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Comparison of RBCA and CalTOX for setting risk-based cleanup levels based on inhalation exposure.

Risk-based corrective action (RBCA) and CalTOX (California EPA) are often used to develop risk-based soil cleanup levels. The determination of the entry parameters, including slope factors, degradation assumption, methodologies, and dispersion models for these two approaches greatly affect the onsite/offsite cleanup levels, risk distribution, and ranking of the influential factors. The subsurface soil-to-ambient air was considered as the only significant exposure pathway in this study. RBCA and CalTOX apply analytical equations and multimedia fugacity model, respectively, to simulate the transport of contaminants from subsurface soil to ambient air. Nine carcinogenic organic contaminants were selected as the target compounds. Environmental monitoring data collected from a contaminated site in southern Taiwan was used as model inputs. In this study, degradation assumption had greater influence on CalTOX evaluation than slope factors. The cleanup soil levels of all target chemicals developed by both models were close under the same slope factors and degradation assumptions, except for vinyl chloride and hexachlorobenzene. Furthermore, RBCA generally had larger offsite dispersion ratios than CalTOX, especially for long distances. The risk distribution obtained by RBCA was much board than by CalTOX. When 95th percentile was considered as the starting point, the SSTLs derived by RBCA were much stricter than by CalTOX. The ranking of influential factors in the onsite risk assessment for these two models were completely different because of their distinct model methodologies.

Body Weight↗

Tolerance to the discriminative stimulus effects of ethanol following chronic inhalation exposure to ethanol in C57BL/6J mice.

A significant consequence of chronic ethanol (EtOH) exposure is the development of tolerance. The present study was designed to investigate tolerance to the discriminative stimulus properties of EtOH following chronic EtOH exposure. Adult male C57BL/6J mice were trained to discriminate EtOH (1.00 g/kg; i.p.) from saline, using a food-reinforced two-lever operant task. Following acquisition and establishment of criterion discrimination performance, a series of generalization tests were conducted to generate a baseline EtOH dose-response curve with a calculated ED50 dose of 0.42 g/kg. Mice were then placed into control (air) or EtOH inhalation chambers for 64 h. In Experiment 1, discriminative stimulus generalization tests with the EtOH ED50 dose conducted 24 h following chronic EtOH (or air) exposure did not yield significantly different EtOH responding, although a trend towards reduced sensitivity to the EtOH cue (tolerance) was evident. In Experiment 2, a cumulative dosing procedure (ED50=0.37 g/kg) was employed, yielding a baseline EtOH dose-response function with a calculated ED50 dose of 0.37 g/kg. At 24 h following chronic EtOH exposure, re-determination of the EtOH dose-response curve revealed a significant shift to the right, with more than a twofold increase in the ED50 value (ED50=1.09 g/kg) compared to the control air exposure condition (ED50=0.49 g/kg). This apparent tolerance to the EtOH cue dissipated in chronic EtOH-exposed mice tested 48 h following the inhalation treatment (ED50=0.51 g/kg). These results demonstrate tolerance to the discriminative stimulus effects of EtOH in C57BL/6J mice following chronic EtOH exposure in inhalation chambers.

Animals↗

Influence of exhaled air on inhalation exposure delivered through a directed-flow nose-only exposure system.

In order to conserve material that is available in limited quantities, "directed-flow" nose-only exposure systems have at times been run at flow rates close to the minute ventilation of the animal. Such low-flow-rate conditions can contribute to a decrease of test substance concentration in inhaled air; near the animal nose, exhaled air and the directed flow of exposure air move in opposite directions. With a Cannon "directed-flow" nose-only exposure system (Lab Products, Maywood, NJ), we investigated the extent to which exposure air plus exhaled air can be inhaled by an animal. A mathematical model and a mechanical simulation of respiration were adopted to predict for a male Fischer 344 rat the concentration of test substance in inhaled air. The mathematical model was based on the assumption of instantaneous mixing. The mechanical simulation of respiration used a Harvard respirator. When the system was operated at an exposure air flow rate greater than 2.5 times the minute ventilation of the animal, the concentration of test substance in the inhaled air was reduced by less than 10%. Under these conditions, the circular jet of air exiting the exposure air delivery tube tended to reach the animal's nose with little dispersion. For exposure air flow rates less than 2 times the minute ventilation, we predict that the interaction of exhaled air and exposure air can be minimized by proportionally reducing the delivery tube diameter. These findings should be applicable to similar "directed-flow" nose-only exposure systems.

Air↗

Lung carcinogenesis in rats after inhalation exposure to (237)NpO2.

