Initiating the risk assessment process for inhaled particulate materials: development of short term inhalation bioassays.

This study describes a short term inhalation bioassay in rats to predict the potential for inhaled particles to produce chronic lung disease in humans (e.g., pulmonary fibrosis). To validate the method, rats were exposed for 6 h or 3 days to various concentrations of two reference materials: (1) a known fibrogenic material (i.e., aerosolized alpha-quartz silica particles in the form of Berkeley Min-U-Sil (Pennsylvania Glass and Sand Company, Pittsburgh, PA), or (2) carbonyl iron (CI) particles, as a negative control. Cells and fluids from groups of sham and dust exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase and protein values were measured in BAL fluids at several times postexposure. Cells were identified, counted, and evaluated for viability. The lungs of additional exposed animals were processed for histopathology. Although particle deposition patterns for the two dusts were similar, brief exposures to silica particles produced a persistent pulmonary inflammatory response characterized by neutrophil recruitment at sites of particle deposition and consistently elevated biomarkers of cytotoxicity in BAL fluids. In addition, alveolar macrophage clearance functions were impaired. Progressive histopathologic lesions were observed within 1 mo after a 3-day exposure. Light and electron microscopy of silica exposed lung tissue revealed a chronically active pulmonary inflammatory response characterized by hyperplasia of Type II alveolar epithelial cells and the infiltration of macrophages and neutrophils into alveoli and interstitial compartments. The lesions were progressive, leading to the development of a multifocal, granulomatous-type pneumonitis within 2 mo postexposure. In contrast to the observed effects of silica, 3-day exposures to CI particles produced no significant adverse biochemical or histopathological effects on pulmonary tissues. These results demonstrate that short term, high dose inhalation exposures of silica produce effects similar to those previously observed using intratracheal instillation or chronic inhalation models and lend support to this method as a reliable short term bioassay for evaluating the pulmonary toxicity and mechanisms associated with exposure to new and untested respirable materials.

Comparison of inducible nitric oxide synthase gene expression and lung inflammation following intratracheal instillation of silica, coal, carbonyl iron, or titanium dioxide in rats.

The pulmonary toxicity of the respirable dusts silica, coal, carbonyl iron, and titanium dioxide on alveolar macrophage (AM) and neutrophil (PMN) inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) production was investigated. Rats were intratracheally instilled with 5 mg/100 g body weight of silica, coal, carbonyl iron, or titanium dioxide. The dust particles averaged less than 5 microns in diameter. Bronchoalveolar lavage was performed 24 h later. Bronchoalveolar lavage cell (BALC) differentials, iNOS gene expression and NO production by BALC (measured indirectly as NO-dependent chemiluminescence), and lavageable lung protein levels were measured. Analyzed on an equal mass basis, silica, coal, and titanium dioxide dusts increased the production of iNOS-dependent NO by AM. Silica and titanium dioxide both increased the levels of iNOS mRNA while carbonyl iron and coal did not. Each dust caused an increase in PMN, indicating an inflammatory response. Carbonyl iron and titanium dioxide decreased the numbers of AM. Levels of acellular lavageable lung protein were increased by silica, carbonyl iron, and titanium dioxide. When exposure was normalized for an equal number of particles, the pneumotoxic dusts, silica and coal, caused more inflammation and NO production than the nuisance dusts, carbonyl iron and titanium dioxide. Therefore, it appears that particle number is a more appropriate metric of exposure than mass when comparing the relative pathogenicity of dusts of different sizes. Furthermore, since the potency of these dusts (on a particle number basis) to increase iNOS gene expression reflects their inflammatory and pathogenic potential, it is proposed that NO may contribute to the early inflammatory damage observed in the lung following dust exposure.

Pharmacokinetics and disposition of methyl t-butyl ether in Fischer-344 rats.

