Search

Organic polymers are materials widely used in our daily lives, such as daily necessities, foods, and medicines. There have been reports recently that cross-linked polyacrylic acid (CL-PAA) can possibly cause serious lung disease. We investigated whether intratracheal instillation of CL-PAA causes pulmonary disorder in rats.Male F344 rats were administered low (0.2 mg/rat) and high (1.0 mg/rat) doses of CL-PAA intratracheally and were dissected 3 days, 1 week, 1 month, 3 months, and 6 months after exposure to examine inflammatory and fibrotic responses in the lungs. Only the high-dose specimens were subjected to ultrasonic dispersion treatment of the administered material.There was a dose-dependent increase in the total cell count, neutrophil count, neutrophil percentage, lactate dehydrogenase (LDH), surfactant protein D (SP-D), cytokine-induced neutrophil chemoattractant (CINC)-1 and CINC-2 values in bronchoalveolar lavage fluid (BALF) from 3 days to at least 3 months after intratracheal administration of CL-PAA. Heme oxygenase-1 (HO-1) in lung tissue was also persistently elevated from 3 days to 6 months after exposure. Alkaline phosphatase (ALP) in BALF was elevated at 3 days and 1 month after exposure only in the high-dose group. Histopathological findings in lung tissue showed inflammatory and fibrotic changes from 3 days after administration, and we observed obvious inflammatory changes for up to 3 months and fibrotic changes for up to 6 months.Intratracheal administration of CL-PAA induced persistent neutrophilic inflammation and fibrosis in the rats' lungs, suggesting that CL-PAA may have inflammogenic and fibrogenic effects.

We conducted inhalation and intratracheal instillation studies in order to examine the effects of tungsten trioxide (WOIn the inhalation study, male 10-week-old Fischer 334 rats were classified into 3 groups. The control, low-dose, and high-dose groups inhaled clean air, 2, and 10 mg/mThe inhalation and instillation of WOOur results suggest that WO

Respirable organic chemicals were originally thought to cause allergic respiratory diseases, such as bronchial asthma and hypersensitivity pneumonitis, and believed not to cause lung disorders derived from inflammatory or fibrotic processes such as pulmonary fibrosis and interstitial pneumonitis. It has recently been reported, however, that exposure to organic chemicals can cause interstitial lung diseases. In this review, we discuss the clinical features of occupational asthma and hypersensitivity pneumonitis, as well as other lung disorders, including interstitial pneumonitis, caused by humidifier disinfectants in Korea and by a cross‐linked acrylic acid‐based polymer (CL‐PAA) in Japan.

BackgroundOrganic chemicals are known to cause allergic diseases such as bronchial asthma and hypersensitivity pneumonitis, and it has been considered that they do not cause irreversible pulmonary fibrosis. It has recently been reported, however, that cross-linked acrylic acid-based polymer, an organic chemical, might cause serious interstitial lung diseases, including pulmonary fibrosis. We investigated whether or not intratracheal instillation exposure to cross-linked polyacrylic acid (CL-PAA) can cause lung disorder in rats.MethodsMale F344 rats were intratracheally instilled with dispersed CL-PAA at low (0.2 mg/rat) and high (1.0 mg/rat) doses, and were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure to examine inflammatory and fibrotic responses and related gene expressions in the lungs. Rat lungs exposed to crystalline silica, asbestos (chrysotile), and NiO and CeO2 nanoparticles were used as comparators.ResultsPersistent increases in total cell count, neutrophil count and neutrophil percentage, and in the concentration of the cytokine-induced neutrophil chemoattractants (CINC)-1, CINC-2 and C-X-C motif chemokine 5 (CXCL5) (which had the highest expression of all chemokines by cDNA microarray using the lung tissue) were observed in bronchoalveolar lavage fluid (BALF) from 3 days until at least 1 month following CL-PAA intratracheal instillation. Persistent increases in heme oxygenase-1 (HO-1) in the lung tissue were also observed from 3 days to 6 months after exposure. Histopathological findings of the lungs demonstrated that extensive inflammation at 3 days was greater than that in exposure to silica, NiO nanoparticles and CeO2 nanoparticles, and equal to or greater than that in asbestos (chrysotile) exposure, and the inflammation continued until 1 month. Fibrotic changes also progressed after 1 month postexposure. Conclusion Our results suggest that CL-PAA may potentially cause strong neutrophil inflammation in the rat and human lung.

