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PubMed1987

Single inhalation exposure to 90SrCl2 in the beagle dog: late biological effects.

Late-occurring biologic effects were studied in beagle dogs that were given graded levels of 90SrCl2 via single brief inhalation exposures and were subsequently observed for their life-span. Due to the soluble chemical form of the aerosol, 90Sr was rapidly translocated from lung and deposited in bone where it was subsequently retained for a long period of time. Radiation-induced lesions were confined to the bone, bone marrow, and adjacent soft tissue. Forty-five primary bone tumors occurred in 31 of 66 exposed dogs. Metastasis occurred from 21 tumors, with the lung being the most frequent site of metastasis (76%). Twenty-seven tumors were classified as different subtypes of osteosarcoma, 14 as hemangiosarcomas, 3 as fibrosarcomas, and 1 as a myxosarcoma. Four carcinomas arising from soft tissues adjacent to bone were also considered to be 90Sr induced. In contrast to bone tumors arising in beagles chronically exposed to 90Sr through ingestion, histologic lesions of radiation osteodystrophy were minimal in this study, indicating that these lesions are not a necessary precursor of osteosarcoma development. The incidences of hemangiosarcomas (31%) and telangiectatic osteosarcomas (11%) in addition to osteosarcomas suggest that the cell of origin for all of these neoplasms is a multipotent mesenchymal cell with the potential for various morphologic expressions dependent on local environmental factors.

Aerosols↗
PubMed2001

The influence of low-level sarin inhalation exposure on spatial memory in rats.

To study the influence of low-level sarin exposure on cognitive functions, the rats were exposed to three various low concentrations of sarin (Levels 1-3) for 60 min in the inhalation chamber. In addition, one group of rats was exposed to Level 2 of sarin repeatedly. Testing of cognitive functions was carried out using the Y-maze evaluating learning and spatial memory. The correct averse behavior of sarin-exposed rats in the Y-maze was tested several times within 6 weeks following sarin inhalation exposure to look for any cognitive impairments. The results were compared to the Y-maze performance of control rats exposed to pure air instead of sarin. While a subtle and short-term deficiency in the Y-maze performance was observed in rats exposed to the Levels 1 and 2 of sarin, the exposure to the Level 3 of sarin caused a significant decrease in the Y-maze performance for a relatively long time. Similar sarin-induced spatial memory impairments were demonstrated in rats exposed repeatedly to the Level 2. A decrease in the Y-maze performance was observed until the end of the third week following the last exposure to sarin. Thus, our findings confirm that both nonconvulsive symptomatic and clinically asymptomatic concentrations of sarin can cause relatively long-term memory impairments in sarin-poisoned rats when the rats are exposed to clinically asymptomatic sarin concentration repeatedly.

Administration, Inhalation↗
PubMed1987

Functional assessment of rabbit alveolar macrophages following intermittent inhalation exposures to sulfuric acid mist.

Sulfuric acid (H2SO4) aerosols are common in both ambient and occupational environments. This study examined the numbers and selected in vitro functional properties of alveolar macrophages recovered from rabbits undergoing inhalation exposure to 0.5 mg/m3 submicrometer (0.3 micron) H2SO4 for 2 hr/day. Bronchoalveolar lavage was performed on Days 3, 7, and 14 during the exposure period (specifically, 24 hr after either 2, 6, or 13 exposures). Total cell numbers and macrophage counts were increased on Day 3, but returned to control levels by Day 7; no change in polymorphonuclear leukocytes was observed at any time point. Macrophage substrate attachment was not affected by exposures to H2SO4, but random mobility was severely depressed at Days 7 and 14. The numbers of phagocytically active macrophages and the level of such activity were increased on Day 3, but became depressed by Day 14. These results demonstrate significant alterations in important functional properties of alveolar macrophages due to short-term intermittent exposures to H2SO4 aerosols; these changes have implications for the ability of the lungs to maintain adequate defense against deposited viable and nonviable particles.

Administration, Inhalation↗
PubMedDate not supplied

Nonspecific bronchial responsiveness assessed in vitro following acute inhalation exposure to ozone and ozone/sulfuric acid mixtures.

