toluene (2000 ppm, 2 h) on extracellular levels of gamma-aminobutyric acid (GABA) within the globus pallidus and the striatum. GABA within the globus pallidus decreased (20%) during and after (26%) exposure to toluene, while no reduction was seen in the striatal GABA level during exposure. After the exposure there was a tendency towards an increase (maximally 37%) in striatal GABA. 2 h of perfusion with tetrodotoxin (10(-6) M) decreased (32%) the extracellular GABA levels within the globus pallidus. The results suggest that the effect of acute toluene exposure varies with brain region and that the GABA output from the striatum to globus pallidus is more affected by the exposure than the GABA release within the striatum.

Administration, Inhalation↗
PubMed1990

Measurement of steady-state blood concentrations in B6C3F1 mice exposed by inhalation to vinylidene fluoride.

The purpose of this study was to obtain data on blood concentrations of vinylidene fluoride (VDF), an important plastics monomer in B6C3F1 mice during inhalation exposure. A new method for sampling blood from mice during the exposures was developed. The technique used a pernasal exposure tube with an outer, sliding cylinder that allowed access to the heart through the thorax. Blood was removed from an anesthetized mouse via heart-puncture while the animal was being exposed to VDF. Concentrations of VDF were measured in blood of mice during 6-h exposures to nominal concentrations of 250, 3750, or 15,000 ppm VDF. A physiological model developed to simulate blood levels of VDF in rats was adapted for mice by incorporating physiologically realistic parameters for mice where appropriate (alveolar ventilation, cardiac output, blood flow to organs, and organ volumes) and by assuming that chemical-specific parameters such as tissue/blood partition coefficients determined for rats could also be applied to mice. Measured steady-state levels of VDF in blood of mice increased with increasing exposure concentration. For both the 15,000 and 3750 ppm VDF exposures, the experimentally determined data fell within the 95% confidence interval predicted by the physiological model. For the 250 ppm VDF exposure, the experimentally determined values for VDF in blood were lower than what was predicted by the model. Model predictions indicated that for mice, as observed for rats, levels of VDF would rise very rapidly, reaching steady-state within minutes of exposure, and that at the end of exposure, blood levels will decline rapidly. At the two lowest exposure concentrations, we were unable to detect VDF in blood taken 15 min or longer after cessation of exposure, suggesting that the post-exposure levels were at or below our limit of detection which was 4 ng VDF/ml blood. For the 15,000 ppm exposure VDF could be detected in blood up to 15 min post exposure.

Administration, Inhalation↗
PubMed2001

Genetic and dietary factors affecting human metabolism of 1,3-butadiene.

The objective of this project was to determine the factors associated with differences in butadiene (BD) inhalation uptake and the rate of metabolism for BD to epoxy butene by monitoring exhaled breath during and after a brief exposure to BD in human volunteers. A total of 133 subjects (equal males and females; four racial groups) provided final data. Volunteers gave informed consent and completed a questionnaire including diet and alcohol use. A venous blood sample was collected for genotyping CYP2E1. Subjects received a 20 min exposure to 2.0 ppm of BD, followed by a 40 min washout period. The total administered dose was 0.6 ppm*h, which is in the range of everyday exposures. Ten, 1 or 2 min exhaled breath samples (five during and five after exposure) were collected using an optimized strategy. BD was determined by GC-FID analysis. Breathing activity (minute ventilation, breath frequency and tidal volume) was measured to estimate alveolar ventilation. After the washout period, 250 mg of chlorzoxazone were administered and urine samples collected for 6 h to measure 2E1 phenotype. The total BD uptake during exposure (inhaled BD minus exhaled) was estimated. A three-compartment PBPK model was fitted to each subject's breath measurements to estimate personal and population model parameters, including in-vivo BD metabolic rate. A hierarchical Bayesian PBPK model was fit by Monte Carlo simulations to estimate model parameters. Regression and ANOVA analyses were performed. Earlier data analysis showed wide ranges for both total uptake BD and metabolic rate. Both varied significantly by sex and age, and showed suggestive differences by race, with Asians having the highest rates. The analyses reported here found no correlation between total BD uptake and metabolic rate. No significant differences were found for oxidation rates by 2E1 genotype or phenotype, but the rates showed trends consistent with reported differences by genotype and phenotype for chlorzoxazone metabolism. No effects on metabolic rate were observed for long-term alcohol consumption, or consumption in the past 24 h. Overall, neither dietary factors nor genetic differences explained much of the wide variability in metabolic rates. Population characteristics, age, sex, and race, were the most important explanatory variables, but a large fraction of the total variability in metabolism remains to be explained.