We reviewed relationship between the radiographic features of the pleural plaque and asbestos lung cancer. Because there is not a consistent opinion about pleural plaques and lung cancer considering some cohort and case-control studies, there is still controversy about whether or not pleural plaques in chest X-rays are a predictor of asbestos lung cancer. Although the usefulness of pleural plaques for screening of lung cancer is controversial, there are many reports that chest computed tomography (CT) imaging is more useful than X-rays in detecting pleural plaques. The presence of pleural plaques in chest CT images does have a tendency to be able to predict asbestos lung cancer.

We analyzed the mRNA expression of chemokines in rat lungs following intratracheal instillation of nanomaterials in order to find useful predictive markers of the pulmonary toxicity of nanomaterials. Nickel oxide (NiO) and cerium dioxide (CeO2) as nanomaterials with high pulmonary toxicity, and titanium dioxide (TiO2) and zinc oxide (ZnO) as nanomaterials with low pulmonary toxicity, were administered into rat lungs (0.8 or 4 mg/kg BW). C-X-C motif chemokine 5 (CXCL5), C-C motif chemokine 2 (CCL2), C-C motif chemokine 7 (CCL7), C-X-C motif chemokine 10 (CXCL10), and C-X-C motif chemokine 11 (CXCL11) were selected using cDNA microarray analysis at one month after instillation of NiO in the high dose group. The mRNA expression of these five genes were evaluated while using real-time quantitative polymerase chain reaction (RT-qPCR) from three days to six months after intratracheal instillation. The receiver operating characteristic (ROC) results showed a considerable relationship between the pulmonary toxicity ranking of nanomaterials and the expression of CXCL5, CCL2, and CCL7 at one week and one month. The expression levels of these three genes also moderately or strongly correlated with inflammation in the lung tissues. Three chemokine genes can be useful as predictive biomarkers for the ranking of the pulmonary toxicity of nanomaterials.

This work determines whether cytokine-induced neutrophil chemoattractants (CINC)-1, CINC-2 and CINC-3 can be markers for predicting high or low pulmonary toxicity of nanomaterials (NMs). We classified NMs of nickel oxide (NiO) and cerium dioxide (CeO2) into high toxicity and NMs of two types of titanium dioxides (TiO2 (P90 and rutile)) and zinc oxide (ZnO) into low toxicity, and we analyzed previous data of CINCs in bronchoalveolar lavage fluid (BALF) of rats from three days to six months after intratracheal instillation (0.2 and 1.0 mg) and inhalation exposure (0.32&ndash, 10.4 mg/m3) of materials (NiO, CeO2, TiO2 (P90 and rutile), ZnO NMs and micron-particles of crystalline silica (SiO2)). The concentration of CINC-1 and CINC-2 in BALF had different increase tendency between high and low pulmonary toxicity of NMs and correlated with the other inflammatory markers in BALF. However, CINC-3 increased only slightly in a dose-dependent manner compared with CINC-1 and CINC-2. Analysis of receiver operating characteristics for the toxicity of NMs by CINC-1 and CINC-2 showed the most accuracy of discrimination of the toxicity at one week or one month after exposure and CINC-1 and CINC-2 in BALF following intratracheal instillation of SiO2 as a high toxicity could accurately predict the toxicity at more than one month after exposure. These data suggest that CINC-1 and CINC-2 may be useful biomarkers for the prediction of pulmonary toxicity of NMs relatively early in both intratracheal instillation and inhalation exposure.