The results of several studies of experimental carcinogenesis suggest that, after inhalation of alpha-particle emitters, lung tumor incidence varies depending on the exposure rate and dose distribution in the tissue. In the case of transuranics, the main influencing factor would be the specific alpha-particle activity of the inhaled actinide. To confirm these results, long-term studies were performed using male Sprague-Dawley rats exposed to (237)NpO(2) by inhalation. The initial lung burdens of the animals ranged from 0. 1 to about 7 kBq. The rats were followed during their life span and weighed regularly, and their lung burdens were determined in vivo and at death to estimate the lung dose. At death, the incidence of lung tumors and their malignancy and histological types were analyzed. The analysis revealed a typically linear-quadratic dose response for incidence of malignant lung neoplasm and a differential dose response for various types of tumors. Although these results confirm the influence of the activity of the inhaled actinide oxide, further experiments are needed to be able to compare a more homogeneous population of animals.

Administration, Inhalation↗

Developmental toxicity induced by inhalation exposure of pregnant rats to N,N-dimethylacetamide.

Developmental toxicity of N,N-dimethylacetamide (DMAC) was examined by exposing pregnant rats by inhalation to DMAC vapor at 0 (control), 100, 300, 450 or 600 ppm (v/v) for 6 h/d during Gestation Days 6 through 19. Fetal body weight and the number of male live fetuses were significantly decreased, along with a tendency of the number of intrauterine deaths to increase. The number of fetuses with visceral and skeletal malformations was significantly increased in the 450 and 600 ppm groups, while the number of fetuses with anasarca as an external malformation was increased at 600 ppm. Observed cardiovascular malformations included ventricular septum defect, persistent truncus arteriosus, malpositioned subclavian branch and retroesophageal subclavian artery. Persistent truncus arteriosus was accompanied by ventricular septal defect (VSD). Incidences of the persistent truncus arteriosus, which was classified as a serious congenital heart disease affecting postnatal survival, were increased at 450 and 600 ppm. Increased liver weights and hepatocellular swelling occurred in the dams exposed to 300 ppm and above, whereas neither hepatocellular necrosis nor increased serum activity of liver transaminases was observed in any of the exposed groups. Maternal body weights were decreased at 450 and 600 ppm. The most sensitive signs of developmental toxicity appeared at the exposure level of 300 ppm which was also the level of slight maternal toxicity. The No-Observed-Adverse-Effect-Level (NOAEL) was determined as 100 ppm for the endpoints of fetal and maternal toxicities. The NOAEL of 100 ppm and the induction of serious cardiovascular malformations occurring at 450 ppm and above were discussed with reference to the existing occupational exposure limit for DMAC.

Acetamides↗

[Fine, ultrafine and nano- particles in the living and working setting: potential health effects and measurement of inhalation exposure].

Recently, experimental evidence has shown that exposure to very fine particles including those ultrafine or nanometric (NP, size < 100 nm) may cause severe health effects after inhalation in ambient and occupational environments (ultrafine particles in urban air, diesel emissions, welding fumes). Although the toxicological mechanisms for these effects have not yet been explained, the considerable body of existing data on occupational and environmental impact of airborne particles provides indications on the characteristics that influence toxicity and dose-response relationships. While for supermicrometric particles it is sufficient measuring exposure in terms of mass, for very fine particles, and in particular for NP, the characteristics that are more biologically relevant include the number, size, surface area, shape, solubility, and chemical reactivity. The rapidly developing field of nanotechnology, based on the use of a variety of NP (engineered or intentionally produced and with unique and specific properties), will certainly create new exposure scenarios which actually are largely unknown. The concern of potential health impact from the exposure to NP, during the last years has accelerated the development of systems for characterizing the exposures associated to the different potential sources of particles in the submicrometer and nanometer size ranges in both the environment and the workplace. In this review the current problems for characterizing the biologically relevant exposure to very fine and nanometric particles are discussed mainly in the context of occupational aerosols.

Humans↗

Olfactory mucosal lesions in F344 rats following inhalation exposure to pyridine at threshold limit value concentrations.

Pyridine is a volatile solvent used as an intermediate in the production of insecticides, herbicides, pharmaceuticals, and dyes. Pyridine is also found in tobacco smoke. Because inhalation is a primary route of exposure to pyridine, we examined the effect of inhaled pyridine on morphology at the portal of entry, the nose. Nasal tissues from F344/N rats exposed using a nose-only mode 6 hr/day for 4 days to either filtered air (controls) or one of two concentrations of pyridine vapor were examined histologically. The rats had been killed 18 hr after the last exposure. The two pyridine concentrations were the current threshold limit value (TLV, 5 ppm) and a high concentration (444 ppm). Olfactory epithelial lesions in rats exposed to both concentrations of pyridine included vacuolar degeneration of sustentacular cells; focal, marked attenuation of the epithelium; loss of vacuolar degeneration of sustentacular cells; focal, marked attenuation of the epithelium; loss of neurons; and the presence of intraepithelial luminal structures. The lesions were only slightly more severe in the rats exposed to 444 ppm compared to those rats exposed to 5 ppm pyridine. The results show that inhalation of pyridine at the current TLV concentration of 5 or 444 ppm causes lesions in the olfactory epithelium of rats.

