Chromate concentration bias in primer paint particles.

Chromate-containing primer paints are used to prevent corrosion on metal surfaces. Chromate contains hexavalent chromium (Cr6+), a human carcinogen. The objective of this research was to determine if there is a bias in the fraction of chromate found in various particle sizes generated during primer painting operations. A solvent-based, aviation primer paint was sprayed using a high-volume, low-pressure spray gun. Paint particles were collected and separated by size with seven-stage cascade impactors. It was determined that particles with a mass aerodynamic diameter < 2.0 microm contained significantly less Cr6+ per dry weight of paint than particles > 2.0 microm (P < 0.001). The median concentration of Cr6+ in particles < 2.0 microm is 18 micro g of Cr/mg of dry paint and the median concentration for particles > 2.0 microm is 70 microg of Cr/mg of dry paint. The mixed paint contains 18.75% strontium chromate, which equates to a ratio of 67 microg of Cr/mg of dry paint. Particles > 2.0 microm are more likely to impact in the upper tracheobronchial regions of the lung where mucociliary clearance is relatively rapid. Additionally, chromate emissions from spraying operations may be overestimated because larger particles, which are more easily trapped on an air filter, contain more chromate than the smaller particles, which are more likely to bypass an air filter.

Acute neurobehavioral effects in rats from exposure to HFC 134a or CFC 12.

1,1,1,2-Tetrafluoroethane (HFC 134a), a chlorine-free hydrofluoroalkane, is internationally replacing billions of pounds of dichlorodifluoromethane (CFC 12) for coolant, refrigerant and aerosol propellant applications. The ALC50 for HFC 134a in rats is 567,000 ppm for 4 h; its potential for cardiac epinephrine sensitization in beagle dogs is acceptable (75,000 ppm); and its capacity to induce carcinogenicity or developmental disorders in animals is minimal. HFC 134a, with a serum half life estimated at 4-11 min, has been accepted for use as a propellant in metered-dose inhalant products, implying a low human toxicity risk from periodic brief exposures. There has been little published human or animal research evaluating possible neurobehavioral toxicity from longer HFC 134a exposures, as may be expected to occur in operational scenarios. In this study, male Wistar rats were exposed to various concentrations of HFC 134a or CFC 12 for up to 30 min while performing in either a rotarod/motorized running wheel apparatus or in an operant chamber The relative neurobehavioral toxicity of CFC 12 and its ozone-depleting substance replacement HFC 134a was assessed by comparing both gross motor system incapacitation and more subtle changes in ability to perform an operant discrimination task. It was shown that exposure to HFC 134a or CFC 12 concentrations from 40,000 to 470,000 ppm, for up to 30 min, induced neurobehavioral deficits in every subject, ranging from reduced operant efficiency to apparent anesthesia. For neurobehavioral endpoints examined in these experiments, HFC 134a inhalation was shown to induce deficits more rapidly, and at lower concentrations when compared to CFC 12 exposure.

A typical path model of tracheobronchial clearance of inhaled particles in rats.

A mathematical description of particle clearance from the ciliated conducting airways (tracheobronchial region) of the lungs in rats was developed, assuming that particles on the mucus blanket behave as a fluid and adhere to principles of fluid flow described by the continuity equation. Effective particle transport velocities for given generations of airways were estimated from reported tracheal mucus velocities. Using typical rat airway geometry and estimated particle transport velocities, solutions of sets of rate equations for transport from each generation of airways were summed to estimate total particle clearance from the tracheobronchial region of the lung as a function of time. Aerosol particle size distribution (MMAD ranging from 0.1 to 4.2 microm, and sigma(g) from 1 to 2.7) and concentration data from several investigators were used to predict short-term, tracheobronchial clearance (retention) in rats up to 24 h following exposure. Comparisons between predicted and observed retention showed an average difference between model predictions, and observed fractional retention of initial lung or body burden was 4.9%, with a tendency toward underprediction of clearance of particles >3.0 microm.

A physiological model for predicting carboxyhemoglobin formation from exposure to carbon monoxide in rats.