Background We analyzed the mRNA expression of chemokines in rat lungs following intratracheal instillation of nanomaterials in order to find useful predictive markers of the pulmonary toxicity of nanomaterials. Four nanomaterials, nickel oxide (NiO) and cerium dioxide (CeO2) as nanomaterials with high pulmonary toxicity, and titanium dioxide (TiO2) and zinc oxide (ZnO) as nanomaterials with low pulmonary toxicity, were intratracheally administered into rat lungs at 0.8 mg/kg BW or 4 mg/kg BW as low and high doses, respectively. Five chemokine genes (C-X-C motif chemokine 5 (CXCL5), C-C motif chemokine 2 (CCL2), C-C motif chemokine 7 (CCL7), C-X-C motif chemokine 10 (CXCL10), and C-X-C motif chemokine 11 (CXCL11) ) were selected using cDNA microarray analysis at 1 month after instillation of NiO in the high dose group. The mRNA expression of these 5 genes in the lung tissues were evaluated at 3 days, 1week, 1 month, 3 months and 6 months after instillation of the 4 nanomaterials, using real-time quantitative polymerase chain reaction (RT-qPCR) during the observation periods. Results An increased expression of CXCL5 in the NiO and CeO2 groups was persistently higher than in the control group, and that in the TiO2 and ZnO groups was transiently higher than in the control group. CCL2 and CCL7 also showed an increasing tendency similar to CXCL5, although there was not a persistent significance. The receiver operating characteristic (ROC) results of nanomaterial toxicity with the expression level of each gene showed a considerable relationship between the pulmonary toxicity ranking of nanomaterials and the expression of CXCL5, CCL2 and CCL7, with area under the curves (AUC) of 0.95 or higher at 1 week and 1 month. The expression levels of these 3 genes also moderately or strongly correlated with the degree of inflammatory cells in the lung tissues. Conclusion Our results suggest that 3 chemokine genes, especially CXCL5, followed by CCL2 and CCL7, can be useful as biomarkers for the ranking of the pulmonary toxicity of nanomaterials.

Objectives Along with technological innovations for improving the efficiency of printing, nanoparticles have been added to the surface of toners, and there is concern about the harmful effects of those components. We investigated, through a long‐term observation following intratracheal instillation using rats, whether exposure to a toner with external additives can cause tumorigenesis. Methods Female Wistar rats were intratracheally instilled with dispersed toner at low (1 mg/rat) and high (2 mg/rat) doses, and the rats were sacrificed at 24 months after exposure, after which we examined pulmonary inflammation, histopathological changes, and DNA damage in the lung. Rats that had deceased before 24 months were dissected at that time as well, to compare tumor development. Results Although alveolar macrophages with pigment deposition in the alveoli were observed in the 1 and 2 mg exposure groups, no significant lung inflammation/fibrosis or tumor was observed. Since immunostaining with 8‐OHdG or γ‐H2AX did not show a remarkable positive reaction, it is thought that toner did not cause severe DNA damage to lung tissue. Conclusion These results suggest that toner with external additives may have low toxicity in the lung.

We compared the concentration of total protein in bronchoalveolar lavage fluid (BALF) exposed to four types of nanomaterials in an inhalation study and in an intratracheal instillation study in order to examine whether the ranking of the harmful effect of nanomaterials following intratracheal instillation accorded with the ranking following inhalation. We used nickel oxide (NiO) nanoparticles and cerium dioxide (CeO2) nanoparticles as high toxicity nanomaterials, and titanium dioxide (TiO2) and zinc oxide (ZnO) nanoparticles as low toxicity nanomaterials. In the inhalation study, rats were exposed to approximately 2 mg/m3 of four nanomaterials for 4 weeks, and the total protein concentrations in the bronchoalveolar lavage fluid (BALF) were examined from 3 days to 3 months after the end of exposure as the endpoint of pulmonary toxicity. In the intratracheal instillation study, rats were exposed to 0.2 or 1 mg of four nanomaterials, and, with the same endpoint, the BALF was analyzed from 3 days to 6 months after the exposure. The inhalation of NiO and CeO2, the high toxicity nanomaterials, induced a significant amount of total protein in the BALF, while the inhalation of ZnO and TiO2, the low toxicity nanomaterials, did not. The intratracheal instillation of NiO and CeO2 resulted in a persistently elevated concentration of total protein in the BALF, while the same result with the intratracheal instillation of ZnO and TiO2 was transient. Taken together, a difference in concentration of total protein in BALF was observed between the high and low toxicity nanomaterials following intratracheal instillation as well as inhalation, suggesting that the ranking of the harmful effects of nanoparticles in intratracheal instillation studies may reflect the ranking in inhalation studies.