Administration, Inhalation↗

1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo.

Subchronic and chronic studies were carried out in the rat and a developmental toxicity study in the rabbit with exposures to 1,1,1,2-tetrafluoroethane (HFC 134a) by inhalation. In the rat repeated exposure to 50,000 ppm HFC 134a for 13, 52, and 104 weeks elicited no effect on clinical condition, growth, and survival, or on a variety of hematological, clinical chemistry, and urinary parameters. Treatment-related pathological changes were seen only at study termination at 2 years and were confined to increased incidence of Leydig cell hyperplasia and adenoma in male rats exposed to 50,000 ppm. The tumors, which were also seen in control animals, were benign and not life-threatening. A battery of in vitro and in vivo tests gave no evidence of genotoxic activity. With exposure to pregnant rabbits, the only treatment-related effects were of minimal maternal toxicity at high exposure concentrations; there were no effects on fetal development. It is concluded that HFC 134a is of very low toxicity and should be an acceptable alternative to CFCs.

Administration, Inhalation↗

Chronic inhalation exposure of rats to nitromethane.

Male and female Long-Evans rats were housed in inhalation chambers and exposed to vapors of nitromethane (NM) at either 100 or 200 ppm. The animals were exposed 7 hr per day, 5 days per week for 2 years. Control groups of rats were also housed in a similar inhalation chamber, but NM was not introduced into the chamber. The animals were observed daily for signs of pharmacologic or toxicologic effect and body weights were recorded periodically. At the 2-year termination of the exposure period, clinical laboratory examinations (serum chemistry and hematology) were performed on selected animals and all surviving animals were sacrificed. All animals were necropsied and subjected to a thorough histopathologic examination. During the study there were no pharmacologic effects from exposure to NM at either 100 or 200 ppm. There was no effect on mortality on either sex at either exposure level. Body weights of male rats exposed to NM were not significantly different from those of control rats, but the body weights of female rats of both exposure groups were slightly less than their controls. There was no effect of exposure of rats of either sex to either level of NM on hematology. There were no clinically significant effects on serum chemistry. There were no effects of exposure to NM on organ weights. There were no significant differences in the nonneoplastic or neoplastic pathology related to exposure to NM.

Administration, Inhalation↗

Biodistribution and excretion of [11C]benzaldehyde by the rat after two-minute inhalation exposures.

1. Based on the decay characteristics of short-lived gamma-emitting radioisotopes a new acute exposure method was developed for studying the kinetics and biodistribution of inhaled toxic agents. Such body-penetrating radiation allows direct, non-invasive determination of the radiation in the animal at any time. 2. Rats exposed to 11C-labelled benzaldehyde for 2 min accumulated an average of 2.5 micrograms of this aldehyde. 3. Inhaled benzaldehyde was rapidly absorbed and at 1.5 min after exposure only 0.8% of the administered dose was resident in the lungs. This aldehyde was quickly distributed with the peak radioactivity in the organs occurring at 1.5 min after exposure. Subsequent loss of radiolabel from tissues was rapid and paralleled the removal from the blood. The adipose tissue cleared most slowly. 4. Benzaldehyde was rapidly excreted via the renal system with the kidneys containing 17% of the total administered activity at 5 min. The excreted radiolabelled compound co-chromatographed with hippuric acid on t.l.c.

Adipose Tissue↗

Maternal-fetal distribution of manganese in the rat following inhalation exposure to manganese sulfate.

