Acute Inhalation Exposure Research Articles

Acute Inhalational Exposure to Chlorodifluoromethane (Freon-22): A Report of 43 Cases

Acute Inhalational Exposure to Chlorodifluoromethane (Freon-22): A Report of 43 Cases

Acute toxicity and cancer risk assessment values for tert-butyl acetate

tert-Butyl acetate (TBAc) is an industrial chemical with potential uses as a degreaser and in architectural coatings. Limited chronic toxicity data exist for TBAc. However, acute inhalation exposure data are available for TBAc. Additionally, TBAc has been demonstrated to be substantially metabolized to tert-butanol (TBA) in rats, and a positive TBA genotoxicity study suggests that TBA may cause oxidative DNA damage. TBA has been shown to induce tumors in both rats and mice, and the Office of Environmental Health Hazard Assessment has calculated an oral cancer potency factor (CSF) for TBA of 3 × 10 −3 (mg/kg-day) −1. Therefore, TBAc should be considered to pose a potential cancer risk to humans because of the metabolic conversion to TBA. An acute 1-h reference exposure level of 1 mg/m 3 can be calculated from the extrapolated no observed adverse effect level of 50 mg/m 3. A CSF of 0.002 (mg/kg-day) −1 can be derived for TBAc, assuming 100% metabolism of TBAc to TBA. An inhalation unit risk value for TBAc of 4 × 10 −7 (μg/m 3) −1 can then be derived from the CSF value for TBAc by assuming a human breathing rate of 20 m 3/day, 70% fractional absorption, and an average human body weight of 70 kg.

A profile of calls to a poison information center regarding older adults.

The authors sought to examine the nature of calls to poison information centers by adults ages 50 and over. The authors used data from the national Toxic Exposure Surveillance System and conducted a retrospective review of all cases reported to an American Association of Poison Control Centers Certified Regional Poison Information Center in 1998 and 1999 (N = 6,365). The results indicated that females' poison experiences were more likely the result of therapeutic error, adverse drug reactions, ingestions, and the acute-on-chronic class. The authors found that older age was inversely associated with acute class, suspected suicide, food poisoning, and inhalation and dermal exposures. Older adults are the greatest consumers of over-the-counter drugs, take multiple medications for various medical conditions, and are experiencing biological changes that affect drug metabolism. Older women may be at especially high risk because of high drug use. Poison prevention education should target older adults.

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 trichloroethylene (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.

Concentration-dependence of biomarkers of exposure of methylenediphenyl-diisocyanate following acute inhalation exposure of rats

Rats were nose-only exposed for 6 h to polymeric methylenediphenyl-diisocyanate (pMDI). Concentrations varied from 0.12 to 12.7 mg/m 3 using a highly respirable aerosol. In regard to the concentration of the monomeric fraction of MDI contained in pMDI, the lowest concentration was in the range of the current workplace limit of MDI which is 0.05 mg/m 3. Biomarkers of exposure were determined in hydrolyzed urine (collection started after cessation of exposure for approximately 18 h; acid hydrolysis) and hydrolyzed hemoglobin (collection of blood approximately 20 h after cessation of exposure; alkaline hydrolysis). The determination revealed two-order of magnitudes higher yields of the biomarkers in urine when compared to hemoglobin. The concentration of analytes from the respective biological matrix was highly correlated with the airborne concentration of pMDI whilst their yields exhibited a reciprocal relationship to the airborne concentration of pMDI. A linear relationship could only be demonstrated by using a logarithmic transformation of data. With respect to the amount of 4,4′-methylenediphenyldianiline creatinine (MDA/g creatinine) in hydrolyzed urine of rats at an exposure level similar to the current workplace concentration of MDI, this marker of exposure was approximately 10-times lower in rats than predicted for humans. This suggests that the extrapolation of animal data to man as well as from one exposure regimen to another, without taking into consideration the different deposition/retention patterns of vapors (⩽0.05 mg/m 3) or aerosols of MDI, might be error prone. In summary, taking into account previous and current experimental evidence, these data substantiate further that the formation of MDI-related biomarkers appear to be governed by spontaneously occurring, scavenging reactions at the portal-of-entry. Comparison of MDI with its corresponding amine support that the analytes determined stem from conjugated MDI rather than in vivo hydrolyzed MDI.

