Carcinogenicity of butyraldehyde in rats by a two-year inhalation study.

We conducted a two-year inhalation study of butyraldehyde using F344/DuCrlCrlj rats. The rats were exposed to 0, 300, 1,000 and 3,000 ppm (v/v) for 6 hr/day, 5 days/ week for 104 weeks using whole-body inhalation chambers. The incidence of squamous cell carcinoma of the nasal cavity was increased in the 3,000 ppm groups of both male and female rats, with Fisher's exact test and the Peto test indicating that the incidence was significant. In addition to squamous cell carcinoma in the nasal cavity, in the 3,000 ppm groups one male had an adenosquamous carcinoma, one male had a carcinosarcoma, one male had a sarcoma NOS (Not Otherwise Specified), and one female had a squamous cell papilloma in the nasal cavity. The combined incidence of squamous cell carcinoma, adenosquamous carcinoma and carcinosarcoma was significantly increased in male rats and the combined incidence of squamous cell papilloma and carcinoma was significantly increased in female. Based on these results, we conclude that there is clear evidence of butyraldehyde carcinogenicity in male and female rats.

Lung carcinogenicity by whole body inhalation exposure to Anatase-type Nano-titanium Dioxide in rats.

To investigate the carcinogenicity of anatase-type nano-titanium dioxide (aNTiO2), F344/DuCrlCrlj rats were exposed to aNTiO2 aerosol at concentrations of 0, 0.5, 2, and 8 mg/m3. The rats were divided into 2 groups: carcinogenicity study groups were exposed for two years, and satellite study groups were exposed for one year followed by recovery for 1 day, 26 weeks, and 52 weeks after the end of exposure. In the carcinogenicity groups, bronchiolo-alveolar carcinomas were observed in two 8 mg/m3-exposed males, showing an increasing trend by Peto's test. However, this incidence was at the upper limit of JBRC's historical control data. Bronchiolo-alveolar adenomas were observed in 1, 2, 3, and 4 rats of the 0, 0.5, 2, and 8 mg/m3-exposed females and were not statistically significant. However, the incidence in the 8 mg/m3-exposed females exceeded JBRC's historical control data. Therefore, we conclude there is equivocal evidence for the carcinogenicity of aNTiO2 in rats. No lung tumors were observed in the satellite groups. Particle-induced non-neoplastic lesions (alveolar epithelial hyperplasia and focal fibrosis) were observed in exposed males and females in both the carcinogenicity and satellite groups. Increased lung weight and neutrophils of bronchoalveolar lavage fluid were observed in the 8 mg/m3-exposed carcinogenicity groups. The aNTiO2 deposited in the lungs of the satellite group rats was decreased at 26 weeks after the end of exposure compared to 1 day after the end of exposure. At 52 weeks after the end of exposure, the decreased level was the same at 26 weeks after the end of exposure.

Exposure of Rats to Multi-Walled Carbon Nanotubes: Correlation of Inhalation Exposure to Lung Burden, Bronchoalveolar Lavage Fluid Findings, and Lung Morphology.

To evaluate lung toxicity due to inhalation of multi-walled carbon nanotubes (MWCNTs) in rats, we developed a unique MWCNT aerosol generator based on dry aerosolization using the aerodynamic cyclone principle. Rats were exposed to MWNT-7 (also known as Mutsui-7 and MWCNT-7) aerosolized using this device. We report here an analysis of previously published data and additional unpublished data obtained in 1-day, 2-week, 13-week, and 2-year inhalation exposure studies. In one-day studies, it was found that approximately 50% of the deposited MWNT-7 fibers were cleared the day after the end of exposure, but that clearance of the remaining fibers was markedly reduced. This is in agreement with the premise that the rapidly cleared fibers were deposited in the ciliated airways while the slowly cleared fibers were deposited beyond the ciliated airways in the respiratory zone. Macrophage clearance of MWNT-7 fibers from the alveoli was limited. Instead of macrophage clearance from the alveoli, containment of MWNT-7 fibers within induced granulomatous lesions was observed. The earliest changes indicative of pulmonary toxicity were seen in the bronchoalveolar lavage fluid. Macrophage-associated inflammation persisted from the one-day exposure to MWNT-7 to the end of the two-year exposure period. Correlation of lung tumor development with MWNT-7 lung burden required incorporating the concept of area under the curve for the duration of the study; the development of lung tumors induced by MWNT-7 correlated with lung burden and the duration of MWNT-7 residence in the lung.

Contribution of toxicological pathology to occupational health: lung carcinogenicity of fibrous and particulate substances in rats.