Methyl t-butyl ether (MTBE) is a commonly used octane booster in gasoline. This study examines the pharmacokinetics and disposition of MTBE in Fischer-344 rats after i.v., oral, dermal and inhalation routes of administration. Groups of male and female rats were given single i.v. (40 mg kg-1), oral (40 and 400 mg kg-1) and dermal (40 and 400 mg kg-1 in occluded chambers) doses of [14C]MTBE. For inhalation studies, rats were exposed nose-only for 6 h to low (400 ppm), high (8000 ppm) and repeated daily 6-h low (400 ppm x 15 days) chamber concentrations of [14C]MTBE. Blood, expired air, and excreta (urine and feces) were collected at selected times up to 7 days post-dose and quantified for 14C content. Plasma concentrations of MTBE and t-butyl alcohol (TBA) were quantified and mean values used for pharmacokinetic analysis. The mean total recoveries of 14C ranged from 91 to 105%. Methyl t-butyl ether was rapidly and completely absorbed after oral and inhalation exposures; dermal absorption was low. After all routes, MTBE was rapidly eliminated from blood (ti = 0.5 h) by exhalation and metabolism to TBA. At the high doses, metabolism was saturated and the proportion of renal 14C excretion decreased relative to the pulmonary route. At 48 h post-exposure, virtually all of the 14C was eliminated. The major metabolites recovered in urine were 2-methyl-1,2-propanediol and alpha-hydroxyisobutyric acid. There were no significant gender or route-dependent differences in the pharmacokinetics and disposition of MTBE.

Oncogenicity studies of inhaled methyl tertiary-butyl ether (MTBE) in CD-1 mice and F-344 rats.

Oncogenicity studies of methyl tertiary-butyl ether (MTBE) vapor were conducted in CD-1 mice and Fischer 344 rats. Fifty animals of each sex per species per group were exposed for 6 h a day, 5 days per week to 0 (control), 400, 3000 and 8000 ppm MTBE vapor in air for 18 months (mice) and 24 months (rats). Both species showed reversible central nervous system depression at 8000 ppm for the first week of exposure, which continued for mice for the study duration. For the 8000 ppm mice, reduced body weight gain and early mortality prior to terminal euthanasia were exposure related. In the males, these deaths appear to be due to exacerbation of uropathy or dysuria, which occurs spontaneously in this strain. Increases in absolute and relative liver (both sexes) and kidney weight (males only) were seen at 3000 and 8000 ppm and decreases in brain and spleen weights were also noted (the latter decreases were without microscopic lesions and occurred at 8000 ppm only). An increase in hepatocellular hypertrophy occurred in both sexes at the two highest concentrations. The only neoplastic lesion found in this study in mice was an increased incidence of hepatocellular adenomas in females at the 8000 ppm exposure. In a follow-up study, a statistically significant elevation of cell proliferation in female mouse liver has been shown to occur following 5 days, but not 28 days, of exposure to 8000 ppm MTBE, suggesting that MTBE induces mitogenesis. For male rats, early euthanasia was required at week 82 and week 97 for the 8000 and 3000 ppm groups, respectively, due to excessive mortality from a severe progressive nephrosis. The end stage of this process appeared earlier in the male rats of all MTBE exposure groups; the incidence of this lesion and mortality for exposed females was comparable to control females. No exposure-related changes in hematological parameters were observed for any group at any time point, but a decrease in corticosterone levels was seen for male rats from the 8000 ppm group. Absolute and relative kidney and liver weight increases occurred in 3000 and 8000 ppm exposure groups, but the liver weight change was not accompanied by histopathological change. At study termination, increases in the incidence and severity of a chronic nephropathy in males from all exposure groups and in females exposed to 3000 and 8000 ppm was associated with secondary lesions of hyperplasia of the parathyroid and mineralization of tissues. Renal tubular cell tumors were increased in male rats exposed to 3000 and 8000 ppm. This may be associated with an accumulation of protein (stainable by Mallory's Heidenhain) in kidney tubular epithelial cells after 4 weeks of exposure. An increased incidence of interstitial cell adenomas of the testes was seen in males exposed to 3000 and 8000 ppm but was believed to be an artefact of an unusually low control incidence and not considered to be exposure related. Based on the above effects, the no-observed-effect level (NOEL) for chronic toxicity is 400 ppm, and the NOEL for carcinogenic effects is 3000 ppm (mice) and 400 ppm (rats).

Evaluation of 13-week inhalation toxicity study on methyl t-butyl ether (MTBE) in Fischer 344 rats.