Clinical approach to chronic beryllium disease and other nonpneumoconiotic interstitial lung diseases.

Exposures in the workplace result in a diverse set of diseases ranging from the pneumoconiosis to other interstitial lung diseases to acute lung injury. Physician awareness of the potential disease manifestations associated with specific exposures is important in defining these diseases and in preventing additional disease. Most occupational diseases mimic other forms of lung disease, including pulmonary fibrosis, sarcoidosis, adult respiratory distress syndrome (ARDS), and bronchiolitis. A "sarcoidosis"-like syndrome, usually limited to the lungs, may result from exposure to bioaerosols and a number of metals. Exposure to beryllium in the workplace produces a granulomatous lung disease clinically indistinguishable from sarcoidosis, chronic beryllium disease (CBD). Beryllium's ability to produce a beryllium-specific immune response is used in the beryllium lymphocyte proliferation tests to confirm a diagnosis of CBD and exclude sarcoidosis. Exposure to other metals must also be considered in the differential diagnosis of sarcoidosis. When an individual presents acutely with ARDS or acute lung injury, an acute inhalational exposure must be considered. Exposure to a number of irritant substances at high levels may cause a "chemical pneumonitis" or acute lung injury, depending on the solubility and physicochemical properties of the substance. Some of the most notable agents include nitrogen and sulfur oxides, phosgene, and smoke breakdown products. Ingestion of paraquat may also result in an ARDS syndrome, with pulmonary fibrosis eventually resulting. Bronchiolitis is a rare manifestation of inhalational exposures but must also be considered in the clinical evaluation of inhalational exposure.

Use of a Hybrid Computational Fluid Dynamics and Physiologically Based Inhalation Model for Interspecies Dosimetry Comparisons of Ester Vapors

Numerous inhalation studies have demonstrated that exposure to high concentrations of a wide range of volatile acids and esters results in cytotoxicity to the nasal olfactory epithelium. Previously, a hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of organic acids in the rodent and human nasal cavity. This study extends this methodology to a representative volatile organic ester, ethyl acrylate (EA). An in vitro exposure of explants of rat olfactory epithelium to EA with and without an esterase inhibitor demonstrated that the organic acid, acrylic acid, released by nasal esterases is primarily responsible for the olfactory cytotoxicity. Estimates of the steady-state concentration of acrylic acid in olfactory tissue were made for the rat nasal cavity by using data from a series of short-term in vivo studies and from the results of CFD–PBPK computer modeling. Appropriate parameterization of the CFD–PBPK model for the human nasal cavity and to accommodate human systemic anatomy, metabolism, and physiology allowed interspecies dose comparisons. The CFD–PBPK model simulations indicate that the olfactory epithelium of the human nasal cavity is exposed to at least 18-fold lower tissue concentrations of acid released from EA than the olfactory epithelium of the rat nasal cavity under the same exposure conditions. The magnitude of this difference varies with the specific exposure scenario that is simulated and with the specific dataset of human esterase activity used for the simulations. The increased olfactory tissue dose in rats relative to humans may be attributed to both the vulnerable location of the rodent olfactory tissue (comprising greater than 50% of the nasal cavity) and the high concentration of rat olfactory esterase activity (comparable to liver esterase activity) relative to human olfactory tissue. These studies suggest that the human olfactory epithelium is protected from vapors of organic esters significantly better than rat olfactory epithelium due to substantive differences in nasal anatomy, nasal and systemic metabolism, systemic physiology, and air flow. Although the accumulation of acrylic acid in the nasal tissues may be a primary concern for nasal irritation and human risk assessment, acute animal inhalation studies to evaluate lethality (LD50-type studies) conducted at very high vapor concentrations of ethyl acrylate indicated that a different mechanism is primarily responsible for mortality. The rodent studies demonstrated that systemic tissue nonprotein sulfhydryl depletion is a primary cause of death at exposure concentrations more than two orders of magnitude above the concentrations that induce nasal irritation. The CFD–PBPK model adequately simulated the severe depletion of glutathione in systemic tissues (e.g., liver and lung) associated with acute inhalation exposures in the 500-1000 ppm range. These results indicate that the CFD–PBPK model can simulate both the low-dose nasal tissue dosimetry associated with irritation and the high-dose systemic tissue dosimetry associated with mortality. In addition, the comparison of simulation results for ethyl acetate and acetone to nasal deposition data suggests that the CFD–PBPK model has general utility as a tool for dosimetry estimates for a wide range of other esters and slowly metabolized vapors.