In order to examine whether intratracheal instillation studies can be useful for determining the harmful effect of nanoparticles, we performed inhalation and intratracheal instillation studies using samples of the same nanoparticles. Nickel oxide nanoparticles (NiO) and titanium dioxide nanoparticles (TiO2) were used as chemicals with high and low toxicities, respectively. In the intratracheal instillation study, rats were exposed to 0.2 or 1 mg of NiO or TiO2. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed from 3 days to 6 months following the single intratracheal instillation. In the inhalation study, rats were exposed to inhaled NiO or TiO2 (1.65, 1.84 mg/m(3), respectively) for 4 weeks. The same endpoints were examined from 3 days to 3 months after the end of exposure. Inhalation of NiO induced an increase in the number of neutrophils in BALF and concentrations of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2 and heme oxygenase (HO)-1. Intratracheal instillation of NiO induced persistent inflammation and upregulation of these cytokines was observed in the rats. However, inhalation of TiO2 did not induce pulmonary inflammation, and intratracheal instillation of TiO2 transiently induced an increase in the number of neutrophils in BALF and the concentrations of CINC-1, CINC-2 and HO-1. Taken together, a difference in pulmonary inflammation was observed between the high and low toxicity nanomaterials in the intratracheal instillation studies, as in the inhalation studies, suggesting that intratracheal instillation studies may be useful for ranking the harmful effects of nanoparticles.

Background In order to examine whether myeloperoxidase (MPO) can be a useful marker for evaluating the pulmonary toxicity of nanomaterials, we analyzed MPO protein in bronchoalveolar lavage fluid (BALF) samples obtained from previous examinations of a rat model. In those examinations we performed intratracheal instillation exposures (dose: 0.2–1.0 mg) and inhalation exposures (exposure concentration: 0.32–10.4 mg/m3) using 9 and 4 nanomaterials with different toxicities, respectively. Based on those previous studies, we set Nickel oxide nanoparticles (NiO), cerium dioxide nanoparticles (CeO2), multi wall carbon nanotubes with short or long length (MWCNT (S) and MWCNT (L)), and single wall carbon nanotube (SWCNT) as chemicals with high toxicity; and titanium dioxide nanoparticles (TiO2 (P90) and TiO2 (Rutile)), zinc oxide nanoparticles (ZnO), and toner with external additives including nanoparticles as chemicals with low toxicity. We measured the concentration of MPO in BALF samples from rats from 3 days to 6 months following a single intratracheal instillation, and from 3 days to 3 months after the end of inhalation exposure. Results Intratracheal instillation of high toxicity NiO, CeO2, MWCNT (S), MWCNT (L), and SWCNT persistently increased the concentration of MPO, and inhalation of NiO and CeO2 increased the MPO in BALF. By contrast, intratracheal instillation of low toxicity TiO2 (P90), TiO2 (Rutile), ZnO, and toner increased the concentration of MPO in BALF only transiently, and inhalation of TiO2 (Rutile) and ZnO induced almost no increase of the MPO. The concentration of MPO correlated with the number of total cells and neutrophils, the concentration of chemokines for neutrophils (cytokine-induced neutrophil chemoattractant (CINC)-1 and heme oxygenase (HO)-1), and the activity of released lactate dehydrogenase (LDH) in BALF. The results from the receiver operating characteristics (ROC) for the toxicity of chemicals by the concentration of MPO proteins in the intratracheal instillation and inhalation exposures showed that the largest areas under the curves (AUC) s in both examinations occurred at 1 month after exposure. Conclusion These data suggest that MPO can be a useful biomarker for the ranking of the pulmonary toxicity of nanomaterials, especially at 1 month after exposure, in both intratracheal instillation and inhalation exposure. Electronic supplementary material The online version of this article (10.1186/s12989-018-0277-x) contains supplementary material, which is available to authorized users.