In this review, we focus on the rat pulmonary carcinogenicity of two solid substances, fibrous multi-walled carbon nanotube (MWCNT) and particulate indium tin oxide (ITO). Inhalation exposure to MWNT-7, a type of MWCNTs, and ITO induced lung carcinogenicity in both male and female rats. Toxicity to the alveolar epithelium is induced by macrophages undergoing frustrated phagocytosis or frustrated degradation of engulfed particles (referred to as frustrated macrophages). Melted macrophage contents contribute significantly to development of hyperplasia of the alveolar epithelium, which eventually results in the induction of lung carcinoma. MWNT-7 and ITO induce secondary genotoxicity; consequently, a no-observed-adverse-effect level can be applied to these materials rather than benchmark doses that are used for non-threshold carcinogens. Thus, establishing occupational exposure limit values for MWNT-7 and ITO based on the existence of a carcinogenic threshold is reasonable.

Carcinogenicity and chronic toxicity of butyl methacrylate in rats and mice by a two-year inhalation study.

We conducted a two-year inhalation study of butyl methacrylate using F344/DuCrlCrlj rats and B6D2F1/Crl mice. Rats were exposed to 0, 30, 125 and 500 ppm (v/v) and mice were exposed to 0, 8, 30 and 125 ppm (v/v) using whole-body inhalation chambers. Non-neoplastic lesions developed in the nasal cavities of both rats and mice, but neoplastic lesions were not found. There was also a positive trend in the incidence of large granular lymphocytic (LGL) leukemia in the spleen of male rats. No changes were observed in female rats. Overall, there is some evidence of carcinogenicity in male rats, but there is no evidence of carcinogenicity in female rats. In male mice, there was a positive trend by Peto's test in the incidence of hepatocellular adenomas, and the incidence of hepatocellular adenomas and hepatocellular carcinomas combined was significantly increased compared to the controls by Fisher's exact test in the 30 ppm exposed male group. In female mice, the incidence of hemangiosarcoma in all organs combined showed a positive trend by Peto's test. Therefore, there is some evidence of carcinogenicity in male mice, and there is equivocal evidence of carcinogenicity in female mice.

Multi-organ carcinogenicity by inhalation exposure to 2-Bromopropane in rats.

OBJECTIVE: The purpose of this study was to investigate the carcinogenicity of 2-bromopropane (2-BP) in rats. METHODS: Male and female F344 rats were exposed by whole body inhalation to 2-BP vapor at concentrations of 0, 67, 200, and 600 ppm for 6 h/day, 5 days/week for 2 years. RESULTS: All rats of both sexes exposed to 600 ppm died or became moribund within 85 weeks. Death/moribundity was caused by 2-BP induced tumors. In males, significantly increased tumors were malignant Zymbal's gland tumors; sebaceous adenoma and basal cell carcinoma of the skin/appendage; adenocarcinoma of the small/large intestine; follicular cell adenoma of the thyroid; fibroma of the subcutis, and malignant lymphoma of the lymph node. In addition, an increased trend in tumor incidence was found in the preputial gland, lung, forestomach, pancreas islet, brain, and spleen. In females, significantly increased tumors were adenocarcinoma and fibroadenoma of the mammary gland, squamous cell papilloma of the vagina, and large granular lymphocytic leukemia of the spleen. In addition, an increased trend in tumor incidence was found in Zymbal's gland, the clitoral gland, skin, large intestine, pancreas islet, uterus, and subcutis. Particularly, malignant Zymbal's gland tumors were induced even in males exposed to the lowest concentration, 67 ppm. CONCLUSION: Two-year inhalation exposure to 2-BP resulted in multi-organ carcinogenicity in rats. Based on sufficient evidence of carcinogenicity in this study, 2-BP has the potential to be a human carcinogen.

Pulmonary dust foci as rat pneumoconiosis lesion induced by titanium dioxide nanoparticles in 13-week inhalation study.