Air pollution may play some role in the recent increase in severity and prevalence of asthma, but the specific chemical components with the ambient pollutant mix that may be responsible have not been delineated. Since ambient exposures involve mixtures, it is essential to examine airway responses to realistic pollutant mixtures. This study examined the ability of single (3-h) inhalation exposures to ozone and to mixtures of ozone plus sulfuric acid to induce nonspecific airway hyperresponsiveness in healthy rabbits. Airway responsiveness was assessed using an in vitro assay involving administration of increasing doses of acetylcholine to bronchial rings obtained from animals exposed to 0.1-0.6 ppm ozone or to mixtures of ozone and 50-125 micrograms/m3 sulfuric acid aerosol; results were compared to those reported previously for sulfuric acid alone. Bronchial hyperresponsiveness to ozone was noted following exposure at all concentrations, but the combination of pollutants results in antagonism. The results support the potential for ozone to induce airway hyperresponsiveness in healthy animals and suggest that interaction with sulfuric acid may reduce the effectiveness of both pollutants.

Acetylcholine↗
PubMed1995

Disposition of butadiene monoepoxide and butadiene diepoxide in various tissues of rats and mice following a low-level inhalation exposure to 1,3-butadiene.

1,3-Butadiene (BD), a chemical used extensively in the production of styrene-butadiene rubber, is carcinogenic in Sprague-Dawley rats and B6C3F1 mice. Chronic inhalation studies revealed profound species differences in the potency and organ-site specificity of BD carcinogenesis between rats and mice. BD is a potent carcinogen in mice and a weak carcinogen in rats. Previous studies from our laboratory and others have shown marked differences between rats and mice in the metabolism of BD, which may account for species differences in carcinogenicity. The purpose of the present study was to examine the production and disposition of two mutagenic BD metabolites, butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2), in blood and other tissues of rats and mice during and following inhalation exposures to a target concentration of 62.5 p.p.m. BD. BDO was increased above background in blood, bone marrow, heart, lung, fat, spleen and thymus tissues of mice after 2 h and 4 h exposures to BD. In rats, levels of BDO were increased in blood, fat, spleen and thymus tissues. No increases in BDO were observed in rat lungs. BDO2, the more mutagenic of the two epoxides, was increased in the blood of rats and mice at 2 and 4 h after initiation of exposure to BD. In mice, BDO2 was detected in all tissues examined immediately following the 4 h exposure. This metabolite was detected in heart, lung, fat, spleen and thymus of rats, but at levels 40- to 160-fold lower than those seen in mice. Immediately after the 4 h exposure, blood levels of BDO2 were 204 +/- 15 pmol/g for mice but were 41-fold lower for rats. In the sensitive mouse target organs, heart and lungs, levels of BDO2 exceeded BDO levels immediately after the exposure. This study shows that the levels of BD epoxides are markedly greater in the mouse BD target organs. The high concentrations of BDO2 in these organs suggest that this compound may be particularly important in BD-induced carcinogenesis. Thus, although BD is oxidatively metabolized by similar metabolic pathways in rats and mice, the substantial quantitative differences in tissue levels of mutagenic epoxides between species may be responsible for the increased sensitivity of mice to BD-induced carcinogenicity.

Administration, Inhalation↗
PubMed1994

Determination of genotoxic and other effects in mice following short term repeated-dose and subchronic inhalation exposure to phosphine.