Characterization of the LOAEL-to-NOAEL Uncertainty Factor for Mild Adverse Effects from Acute Inhalation Exposures

This analysis was undertaken to reduce uncertainty in acute inhalation risk assessment for mild acute effects. Applying uncertainty factors (UFs) to the no-observed-adverse-effect level (NOAEL) is the primary approach used in threshold-based risk assessments. When a NOAEL is unavailable, a UF of 10 is often applied to a lowest-observed-adverse-effect level (LOAEL) to estimate the NOAEL. We evaluated the LOAEL-to-NOAEL relationship for mild acute inhalation toxicity for 215 data sets for 36 hazardous air pollutants. The LOAEL-to-NOAEL ratios were 2.0, 5.0, 6.3, and 10.0 for the 50th, 90th, 95th, and 99th percentile, respectively. The 90% confidence interval for the 95th percentile was 5.0–7.5. Consequently, based on previous dose placement practice, the LOAEL-to-NOAEL UF of 6 would be protective for 95% of the responses, and a value of 10 would be protective of 99% of the responses. The ratio values were not associated with the size of the experimental group. There was little variability among species, particularly at the median. This analysis is reflective only of mild acute inhalation toxicity. For other exposure routes, exposure durations, or more severe toxicity, the distributions are likely to be different.

Lung expression of cytochrome P450 1A1 as a possible biomarker of exposure to diesel exhaust particles.

Polycyclic aromatic hydrocarbons (PAH) and reactive oxygen species (ROS) derived from diesel exhaust particles (DEP) are implicated in the pathophysiology of respiratory diseases. Cytochrome P450 (Cyp) 1A1 can be induced by several kinds of PAH and produce ROS. We determined whether acute inhalation exposure to DEP induced the expression of Cyp 1A1 in murine lung. Intratracheal instillation of DEP dose-dependently increased the lung expression of Cyp 1A1 at the levels of both mRNA and protein, whereas DEP decreased expression in the lung of aryl hydrocarbon receptors in a dose-dependent manner. In contrast, charcoal particles as the control did not affect the expression of these molecules. These results suggest that the lung expression of Cyp 1A1 can be a biomarker of acute inhalation exposure to DEP and may be implicated in an accelerated production of ROS and the subsequent aggravation of lung injury.

Olfactory mucosal necrosis in male CD rats following acute inhalation exposure to hydrogen sulfide: reversibility and the possible role of regional metabolism.

Hydrogen sulfide (H2S) is a potent inhibitor of cytochrome oxidase (CO) and is associated with dysosmia and anosmia in humans and nasal lesions in exposed rodents. An improved understanding of the pathogenesis of these lesions is needed to determine their toxicological relevance. We exposed 10-week-old male CD rats to 0, 30, 80, 200, or 400 ppm H2S for 3 hours/day for 1 or 5 days consecutively. The nose was histologically examined 24 hours after H2S exposure, and lesion recovery was assessed at 2 and 6 weeks following the 5-day exposure. A single 3-hour exposure to > or = 80 ppm H2S resulted in regeneration of the respiratory mucosa and full thickness necrosis of the olfactory mucosa localized to the ventral and dorsal meatus, respectively. Repeated exposure to the same concentrations caused necrosis of the olfactory mucosa with early mucosal regeneration that extended from the dorsal medial meatus to the caudal regions of the ethmoid recess. Acute exposure to 400 ppm H2S induced severe mitochondrial swelling in sustentacular cells and olfactory neurons, which progressed to olfactory epithelial necrosis and sloughing. CO immunoreactive cells were more frequently observed in regions of the olfactory mucosa commonly affected by H2S than in regions that were not. These findings demonstrate that acute exposure to >80 ppm H2S resulted in reversible lesions in the respiratory and olfactory mucosae of the CD rat and that CO immunoreactivity may be a susceptibility factor for H2S-induced olfactory toxicity in the rat.

