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Biomedical subjects

Yoko Ishihara

Publications and source records attributed to Yoko Ishihara.

At least 19 recordsLinked to original sources

Estimation of visual outcome without treatment in patients with subfoveal choroidal neovascularization in pathologic myopia.

OBJECTIVE: To clarify prognostic factors of long-term visual outcome without treatment in patients with myopic choroidal neovascularization (CNV) and estimate a regression equation to predict visual acuity at 5 years after CNV onset. METHODS: Fifty-four eyes of 54 consecutive patients with high myopia and subfoveal CNV who did not receive treatment were identified using clinical records from 1988 to 2004. Photodynamic therapy not approved for myopic CNV in Japan during this period. The association of best-corrected visual acuity (BCVA) at 5 years after CNV onset with patient age, refractive error, axial length, initial BCVA, myopic retinopathy grade, duration of persistent hemorrhage, CNV size at onset, and size of hemorrhage around the CNV was analyzed using Spearman's correlation and multiple linear regression analysis. RESULTS: BCVA at 5 years after onset was significantly associated with patient age, CNV size, and initial BCVA (P<0.05, Spearman's correlation). The regression equation estimating BCVA at 5 years after CNV onset was based on age and initial BCVA (R2=0.43). When subjects were divided into groups according to age (<40 and >or=40 years), CNV size, axial length and duration of persistent hemorrhage influenced BCVA at 5 years in patients under 40 years; while only initial BCVA was an influence in those at least 40 years old. CONCLUSIONS: We developed a linear predictive model to estimate BCVA at 5 years after onset of myopic CNV without treatment based on the identified prognostic factors. This information might be important for managing patients with myopic CNV.

Adult↗

Curcumin inhibits the proliferation and mineralization of cultured osteoblasts.

The effects of curcumin, which is an important constituent of rhizomes of the plant Curcuma longa Linn, on the metabolism of osteoblasts were examined in cultures of rat calvarial osteoblastic cells (ROB cells). The proliferation of cells was markedly inhibited upon exposure of cells to curcumin at 5x10(-6) to 1x10(-5) M. Curcumin at 1x10(-5) M did not induce apoptosis in ROB cells but arrested cells at the G1 phase of the cell cycle. In addition, curcumin stimulated the expression of mRNA for p21(WAF1/CIP1), which inhibits the activity of cyclin-dependent kinases, and inhibited the phosphorylation of histone H1. Furthermore, curcumin reduced the rate of deposition of calcium and the formation of mineralized nodules. Our results indicate that curcumin might inhibit the proliferation and mineralization of osteoblastic cells through the expression of p21(WAF1/CIP1).

Animals↗

Isolation and characterization of a novel immunomodulatory alpha-glucan-protein complex from the mycelium of Tricholoma matsutake in basidiomycetes.

Tricholoma matsutake, a high-class edible mushroom in Japan, has been reported to have excellent biological activities, but difficulty in cultivating the fruit bodies and limited bulk availability have restricted detailed studies. We have developed a method of culturing in tanks, enabling the bulk supply of the mycelia. The preparation (CM6271) exerts modulative effects on the immune competence of mice and rats. In this study, a sodium hydroxide extract of CM6271 was defatted followed by fractionation with a combination of ion exchange chromatography and gel filtration in order to identify the components involved in the expression of the activity, and a single peak fraction (MPG-1) was obtained with reversed phase chromatography. MPG-1 was a glycoprotein (sugar:protein ratio, 94.3:5.7) with a relative molecular mass of 360 kDa, and the sugar moiety contained about 90% glucose. NMR spectra and methylation analysis revealed that the alpha-1,4-linkage was the predominant glucan linkage with alpha-1,6- and alpha-1,2-linkages in the minority. The amino acid composition in the protein moiety was rich in glutamine, alanine, asparagine, leucine, glycine, valine, serine, threonine, isoleucine, and proline. MPG-1 was resistant to degradation with amylase or protease. The oral administration of MPG-1 promoted, in a dose-dependent manner, the recovery of the mouse natural killer cell activity and serum IL-12 level that had been reduced by the loading of restraint stress. The dose of MPG-1 (25 mg/kg) required for the expression of the effect decreases to 1/12 of that of CM6271 (300 mg/kg). Furthermore, MPG-1 formed a complex with TGF-beta1 in vitro, modulating the biological activity of TGF-beta1 by binding to its active form. These results indicate that the mycelium of T. matsutake contains a novel alpha-glucan-protein complex with immunomodulatory activities.