Phosphine is an important fumigant in the grain industry and has been reported to be genotoxic in occupationally exposed fumigators. This study reports on the effects of phosphine inhalation exposure at up to, and exceeding, occupational relevant levels in a subchronic (0.3, 1.0 and 4.5 ppm, 13 weeks) and a short term repeated-dose (5.5 ppm, 2 weeks) study in both sexes of Balb-c mice. The following end-points were examined: micronucleus induction in bone marrow, peripheral blood, spleen lymphocytes and skin keratinocytes, mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in lymphocytes, and weight gain and relative organ weights (kidneys, lungs, liver, heart, brain and spleen). After subchronic exposure, there was a highly significant negative linear correlation between proportional weight gain and exposure in both sexes (multiple linear regression, r = -0.56, P < 0.0001), with female mice showing a greater effect. Females also showed an increase in relative organ weights at the highest test dose, in contrast to males where there was a slight decrease. A statistically significant increase in micronucleus frequency was seen in the bone marrow and spleen lymphocytes of both sexes, but only at the highest concentration. The short term repeated-dose study revealed a slight decrease in weight gain in both sexes, with a greater effect in females. It is concluded that phosphine is weakly genotoxic in both sexes of mice, and has an effect on weight gain. However, the weak genotoxic effect may not be biologically significant as it was seen only in the subchronic study and only at the highest test concentration of 4.5 +/- 0.8 ppm (approaching the LD50). Although such exposure conditions are unlikely to be encountered in an occupational environment, caution should continue to be exercised in the use of phosphine until more data become available.

Animals↗
PubMedDate not supplied

Toxicological evaluation of 1-chloroacetophenone and dibenz[b,f]-1,4-oxazepine after repeated inhalation exposure in mice.

Toxicological evaluation was made on the effects of two peripheral sensory irritants (tear gases): 1-chloroacetophenone (CN) and dibenz[b,f]-1,4-oxazepine (CR). Animals had a 15-min daily inhalation exposure to average vapour concentrations of 87.6 mg CN m-3 or 1008 mg CR m-3 (both equal to 0.05 LC50) for 5 or 10 days and were sacrificed 24 h after the last exposure, when biochemical and histopathological observations were made. Both chemicals caused a significant decrease in body weight gain. Histological changes in lung, liver and kidneys were more severe after 10 than after 5 days of exposure and were more severe in CN-exposed than in CR-exposed mice. Organ weight to body weight ratios remained normal except for the spleen to body weight ratio, which decreased in CN-exposed mice after both 5 and 10 days of exposure. Biochemical indicators showed a toxic response only in CN-exposed mice, but the only consistent change was an increase in blood glucose. Hepatic alkaline phosphatase was not influenced, malondialdehyde concentration and acid phosphatase activity were increased only after 5 days of exposure and liver GSH concentration decreased after 10 days of exposure. Results indicate that CN is not only more toxic than CR in absolute terms but is also more toxic at the 5% level of their LC50.

Administration, Inhalation↗
PubMed1994

Toxicity of an anthraquinone violet dye mixture following inhalation exposure, intratracheal instillation, or gavage.

Anthraquinone dyes are utilized by the military in colored-smoke grenades. During production, workers in munitions plants may be exposed to fugitive emissions of these dyes or mixtures thereof. The effects of a prototype violet dye mixture (VDM) consisting of Disperse Red 11 (DR11), [1,4-diamino-2-methoxy-anthraquinone] and Disperse Blue 3 (DB3) [1-methylamino-4-hydroxyethylamino-anthraquinone] on F344 male and female rats have been investigated. Acute 1-day inhalation exposures (6 hr) to VDM were conducted at 1000, 300, 100, 70, 40, and 10 mg/m3, with an additional exposure to 40 mg/m3 6 hr/day for 5 days; 4.22 +/- 2.1 microns (MMAD +/- delta g). Lung burdens of dye, general histopathology, and/or liver function were evaluated at 0, 3, and 7 days postexposure. Unexpected lethality due to severe liver damage was observed with acute exposures of > or = 300 mg/m3 and in the 5-day 40 mg/m3 exposures. Centrilobular degeneration and necrosis of liver cells was concentration-dependent with inhalation of VDM > or = 40 mg/m3. In addition, nasal olfactory epithelium exhibited degeneration and necrosis with acute exposures > or = 10 mg/m3. Lung instillations at 250, 500, and 1000 micrograms of the VDM revealed no lung or liver toxicity. Because per os exposure due to preening was suspected as a major exposure route, a gavage study with the VDM and its two component dyes DR11 and DB3 (800 mg/kg) was undertaken. One day following gavage with DR11 or DB3, serum enzymes indicative of liver toxicity (LDH, SGPT, SDH, and ICDH) were slightly elevated (1-6x control). However, rats gavaged with VDM had serum enzyme levels 10-100x control by Day 1 after gavage, indicating acute liver toxicity. Activities of liver enzymes involved in xenobiotic and glutathione metabolism were also acutely affected. All of the dyes caused various degrees of induction of glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, and nonprotein sulfhydryls. The enzymes involved in xenobiotic metabolism (glutathione S-transferase, NADPH cytochrome-c reductase, and P450) were also elevated by the two component dyes, in contrast to their significant depression with VDM treatment. The similarity between the liver and olfactory epithelium effects of these compounds and the lack of pulmonary tissue effects is not fully understood, but the interaction of the individual dyes as VDM emphasizes the need to assess chemicals such as the anthraquinones as their likely-to-be-encountered mixtures.