A time-dependent simulation model, based on the Coburn-Forster-Kane equation, was written in Advanced Continuous Simulation Language to predict carboxyhemoglobin (HbCO) formation and dissociation in F-344 rats during and after exposure to 500 parts/million CO for 1 h. Blood-gas analysis and CO-oximetry were performed on samples collected during exposure and off-gassing of CO. Volume displacement plethysmography was used to measure minute ventilation (VE) during exposure. CO diffusing capacity in the lung (DLCO) was also measured. Other model parameters measured in the animals included blood pH, total blood volume, and Hb concentration. Comparisons between model predictions using values for VE, DLCO, and the Haldane coefficient cited in the literature and predictions using measured VE, DLCO, and calculated Haldane coefficient for individual animals were made. General model predictions using values for model parameters derived from the literature agreed with published HbCO values by a factor of 0.987 but failed to simulate experimental data. On average, the general model overpredicted measured HbCO level by nearly 9%. A specific model using the means of measured variables predicted HbCO concentration within a factor of 0.993. When experimentally observed parameter fluctuations were included, the specific model predictions reflected experimental effects on HbCO formation.

Breathing zone particle size and lead concentration from sanding operations to remove lead based paints.

The relationship between lead concentration in the dry film of lead based paints applied to steel bulkheads aboard ship, the lead concentration found in the air when the paint is removed by mechanical means, and blood lead concentrations of workers involved in lead based paint removal has not been well characterized. Intuitively a direct relationship must exist but confounding factors confuse the issue. Simultaneous sampling procedures from the same paint removal operation may differ by several orders of magnitude. The process from dried film to aerosol (airborne dust) exposure, and on to dose can be separated into two major phases; (1) generation of the dust and its transport through the air to the worker and (2) uptake and dose related factors within the body. Both phases involve complex interactions and there are a number of factors within each phase that significantly affect the potential lead dose for the worker. This study attempts to clarify the mechanisms involved in the generation and transportation of the dust to the worker by evaluating the relationship of a number of key factors on particle size and lead distribution within the aerosol dust generated when lead based paint is removed by sanding. The study examined the relationship between particle size in the dust and grit size of the abrasive. It also examined the distribution of lead within selected particle sizes. The Mass Median Aerodynamic Diameter (MMAD) was used as an indicator of change in the particle size distribution. Particle size distributions were evaluated using a TSI Aerodynamic Particle Sizer, a five stage cyclone and scanning electron microscopy. Lead distribution was determined using the five stage cyclone, and personal or area samples analyzed using inductively coupled plasma (ICP). Mass concentrations were evaluated using a MIE Mass Concentration Analyzer and gravimetric analysis of filter samples collected in the breathing zone. Student's t-tests were used to evaluate changes in MMADs, mass concentrations and other indices for inter and intra-grit size samples. Correlation coefficients (Pearson's r) were used to determine the relationship between factors. Findings of the research indicated that the particle size distribution in the dust is directly related to the grit size of the abrasive (i.e. inversely related to the abrasive grit number). Particulate mass concentrations of dust varied directly with abrasive grit number. The distribution of lead did not appear to be affected by grit size of the abrasive in that the lead distribution within the particle size ranges remained homogeneous and consistent with the lead concentration in the dried film. Mass concentrations of lead in air samples varied directly with lead concentration in the bulk coating. Results of this project, coordinated with deposition modeling and bioavailability studies will be useful in the development of a model to characterize lead dose to workers based on known parameters within the work specifications.

Acute lung injury, acute respiratory distress syndrome and inhalation injury: an overview.