Animals↗

Abdominal wall and thigh abscess resulting from the penetration of ascending colon cancer.

An unusual case is described in which an abdominal wall and thigh abscess was an initial symptom of ascending colon cancer. A 76-year-old woman was referred to our hospital for investigation of fever and abdominal and thigh swelling. Computed tomography revealed a right abdominal wall, retroperitoneal, psoas and thigh abscess formation suspected to be caused by colon perforation. Due to the patient's poor general condition, local drainage of the abscess was performed on the following day of hospitalization. Histological examination of necrotic tissues removed form the retroperitoneal cavity demonstrated adenocarcinoma of the colon. The patient subsequently underwent right hemicolectomy with lymph nodal dissection after 19 days of the drainage procedure and was transferred to another hospital on the 49th day following the second surgery.

Abdominal Wall↗

Factors controlling the complex architecture of native and modified cyclodextrins with dipeptide (Z-Glu-Tyr) studied by microcalorimetry and NMR spectroscopy: critical effects of peripheral bis-trimethylamination and cavity size.

Complex stability constant (K), standard free energy (DeltaG degrees ), reaction enthalpy (DeltaH degrees ), and entropy change (TDeltaS degrees ) for 1:1 inclusion complexation of the diastereomeric dipeptides Z-d/l-Glu-l-Tyr (Z = benzyloxycarbonyl) and its component amino acids (Z-d/l-Glu and N-Ac-Tyr) with native alpha-, beta-, and gamma-cyclodextrins (CDs) and A,X-modified bis(6-trimethylammonio-6-deoxy)-beta-CDs (AX-TMA(2)-beta-CDs) were determined in buffer solution (pH 6.9) at T = 298.15 K by isothermal titration microcalorimetry. Concurrent NMR spectral examinations revealed that the penetration mode and the resulting complex architecture are dramatically altered by the peripheral modification and also by the CD's cavity size. Upon complexation of the ditopic Z-Glu-Tyr guest, native alpha- and beta-CDs preferentially bind the Z's phenyl group, whereas AX-TMA(2)-beta-CDs predominantly include the Tyr's phenol moiety. In contrast, native gamma-CD includes both of the aromatic moieties simultaneously in the same cavity. Furthermore, for isomeric AB-, AC, and AD-TMA(2)-beta-CDs, an inversion of enantioselectivity and a switching of the penetration mode were observed, critically depending on the position of TMA substituents.

Calorimetry↗

Inhibition of ossification in vivo and differentiation of osteoblasts in vitro by tributyltin.

Tributyltin is ubiquitous in the environment and an endocrine disruptor for many wildlife species. However, minimal information is available regarding the effect of this chemical on bone formation. When tributyltin chloride (TBT) (1mg/kg body weight) was administered subcutaneously to pregnant mice at 10, 12, and 14 days post coitus (dpc), fetuses at 17.5 days post coitus revealed the inhibition of calcification of supraoccipital bone. In contrast, 1mg/kg body weight monobutyltin trichloride (MBT) did not affect the fetal skeleton. Therefore, we examined the effects of TBT and its metabolites (dibutyltin dichloride, DBT, and MBT) on bone metabolism using rat calvarial osteoblast-like cells (ROB cells). The viability of ROB cells was not affected by the exposure of the cells to 10(-10) to 10(-7)M TBT. However, TBT reduced the activity of alkaline phosphatase (ALPase) and the rate of deposition of calcium of ROB cells. In addition, the expression levels of mRNA for ALPase and osteocalcin, which are markers of osteoblastic differentiation, were depressed by the treatment with TBT. TBT inhibited ALPase activity and the deposition of calcium to a greater extent than did DBT. MBT had no effect on the osteoblast differentiation of ROB cells. Tributyltin is known to inhibit the activity of aromatase. However, the aromatase inhibitor aminoglutethimide did not reproduce the inhibitory effects of TBT on osteoblast differentiation. Our findings indicate that TBT might have critical effects on the formation of bone both in vivo and in vitro although its action mechanism is not clarified.

Animals↗

Cancer-related attitudes: A comparative study in Japan and the US.