Administration, Inhalation↗
PubMed1995

Toxic effects of acute inhalation exposure to 1,2,4-trimethylbenzene (pseudocumene) in experimental animals.

Neurotoxic and sensory respiratory irritation effects of 1,2,4-trimethylbenzene (pseudocumene) in male rats and male Balb/C mice were investigated in condition of acute inhalation exposure. Rotarod performance and pain sensitivity behaviour were tested in rats exposed to pseudocumene at concentrations of 1230-9840 mg/m3 (250-2000 ppm) immediately after termination of a four-hour exposure. The respiratory rate was measured in mice by the whole body plethysmographic method in 6 min duration exposure to various concentrations of pseudocumene. Exposure to pseudocumene resulted in concentration-dependent disturbances in rotarod performance, decrease in pain sensitivity in rats and depression of respiratory rate in mice. The EC50 value for rotarod performance behaviour disturbances was 4693 mg/m3 (954 ppm) and for decrease pain sensitivity EC50 was 5682 mg/m3 (1155 ppm). The concentration depressing the respiratory rate to 50% (RD50) was 2843 mg/m3 (578 ppm). As based on RD50 value the MAC values for pseudocumene 85 mg/m3 (17.0 ppm) is suggested.

Administration, Inhalation↗
PubMed1998

Toxic effects of acute inhalation exposure to 1-methylnaphthalene and 2-methylnaphthalene in experimental animals.

Neurotoxic and sensory respiratory irritation effects of 1-methylnaphthalene and 2-methylnaphthalene in male rats and male Balb/C mice were investigated under conditions of acute inhalation exposure. Rotarod performance and pain sensitivity behaviour were tested in rats exposed to 1-methylnaphthalene at concentrations of 152-407 mg/m3, and 2-methylnaphthalene at concentrations of 229-522 mg/m3 immediately after termination of a four-hour exposure. The respiratory rate was measured in mice by the whole body pletysmographic method in 6 min duration exposure to various concentrations of 1-methylnaphthalene and 2-methylnaphthalene. Exposure to both methylated naphthalene derivatives resulted in concentration-dependent decrease in pain sensitivity in rats and depression of respiratory rate and mice. At the concentrations applied no statistically significant disturbances in rotarod performance behaviour were observed. The concentrations depressing the respiratory rate to 50% (RD50) were 129 mg/m3 and 67 mg/m3, for 1-methylnaphthalene and 2-methylnaphthalene, respectively. As based on RD50 values, the MAC values of 4 mg/m3 for 1-methylnaphthalene, and of 2 mg/m3 for 2-methylnaphthalene are suggested.

Administration, Inhalation↗
PubMed1996

Gender and species differences in the metabolism of 1,3-butadiene to butadiene monoepoxide and butadiene diepoxide in rodents following low-level inhalation exposures.