US EPA's acute reference exposure methodology for acute inhalation exposures

The US Environmental Protection Agency (EPA) National Center for Environmental Assessment is engaged in the development of a methodology for Agency use to perform risk assessments for non-cancer effects due to acute inhalation exposures. The methodology will provide general guidance for deriving chemical-specific acute exposure benchmarks called acute reference exposures (AREs). Chemical-specific AREs are analogous to reference concentrations (RfCs) for chronic non-cancer effects and will be incorporated in chemical-specific files in the US EPA's Integrated Risk Information System (IRIS) as they are developed and reviewed. AREs will have wide applicability in assessing the potential health risks of accidental and routine acute releases of chemicals to the environment. The proposed methodology for ARE development provides a framework for choosing an optimal derivation approach, depending on the type of data available, from the no-observed-adverse-effect level (NOAEL), benchmark concentration (BMC), or categorical regression approaches. Uncertainty factors are applied to the point of departure, determined by one of the recommended approaches, to derive the ARE. Due to the capability to use more exposure–response information than the NOAEL approach allows, exposure–response analyses such as BMC and categorical regression are favored as methods to develop the point of departure when the available database will support such analyses. The NOAEL approach is suitable when the data are insufficient to support exposure–response modeling. Applications of the proposed ARE methodology are illustrated by the derivation of example AREs for hydrogen sulfide and hexachlorocyclopentadiene, which showcase the categorical regression and NOAEL approaches, respectively. In addition, a recent review of the proposed ARE methodology by the US EPA Risk Assessment Forum is discussed.

Proposal for reference concentrations (RfC) for inhalation exposure to methanol

A tentative reference concentration (RfC) for methanol in ambient air, i.e. an exposure concentration below which adverse effects are not expected to occur, was derived from the analysis of the toxicological data available in the literature. Well-documented studies that correlate environmental levels of methanol with observed toxic effects have not been found in the literature, nor have any long-term epidemiological studies of chronic low-level occupational exposure been found. Assessment of RfC for acute inhalation exposure is based on a human study ( n=26 subjects) with a ‘tentative’ NOAEL of 262 mg/m 3. The calculated RfC for 1 h exposure is 104.8 mg/m 3. The RfC is given a low confidence rating as there was only one methanol concentration used. A well designed study on monkeys served as the basis for the assessment of RfC for chronic inhalation exposure. In this study, 13.1 and 131 mg/m 3 were considered as NOAEL and LOAEL, respectively. The calculated RfC is 0.38 mg/m 3. The overall database is weak, lacking data on reproductive and developmental endpoints in human or non-human primates. Nevertheless, the RfC is given a medium confidence rating because of the strength of the principal study.

Acute exposure to the abused inhalant, isobutyl nitrite, reduced T cell responsiveness and spleen cellularity

Isobutyl nitrite is an inhalant abused principally by male homosexuals. We have reported that subchronic inhalation exposure (45 min/day for 14 days) to 900 ppm isobutyl nitrite was immunosuppressive. In the present study, the effects of acute exposure to the inhalant were examined. Mice were exposed in an inhalation chamber to 900 ppm isobutyl nitrite for 45 min. One day later, spleen cellularity was reduced by 39% without selectively depleting CD4 + or CD8 + cells. The numbers of peripheral blood leukocytes and peritoneal cells were also reduced. Following acute inhalation exposure, T cell proliferative responses stimulated with allogeneic cells or anti-CD3 and anti-CD28 antibodies were inhibited, while mitogen-induced responses were not affected. Purified T cells exposed to the inhalant also had compromised responses, suggesting a direct effect on T cells. However, the cumulative effects of multiple exposures were necessary to inhibit T-dependent antibody responses or T cell or macrophage cytotoxicity.

ACUTE INHALATION EXPOSURE TO CYCLOHEXANE AND SCHEDULE-CONTROLLED OPERANT PERFORMANCE IN RATS: COMPARISON TO D-AMPHETAMINE AND CHLORPROMAZINE