The cancer-related attitudes and beliefs of adults living in central Japan (N = 357) were compared to those of respondents in a US state (Hawaii) (N = 223) consisting of both Japanese (n = 106) and Caucasian (n = 117) individuals. Almost all US subjects endorsed doctors disclosing cancer diagnoses to their patients, while a minority of the Japan sample supported cancer disclosure as a general practice. However, the majority of Japan respondents expressed a personal preference to be told if they themselves were diagnosed with cancer, as did virtually all US respondents. US subjects were more optimistic than Japanese subjects about cancer's curability, both at the present time and in the future; Japanese Americans scored intermediate between Japanese and Caucasian Americans. Word-association data indicated that cancer was most likely to be associated with death by Japanese respondents. The data support the continued international differences in views about cancer and suggest that some of these differences persist over many generations of US residence.

Adult↗

Health attitudes and behaviors: comparison of Japanese and Americans of Japanese and European Ancestry.

Adults living in Japan (N = 357) and the US (N = 223) completed semi-structured interviews assessing health-related attitudes and practices. The US respondents were of Japanese (N = 106) and European (N = 117) ancestry. Results indicated considerable similarity between the two US groups and significant differences between the Japanese and American respondents. The Japanese respondents placed less priority on health, had less belief in the efficacy of health screening tests, lower levels of internal health locus of control (HLOC), and higher levels of chance and powerful-others HLOC. While Japanese and Americans had similar overall levels of healthy behaviors, the Japanese were less likely to have obtained health screening tests (especially gynecologic exams). The findings have implications for adapting health promotion programs in the context of Japanese and American cultures.

Asian People↗

Inhibition of decrease in natural killer cell activity in repeatedly restraint-stressed mice by a biological response modifier derived from cultured mycelia of the basidiomycete Tricholoma matsutake.

OBJECTIVE: To develop a method to cope with stress-induced reduction in immunocompetence, we evaluated the immunomodulatory activities of a biological response modifier derived from the mycelia of the basidiomycete Tricholoma matsutake (CM6271) in mice under repeated restraint stress. METHODS: C57BL/6 mice were inserted, one per tube, into 50-ml polypropylene tubes into which more than 30 ventilation holes had been drilled, and were restrained everyday for 20 days in this fashion for set periods of time. Natural killer (NK) cell activity and NK1.1-positive cell counts in the spleen, ACTH and corticosterone levels in the blood were determined. CM6271 was orally administered daily during the restraint stress period. RESULTS: (1) When the mice were restrained in a confined space for 6 h per day for 20 days, the NK cell activity and the NK1.1-positive cell counts in the spleen significantly decreased after day 5 with an increase in the blood ACTH and corticosterone levels. (2) Oral administration of CM6271 during the restraint stress period significantly prevented the stress-induced decrease in NK cell activity. The effect was dependent on the timing, duration, and doses administered. (3) CM6271 did not significantly affect the splenic NK1.1-positive cell counts or the levels of blood ACTH and corticosterone in restraint-stressed mice. CONCLUSION: The above findings suggest that CM6271 inhibits the restraint stress-induced decrease of NK cell activity in a timing of administration and dose-dependent manner.

Animals↗

Factors associated with the development of chorioretinal atrophy around choroidal neovascularization in pathologic myopia.

PURPOSE: To examine the influencing factors on the development of chorioretinal atrophy, which is the main cause of long-term visual decrease in myopic choroidal neovascularization (CNV), in a large series of highly myopic patients. METHODS: Sixty-five patients (81 eyes) with myopic CNV were studied retrospectively. The influence of the patient's age, refractive error, axial length, visual acuity at onset of CNV, size of CNV, and grade of myopic retinopathy on the extent of chorioretinal atrophy more than 3 years after CNV onset was investigated by means of multiple linear regression analysis. RESULTS: Seventy-seven of 81 eyes (95.1%) developed chorioretinal atrophy around myopic CNV during the follow-up period. Multiple linear regression revealed that age was the most influencing factor for the development of chorioretinal atrophy in all the subjects. When we divided the subjects into two groups according to their age, however, CNV size was the only factor to influence the development of chorioretinal atrophy in the patients younger than 40 years, whereas age was still the only influencing factor in those older than 40 years. CONCLUSIONS: The factors influencing the development of chorioretinal atrophy differ according to patient age. Local factors, such as CNV size, determine the tendency to develop chorioretinal atrophy in young patients. Systemic factors, such as patient age, play a greater part in older subjects.