Levels of butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2) were compared in tissues of male Sprague-Dawley rats and male B6C3F1 mice and in tissues of male and female Sprague-Dawley rats following inhalation exposures to 62.5 ppm 1,3-butadiene (BD). In male rats, BDO2 levels were highest in blood and were present at a concentration of only 5 +/- 1 pmol/g. Following a 6-h exposure, the concentration of BDO2 in the blood, femurs, lung and fat of female rats was 3 to 7-fold that of male rats. Levels of BDO were similar in tissues of female and male rats. Generally, levels of BDO were approximately 3 to 8-fold greater in mouse tissues as compared with rat tissues following 4-h exposures to BD. In blood, 204 +/- 15 pmol/g BDO2 was detected in male mice, while in rats, blood BDO2 levels were 5 +/- 1 pmol/g. This study shows marked species differences in tissue levels of BD epoxides, particularly BDO2, in rats and mice, and is the first to show gender differences in BD metabolism.

Administration, Inhalation↗
PubMed1976

A study of the inhalation of pentachlorophenol by rats. Part II. A new inhalation exposure system for high doses in short exposure time.

An exposure system has been designed which is applicable for short time, acute exposures of rats to the aerosol of pesticides. The aerosol is generated by compressed air aspiration. Larger droplets are removed by a cyclone separation. The exposure chamber has 12 inhalation sites separated from the animal containers by rubber seals which insure inhalation as the only route of exposure.

Aerosols↗
PubMed2000

Biotransformation and kinetics of excretion of tert-amyl-methyl ether in humans and rats after inhalation exposure.

tert-Amyl methyl ether (TAME) may be widely used as an additive to gasoline in the future. The presence of this ether in gasoline reduces the tail pipe emission of pollutants. Therefore, widespread human exposure to TAME may occur. To contribute to the characterization of potential adverse effects of TAME, its biotransformation was compared in humans and rats after inhalation exposure. Human volunteers (three males and three females) and rats (five males and five females) were exposed to 4 (3.8 +/- 0.2) and 40 (38.4 +/- 1.7) ppm TAME for 4 h in a dynamic exposure system. Urine samples were collected for 72 h in 6-h intervals and blood samples were taken at regular intervals for 48 h in humans. In urine, the TAME metabolites tert-amyl alcohol (t-amyl alcohol), 2-methyl-2, 3-butane diol, 2-hydroxy-2-methylbutyric acid, and 3-hydroxy-3-methylbutyric acid were quantified. TAME and t-amyl alcohol were determined in blood samples. After the end of the exposure period, blood concentrations of TAME were 4.4 +/- 1.7 microM in humans and 9.6 +/- 1.4 microM in rats after 40 ppm TAME, and 0.6 +/- 0.1 microM in humans and 1.4 +/- 0.8 microM in rats after 4 ppm. TAME was rapidly cleared from blood in both rats and humans. The blood concentrations of t-amyl alcohol were 9.2 +/- 1.8 microM in humans and 8.1 +/- 1.5 microM in rats after 40 ppm TAME, and 1.0 +/- 0.3 microM in humans and 1.8 +/- 0.2 microM in rats after 4 ppm TAME. t-Amyl alcohol was also rapidly cleared from blood. In urine of humans, 2-methyl-2,3-butane diol, 2-hydroxy-2-methylbutyric acid, and 3-hydroxy-3-methylbutyric acid were recovered as major excretory products in urine. In rats, 2-methyl-2,3-butane diol and its glucuronide were major TAME metabolites. t-Amyl alcohol and its glucuronide were minor TAME metabolites in both species. All metabolites of TAME excreted with urine in rats were rapidly eliminated, with elimination half-lives of less than 6 h. Metabolite excretion in humans was slower and elimination half-lives of the different metabolites were between 6 and 40 h in humans. The obtained data indicate differences in TAME biotransformation and excretion between rats and humans. In rats, TAME metabolites are rapidly excreted. In humans, metabolic pathways are different and metabolite excretion is slower. Recovery of TAME metabolites in urine was higher in humans as compared to rats, suggesting more intensive biotransformation of TAME in humans.

Administration, Inhalation↗
PubMed1998

Toxic effects of acute inhalation exposure to 1,2,4,5-tetramethylbenzene (durene) in experimental animals.