Introduction In Japan, people scoring 8 to 14 points by the Alcohol Use Disorder Identification Test (AUDIT) are recommended to receive the health guidance to avoid risk of alcoholism and those scoring 15 or higher are considered to need the specialised medical treatment of their problem drinking. There are many risk factors of alcohol related disorders among workers such as a managerial role, a shift work, smoking (Brinkman index 400 or more) and the result of the alcohol patch test; however, they have not been verified by the scores of AUDIT. Methods We conducted a survey using a self-administered questionnaire including AUDIT among 2915 employees of a manufacturing worksite who received a periodic medical examination in fiscal 2015. We used binomial logistic regression analysis to explore the risk factors to predict development of the condition scoring 15+points by AUDIT among various independent variables: age, managerial position, shift work, smoking, the result of the alcohol patch test to screen variant aldehyde dehydrogenase. Statistically significant level was set at p Result We analysed the data obtained from 2299 male employees under 60-year-old who answered to all questions, and found 183 workers (8.0%) scored 15+points by AUDIT. The significantly increased risks were found with managerial roles (OR: 1.74), with negative result of the alcohol patch tests (OR: 6.87) and with smoking habit (OR: 1.71); however, the significant relationship was not found with shift work. Discussion Our result may reflect the tendency that managers are likely to excuse their drinking habit as a means of business practice and communication, and people with high social standing can afford to drink. There may be a synergistic effect between drinking and smoking. Occupational health should be more cautious to prevent problem drinking based on personal and social characteristics.

Introduction Workers often drink alcohol for releasing stress. However, many reports show that heavy drinking is a risk of depression. Some mentioned the influence of not only the amount of drinking alcohol but also the wrong way of using alcohol like binge drinking should be examined. Alcohol Use Disorders Identification Test (AUDIT) can evaluate the way of one’s using alcohol and the amount of drinking. Thus it is able to examine the more accurate influence of alcohol for depression. In this study, we analysed the relationship between AUDIT score and depression from work-related stress by The Brief Job Stress Questionnaire (BJSQ). Methods 4799 workers in a manufacturing company participated in this study. We analysed the data obtained from 4709 male employees without any missing value in logistic analysis and categorised depression as the dependent variable (13:high score group, 12≧: low score group), AUDIT score (0–14: group I, 15–19: group II, 20-: group III), job status (managerial or not), overtime work (per month, 80 hours: severe), quantitative overload (high/middle/low), qualitative overload (high/middle/low), stress with interpersonal relationships (high/middle/low), and job control (high/middle/low), as independent variables. Results Depression tended to be higher in group II of AUDIT(OR: 1.40, 95% CI: 0.99 to 1.96, p=0.54) and group III (OR: 2.45, 95% CI: 1.36 to 4.42, p=0.003). About overtime-work, the severe group was more depressive than mild group (OR: 2.38, 95% CI: 1.45 to 3.90, p Conclusion Higher AUDIT score seemed to show higher risk of developing depression. The wrong way of using alcohol may be an exacerbating factor of depression. We should be careful to drinking on the purpose of releasing stress.

We investigated the harmful effects of exposure to a toner with external additives by a long-term inhalation study using rats, examining pulmonary inflammation, oxidative stress, and histopathological changes in the lung. Wistar rats were exposed to a well-dispersed toner (mean of MMAD: 2.1 μm) at three mass concentrations of 1, 4, and 16 mg/m3for 22.5 months, and the rats were sacrificed after 6 months, 12 months, and 22.5 months of exposure. The low and medium concentrations did not induce statistically significant pulmonary inflammation, but the high concentration did, and, in addition, a histopathological examination showed fibrosis in the lung. Although lung tumor was observed in one sample of high exposure for 22.5 months, the cause was not statistically significant. On the other hand, a persistent increase in 8-OHdG was observed in the high exposure group, indicating that DNA damage by oxidative stress with persistent inflammation leads to the formation of tumorigenesis. The results of our studies show that toners with external additives lead to pulmonary inflammation, oxidative stress, and fibrosis only at lung burdens beyond overload. These data suggest that toners with external additives may have low toxicity in the lung.