Methyl-t-butyl ether (MTBE) is widely used as an octane enhancing agent in gasoline. A 13-week inhalation study was conducted in Fischer 344 rats to provide information on potential target organs and toxicity of MTBE, and to ascertain a no-observed-adverse-effect level (NOAEL) for MTBE. Male and female Fischer 344 rats were exposed to target doses of MTBE vapor of 0, 800, 4000 and 8000 ppm for 6 h a day, 5 days per week for 13 weeks: MTBE produced no mortalities. At 8000 ppm, males and females showed a decrease in body weights compared to controls. The only notable effect on clinical observation was ataxia at 8000 ppm, which was apparent during the first 4 weeks of treatment. Mild hematological and clinical chemistry changes were observed in the 8000 ppm group. At 8000 ppm, animals showed increased serum levels of corticosteroids, which suggest some stress-like effect. At necropsy, there were no treatment-related gross lesions. Absolute and relative organ weights (liver, adrenals and kidneys) were increased in both sexes at 4000 and 8000 ppm, but there were no microscopic lesions in these tissues with the exception of the kidney. Microscopic examination of other tissues revealed no effects with the exception that at 8000 ppm, male rats showed: mild increased size of hyaline droplets within the kidney, mild increase in hemosiderosis in the spleen and higher incidence of hyperplasia in the lymph nodes. The highest NOAEL was judged at 800 ppm.

Pulmonary endocrine cell hyperplasia and papilloma in rats induced by intratracheal injections of extract from particulate air pollutants.

We investigated the effect of intratracheal injections of an extract of suspended particulate matter (SPM) obtained from the urban ambient air of Tokyo, upon the development of proliferative lesions of pulmonary endocrine cells (PECs) in the rat. We also examined the modification effects of nitrogen dioxide, sulfur dioxide, or both of them on the PEC lesions. Male F344 rats were divided into six experimental groups of 5 animals each. Twenty animals were treated with intratracheal instillations of SPM admixed with carbon once a week for 4 weeks with or without additional gaseous exposure (6 ppm nitrogen dioxide or 4 ppm sulfur dioxide) 16 hrs a day for 11 months. Five animals were given intratracheal injections of carbon suspended in saline and the other five were untreated. The subcardiac lobes of the right lung were fixed with 4% paraformaldehyde, and embedded in paraffin. PEC hyperplasias and papillomas were counted in 200 serial sections, 4 microns thick. The average incidences of PEC hyperplasia in the untreated animals and in those treated with carbon were 194 and 200/cm3, respectively. The average incidences of PEC hyperplasia in the animals exposed to SPM tar only, SPM tar plus nitrogen dioxide and sulfur dioxide, SPM tar with nitrogen dioxide and SPM tar with sulfur dioxide were 376, 378, 372 and 349/cm3, respectively. These were significantly higher than the levels of the control animals, and additional gaseous stimuli had no effect on the incidence of PEC hyperplasia. Besides PEC hyperplasia, a few PEC papillomas were found in the animals treated with SPM tar, regardless of gaseous exposure, but in the control animals no papilloma was evident. Thus, compounds in airborne particulates are considered to be responsible for the development of PEC hyperplasias and papillomas.

The construction and validation of a high containment nose-only rodent inhalation facility.

A new nose-only inhalation facility for rodents has been designed and built for operation within a high containment glove box facility. All operations using the equipment, whether concerned with aerosol generation or animal handling and exposure are conducted under high containment with total operator protection. The facility has been used to investigate known carcinogenic fibres such as the amphiboles. It has been designed to be resistant to most chemicals, under the conditions of an experiment, and can be used with radioactive material within the limitations which would be imposed for radiological protection. This paper describes the construction and validation of the equipment using titanium dioxide.

CS2-mediated cross-linking of erythrocyte spectrin and neurofilament protein: dose response and temporal relationship to the formation of axonal swellings.