Atrophy↗

Expression of matrix metalloproteinase, tissue inhibitors of metalloproteinase and adhesion molecules in silicotic mice with lung tumor metastasis.

The number of metastatic foci in silicotic mice is approximately 1.5-fold that in normal mice and in mice treated with TiO2 as inert particles. Expression of matrix metalloproteinases (MMPs) tissue inhibitors of metalloproteinases (TIMPs) and selectins was investigated in silicotic mice with lung tumor metastasis. Expression of MMP-9 and P-selectin mRNA, but not MMP-2 and E-selectin, increased significantly, showing decreases of the ratio of expression in TIMPs/MMP-9 in tumor-bearing silicotic mice compared with the tumor-bearing normal mice and mice treated with TiO2. Pretreatment with anti-P-selectin antibody inhibited number of metastatic foci significantly in silicotic mice, while pretreatment of animals with anti MMP-9 antibody showed slight decrease of metastatic foci. This evidence indicated that up-regulation of P-selectin expression contributed to enhanced rate of tumor metastasis in lung with silicosis.

Animals↗

Chronic diesel exhaust exposures of rats demonstrate concentration and time-dependent effects on pulmonary inflammation.

Long-term, repeated exposure to particles in air pollution increases the risk for chronic respiratory diseases and cardiorespiratory mortality. The biological linkages remain poorly understood in chronic exposure to particle matter. To elucidate and verify these linkages, we investigated long-term exposure to diesel emission with respect to dose dependence and the effect of components without particles from diesel emission in rats. Wistar rats were exposed to filtered air (C group), diesel exhaust at low (L group), medium (M group), and high level (H group), or at a medium concentration diesel exhaust without particulate matter (MG group), for 16 h/day, 6 days/wk, for 6, 12, 18, or 24 mo. Anesthetized animals were sacrificed and bronchoalveolar lavage (BAL) fluid from the lung and blood from the right ventricle were collected. Various biomarkers of inflammation and components of mucus and surfactant were determined. Changes in total cell counts and cell differentiation, total protein, mucus and surfactant components, and prostaglandin E(2) in BAL fluid, but not biomarkers in plasma, showed statistical differences among the C, L, M, and H groups during the experimental period. The changes in these biomarkers in the H group were greater than those in the M group, whereas those in the L group showed no significant changes compared with those in the C group during the experimental period. The onset of significant changes in inflammatory cells and these biomarkers in BAL fluid for the M and H groups was at 6 to 12 mo of exposure. The maximum level was reached at 12 to 18 mo of exposure. Although BAL prostaglandin E(2) decreased significantly at 6 mo of exposure in the M and H groups, this trend was not observed in the C and L groups. Animals exposed to a medium level of diesel exhaust without particulate matter showed significantly less inflammatory cells and various biomarkers in BAL fluid than animals exposed to the same level of diesel exhaust with particulate matter during the experimental period. These findings suggest that biological response to inhaled particles is aggravated during chronic exposure to diesel exhaust dose-dependently. Inflammation and overproduction of mucus and surfactant components reached a plateau at 12 or 18 mo of exposure during a 24-mo experimental period. No adverse effect of particles (less than 1.0 mg particles/m(3) of diesel emission) was observed in these rats. However, our data suggest that particulate matter plays an important role during development of chronic lung injury induced by diesel emission exhaust.

Animals↗

Enhanced recovery of NK cell activity in mice under restraint stress by the administration of a biological response modifier derived from the mycelia of the basidiomycete Tricholoma matsutake.

Some types of stressor act on the immune system via the network comprising the endocrine-immune-nervous systems, and are reportedly responsible for the onset of diseases as well as giving impetus to their advance. It is important for the maintenance and promotion of health to cope with stress-induced changes in immunocompetence. Therefore, we studied the effects of administration of a novel biological response modifier (CM6271) derived from the mycelia of the basidiomycete Tricholoma matsutake on the NK cell activity in mice under restraint stress, in order to evaluate its potential to modulate immune responsiveness in stress-loaded individuals. (1) When C57BL/6 mice were restrained in 50-ml tubes for more than 6 h, splenic NK cell activity decreased significantly, but recovered gradually after the mice were released. The extent of the reduction of activity and the degree of recovery depended on the duration of the restraint. (2) The oral administration of CM6271 caused a significant acceleration of the recovery of the activity. This effect was dependent on the timing of administration and the dose given. (3) The administration of CM6271 had no clear effect on the blood levels of ACTH, corticosterone or lipid peroxide levels in the liver. These findings suggest that CM6271 promotes recovery from the decrease in NK cell activity induced by restraint stress.