NiO nanoparticles were administered to rat lungs via intratracheal instillation or inhalation. During pulmonary toxicity caused by NiO nanoparticles, the induction of oxidative stress is a major factor. Both intratracheal instillation and inhalation of NiO nanoparticles induced pulmonary oxidative stress. The oxidative stress response protein, heme oxygenase-1 (HO-1), was induced by the administration of NiO nanoparticles at both the protein and gene expression level. Additionally, certain oxidative-stress markers in the lung, such as 8-iso-prostaglandin F2α, thioredoxin, and inducible nitric oxide synthase were increased. Furthermore, the concentration of myeloperoxidase (MPO) in the lung was also increased by the administration of NiO nanoparticles. When the amount of NiO in the lung is similar, the responses against pulmonary oxidative stress of intratracheal instillation and inhalation are also similar. However, the state of pulmonary oxidative stress in the early phase was different between intratracheal instillation and inhalation, even if the amount of NiO in the lung was similar. Inhalation causes milder oxidative stress than that caused by intratracheal instillation. On evaluation of the nanoparticle-induced pulmonary oxidative stress in the early phase, we should understand the different states of oxidative stress induced by intratracheal instillation and inhalation.

The hazards of various types of nanoparticles with high functionality have not been fully assessed. We investigated the usefulness of biopersistence as a hazard indicator of nanoparticles by performing inhalation and intratracheal instillation studies and comparing the biopersistence of two nanoparticles with different toxicities: NiO and TiO2 nanoparticles with high and low toxicity among nanoparticles, respectively. In the 4-week inhalation studies, the average exposure concentrations were 0.32 and 1.65 mg/m3 for NiO, and 0.50 and 1.84 mg/m3 for TiO2. In the instillation studies, 0.2 and 1.0 mg of NiO nanoparticles and 0.2, 0.36, and 1.0 mg of TiO2 were dispersed in 0.4 mL water and instilled to rats. After the exposure, the lung burden in each of five rats was determined by Inductively Coupled Plasma-Atomic Emission Spectrometer (ICP-AES) from 3 days to 3 months for inhalation studies and to 6 months for instillation studies. In both the inhalation and instillation studies, NiO nanoparticles persisted for longer in the lung compared with TiO2 nanoparticles, and the calculated biological half times (BHTs) of the NiO nanoparticles was longer than that of the TiO2 nanoparticles. Biopersistence also correlated with histopathological changes, inflammatory response, and other biomarkers in bronchoalveolar lavage fluid (BALF) after the exposure to nanoparticles. These results suggested that the biopersistence is a good indicator of the hazards of nanoparticles.

Previously we reported that nickel oxide nanoparticles (NiO) induced pulmonary inflammation of rat by intratracheal instillation. The objective of this study is to identify new genes which is useful for evaluating pulmonary inflammation induced by NiO. Rats were exposed to 0.2mg or 1mg of NiO and total RNAs were isolated from lung at 3 days, 7 days, 1 month, 3 months, 6 months, 12 months and 24 months after the end of exposure. Analysis of cDNA microarray was performed with total RNA at 1 month after the end of exposure and revealed that 450 kinds of mRNAs were up-regulated over 2 times and 388 kinds of mRNAs were down-regulated compared with control. Among up-regulated 450 mRNAs, 16 kinds of mRNAs were up-regulated over 8 times. Six of 16 kinds of mRNAs (Ccl2,Ccl7,Cxcl-5,Cxcl-10,Cxcl-11 and Mmp12) were involved in inflammation and investigated until 24 months post-exposure by real-time PCR. Expression peak is different in each gene, but gene expression levels of Ccl2,Ccl7,Cxcl-10 and Cxcl-11 were decreased to almost same level of control and those of Cxcl-5 and Mmp12 were continuously up-regulated until 24 months. These 6 genes might be useful markers for evaluation of pulmonary inflammation by nickel oxide nanoparticles. This work is partially supported by “Development of innovative methodology for safety assessment of industrial nanomaterials" by Ministry of Economy, Trade and Industry (METI) of Japan.