Using model proteins, a mechanism for CS2-mediated covalent cross-linking of proteins has been demonstrated previously. The biologic importance of CS2-promoted protein cross-linking is apparent as a possible dosimeter of CS2 exposure and as a potential mechanism to account for the identical neuropathies produced by 2,5-hexanedione and CS2. The present investigation examines the utility of erythrocyte spectrin cross-linking as a biomarker of effect for inhalation exposure to CS2 and examines the ability of CS2 to cross-link neurofilament proteins, a potential neurotoxic target. Rats were exposed to CS2 via inhalation at control, 50-, 500-, and 800-ppm levels for 2, 4, 8, and 13 weeks and spectrin dimer formation was quantified using denaturing gel electrophoresis and densitometry. Neurofilament preparations were also obtained from spinal cords and examined for cross-linking using Western blotting methods. The results obtained for protein cross-linking were compared to morphologic changes in the cervical and lumbar spinal cord using light and electron microscopy. The spectrin dimer exhibited a cumulative dose response and was detectable at both the 50-ppm level employed that did not produce axonal swellings and prior to the development of axonal swellings for the 500- and 800-ppm levels used. Neurofilament protein cross-linking involved all three subunits and the temporal relationship of cross-linking was consistent with a contributing role in the development of axonal swellings. These results establish the sensitivity of spectrin cross-linking for evaluating inhalation exposures and extend the similarities observed for 2,5-hexanedione and CS2 in both clinical settings and in vitro models to their effects exerted on neurofilaments in the axon.

Risk assessment of inhaled chloroform based on its mode of action.

The development of scientifically sound risk assessments based on mechanistic data will enable society to better allocate scarce resources. Inadequate risk assessments may result in potentially dangerous levels of hazardous chemicals, whereas overly conservative estimates can result in unnecessary loss of products or industries and waste limited resources. Risk models are used to extrapolate from high-dose rodent studies to estimate potential effects in humans at low environmental exposures and determine a virtually safe dose (VSD). When information to the contrary is not available, the linearized multistage (LMS) model, a conservative model that assumes some risk of cancer at any dose, is traditionally employed. In the case of airborne chloroform, the dose at which an increased lifetime cancer risk of 10(-6) could be calculated was chosen as the target VSD. Applying the LMS model to the mouse liver tumor data from a corn-oil gavage bioassay yields a VSD of 0.000008 ppm chloroform in the air. The weight of evidence indicates that chloroform is not directly mutagenic but, rather, acts through a nongenotoxic-cytotoxic mode of action. In this case, tumor formation results from events secondary to induced cytolethality and regenerative cell proliferation. Toxicity is not observed in rodents when chloroform is not converted to toxic metabolites at a rate sufficient to kill cells. Thus, tumors would not be anticipated at doses that do not induce cytolethality, contrary to the predictions of the LMS model. Inhalation studies in rodents show no cytolethality or regenerative cell proliferation in mouse liver at a chloroform concentration of 10 ppm as the no observed effect level (NOEL) or below. Using that NOEL and a safety factor approach, one can develop a VSD of 0.01 ppm. Integrating these data into the risk assessment process will yield risk estimates that are appropriate to the route of administration and consistent with the mode of action.

Effect of inhaled salmeterol on sulfur dioxide-induced bronchoconstriction in asthmatic subjects.

UNLABELLED: This study tested the capability of a single 42-microgram dose of inhaled salmeterol xinafoate, a long-acting beta 2-agonist, to protect against bronchoconstrictive effects of exposure to 0.75 ppm sulfur dioxide (SO2) during exercise, for up to 24 h. Ten SO2-responsive adult volunteers with stable asthma were studied under 4 conditions of drug pretreatment/exposure, administered in random order, double-blind: salmeterol/SO2, placebo/SO2, salmeterol/clean air, and placebo/clean air. Each subject underwent 10-min exposure/exercise challenges in a chamber 1, 12, 18, and 24 h after pretreatment. Exercise ventilation rates averaged 29 L/min. Response was measured as the decrement in FEV1 between preexposure and postexposure (lowest value within 30 min). After salmeterol, mean decrement post-SO2 was 7% at 1 h and 12% at 12 h. At 18 and 24 h after salmeterol, and at all times after placebo, mean decrements were 25 to 30%. After 18 and 24 h, salmeterol still improved base-line FEV1 relative to placebo, although improvement was not statistically significant at 24 h. Acute symptom increases accompanied FEV1 decrements. CONCLUSION: In our asthmatic subjects, pretreatment with salmeterol imparted clinically and statistically significant (p < 0.01) protection against bronchoconstriction induced by SO2/exercise for at least 12 h, and maintained an improvement in lung function for as much as 18 h.