Adrenocorticotropic Hormone↗

Expression and mutation of p53 gene in the lung of mice intratracheal injected with crystalline silica.

The genotoxic effect of crystalline silica (Qt) in the lung was studied to clarify that silicosis conferred a significant increase in risk subsequent lung cancer. C57BL/6N mice received a single tracheal injection of Qt at dose of 2 mg/mouse. Lung p53mRNA was suppressed significantly, but no change of p21mRNA 15 months after treatment. Mutation of p53 gene was not identified at 15 months in the Qt group. Silicotic lesions were observed in the lungs of Qt group, but silicosis with pulmonary neoplasia was no detected. These results indicated that genetic changes in the silicotic lung might lead to facilitation of carcinogenesis.

Animals↗

Effects of surface characteristics of potassium titanate whisker samples on acute lung injury induced by a single intratracheal administration in rats.

We compared in vivo biological effects, focusing on lung inflammatory responses after a single intratracheal administration of two types of well-characterized whiskers: potassium octatitanate and potassium hexatitanate, which have similar fiber sizes and chemical compositions, except their surface morphology. The geometrical mean of length (microm), width (microm), and geometric standard deviation (GSD) are: K(2)Ti(8)O(17) (PT1), 6.0[2.0], 0.35[1.51], having rough surface; K(2)Ti(6)O(13) (PT2), 5.0[2.18], 0.31[1.63], having smooth surface. Sixty male Wistar rats (8 wk old) under anesthesia were injected intratracheally with 2 doses of fibers (0.2 mg/0.5 ml/rat, 1.0 mg/0.5 ml/rat) or the same amount of saline solution (group C). Animals were sacrificed on days 1, 3, and 7 after fiber administration, and then the lung tissue and bronchoalveolar lavage (BAL) were collected. There were no obvious differences among the three groups in the yield of BAL fluid. Total protein concentration in BAL increased significantly from day 1; BAL fucose level increased significantly from day 3 in a dose-dependent manner, which gradually recovered by day 7 in groups PT1 and PT2. BAL total protein and fucose in group PT1 increased significantly compared with those in group PT2 at a dose level of 1.0 mg. A dose-independent increase of beta-glucuronidase activity and decrease of superoxide dismutase activity were observed in both fibers. BAL tumor necrosis factor-alpha (TNF-alpha) increased significantly in animals treated with 1.0 mg dosage of PT1 and PT2 on day 1. However, BAL IL-1beta did not show any marked change during the experimental period in animals treated with both fibers. On day 1, BAL cytokine-induced neutrophil attractants (CINC)/growth-related gene product (GRO) increased significantly in the PT1 group treated with 0.2 and 1.0 mg dosage. On day 3, the group treated with 1.0 mg PT1 showed significant increase of CINC/GRO compared with the group treated with 1.0 mg PT2, which recovered to the control level on day 7. Expression of various chemokine mRNAs (MCP-3, MIP-1alpha, RANTES, and eotaxin) increased in rats treated with PT1 or PT2 on day 1 and/or day 3. Increase of gene expression in the PT1 group was greater than that of the PT2 group at 0.2 mg dosage level. These results suggest that differences in the surface morphology of the whisker fibers of similar length and diameter, density, and chemical composition appear to be related to the facilitation of macrophage phagocytes in the macrophage-derived biological effects in acute lung injury induced by inhaled fibers.

Animals↗

Inflammatory responses and mucus secretion in rats with acute bronchiolitis induced by nickel chloride.