Acute Lung Injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS) are severe respiratory diseases that have a very poor prognosis and have numerous causes. Despite a great deal of research and investigation since the initial description of ARDS 30 years ago many questions about the pathogenesis, treatment and outcome of the disease remain unanswered. Although there is evidence to suggest that outcome of ALI and ARDS is improving, the reasons why are unknown and there is not yet a well developed treatment for these diseases. Inhalation injury resulting from exposure to pyrolysis and combustion atmospheres is among the causes of ALI/ARDS. Little is known of the mechanisms of fire related inhalation injury that results in the development of ALI/ARDS. There is a paucity of information about fire atmosphere exposure response relationships for smoke-induced inhalation injury. Although there is considerable information about the pulmonary toxicity of many of the more common constituents of fire atmospheres, little is known about the pulmonary toxicity of mixtures of these constituents. Fire related pulmonary health risks are of particular concern to the Navy due to the limited opportunity to escape the inhalation hazards posed by shipboard fires. Consequently the Naval Medical Research Institute Detachment (Toxicology) has undertaken a research program to develop research models of combustion atmosphere induced ALI/ARDS which can be exploited to systematically address some of the questions surrounding fire related ALI/ARDS. ALI/ARDS has been the topic of a vast amount of research, numerous symposia, working groups and their published proceedings, book chapters, and books. Less information is available regarding experimental models of smoke induced lung damage, however the literature on the subject is extensive. Consequently this article is intended to provide the reader with a primer or cursory "overview" of ALI and ARDS from a toxicological perspective and should not be considered comprehensive.

Calculation of exposure chamber leak rate with thermal correction: a measure of chamber integrity.

A method for assessing inhalation exposure chamber integrity by calculation of leak rate was modified to account for temporal changes of temperature in the chamber. In a well-sealed chamber, accounting for thermal effect brought observed leak rates into better agreement with predicted values. Mean estimates of chamber leak rate without thermal correction ranged from 2.9 to 40.6 cm3/min whereas those with thermal correction ranged from 9.6 to 14.3 cm3/min. The average change in estimate of chamber leak rate brought about by correcting for thermal effect was 16.8 cm3/min per K change of temperature in the chamber. Accounting for thermal effect reduced the coefficient of variation for repeated estimates (n = 10) of chamber leak rate from 65 to 15%. The use of temperature-corrected calculation of chamber leak rate minimizes thermal artifact thereby improving decisions about chamber operation based on assessment of chamber integrity.

Evaluation of the respiratory tract after acute exposure to a pyrotechnically generated aerosol fire suppressant.

Fischer 344 rats (250-300 g) were exposed to the resulting aerosols from the pyrolysis of Spectrex Fire Extinguishant (SFE) Formulation A, a pyrotechnically generated aerosol fire suppressant, at a loading equivalent of 50 or 80 g m(-3) air for 15 or 60 min. Exposures were conducted in a 700-1 whole-body inhalation chamber under static conditions. The chamber atmosphere was analyzed for mass aerosol concentration and size distribution. Clinical observations were taken throughout the exposure. Animals were euthanized at 1 h, 6 h, 24 h, 7 days or 14 days post-exposure and underwent histopathological examination, enzyme analyses and wet/dry lung weight determination. No deaths occurred during the study. Animals exhibited signs of dyspnea, coughing, lack of coordination and lethargy during each exposure. These signs became more pronounced as the load and exposure length increased. No lesions were noted in the trachea, lung, heart or abdominal organs upon gross examination. A reversible pulmonary edema and olfactory necrosis were observed only in those animals exposed to an SFE loading equivalent to 80 g m(-3) for 60 min. Protein concentrations increased in the bronchoalveolar lavage but no changes in enzyme levels were observed. There was no significant difference between the control groups and the exposure groups for wet/dry lung weight determination.

Effect of exposure route on measurement of blood pressure by tail cuff in F-344 rats exposed to OTTO Fuel II.

Male Fischer-344 rats demonstrated a dose-response of blood pressure (BP) to increasing doses of propylene glycol dinitrate (PGDN), the major constituent of OTTO Fuel II (OFII) following administration by subcutaneous injection. Dermal application of the same doses to separate groups of rats resulted in variable responses of BP that were unrelated to dose. A nose-only exposure system was developed but no effect on BP was observed in rats exposed to a nearly saturated atmosphere of PGDN (approx. 750 mg/m3 at 25 degrees C). This study has indicated both the difficulties associated with the use of tail cuff measurement of BP and the need for either a more sensitive or more specific biomarker of effect for exposure to nitrate esters.