[The genetic activity of superlow doses of antitumor antibiotics and 2-nitrofluorene: the ecological aspects of the problem]. / Geneticheskaia aktivnost' supermalykh doz protivoopukholevykh antibiotikov i 2-nitrofluorena: ékologicheskie aspekty problemy.

The genetic (mutagenic) activity of ultralow doses (below 1 x 10(-12)M of the antitumor antibiotics, anthracyclines and bleomycin, as well as the typical pollutant and component of the urban atmosphere 2-nitrofluorene, was studied on the model of Salmonella typhimurium LT2 TA98 his D3052. It was shown for the first time that carminomycin and 2-nitrofluorene at 1 x 10(-17) and 1 x 10(-22) M induced a two- to threefold increase in the number of revertants-prototrophs over the spontaneous background. The areas of increase (1 x 10(-15) M) and decrease (1 x 10(-19) and 1 x 10(-21) M) in the number of mutants, as compared with the spontaneous background, were found in the curve of dose dependence of the number of mutants in the presence of bleomycin. The results obtained were discussed in terms of their ecological importance.

Ozone toxicity in the rat. III. Effect of changes in ambient temperature on pulmonary parameters.

Pulmonary toxicity of ozone (O3) was examined in adult male Fischer 344 rats exposed to 0.5 parts/million O3 for either 6 or 23 h/day over 5 days while maintained at an ambient temperature (Ta) of either 10, 22, or 34 degrees C. Toxicity was evaluated by using changes in lung volumes and the concentrations of constituents of bronchoalveolar lavage fluid that signal lung injury and/or inflammation. Results indicated that toxicity increased as Ta decreased. Exposures conducted at 10 degrees C were associated with the greatest decreases in body weight and total lung capacity and the greatest increases in lavageable protein, lysozyme, alkaline phosphatase activity, and percent neutrophils. O3 effects not modified by Ta included increases in residual volume and lavageable potassium, glucose, urea, and ascorbic acid with exposure at 34 degrees C. Most effects were attenuated during the 5 exposure days and/or returned to normal levels after 7 air recovery days, regardless of prior O3 exposure or Ta. It is possible that Ta-induced changes in metabolic rate may have altered ventilation and, therefore, the O3 doses among rats exposed at the three different Ta levels.

Comparison of contact site cancer potency across dose routes: case study with epichlorohydrin.

Risk assessment for airborne carcinogens is often limited by a lack of inhalation bioassay data. While extrapolation from oral-based cancer potency factors may be possible for some agents, this is not considered feasible for contact site carcinogens. The change in contact sites (oral: g.i. tract; inhalation: respiratory tract) when switching dose routes leads to possible differences in tissue sensitivity as well as chemical delivery. This research evaluates the feasibility to extrapolate across dose routes for a contact site carcinogen through a case study with epichlorohydrin (EPI). EPI cancer potency at contact sites is compared across three bioassays involving different dose routes (gavage, drinking water, inhalation) through the use of dosimetry models to adjust for EPI delivery to contact sites. Results indicate a large disparity (two orders of magnitude) in potency across the three routes of administration when expressed as the externally applied dose. However, when expressed as peak delivered dose, inhalation and oral potency estimates are similar and overall, the three potency estimates are within a factor of seven. The results suggest that contact site response to EPI is more dependent upon the rate than the route of delivery, with peak concentration the best way to extrapolate across dose routes. These results cannot be projected to other carcinogens without further study.

Air pollution and mortality in Valencia, Spain: a study using the APHEA methodology.