The effects of inhaled particulate matter in the workplace and outdoor environment on sensitive subpopulations are not sufficiently investigated in human and animal models. Thus, animal models for pulmonary diseases are necessary for appropriate risk assessment of toxic materials. We studied biochemical characteristics of an acute inflammatory process induced by inhalation of nickel chloride aerosols in rats. Acute bronchiolitis was induced by inhalation of nickel chloride aerosols for 5 days in Wistar rats according to the method described by Kyono et al. (1999). Deterioration and recovery from inflammatory responses were evaluated by analyzing markers of inflammation in bronchoalveolar lavage (BAL) fluid. Experimental animals were sacrificed during and after the nickel aerosol exposure period. The number of neutrophils markedly increased to approximately 0.5 x 10(3) cells/microl BAL fluid during nickel aerosol exposure, accompanied by increase of total protein, soluble L-selectin, cytokine-induced neutrophil chemoattractant/growth-regulated gene products (CINC/GRO), elastolytic activity, trypsin inhibitory capacity, beta-glucuronidase activity, fucose, and sialic acid in BAL fluid compared with those of the control group. There was correlation between number of leukocytes and soluble L-selectin concentration. The number of pulmonary macrophages in BAL fluid decreased to approximately 15% of those of the control group on the days of nickel aerosol exposure. The level of CINC/GRO recovered to that of the control group on day 3 after cessation of the nickel aerosol exposure. However, other inflammatory markers remained at the elevated levels. Changes in the markers of inflammation during and after the nickel aerosol exposure were consistent with previously reported morphological findings. The results indicated that this animal model is potentially useful as an acute bronchiolitis model.

Animals↗

Dose-response assessment and effect of particles in guinea pigs exposed chronically to diesel exhaust: analysis of various biological markers in pulmonary alveolar lavage fluid and circulating blood.

To elucidate dose-response and other effects of diesel particles in guinea pigs chronically exposed to diesel exhaust, various biomarkers for chronic obstructive lung diseases were studied using bronchoalveolar lavage (BAL) fluid and blood specimens. Guinea pigs were exposed 16 h/day, 6 days/wk, for 6, 12, 18, or 24 mo to filtered air (control group, n = 8-10), a low level of diesel exhaust (L group: NO(2) = 0.22 +/- 0.03 ppm; SO(2) = 0.6 +/- 0.19 ppm; particles = 0.21 +/- 0.07 mg/m(3), n = 8-10), medium level of diesel exhaust (M group; NO(2) = 1.07 +/- 0.09 ppm; SO(2) = 2.83 +/- 0.73 ppm; particles = 1.14 +/- 0.26 mg/m(3), n = 8-10), and high level of diesel exhaust (H group: NO(2) = 2.88 +/- 0.29 ppm; SO(2) = 6.49 +/- 1.75 ppm; particles = 2.94 +/- 0.69 mg/m(3), n = 8-10), or at a medium concentration of diesel exhaust without particulate matters (MG group: NO(2) = 1.01 +/- 0.09 ppm;#10; SO(2) = 2.66 +/- 0.64 ppm; particles = 0.01 +/- 0.01 mg/m(3), n = 8-10). Anesthetized animals were sacrificed and BAL fluid from the lung and blood from right ventricle were collected. Various biomarkers of inflammation, components of mucus and surfactant, bronchoconstrictors were determined. Changes of leukotriene C4 in plasma, eosinophil counts, biomarkers of inflammation and cytotoxicity, and mucus and surfactant components in BAL fluid were statistically different among the C, L, M, and H groups after adjustment for the exposure period and group-by-exposure period with respect to their interactions in two-way analysis of variance (ANOVA). The levels of these biomarkers in the H group were higher than those of the M group, whereas those of the L group showed no significant changes compared with those of the C group during experimental period. Onset of significant changes of these biomarkers for the M group was at 18 mo of exposure, whereas that for the H group was at 12 mo of exposure, which resulted in changes in the levels of biomarkers in BAL fluid. Although numbers of eosinophils in BAL fluid increased significantly in the M and H groups at 12 mo, only leukotriene C4 increased at 18 and 24 mo in blood and at 24 mo in BAL fluid. Animals exposed to the medium level of diesel exhaust without particulate matter showed significantly less increase of these biomarkers as compared with animals exposed to the same level of diesel exhaust with particulate matters. These findings indicate that chronic exposure to diesel exhaust induced continuous inflammation, overproduction of mucus, and phospholipids in the lung. Animals exposed to the high dose of diesel exhaust showed a plateau of biological responses at 12 mo of exposure. Particulate matter in diesel exhaust appears to play an important role in development of lung injury by chronic emission exhaust exposure.

Administration, Inhalation↗