Studies examining the pharmacokinetics of manganese during pregnancy have largely focused on the oral route of exposure and have shown that the amount of manganese that crosses the rodent placenta is low. However, limited information exists regarding the distribution of manganese in fetal tissues following inhalation. The objective of this study was to determine manganese body burden in CD rats and fetuses following inhalation of a MnSO4 aerosol during pregnancy. Animals were evaluated following pre-breeding (2 weeks), mating (up to 14 days) and gestational (from gestation day (GD) 0 though 20) exposure to air or MnSO4 (0.05, 0.5, or 1 mg Mn/m(3)) for 6h/day, 7 days/week. The following maternal samples were collected for manganese analysis: whole blood, lung, pancreas, liver, brain, femur, and placenta. Fetal tissues were examined on GD 20 and included whole blood, lung, liver, brain, and skull cap. Maternal lung manganese concentrations were increased following exposure to MnSO4 at >or=0.05 mg Mn/m(3). Maternal brain and placenta manganese concentrations were increased following exposure of pregnant rats to MnSO4 at >or=0.5 mg Mn/m(3). Increased fetal liver manganese concentrations were observed following in utero exposure to MnSO4 at >or=0.5 mg Mn/m(3). Manganese concentrations within all other fetal tissues were not different from air-exposed controls. The results of this study demonstrate that the placenta partially sequesters inhaled manganese, thereby limiting exposure to the fetus.

Animals↗

Molecular dosimetry of N7-(2-hydroxypropyl)guanine in tissues of F344 rats after inhalation exposure to propylene oxide.

Propylene oxide (PO) is a high-volume chemical intermediate that causes a low incidence of nasal tumors in rodents exposed to high concentrations (> or =300 p.p.m.). PO reacts with DNA forming mainly N7-(2-hydroxypropyl)guanine (7-HPG). The exposure-dependent accumulation of 7-HPG in nasal respiratory epithelium (NRE), lung and liver was determined in male F344 rats exposed to PO (0, 5, 25, 50, 300 or 500 p.p.m.) by the inhalation route for 3 or 20 days (6 h/day; 5 days/week). These exposures ranged from low concentrations, such as those potentially occurring in the workplace, to high concentrations that proved to be carcinogenic in rodents. Analysis of 7-HPG in DNA by gas chromatography-high-resolution mass spectrometry (GC-HRMS) showed a linear response in 7-HPG for all three tissues after 3 days of exposure, and for NRE and lung after 20 days of exposure. A slightly sublinear response in 7-HPG was observed in liver after 20 days of exposure. For both exposure periods, the NRE had the highest concentration of 7-HPG, followed by lung and liver. The amount of 7-HPG in NRE was seven and 17 times higher than in lung and liver, respectively, for the 3 day exposures. For the 20 day exposures, the concentration of 7-HPG in NRE was six and 13 times higher than that in lung and liver, respectively, over the concentration range studied. These results demonstrate a much higher extent of DNA alkylation in the target tissue for carcinogenesis, than in non-target tissues. As PO-induced tumor formation was highly sublinear, occurring only at high vapor concentrations, whereas 7-HPG adducts were shown to be linearly dependent on airborne concentration, these results suggest that 7-HPG is not sufficient for PO nasal carcinogenesis and that other factors such as increased cell proliferation may be important in determining the tumor exposure response.

Alkylation↗

Inhalation exposure of rats to metal aerosol. I. Effects on pulmonary surfactant and ascorbic acid.

Female albino Wistar rats were exposed to less than 5 microns particles separated from nickel refinery waste. The generated aerosol of 50 mg m-3 mainly consisted of metal oxides, the most toxic being NiO and Cr2O3. The exposure of 5 h per day, 5 days per week, lasted for 4 weeks or 4 months. At the end of the exposure period the amounts of pulmonary surfactant and ascorbic acid were estimated in both exposed and control rats. The amount of pulmonary surfactant was elevated after both exposure times, while ascorbic acid increased significantly (P less than 0.02) only after 4 weeks of exposure.

Administration, Inhalation↗

Pulmonary inflammation and fibrosis following subacute inhalational exposure to silica: determinants of progression.

To evaluate components of the pulmonary cellular response to inhaled silica that might be determinants of progression to fibrosis, we developed a model of the early stages of chronic human silicosis. Groups of mice were subacutely exposed either to alpha-quartz or to nonfibrogenic titanium dioxide dust as a control. Induction of lesions by inhaled silica was dependent upon the size distribution and dose of the particles. A novel observation was that low intensity exposure to silica evoked reversible inflammatory lesions that were characterized by focal aggregation of particle-laden alveolar macrophages near terminal airways. In contrast, higher intensity exposure elicited progressive pulmonary inflammation, including a significant perivascular influx of T-lymphocytes early in the response. The airspace inflammatory lesions exhibited a statistically significant decline in numerical density over time. Meanwhile, deposition of collagen was observed at perivascular locations, which were anatomically distinct from the initial foci of inflammation, and the numerical density of fibrotic lesions increased significantly with time. We speculate that this pattern of response might be related to alveolar clearance mechanisms being overwhelmed, followed by translocation and sequestration of particles in the interstitium, subsequently leading to T-lymphocyte recruitment and ultimately to the development of fibrosis.