Administration, Inhalation↗
PubMed1989

An evaluation of the toxicity of carbon fiber composites for lung cells in vitro and in vivo.

Carbon fiber composite materials are used in a variety of applications in industries, and machining processes often generate aerosols of these materials in the workplace. Because the potential health effects of these particles are uncertain, we evaluated the toxicity of a series of carbon fiber composites in vitro using rabbit alveolar macrophages and in vivo using direct intratracheal injection into rat lungs. For comparison, we studied two reference materials, Al2O3 and alpha-quartz, which are inert and toxic, respectively. We measured cytotoxicity in vitro for rabbit alveolar macrophages by trypan blue exclusion and by the release of 51Cr from prelabeled macrophages. We also injected the samples intratracheally into specific pathogen-free rats and 1 month later lavaged the lungs to recover airway cells and fluid. In each of the assays, the quartz was the most toxic substance tested, causing marked cytotoxicity for alveolar macrophages and large increases in airway cells and neutrophils in the rat lungs, whereas the Al2O3 was consistently the least toxic. Three of the composite samples consistently showed little toxicity, whereas two were consistently toxic for alveolar macrophages and caused significant accumulations of airway cells and neutrophils in the rat lungs. The results of the in vitro and in vivo studies produced a similar ranking of toxicity for all of the samples. These studies show that in vitro and in vivo testing is a useful approach to the evaluation of the potential biologic effects of new materials in the lungs. Although these carbon fiber composites appear to be much less toxic than quartz, the data suggest that two of the composites are not inert. Exposure limits more strict than those for nuisance dusts should be used in the workplace for these two composites. Longer term inhalation exposure studies using these two composites are warranted in order to better define their effects in the lungs.

Animals↗
PubMed1999

Modulation of bronchial epithelial cell barrier function by in vitro jet propulsion fuel 8 exposure.

The loss of epithelial barrier integrity in bronchial and bronchiolar airways may be an initiating factor in the observed onset of toxicant-induced lung injuries. Acute 1-h inhalation exposures to aerosolized jet propulsion fuel 8 (JP-8) have been shown to induce cellular and morphological indications of pulmonary toxicity that was associated with increased respiratory permeability to 99mTc-DTPA. To address the hypothesis that JP-8 jet fuel-induced lung injury is initiated through a disruption in the airway epithelial barrier function, paracellular mannitol flux of BEAS-2B human bronchial epithelial cells was measured. Incubation of confluent cell cultures with non-cytotoxic concentrations of JP-8 or n-tetradecane (C14), a primary constituent of JP-8, for a 1-h exposure period resulted in dose-dependent increases of paracellular flux. Following exposures of 0.17, 0.33, 0.50, or 0.67 mg/ml, mannitol flux increased above vehicle controls by 10, 14, 29, and 52%, respectively, during a 2-h incubation period immediately after each JP-8 exposure. C14 caused greater mannitol flux increases of 37, 42, 63, and 78%, respectively, following identical exposure conditions. The effect on transepithelial mannitol flux reached a maximum at 12 h and spontaneously reversed to control values over a 48-h recovery period, for both JP-8 and C14 exposure. These data indicate that non-cytotoxic exposures to JP-8 or C14 exert a noxious effect on bronchial epithelial barrier function that may preclude pathological lung injury.

Alkanes↗
PubMed1988

Inhalation toxicity of methyl difluoromalonyl fluoride in rats.