Neurotoxic and sensory respiratory irritation effects of 1,2,4,5-tetramethylbenzene (durene) in male rats and male Balb/C mice were investigated in the condition of acute inhalation exposure. Rotarod performance and pain sensitivity behaviour were tested in rats exposed to durene at concentrations of 880, 1100 and 1280 mg/m3 immediately after termination of a four-hour exposure. The respiratory rate was measured in mice by the whole body pletysmographic method in a 6-min exposure to various concentrations of durene. Exposure to durene resulted in concentration-dependent decrease in pain sensitivity in rats and depression of respiratory rate in mice. At applied durene concentrations, no statistically significant disturbances in rotarod performance behaviour were observed. The concentration depressing the respiratory rate to 50% (RD50) was 838 mg/m3. As based on RD50 value, MAC of 25 mg/m3 is suggested for durene.

Administration, Inhalation↗
PubMed1998

Trichloroethene levels in human blood and exhaled breath from controlled inhalation exposure.

The organic constituents of exhaled human breath are representative of bloodborne concentrations through gas exchange in the blood/breath interface in the lungs. The presence of specific compounds can be an indicator of recent exposure or represent a biological response of the subject. For volatile organic compounds, sampling and analysis of breath is preferred to direct measurement from blood samples because breath collection is noninvasive, potentially infectious waste is avoided, the sample supply is essentially limitless, and the measurement of gas-phase analytes is much simpler in a gas matrix rather than in a complex biological tissue such as blood. However, to assess the distribution of a contaminant in the body requires a reasonable estimate of the blood level. We have investigated the use of noninvasive breath measurements as a surrogate for blood measurements for (high) occupational levels of trichloroethene in a controlled exposure experiment. Subjects were placed in an exposure chamber for 24 hr; they were exposed to 100 parts per million by volume trichloroethene for the initial 4 hr and to purified air for the remaining 20 hr. Matched breath and blood samples were collected periodically during the experiment. We modeled the resulting concentration data with respect to their time course and assessed the blood/breath relationship during the exposure (uptake) period and during the postexposure (elimination) period. Estimates for peak blood levels, compartmental distribution, and time constants were calculated from breath data and compared to direct blood measurements to assess the validity of the breath measurement methodology. Blood/breath partition coefficients were studied during both uptake and elimination. At equilibrium conditions at the end of the exposure, we could predict actual blood levels using breath elimination curve calculations and a literature value partition coefficient with a mean ratio of calculated:measured of 0.98 and standard error (SE) = 0.12 across all subjects. blood/breath comparisons at equilibrium resulted in calculated in vivo partition coefficients with a mean of 10.8 and SE = 0.60 across all subjects and experiments and 9.69 with SE = 0.93 for elimination-only experiments. We found that about 78% of trichloroethene entering the body during inhalation exposure is metabolized, stored, or excreted through routes other than exhalation.

Administration, Inhalation↗
PubMed2002

DNA adducts of styrene-7,8-oxide in target and non-target organs for tumor induction in rat and mouse after repeated inhalation exposure to styrene.

Styrene by inhalation had been shown to increase the lung tumor incidence in mice at 20 ppm and higher, but was not carcinogenic in rats at up to 1000 ppm. Styrene-7,8-oxide, the major metabolic intermediate, has weak electrophilic reactivity. Therefore, DNA adduct formation was expected at a low level and a 32P-postlabeling method for a determination of the two regioisomeric 2'-deoxyguanosyl-O6-adducts at the alpha(7)- and beta(8)-positions had been established. The first question was whether DNA adducts could be measured in the rat at the end of the 2 years exposure of a bioassay for carcinogenicity, even though tumor incidence was not increased. Liver samples of male and female CD rats were available for DNA adduct analysis. Adducts were above the limit of detection only in the highest dose group (1000 ppm), with median levels of 9 and 8 adducts per 10(7) nucleotides in males and females, respectively (sum of alpha- and beta-adducts). The result indicates that the rat liver tolerated a relatively high steady-state level of styrene-induced DNA adducts without detectable increase in tumor formation. The second question was whether different DNA adduct levels in the lung of rats and mice could account for the species difference in tumor incidence. Groups of female CD-1 mice were exposed for 2 weeks to 0, 40, and 160 ppm styrene (6h per day; 5 days per week), female CD rats were exposed to 0 and 500 ppm. In none of the lung DNA samples were adducts above a limit of detection of 1 adduct per 10(7) DNA nucleotides. The data indicate that species- and organ-specific tumor induction by styrene is not reflected by DNA adduct levels determined in tissue homogenate. The particular susceptibility of the mouse lung might have to be based on other reactive metabolites and DNA adducts, indirect DNA damage and/or cell-type specific toxicity and tumor promotion.