Effects of a 13-week chloropentafluorobenzene inhalation exposure of Fischer 344 rats and B6C3F1 mice.

Chloropentafluorobenzene (CPFB) has been identified as a candidate simulant for nonpersistent chemical warfare agents. Acute toxicity studies have shown that CPFB has limited adverse effects on laboratory animals. A 21-day inhalation study of rats and mice to 2.5, 0.8, and 0.25 mg CPFB/liter resulted in reduced weight gain in male and female rats exposed at the high concentration only and identified the liver as a potential target organ. This multiconcentration inhalation study was designed to detect a no-observable-effect level associated with repeated exposure to CPFB. Male and female rats and mice were exposed to 250, 50, or 10 mg CPFB/m3 (0.25, 0.05, or 0.01 mg CPFB/liter) for 13 weeks. No treatment-related effects on body weight, clinical chemistries, mortality, absolute or relative organ weight or histopathology were noted.

Augmentation of elastase-induced emphysema by cigarette smoke. Effects of reduced nicotine content.

To examine the role of nicotine in the augmentation of elastase-induced emphysema by cigarette smoke, animals that had been pretreated with porcine pancreatic elastase (PPE) were exposed to cigarette smokes that had a five-fold difference in their nicotine concentrations. Young adult female Long-Evans rats were divided into seven groups: (1) untreated controls; (2) low nicotine cigarette smoke exposure (Kentucky 2A1 reference cigarettes; 35.0 mg total particulate matter, 0.42 mg nicotine, and 0.38 mg nitrogen oxides per cigarette); (3) high nicotine cigarette smoke exposure (Kentucky 2R1 reference cigarettes; 38.8 mg total particulate matter, 2.2 mg nicotine, and 0.34 mg nitrogen oxides per cigarette; (4) PPE alone; (5) PPE + sham smoke exposure; (6) PPE + 2A1 smoke exposure; and (7) PPE + 2R1 smoke exposure. Three days after intratracheal administration of PPE (400 IU/kg), animals in the smoke-treated groups were exposed to 10 puffs of cigarette smoke daily, 7 days/wk for 14 wk. Sham-treated animals received room air in place of cigarette smoke. After the exposures, pulmonary function tests were performed under general anesthesia. Whole lungs were examined for gross pathologic changes, and samples of lung tissue were harvested for quantitative morphometry. Cigarette smoke exposure alone did not produce significant changes in pulmonary function or structure. On the other hand, treatment with elastase alone produced a constellation of pulmonary functional and structural changes that were pathognomonic of emphysema. Exposure to 2R1 but not 2A1 cigarette smoke significantly augmented the emphysematous changes produced by PPE.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA adduct formation by alachlor metabolites.

The extent of DNA adduct formation by alachlor [ArN(CH2OCH3)C(O)CH2Cl wherein Ar is 2,6-diethylphenyl] and its metabolites is used as a guide to deduce the causal agent(s) in the carcinogenicity of this major herbicide. [14C-phenyl]Alachlor is compared to its two metabolic cleavage products, [14C-phenyl]2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA) [ArNHC(O)CH2Cl] and [14C-phenyl]2,6-diethylaniline (DEA) (ArNH2), and to [14C-methoxy]alachlor in various in vitro and in vivo systems. Horseradish peroxidase and hydrogen peroxide activate DEA, but not CDEPA or alachlor, for formation of adducts with calf thymus DNA, which probably involves 2,6-diethylnitrosobenzene (ArNO) as an intermediate. Mouse liver microsomes and NADPH are both required to enhance the binding from each labeled preparation to calf thymus DNA; 4-fold higher labeling is observed from [14C-methoxy]- than from [14C-phenyl]alachlor. This 4-fold preferential DNA labeling from the 14C-methoxy compound is likewise found in the liver of mice treated intraperitoneally. Mouse liver protein and hemoglobin are also labeled, in vivo, with [14C-phenyl]alachlor, -CDEPA and -DEA, and, as with the DNA, the labeling of these proteins is 1.5- to 2-fold higher with [14C-methoxy]alachlor. Metabolic studies indicate that ArN(CH2OCH2OH)C(O)CH2Cl is an intermediate in forming CDEPA and presumably formaldehyde in the mouse liver microsomal mixed-function oxidase system and in yielding the O-glucuronide of ArN(CH2OH)C(O)CH2Cl in the urine of alachlor-treated mice. These findings point to the N-CH2OCH2OH metabolite or formaldehyde as a reactive intermediate in forming a DNA-adduct and as a candidate proximate carcinogen.