The objective of this study is whether or not cerium dioxide (CeO 2 ) nanoparticle has the pulmonary toxicity. We performed inhalation and intratracheal instillation studies using same sample of cerium oxide nanoparticles, and examined the pulmonary inflammation in both studies. In intratracheal instillation study, rats were exposed to 0.2 mg or 1 mg of CeO 2 . In inhalation study, rats were exposed to inhaled CeO 2 ( 2.1 mg/m 3 ; low concentration, 10.2 mg/m 3 ; high concentration ) for 4 weeks ( 6 hours/day, 5 days/week). Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed at 3 days, 1month and 3 months after end of exposure in both studies. Inhalation studies showed that neutrophil number was increased in BALF of low and high concentration groups, and peaked on the 1 month. Intratracheal instillation studies also showed that neutrophil number in BALF was increased, reached a peak level of 1 week, and returned to negative control level at 6 months. If these endpoints of inflammation data by CeO 2 nanoparticle were compared with previous data by nickel oxide nanoparticle (high inflammatory potentials) and titanium dioxide nanoparticles (low inflammatory potentials), the level of inflammation by CeO 2 nanoparticle was approximately between nickel oxide and titanium dioxide nanoparticles. Taken together, we suggested that the inflammatory potentials of CeO 2 nanoparticle may be intermediate. This work is partially supported by “Development of innovative methodology for safety assessment of industrial nanomaterials" by Ministry of Economy, Trade and Industry (METI) of Japan.

We performed the two inhalation exposures, whole-body inhalation and nose-only inhalation, to investigate the pulmonary deposition and health effects of the two inhalation methods.In both methods, we exposed rats to the same TiO2 nanoparticles at almost the same exposure concentration for 6 h and compared the deposited amounts of nanoparticles and histopathological changes in the lungs. Rats were exposed to rutile-type TiO2 nanoparticles generated by the spray-dry method for 6 h. The exposure concentration in the whole-body chamber was 4.10 ± 1.07 mg/m(3), and that in nose-only chamber was 4.01 ± 1.11 mg/m(3). The particle sizes were 230 and 180 nm, respectively. A control group was exposed to fresh air.The amounts of TiO2 deposited in the lungs as measured by ICP-AES after acid digestion just after the exposure were: 42.6 ± 3.5 μg in the whole-body exposure and 46.0 ± 7.7 μg in the nose-only exposure groups. The histopathological evaluation was the same in both exposure groups: no infiltration of inflammatory cells in the alveolar space and interstitium, and no fibrosis.The two inhalation methods using the same material under the same exposure conditions resulted in the same particle deposition and histopathology in the lung.

In order to investigate the pulmonary toxicity of titanium dioxide (TiO2) nanoparticles, we performed an intratracheal instillation study with rats of well-dispersed TiO2 nanoparticles and examined the pulmonary inflammation and histopathological changes in the lung. Wistar Hannover rats were intratracheally administered 0.2 mg (0.66 mg/kg) and 1.0 mg (3.3 mg/kg) of well-dispersed TiO2 nanoparticles (P90; diameter of agglomerates: 25 nm), then the pulmonary inflammation responses were examined from 3 days to 6 months after the instillation, and the pathological features were examined up to 24 months. Transient inflammation and the upregulation of chemokines in the broncho-alveolar lavage fluid were observed for 1 month. No respiratory tumors or severe fibrosis were observed during the recovery time. These data suggest that transient inflammation induced by TiO2 may not lead to chronic, irreversible legions in the lung, and that TiO2 nanoparticles may not have a high potential for lung disorder.

We conducted inhalation and intratracheal instillation studies of zinc oxide (ZnO) nanoparticles in order to examine their pulmonary toxicity. F344 rats were received intratracheal instillation at 0.2 or 1 mg of ZnO nanoparticles with a primary diameter of 35 nm that were well-dispersed in distilled water. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed at three days, one week, one month, three months, and six months after the instillation. As the inhalation study, rats were exposed to a concentration of inhaled ZnO nanoparticles (2 and 10 mg/m³) for four weeks (6 h/day, 5 days/week). The same endpoints as in the intratracheal instillation study were analyzed at three days, one month, and three months after the end of the exposure. In the intratracheal instillation study, both the 0.2 and the 1.0 mg ZnO groups had a transient increase in the total cell and neutrophil count in the BALF and in the expression of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2, chemokine for neutrophil, and heme oxygenase-1 (HO-1), an oxidative stress marker, in the BALF. In the inhalation study, transient increases in total cell and neutrophil count, CINC-1,-2 and HO-1 in the BALF were observed in the high concentration groups. Neither of the studies of ZnO nanoparticles showed persistent inflammation in the rat lung, suggesting that well-dispersed ZnO nanoparticles have low toxicity.