Methyl 2,2-difluoromalonyl fluoride (MMF) is highly toxic by inhalation producing mortality in rats exposed for 4 hours to 0.55 mg/L. Repeated inhalation exposures of rats to 0.009 mg/L produced irritation but no other signs of a toxic response. Mortality was encountered following repeated exposures to 0.066 mg/L.

Administration, Inhalation↗
PubMed1995

Comparative carcinogenic effects of nickel subsulfide, nickel oxide, or nickel sulfate hexahydrate chronic exposures in the lung.

The relative toxicity and carcinogenicity of nickel sulfate hexahydrate (NiSO4.6H2O), nickel subsulfide (Ni3S2), and nickel oxide (NiO) were studied in F344/N rats and B6C3F1 mice after inhalation exposure for 6 h/day, 5 days/week for 2 years. Nickel subsulfide (0.15 and 1 mg/m3) and nickel oxide (1.25 and 2.5 mg/m3) caused an exposure-related increased incidence of alveolar/bronchiolar neoplasms and adrenal medulla neoplasms in male and female rats. Nickel oxide caused an equivocal exposure-related increase in alveolar/bronchiolar neoplasms in female mice. No exposure-related neoplastic responses occurred in rats or mice exposed to nickel sulfate or in mice exposed to nickel subsulfide. These findings are consistent with results from other studies, which show that nickel subsulfide and nickel oxide reach the nucleus in greater amounts than the do water-soluble nickel compounds such as nickel sulfate. It has been proposed that the more water-insoluble particles are phagocytized, whereas the vacuoles containing nickel migrate to the nuclear membrane, where they release nickel ions that effect DNA damage. The findings from these experimental studies show that chronic exposure to nickel can cause lung neoplasms in rats, and that this response is related to exposure to specific types of nickel compounds.

Animals↗
PubMed2005

Overview of personal occupational exposure levels to inhalable dust, endotoxin, beta(1-->3)-glucan and fungal extracellular polysaccharides in the waste management chain.

INTRODUCTION: In the past decade, we studied occupational bioaerosol exposures in various sites of the waste management chain. In this paper we present an overview of exposure levels of inhalable dust, endotoxin, beta(1-->3)-glucan (known or probable inducers of airways inflammation), and extracellular polysaccharide antigens of Aspergillus and Penicillium species (EPS-Pen/Asp; a common and probably more specific marker of fungal exposure). METHODS: Over 450 personal bioaerosol samples were taken. Mixed regression analyses were performed to estimate exposure determinants, between- and within-worker variance of exposure, and determinants of these variances. Furthermore, we explored whether the type of waste affected the bioaerosol composition of the dust. RESULTS: Endotoxin and glucan exposure levels were relatively low and comparable for waste collection and transferral, green waste composting and use of biomass in power plants. Exposure levels were 5-20 times higher in domestic waste transferral with sorting, and composting of both domestic and domestic and green waste ( approximately 300-1000 EU m(-3) for endotoxin, and 5-10 mug m(-3) for glucan). Observed exposure exceeded Dutch occupational exposure limits at all sites. EPS-Pen/Asp exposure was detected in 20% of waste collectors and 49% of compost workers. Exposure variability within tasks was large (geometric standard deviation > 2), with smaller between-worker than within-worker variance. Type of company and waste largely explained between-worker variance (40-90%), although within companies no major task-related determinants could be established. Markers of exposure correlated moderately to strongly. Relative endotoxin and glucan content in the dust was only weakly associated with handled waste. CONCLUSIONS: Occupational bioaerosol exposure in the waste management chain is lowest for outdoor handling of waste and highest when waste is handled indoors. However, exposure variability is large, with greater within-worker than between-worker variance. Occupational exposure limits for organic dust and endotoxins are frequently exceeded, suggesting workers are at risk of developing adverse health effects.

Air Pollutants, Occupational↗
PubMed1977

Effect of ozone on bronchomotor response to inhaled histamine aerosol in dogs.