Acute-Phase Reaction↗

A histopathologic study of the nervous system after inhalation exposure of 1-bromopropane in rat.

1-Bromopropane (1-BP) has recently become known as an alternative cleaning material with less damage to the ozone layer. However, its toxicity is not fully evaluated. This study was designed to investigate the repeated inhalation toxicity of 1-BP on the nervous systems in Sprague-Dawley rats. The experiment was done by repeated exposure of the rats to 0, 200, 500, and 1250 ppm for 6 h per day, 5 days a week, for 13 weeks, respectively. Morphologic studies were done for the central nervous system, sacral and peroneal nerves. The serial sections of the brain and spinal cord of 1-BP inhalation groups revealed no pathological features either in the gray or white matter. The nerve fiber teasing, light and electron microscopic studies of the sacral and peroneal nerve fibers showed no significant difference between 1-BP inhalation groups and the control group. From these results, it is concluded that the nervous system is histologically resistant to the repeated inhalation of 1-BP up to 1250 ppm for 13 weeks. Experiments with higher concentrations of 1-BP and the functional studies are necessary to clarify the 1-BP toxicity.

Animals↗

Chronic inhalation exposure of rats to vapors of nitroethane.

Male and female Long-Evans rats were exposed in inhalation chambers to vapors of nitroethane at concentrations of 100 or 200 ppm, 7 hr per day, 5 days per week for 2 years. During the study, general observations were made daily and body weights were obtained weekly for the first 6 months of the study and biweekly thereafter. Any rats that were found dead or sacrificed moribund during the 2-year exposure phase of the study were given a thorough gross examination and tissues were retained for microscopic examination. After 2 years of inhalation of nitroethane, all surviving rats were sacrificed and subjected to the same thorough gross examination. Blood samples were obtained from representative groups of animals for hematology and serum chemistry studies. All rats were examined histopathologically. Exposure of the rats to nitroethane had no pharmacologic effects nor were there any effects on mortality of rats of either sex at either level of exposure. Throughout most of the investigation, body weights of both sexes of both exposed groups were slightly less than those of respective controls, but lack of a well-defined dose-response relationship suggested the involvement of factors other than just exposure to nitroethane. There were no effects of exposure to nitroethane on hematology nor were there any biologically significant effects of exposure to nitroethane on clinical chemistry or on organ weights. No significant nonneoplastic or neoplastic pathology was found as a consequence of exposure of the rats to nitroethane.

Administration, Inhalation↗

Effects of acute inhalation exposure to isoamyl nitrite on the hypothalamo-pituitary-adrenal axis in male Sprague-Dawley rats.

Isoamyl nitrite (IAN) is a member of the family of volatile organic nitrites that exert vasodilatory effects and have recently exhibited a considerable potential for inhalation abuse. In an effort to provide mechanistic insight into the neurotoxic effects and abuse potential of these agents, the present study was designed to evaluate the acute effects of IAN on the hypothalamo-pituitary-adrenal (HPA) axis. Attempts were also made to correlate the neuroendocrine effects of IAN with its pharmacokinetic profile. Male Sprague-Dawley rats were exposed to 600 or 1200 ppm IAN by inhalation for 10 or 30 min. Following exposure, adrenocorticotropic hormone (ACTH) and corticosterone in plasma and corticotropin-releasing factor (CRF) in three brain regions (hypothalamus, hippocampus, and frontal cortex) were determined by radioimmunoassay. Levels of IAN in the three brain regions as well as in blood were measured by gas chromatography to determine the target tissue concentrations responsible for neuroendocrine changes. Uptake of IAN into blood and all brain regions was very rapid, as stable concentrations were achieved within 10 min of exposure and maintained for 30 min of continuous inhalation. Plasma corticosterone decreased significantly after 10 min inhalation of both IAN doses, and returned to control levels after 30 min. Moreover, plasma ACTH was significantly increased by 10 and 30 min of exposure to 600 and 1200 ppm IAN, while hypothalamic CRF increased significantly after 30 min of exposure to the 600 ppm dose. These latter findings suggest activation of the hypothalamus and pituitary due to a reduction in negative feedback resulting from the initial decrease in corticosterone. Although plasma ACTH was greatly increased after 30 min, plasma corticosterone levels were unchanged, indicating that IAN primarily acts to inhibit the synthesis or secretion of adrenal steroids and that activation of the HPA axis is not involved in the behavioral manifestations of IAN inhalation. These compensatory effects of HPA axis regulation, and possibly the vasodilatory properties of IAN, also likely precluded the establishment of definitive relationships between observed changes in hormone levels and blood or regional brain concentrations of the inhalant.

Administration, Inhalation↗