Toxicant distribution in the Thomas Domes.

Measurement of test article concentration distribution for light gases have been made in the Thomas Dome inhalation chambers at Wright-Patterson Air Force Base, using propane as a test agent. The method used to analyze for inhomogeneities in test article spatial distribution deliberately varies the dome operational parameters rather than requiring extreme operational stability. The variation in test article concentration is analyzed by regression to determine which operational parameters most influence the test agent distribution. Unaccounted concentration variability is assumed to be the inherent spatial variation of the test article in the dome. The propane studies indicated that the spatial variation within the dome was 6.4% of the mean and that room air temperature at the top of the dome, propane analyzer baseline stability, and dome pressure were (listed in order of decreasing importance) the variables influencing the test article distribution.

Augmentation of elastase-induced emphysema by cigarette smoke. Description of a model and a review of possible mechanisms.

Rats were treated with a single endotracheal dose of purified porcine pancreatic elastase (400 IU/kg), exposed to undiluted cigarette smoke from Kentucky 2RI reference cigarettes (one 35-ml puff/min for 10 min daily, 5 days per week, for 12 wk) or with a combination of elastase followed by smoke exposure. A number of significant functional abnormalities were observed in the lungs of rats receiving elastase; these included reduced spontaneous ventilation, enlarged subdivisions of lung volume, loss of elastic recoil, and diminished gas exchange capacity. Rats receiving both elastase and cigarette smoke had significantly more severe pulmonary dysfunction than did rats treated with elastase alone. Morphometric measurements of mean linear intercept demonstrated a loss of alveolar fine structure, with enlargement of distal air spaces in elastase-treated rats. These changes were significantly more severe in rats treated with both elastase and cigarette smoke. Pulmonary function tests and morphometric measurements in sham-treated rats and in rats exposed to cigarette smoke only were not significantly different from those in untreated control animals. It is concluded that elastase-induced emphysema in rats is enhanced by exposure to whole cigarette smoke.

3-Substituted 2-halopropenals: mutagenicity, detoxification and formation from 3-substituted 2,3-dihalopropanal promutagens.

The mutagenicity of halopropenals for Salmonella typhimurium strain TA100 is as follows (revertants/nmole): 2-halopropenals [H2C = C(X)CHO], F = less than 0.6, Cl = 135, Br = 1140 and I = less than 2.4; 3-substituted-2-halopropenals [CH3CH = C(X)CHO], Cl = 68 and Br = 108; [C6H5CH = C(X)CHO], Cl = less than 1 and Br = 5; [ClCH = C(Cl)CHO], 91; [CH3(CH2)2CH = C(Br)CHO], less than 1; [(CH3)2C = C(Br)CHO], less than 0.5. Each of the active compounds is detoxified by the liver S9 fraction. Glutathione also detoxifies the 2-halopropenals and 2-halobutenals, more rapidly for the bromo than the chloro analogs. The mutagenic potency on metabolic activation of the herbicide diallate by microsomes or the S9 fraction is attributable to approximately 50% conversion to 2-chloropropenal when corrected for detoxification in these systems or with GSH. There is no correlation between mutagenicity and reactivity with the model thiol, 4-nitrobenzenethiol. The mutagenicity of 2,3-dichloro- and 2,3-dibromo-propanals and the corresponding dihalobutanals is accounted for by their rapid dehydrohalogenation to the corresponding 2-haloalkenals under physiological conditions. Chemicals that are metabolized to 2,3-dichloropropanal, 2,3-dichlorobutanal, their dibromo analogs, or to the corresponding 2-halopropenals and 2-halobutenals should therefore be considered as candidate promutagens.