To study the effect of ozone on bronchial reactivity to inhaled histamine diphosphate aerosol, we performed 14 experiments on 5 dogs anesthetized with pentobarbital sodium (25-30 mg/kg, iv) and ventilated with a Harvard respirator. Prior to ozone exposure, inhalation of histamine aerosol (2% solution; 5 breaths) increased total pulmonary resistance (RL) 5.1 +/- 0.5 cmH2O/1 per s (mean +/- SE). One day after ozone exposure (0.7-1.2 ppm; 2 h), the base-line RL was not significantly changed (P greater than 0.05), but the increase of RL caused by histamine (10.7 +/- 1.1 cmH2O/1 per s) was greater than in the control state (P less than 0.01). When the dogs were pretreated with atropine sulfate aerosol (1.5% solution; 10 breaths), the increase of RL after histamine was decreased to 3.8 +/- 0.3 cmH2O/1 per s before ozone, and this was not significantly different after ozone (4.5 +/- 1.1 cmH2O/1 per s; P greater than 0.5). Cooling blockade of conduction in the vagus nerves diminished the increase of RL after histamine to 3.9 +/- 0.5 cmH2O/1 per s before ozone, and this was not significantly different after ozone (4.4 +/- 0.6 cmH2O/1 per s; P less than 0.5). Since both atropine and vagal cooling abolished the ozone-induced bronchial hyperirritability, we conclude that it is mediated via vagal cholinergic pathways.

Aerosols↗
PubMed1990

Exposure to methyl isobutyl ketone: toxicokinetics and occurrence of irritative and CNS symptoms in man.

The toxicokinetics as well as irritative effects and CNS symptoms of methyl isobutyl ketone (MIBK) were studied in human volunteers during inhalation exposure. The volunteers were exposed (2h, 50 W) in an exposure chamber on four different occasions to about 10, 100 and 200 mg/m3 MIBK and to a combination of about 100 mg/m3 MIBK and 150 mg/m3 toluene. The relative pulmonary uptake of MIBK was about 60% and the total uptake increased linearly with increasing exposure concentration. The concentration of MIBK in blood rose rapidly after the onset of exposure and no plateau level was reached during exposure. No tendency for saturation kinetics could be observed within the dose interval and the apparent blood clearance was 1.61/h/kg at all exposure levels. The concentration of unchanged MIBK in the urine after exposure was proportional with the total uptake. Only 0.04% of the total MIBK dose was eliminated unchanged via the kidneys within 3 h post exposure. The concentrations of the metabolites 4-hydroxy-4-methyl-2-pentanone and 4-methyl-2-pentanol were below the detection limit (5 nmol/l). Irritative and CNS symptoms occurred during exposure. The degree of both irritative and CNS symptoms increased during exposure to 100 and 200 mg/m3 compared with 10 mg/m3, but combination exposure with toluene exhibited the most pronounced effect. There were no significant effects from exposure on the performance of a simple reaction time task or a test of mental arithmetic.

Administration, Inhalation↗
PubMed1982

Metabolic interaction between m-xylene and ethanol.

Ingestion of a moderate dose of ethanol (0.8 g/kg) by volunteers prior to 4-h inhalation exposure to m-xylene (6.0 or 11.5 mmol/m3) caused marked alterations in xylene kinetics. After ethanol intake the blood xylene level rose about 1.5-2.0-fold and urinary methylhippuric acid excretion declined by about 50% suggesting that ethanol decreased the metabolic clearance of xylene by about one half during xylene inhalation. This effect was noticeable up until a few hours after completed xylene exposure. Urinary excretion of 2,4-xylenol, the minor m-xylene metabolite, was generally not decreased by ethanol and sometimes the reverse seemed to be the case. The disturbance of xylene kinetics can be hypothesized to be caused mainly by ethanol-mediated inhibition of microsomal metabolism. When four volunteers who ingested ethanol prior to m-xylene inhalation at the higher concentration were monitored for blood acetaldehyde, transiently raised levels were found without notable effects on ethanol elimination. This observation may explain why some individuals experienced dizziness and nausea during the combined ethanol-xylene exposure.

Acetaldehyde↗
PubMed1996

Refinement and verification of the physiologically based dosimetry description for acrylonitrile in rats.