Adult male rats pressed a lever on a multiple fixed ratio-fixed interval (FR20-FI120 sec) schedule of food presentation, and after attaining a stable baseline subjects received an acute inhalation exposure to cyclohexane vapor (0 ppm, 500 ppm, 2000 ppm, or 7000 ppm) for 6 hr. During the operant session that began 30 min after termination of exposure, FR running rate for the 7000 ppm group decreased 11% relative to performance on the previous day. FR post-reinforcement pause duration and the rate and pattern of FI performance were unaffected. Cyclohexane exposures of 500 or 2000 ppm had no detectable effects. No enduring effects of cyclohexane occurred up to 2 weeks after exposure. An independent set of rats, trained under nominally identical conditions, received various doses (i.p.) of d-amphetamine (AMPH) or chlorpromazine (CPZ) at 1–2 week intervals. Effective doses of AMPH decreased FR running rate, decreased FR post-reinforcement pause duration and increased FI rate of response. AMPH also decreased the FI index of curvature, indicating a change from an accelerating rate during the FI to a more constant rate. Effective doses of CPZ decreased FR rate, increased FR pause duration, decreased FI rate, and decreased FI index of curvature. Thus, schedule-controlled operant procedures that were sensitive to the effects of psychoactive drugs were able to identify only a minor and transient effect of the highest concentration (7000 ppm) of cyclohexane vapor on operant performance.

Toxicological Studies of a Representative Xerox Reprographic Toner

Typical Xerox reprographic toners consist of a thermoplastic polymer as the major component, a colorant (carbon black or color pigment), and low quantities of additives such as charge control and/or lubricating agents. Another type of Xerox toner contains iron oxides and a polymer as the major components. Among all toners marketed by Xerox Corporation, the original 1075 toner (being discontinued and reformulated) was a major safety concern, because it contained approximately 2% cetylpyridinium chloride (CPC) as a charge control agent. CPC by itself is very toxic and causes severe irritation to the eye and skin. Although CPC has been used in very low concentrations in consumer products such as mouthwash, it was unknown whether a 50-fold dilution of CPC in the toner formulation would represent any safety issue. Therefore, a series of toxicological testing on the original 1075 toner was conducted. The test results indicate that the original Xerox 1075 toner was practically nontoxic following acute oral, dermal, and inhalation exposures; nonirritating to the eye; nonir-ritating/nonsensitizing to the skin; nonmutagenic in a battery of short-term assays (Ames Salmnonella/microsome assay, mouse lym-phoma assay, in vitro sister chromatid exchange assay in Chinese hamster ovarian cells, and in vitro BALB/3T3 cell transformation assay); and nonteratogenic in rats when inhaling the toner dust up to 1.2 g/m3. In addition, no mutagenic responses were observed from testing the urine or feces (by Ames test) and bone marrow (by examining micronucleus formation) of rats exposed to the toner dust at 1.3 g/m3 at the end of a subchronic inhalation study. Because all Xerox toners are alike, the toxicology of the original Xerox 1075 toner was considered a “worst-case” situation, relative to health and safety. However, it did not appear to represent any health and safety issue. The results of this study, together with the fact that no evidence of carcinogenicity was found in the Xerox chronic inhalation study on toner, indicate that Xerox toners are not safety hazards, with respect to the end points indicated in this report.

SHORT-TERM EXPOSURES OF RATS TO AIRBORNE HYDROGEN FLUORIDE

A series of acute inhalation exposures was performed with airborne hydrogen fluoride (HF) to establish the concentration response for nonlethal effects in the rat. Exposures were either 2 or 10 min long; concentrations ranged from 135 to 8621 ppm. Three additional exposures (20 to 48 ppm) were performed for 60 min. A mouth-breathing (MB) model with a tracheal cannula was used in most of the exposures to maximize delivery of the HF to the lower respiratory tract. Endpoints on the day after exposure included hematology, serum chemistry, bronchoalveolar lavage, pulmonary function, organ weights, and histopathology. Nasal resistance was measured in nose-breathing (NB) groups. Effects of exposure were generally limited to the respiratory tract and included alveolitis, bronchial lesions, altered parameters of pulmonary function and bronchoalveolar lavage, and mucosal necrosis, inflammation, and fibrinopurulent exudate in airways. Observed changes were concentration related and appeared more pronounced in major airways near the point of entry (trachea in MB animals and nose in NB animals). One group of MB animals exposed for 10 min to 1454 ppm was evaluated at 3 and 14 wk after exposure; the acute effects had resolved by those times. The effects of 2-min exposures were consistently more severe than those from 10-min exposures to the same product of concentration x time. Exposures of MB animals for 60 min to 20 or 48 ppm HF did not result in observable adverse effects, although quasistatic pressure-volume curves were shifted upward slightly after 48 ppm. These data provide an integrated picture of the concentration-related effects of short nonlethal exposures to HF.