STUDY OBJECTIVE: To assess the short term relationship between daily air pollution indicators (black smoke and sulphur dioxide (SO2)) and mortality in Valencia. DESIGN: This was an ecological study using time series data with application of Poisson regression. Daily variations in four selected outcome variables (total mortality, mortality in those over 70 years of age, and cardiovascular and respiratory mortality) were considered in relation to daily variations in air pollution levels for the period 1991-93. SETTING: The city of Valencia, Spain. MAIN RESULTS: The mean daily mortality was 17.5, and the average daily levels of air pollutants from the three monitoring stations included in the study were, 67.7 micrograms/m3 for black smoke, and 39.9 micrograms/ m3 for SO2. A significant positive association between black smoke and three of the four outcomes in the study was found. The estimated relative risk (RR) of dying corresponding to a 10 micrograms/m3 increase in mean daily black smoke over the whole period was 1.009 (95% confidence interval (95% CI): 1.003, 1.015). For mortality in the group aged more than 70 years and for cardiovascular mortality, the RRs were 1.008 (95% CI: 1.001, 1.016) and 1.012 (95% CI: 1.003, 1.022) respectively. The association with SO2 was less clear: it was only evident during the warm season. The estimated RRs in this case were 1.007 (95% CI: 0.999, 1.015) for total mortality, 1.009 (95% CI: 1.00, 1.21) for total mortality in those older than 70, and 1.012 (95% CI: 0.995, 1.026) for cardiovascular deaths. No significant association was found between mortality from respiratory diseases and either of the two pollutants. CONCLUSIONS: A positive relationship between air pollution and mortality was found in the short term, as has been shown in an important number of studies carried out elsewhere. Although the current levels of particulate air pollution in Valencia are not very high, they could have an effect on the number of premature deaths. Despite the fact that the association is weak, it is important at the public health level both because of the numbers of population exposed and the possibility of establishing control measures.

The South Karelia Air Pollution Study: effects of low-level exposure to malodorous sulfur compounds on symptoms.

Exposure to very low levels of ambient-air malodorous sulfur compounds and their effect on eye irritation, respiratory-tract symptoms, and central nervous system symptoms in adults were assessed. A cross-sectional self-administered questionnaire (response rate = 77%) was distributed during March and April 1992 to adults (n = 336) who lived in a neighborhood that contained a pulp mill and in a nonpolluted reference community (n = 380). In the exposed community, the measured annual mean concentrations of total reduced sulfur compounds and sulfur dioxide measured in two stations were 2 to 3 micrograms/m3 and 1 micrograms/m3, respectively. In the reference community, the annual mean concentration of sulfur dioxide was 1 micrograms/m3. The residents of the community near the pulp mill reported an excess of cough, respiratory infections, and headache during the previous 4 wk, as well as during the preceding 12 mo. The relative risk for headache was increased significantly in the exposed community, compared with the reference area: the adjusted odds ratio (aOR) was 1.83 (95% confidence interval [95% CI] = 1.06-3.15] during the previous 4 wk and 1.70 (95% CI = 1.05-2.73) during the preceding 12 mo. The relative risk for cough was also increased during the preceding 12 mo (aOR = 1.64, 95% CI = 1.01-2.64). These results indicated that adverse health effects of malodorous sulfur compounds occur at lower concentrations than reported previously.

Increased immune and inflammatory responses to dust mite antigen in rats exposed to 5 ppm NO2.

Immune hypersensitivity to house dust mite antigen (HDM) is a frequent cause of respiratory allergy. The objective of this study was to determine whether exposure to NO2, a common indoor air pollutant, modulates immune responses to HDM and influences immune-mediated lung disease. Brown Norway rats were immunized ip with 100 micrograms semipurified antigen and Bordetella pertussis adjuvant and challenged 2 weeks later with an intratracheal injection of 50 micrograms of a crude antigen preparation. Exposure to 5 ppm NO2 for 3 hr after both immunization and challenge procedures resulted in significantly higher levels of antigen-specific serum IgE, local IgA, IgG, and IgE antibody than air controls, and increased numbers of inflammatory cells in the lungs. Lymphocyte responsiveness to antigen in the spleen and MLN was also significantly higher in NO2-exposed animals. These data show that exposure to a common air pollutant can upregulate specific immune responses and subsequent immune-mediated pulmonary inflammation.

Evaluation of the subacute pulmonary and testicular inhalation toxicity of diborane in rats.