The physiologically based dosimetry description for acrylonitrile (ACN) and its mutagenic epoxide metabolite 2-cyanoethylene oxide (CEO) in F-344 rats (M. L. Gargas, M. E. Anderson, S.K.O. Teo, R. Batra, T. R. Fennell, and G. L. Kedderis, 1995, Toxicol. Appl. Pharmacol. 134, 185-194) has been refined to include a physiological stomach compartment and the reactions of ACN with tissue glutathione (GSH). The second-order rate constant for reaction of ACN and GSH at pH 7.3 was measured and included in the dosimetry description. Metabolic parameters for ACN and CEO were estimated from oral bolus pharmacokinetic studies and previously obtained iv bolus data (3.4, 47, 55, or 84 mg ACN/kg). Rats were given bolus oral doses of 3, 10, or 30 mg ACN/kg in water, and blood samples were collected at selected time points. ACN and CEO blood concentrations were determined by gas chromatography. The brain and liver concentrations of ACN and CEO were also measured after 10 mg ACN/kg po. ACN elimination from blood was described by saturable P450 epoxidation (Vmax of 5.0 mg/hr/kg and K(M) of 1.5 mg/liter) and first-order GSH conjugation (73 hr(-1)/kg). CEO elimination was described by first-order GSH conjugation (500 hr(-1)/kg). The pharmacokinetic data were well simulated, although CEO blood concentrations after bolus oral dosing were somewhat overestimated. Sensitivity analysis of the dosimetry description indicated that the inhalation exposure route was much more sensitive to changes in metabolic and physiological parameters than either the iv or oral bolus routes. Therefore, inhalation pharmacokinetic data were obtained and compared to simulations of the dosimetry description. Rats were exposed to 186, 254, or 291 ppm ACN for 3 hr. ACN and CEO concentrations were measured in blood, brain, and liver at selected postexposure time points. The dosimetry description accurately simulated the ACN inhalation pharmacokinetic data, providing verification of the parameter estimates. The verified rat dosimetry description for ACN and CEO will be used as the basis for development of a dosimetry description for ACN in people.

Acrylonitrile↗
PubMed1997

Biological monitoring of the fungicide epoxiconazol during application.

A method was developed for the biological monitoring of the fungicide epoxiconazol (Opus; BASF). Comparison of the urine levels of a hydroxylated metabolite after dermal application to the levels after oral intake revealed a dermal absorption of 1-2.5% of the dose. In a field study with 10 applicators a dermal exposure ranging between 60 and 10,000 microgram/person/day was determined from the urine levels of a hydroxylated metabolite; the contribution of the inhalation exposure was found to be negligible. From these data an incorporation of 1 to 100 microgram epoxiconazol/person/day could be derived. The measured exposure was compared to two commonly used exposure models. The model calculation resulted in a dermal exposure of 555 microgram/person/day (German BBA model) and 2115 microgram/person/day (British POEM), respectively, which is in accordance with the actually measured exposure.

Adult↗
PubMedDate not supplied

Exposure to tap water during pregnancy.

Studies of disinfection byproducts (DBPs) in drinking water and risk of adverse reproductive outcome have usually relied on approximate measures of exposure. Individual differences in consumption of bottled or filtered water, variability in tap water consumption at home and at work, dermal and inhalation exposure to volatile contaminants, and changes in residency during pregnancy may lead to exposure misclassification. We characterized exposures to tap water and other risk factors among 71 pregnant and 43 non-pregnant women attending public health clinics. Nearly all residences had a municipal water source, but 25% of women drank filtered or bottled water. Fifty percent of the women in our sample reported working outside the home where, on average, one third of their daily water intake took place. Pregnant women consumed more water than non-pregnant women (3.4 vs. 3.0 total l/day), especially cold tap water at home (1.8 vs. 1.3 l/day, 95% CI for the difference=0.1, 0.9). Patterns of showering were similar for both groups of women, but pregnant women were more likely to bathe and to bathe more frequently. The prevalence of smoking was lower among pregnant women (22.5% vs. 32.6%), as was the consumption of alcohol (4.2% vs. 53.5%, 95% CI for the difference=-64.9, -33.7). Thirty-two percent of women had moved during their current pregnancy. The data reaffirm the importance of collecting individual-level data for water consumption and exposure to potential confounders to avoid misclassification bias. This study is the first to target women of low socio-economic status (SES) and therefore of particular interest in studies of adverse reproductive outcomes for which this group is at increased risk.