Assessment of pyrethroid-induced paraesthesias: comparison of animal model and human data

The quantification of upper respiratory tract (URT) sensory irritation is considered to be important in rodent inhalation studies, since it may be also used as an endpoint mimicking trigeminal paraesthesias observed in humans. URT sensory irritation is known to be associated with rodent-specific secondary physiological effects such as depression of body temperature and changes in heart rate. In acutely exposed rats, these endpoints have been addressed by telemetrical measurements. The analysis of the ventilation pattern during acute inhalation studies of rats exposed to the α-cyano-pyrethroid cyfluthrin demonstrates that concentration-dependent URT sensory irritation was associated with a hypothermic response. The no-effect levels (NO(A)EL) based on the URT sensory irritation endpoint following acute inhalation exposure for 1 h and following a repeated 4-week or 13-week inhalation exposure for 6 h/day on 5 days/week were virtually identical (≈0.1 mg/m 3 air). An additional objective was to examine whether human volunteers experience comparable signs when acutely exposed for 1 h to airborne concentrations slightly above or in the range of the NO(A)EL. In human volunteers there were no clinically significant or pyrethroid related abnormalities in vital signs, ECG’s or in any clinical laboratory tests after either exposure, although transient effects related to URT (sensory) irritation were reported. In conclusion, an initial actual exposure concentration of ≈0.1 mg cyfluthrin/m 3 air appears to be in the range of the sensory irritant threshold concentration for both rats and humans. Thus, with regard to physiological afferent portal-of-entry effects, the interspecies response was consistent.

Acute effects of 10-minute exposure to hydrogen fluoride in rats and derivation of a short-term exposure limit for humans.

A series of acute inhalation exposures of female rats was conducted with hydrogen fluoride (HF) to establish a concentration-response curve for nonlethal exposures. Durations of 2 and 10 min were used to simulate possible short-term exposures. Concentrations of HF ranged from 593 to 8621 ppm for 2-min exposures and from 135 to 1764 ppm for 10-min exposures. Additional exposures were performed for 60 min at 20 and 48 ppm HF for comparison to existing Emergency Response Planning Guidelines. Animals were evaluated on the day after exposure for changes in parameters of bronchoalveolar lavage, pulmonary function, hematology, serum chemistry, body weight, organ weights, and histopathology. Most exposures were performed with orally cannulated animals to bypass absorption of HF in the nose and achieve maximum delivery of HF to the lower airways. One of the primary uses of the resulting data was to estimate a concentration to which most people could be exposed for 10 min without severe of irreversible health effects. This level was 130 ppm. It was predicted that irritation would occur at this concentration, but the effects on t he respiratory tract would not be "serious" and would be expected to be reversible. The results of this experiment and the subsequent analysis of the data provide an important aid in he planning of responses to an accidental release of HF.

Evaluation of pulmonary toxicity of heavy metal compounds

The present report describes toxicological approaches to evaluate inflammatory potency of heavy metal compounds deposited in the lung. Although inhalation exposure is a well-accepted method to study effects of pulmonary toxicants, it requires expensive facilities and many man-hours to complete experiments. Intratracheal (i.t.) instillation, an alternative and simple method to expose animals to toxicants via airways, has been proved to be useful to investigate the pulmonary clearance of heavy metals. However, acute inhalation exposure caused more severe inflammatory lung injury than i. t. instillation when the same amount of nickel sulfate was administered in the rat. Among several biochemical inflammatory indices such as some enzyme activities and the protein concentration in bronchoalveolar lavage (BAL) fluid, only lactate dehydrogenase (LDH) activity increased linearly with a wide range of doses of heavy metals. The increase in polymorphonuclear leukocytes (PMN) in BAL fluid, a cytological index of inflammatory responses of the lung, is believed to reflect pulmonary toxicity of heavy metals. However, more extensive study is required to elucidate the mechanism of transpulmonary PMN infiltration upon heavy metal insult. In addition to the linearity between LDH activity in BAL fluid and doses of heavy metals, the increase in this cytosolic enzyme activity is associated with cell lysis in the bronchoalveolar milieu and appears to be the best index to evaluate pulmonary inflammatory potency of heavy metals.

Toxic effects of 1,2,4-trimethylbenzene (pseudocumene) after acute and subchronic inhalation exposure

Toxic effects of 1,2,4-trimethylbenzene (pseudocumene) after acute and subchronic inhalation exposure