This study aimed to clarify the subacute pulmonary and testicular inhalation toxicity of diborane (B2H6, CAS: 19287-45-7) in rats. Male Wistar rats were exposed for 8 weeks to 0.11 or 0.96 ppm of diborane for 6 hr/day, 5 days/week. The control group was exposed to filtered air. Bronchoalveolar lavage fluid (BALF), hematological, biochemical, and histopathological examinations were conducted. Sperm counts and spermatic morphological changes were examined in epididymides, and histopathological examination was carries out in testes. BALF examinations revealed that the percentage of neutrophils increased in a dose-dependent manner and that of macrophages decreased in rats exposed to 0.96 ppm. Quantities of total and individual phospholipids in BALF increased in rats exposed to 0.96 ppm. The proportion of phosphatidylglycerol plus sphingomyelin decreased, and phosphatidylethanolamine and phosphatidylinositol increased in rats exposed to 0.96 ppm. LDH increased in rats exposed to 0.96 ppm, and ALP showed a dose-dependent increase. In serum, alpha 1-antitrypsin and superoxide dismutase activities increased in rats exposed to 0.11 or 0.96 ppm. These changes showed dose-dependent effects on the lung in rats exposed to diborane, possibly indicating that the hyperenergia of type II cells with proliferation and/or hypertrophy without histopathological changes occurred even in rats exposed to 0.11 ppm. Testicular examinations revealed no particular findings. The TLV-TWA of diborane (0.1 ppm) seems to be high and possibly unsafe, considering that the no-observed-effect level over 8 weeks for rat lung was under 0.11 ppm.

Uncertainty and variation in indirect exposure assessments: an analysis of exposure to tetrachlorodibenzo-p-dioxin from a beef consumption pathway.

Indirect exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other toxic materials released in incinerator emissions have been identified as a significant concern for human health. As a result, regulatory agencies and researchers have developed specific approaches for evaluating exposures from indirect pathways. This paper presents a quantitative assessment of the effect of uncertainty and variation in exposure parameters on the resulting estimates of TCDD dose rates received by individuals indirectly exposed to incinerator emissions through the consumption of home-grown beef. The assessment uses a nested Monte Carlo model that separately characterizes uncertainty and variation in dose rate estimates. Uncertainty resulting from limited data on the fate and transport of TCDD are evaluated, and variations in estimated dose rates in the exposed population that result from location-specific parameters and individuals' behaviors are characterized. The analysis indicates that lifetime average daily dose rates for individuals living within 10 km of a hypothetical incinerator range over three orders of magnitude. In contrast, the uncertainty in the dose rate distribution appears to vary by less than one order of magnitude, based on the sources of uncertainty included in this analysis. Current guidance for predicting exposures from indirect exposure pathways was found to overestimate the intakes for typical and high-end individuals.

Changes in the nasal epithelium of rats exposed by inhalation to mixtures of formaldehyde, acetaldehyde, and acrolein.

Formaldehyde, acetaldehyde, and acrolein are well-known upper respiratory tract irritants and occur simultaneously as pollutants in many indoor and outdoor environments. The upper respiratory tract, and especially the nose, is the prime target for inhaled aldehydes. To study possible additive or interactive effects on the nasal epithelium we carried out 1- and 3-day inhalation studies (6 hr/day) with formaldehyde (1.0, 3.2, and 6.4 ppm), acetaldehyde (750 and 1500 ppm), acrolein (0.25, 0.67, and 1.40 ppm), or mixtures of these aldehydes, using male Wistar rats and exposure concentrations varying from clearly nontoxic to toxic. The (mixtures of) aldehydes were studied for histopathological and biochemical changes in the respiratory and olfactory epithelium of the nose. In addition, cell proliferation was determined by incorporation of bromodeoxyuridine and proliferating cell nuclear antigen expression. Effects were primarily observed after 3 days of exposure. Histopathological changes and cell proliferation of the nasal epithelium induced by mixtures of the three aldehydes appeared to be more severe and more extensive in both the respiratory and the olfactory part of the nose than those observed after exposure to the individual aldehydes at comparable exposure levels. As far as nasal histopathological changes and cell proliferation are concerned neither dose addition nor potentiating interactions occurred at no-toxic-effect levels, except for a possible potentiating effect of acetaldehyde at noneffect levels. The results did not indicate a major role for aldehyde dehydrogenases in the biotransformation of the aldehydes studied. Activities of glutathione S-transferase and glutathione reductase after 3 days of exposure to acrolein, alone or in combination with formaldehyde and acetaldehyde, were depressed whereas the glutathione peroxidase activity was elevated. No decrease of nonprotein sulphydryl levels were observed. These findings suggest that, for no-toxic-effect levels, combined exposure to these aldehydes with the same target organ (nose) and exerting the same type of adverse effect (nasal cytotoxicity), but partly with different target sites (different regions of the nasal mucosa), is not associated with a greater hazard than that associated with exposure to the individual chemicals.