Adolescent↗
PubMed2001

Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations.

This study was undertaken to determine the effects of occupation, lifestyle and the genetic polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases micro1 (GSTM1) and 1 (GSTT1) on the concentrations of urinary 1-hydroxypyrene (1-OHP) and 2-naphthol among Korean coke oven workers and university students. The study subjects included 90 coke oven workers and 128 university students. A questionnaire was used to obtain detailed data about the work area, smoking habits and food intake of subjects. Associations between urinary polycyclic aromatic hydrocarbon (PAH) concentrations and occupation, smoking status, total airborne PAH level and genetic polymorphisms were tested. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers than in students and correlated significantly with work area. Urinary 2-naphthol concentrations increased with an increase in the level of cigarette smoking in students. Total airborne PAH level correlated with urinary 1-OHP concentration in coke oven workers. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers with the c1/c2 or c2/c2 genotype of CYP2E1 than in those with the c1/c1 genotype. Urinary 2-naphthol concentrations were higher in GSTM1-null workers than in GSTM1-positive workers. In multiple regression analysis CYP2E1 was a significant factor determining urinary 1-OHP concentrations in coke oven workers. CYP2E1 and GSTM1 were significant determinants for urinary 2-naphthol concentrations in coke oven workers and GSTM1 and smoking were prognosticators among university students. Urinary 1-OHP is a better indicator of occupational exposure to PAH in coke oven workers than 2-naphthol, whereas urinary 2-naphthol may be more sensitive for non-occupational inhalation exposure to PAH. In occupationally exposed populations CYP2E1 and GSTM1 appear to play an important role in the metabolism of pyrene and naphthalene. In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol.

Base Sequence↗
PubMed2004

Immune mediators in a murine model for occupational asthma: studies with toluene diisocyanate.

Isocyanate-induced asthma, which is the most common type of occupational asthma, has been difficult to diagnose and control, in part, because the biological mechanisms responsible for the disease and the determinants of exposure are not fully defined. To help address these issues, we recently established a murine model of toluene diisocyanate (TDI) asthma using inhalation exposure paradigms consistent with potential workplace exposure. In order to confirm our hypothesis that TDI-induce asthma, like allergic asthma, is predominantly a Th2 response, the ability of mice that were deficient in CD4 or CD8 cells or specific Th1 and Th2 cytokines to develop TDI asthma was examined. The development of allergic asthma was evaluated by monitoring lungs for the presence of eosinophilia, goblet cell metaplasia, epithelial cell alterations, airway hyperreactivity (AHR), and Th2 and Th1 cytokine expression, as well as serum IgE levels and TDI-specific IgG antibodies. Transgenic CD8 or CD4 knockout (KO) mice exhibited significant reductions in AHR, cytokine expression, serum antibody levels, airway inflammation, and histopathological lesions, although in a number of the endpoints the effects were more attenuated in CD4 KO mice. IFNgamma depletion ablated the increase in AHR in TDI-allergic mice, but had only slight to moderate effects on airway histopathology, serum antibody levels, and cytokine expression compared to sensitized/challenged controls. IL-4 and IL-13 deficiency had moderate inhibitory effects, while combined IL-4/IL-13 depletion effectively prevented almost all asthma-associated pathologies. Taken together, these results indicate that TDI asthma, like immune-mediated asthma produced by large-molecular-weight materials, is driven primarily by CD4+ T cells and is dependent upon the expression of Th2 cytokines. However, as with protein-induced asthma models, certain pathologies are influenced by CD8+ T cells and Th1-derived cytokines, such as AHR and cytokine production.

Allergens↗