Administration, Inhalation↗
PubMed2003

Acrylamide: a comparison of metabolism and hemoglobin adducts in rodents following dermal, intraperitoneal, oral, or inhalation exposure.

Acrylamide (AM), which is used to manufacture polymers, is carcinogenic and a reproductive and neurological toxicant. The objective of this study was to compare the metabolism of AM administered orally (po), dermally, intraperitoneally (ip), or by inhalation, and to measure the hemoglobin adducts produced. Rats and mice were exposed to 2.9 ppm [1,2,3-13C] and [2,3-14C]AM for 6 h. [2,3-14C]AM (162 mg/kg) or [1,2,3-13C]AM (13 8 mg/kg) in water was administered dermally to rats for 24 h, and [1,2,3-13C]AM was administered ip (47 mg/kg). Urine and feces were collected for 24 h. Urine was the major elimination route in rats (ip, 62% and po, 53% of the dose; dermal, 44% of the absorbed dose; inhalation, 31% of the recovered radioactivity) and mice (inhalation, 27% of the recovered radioactivity). Signals in the 13C-NMR spectra of urine were assigned to previously identified metabolites derived from AM glutathione conjugation (AM-GSH) and conversion to glycidamide (GA). AM-GSH was a major metabolic route in rats accounting for 69% (ip), 71% (po), 52% (dermal), and 64% (inhalation). In mice, AM-GSH accounted for only 27% (inhalation) of the total urinary metabolites. The remaining urinary metabolites were derived from GA. Valine hemoglobin adducts of AM and GA were characterized using liquid chromatography-mass spectrometry. The ratio of AM to GA adducts paralleled the flux through pathways based on urinary metabolites. This study demonstrates marked species differences in the metabolism and internal dose (Hb-adducts) of AM following inhalation exposure and marked differences in uptake comparing dermal with po and ip administration.

Acrylamide↗
PubMed1989

Lung toxicity after 13-week inhalation exposure to nickel oxide, nickel subsulfide, or nickel sulfate hexahydrate in F344/N rats and B6C3F1 mice.

The relative toxicity of nickel oxide (NiO), nickel sulfate hexahydrate (NiSO4.6H2O), and nickel subsulfide (Ni3S2) was studied in F344/N rats and B6C3F1 mice after inhalation exposure for 6 hr/day, 5 days/week, for 13 weeks. Exposure concentrations used (as mg Ni/m3) were 0.4-7.9 for NiO, 0.02-0.4 for NiSO4.6H2O, and 0.11-1.8 for Ni3S2. No exposure-related effects on mortality and only minor effects on body weight gain were seen in rats or mice. The most sensitive parameter for nickel toxicity was histopathologic change in the lungs of exposed animals were chronic active inflammation, fibrosis, and alveolar macrophage hyperplasia were associated with nickel exposure. There was an exposure-related increase in lung weight in rats and mice. Equilibrium levels of nickel in the lung were reached by 13 weeks of nickel sulfate and nickel subsulfide exposure, whereas lung levels of nickel continued to increase throughout exposure to nickel oxide. Additional exposure-related histopathologic lesions in treated animals included atrophy of the olfactory epithelium after nickel sulfate and nickel subsulfide exposure. No nasal lesions were seen after nickel oxide exposure. Lymphoid hyperplasia of the bronchial lymph nodes developed in animals exposed to all three nickel compounds. The order of toxicity corresponded to the water solubility of the nickel compounds, with nickel sulfate being most toxic, followed by nickel subsulfide and nickel oxide.

Administration, Inhalation↗