Pulmonary mechanical, ventilatory, and gas exchange abnormalities in rats with monocrotaline-induced pulmonary hypertension.

Recent clinical studies have suggested that peripheral airways dysfunction contributes to the pathogenesis of idiopathic pulmonary hypertension. To determine whether similar peripheral airways defects occur in a common animal model of pulmonary hypertension, pulmonary function tests were performed in adult male rats rendered pulmonary hypertensive with a single subcutaneous injection of monocrotaline. At 20 days post treatment, animals exhibited well-developed right ventricular hypertrophy coincident with significant changes in lung volumes, pulmonary mechanics, and gas exchange function indicative of a severe combined restrictive and obstructive airways disorder. Morphologic changes in alveolar integrity compatible with such a pulmonary defect also were observed in monocrotaline-treated animals. The specific changes in pulmonary function observed in monocrotaline-treated rats were qualitatively similar to abnormalities reported in patients with idiopathic pulmonary hypertension. These results demonstrate that significant pulmonary mechanical, ventilatory, and gas exchange dysfunction is present in rats with monocrotaline-induced pulmonary hypertension and highlight the suitability of this model for investigating a potential contributory role of pulmonary function abnormalities in the pathogenesis of this disorder.

The role of nicotine in the pathogenesis of pulmonary emphysema.

An investigation was undertaken to evaluate the potential role of nicotine in the pathogenesis of pulmonary emphysema. The acute lethality and the pulmonary toxicity of a single endotracheally administered dose of nicotine were studied in Long-Evans rats. The 24-h LD50 of nicotine was established at 19.3 +/- SD 5.4 mg/kg. Subsequently, rats were treated with either nicotine alone (3 or 7.5 mg/kg), porcine pancreatic elastase (PPE) alone (200 IU/kg) or PPE (200 IU/kg) followed 5 days later by nicotine (3 mg/kg). The selected dose of PPE was below the threshold dose for induction of emphysematous lesions. Cage and sham-treated control groups also were included in the investigation. Four weeks after treatment, extensive physiologic tests were conducted to evaluate the ventilatory, mechanical, and gas exchange functions of the lungs. Lung tissue specimens also were taken for estimation of tissue volume density. Although a few isolated incidents of significant intergroup differences were observed, no distinctive pattern of functional or structural change reminiscent of emphysema was noted in any of the experimental groups. It is concluded that endotracheal instillation of a single, relatively high, dose of nicotine neither induces nor augments the development of pulmonary emphysema in the rat.

Effects of the Clara cell toxin, 4-ipomeanol, on pulmonary function in rats.

The naturally occurring compound, 4-ipomeanol (IPO, 1-[3-furyl]-4-hydroxy-1-pentanone), selectively damages the nonciliated epithelial (Clara) cells of the terminal bronchioles. Because information is not available concerning functional changes in IPO-treated lungs, an investigation was undertaken to evaluate the in vivo pulmonary ventilatory, mechanical, and gas exchange functions of female Long-Evans rats 24 h after treatment with a single intraperitoneal dose of 1 or 5 mg IPO/kg body wt. A preliminary toxicity study established the 24-h LD50 for intraperitoneally administered IPO at 19 +/- 3 (SD) mg/kg. Significant increases in lung fluid occurred in animals treated with 15 mg IPO/kg, and histological evidence of pulmonary edema was observed in animals treated with 10 mg IPO/kg. Treatment of rats with 5 mg IPO/kg caused a significant decrease in tidal volume and a significant increase in respiratory rate and functional residual capacity-to-total lung capacity ratio (%). In rats treated with 1 mg IPO/kg, pulmonary functions were minimally affected. The functional changes observed in IPO-treated animals can be attributed to swelling and possible dysfunction of Clara cells, with subsequent alveolar interstitial edema and stimulation of juxtapulmonary capillary receptors, or to a direct effect of the toxin on respiratory control mechanisms.