BACKGROUND: Most toxicological studies on titanium dioxide (TiO2) particles to date have concentrated on carcinogenicity and acute toxicity, with few studies focusing of pneumoconiosis, which is a variety of airspace and interstitial lung diseases caused by particle-laden macrophages. The present study examined rat pulmonary lesions associated with pneumoconiosis after inhalation exposure to TiO2 nanoparticles (NPs). METHODS: Male and female F344 rats were exposed to 6.3, 12.5, 25, or 50 mg/m3 anatase type TiO2 NPs for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. After the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. RESULTS: Numerous milky white spots were present in the lungs after exposure to 25 and 50 mg/m3 TiO2 NPs. Histopathological analysis revealed that the spots were alveolar lesions, characterized predominantly by the agglomeration of particle-laden macrophages and the presence of reactive alveolar epithelial type 2 cell (AEC2) hyperplasia. We defined this characteristic lesion as pulmonary dust foci (PDF). The PDF is an inflammatory niche, with decreased vascular endothelial cells in the interstitium, and proliferating AEC2 transformed into alveolar epithelial progenitor cells. In the present study, the AEC2 in the PDF had acquired DNA damage. Based on PDF induction, the lowest observed adverse effect concentration for pulmonary disorders in male and female rats was 12.5 mg/m3 and 6.3 mg/m3, respectively. The no observed adverse effect concentration for male rats was 6.3 mg/m3. There was a sex difference in lung lesion development, with females showing more pronounced lesion parameters than males. CONCLUSIONS: Inhalation exposure to TiO2 NPs caused PDF, an air-space lesion which is an alveolar inflammatory niche containing particle-laden macrophages and proliferating AEC2. These PDFs histopathologically resemble some pneumoconiosis lesions (pulmonary siderosis and hard metal pneumoconiosis) in workers and lung disease in smokers, suggesting that PDFs caused by exposure to TiO2 NPs in rats are an early pneumoconiosis lesion and may be a common alveolar reaction in mammals.

No evidence for carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model.

With the rapid development of alternative methods based on the spirit of animal welfare, the publications of animal studies evaluating endpoints such as cancer have been extremely reduced. We performed a 26-week inhalation exposure studies of titanium dioxide nanoparticles (TiO2 NPs) using CByB6F1-Tg(HRAS)2Jic (rasH2) mice model for detecting carcinogenicity. Male and female rasH2 mice were exposed to 2, 8 or 32 mg/m3 of TiO2 NPs for 6 h/day, 5 days/week for 26 weeks. All tissues and blood were collected and subjected to biological and histopathological analyses. TiO2 NPs exposure induced deposition of particles in lungs in a dose-dependent manner in each exposure group. Exposure to TiO2 NPs, as well as other organs, did not increase the incidence of lung tumors in any group, and pulmonary fibrosis and pre-neoplastic lesions were not observed in all groups. Finally, the cell proliferative activity of alveolar epithelial type 2 cells was examined, and it was not increased by exposure to TiO2 NPs. This is the first report showing the lack of pulmonary fibrogenicity and carcinogenicity (no evidence of carcinogenic activity) of TiO2 NPs in 26-week inhalation study in rasH2 mice exposed up to 32 mg/m3, which is considered to be a high concentration.

Carcinogenicity and chronic toxicity of acrolein in rats and mice by two-year inhalation study.

The carcinogenicity and chronic toxicity of acrolein was examined by whole body inhalation to groups of 50 F344/DuCrlCrlj rats and 50 B6D2F1/Crlj mice of both sexes for two years. The concentration of acrolein was 0, 0.1, 0.5 or 2 ppm (v/v) for male and female rats; and 0, 0.1, 0.4 or 1.6 ppm for male and female mice. Two-year administration of acrolein induced the squamous cell carcinomas in nasal cavity which is rare tumor in one male and two female rats. In females, rhabdomyoma in nasal cavity was observed in four rats exposed to 2 ppm. In mice, since the survival rate of male and female of mice control group were lowered than 25% in late of the administration periods due to renal lesion and/or amyloid deposition, the mice study was terminated at 93rd week in males, and was terminated at 99th week in females. The incidences of adenomas in nasal cavity were observed in 16 females and significantly increased only in female mice. Thus, acrolein is carcinogenic in two species, i.e. rats and mice. Additionally, non-neoplastic nasal cavity lesions in rats and mice were observed.

Carcinogenicity of butyl 2,3-epoxypropyl ether in rats and mice by whole body inhalation for two years.

Butyl 2,3-epoxypropyl ether (CAS No. 2426-08-6, synonym: n-butylglycidyl ether, BGE) was exposed by whole body inhalation to F344 rats and BDF1 mice of both sexes (50 animals per group) 6 hours per day, 5 days per week for 104 weeks at targeted concentrations of 0, 10, 30 or 90 ppm (v/v) for rats and 0, 5, 15 or 45 ppm for mice. In rats, 90 ppm of BGE increased the incidences of nasal squamous cell carcinomas in both sexes. Nasal adenomas and splenic mononuclear cell leukemia were increased in male rats exposed to 30 ppm. Splenic mononuclear cell leukemia was increased in female rats by trend test. Non-neoplastic nasal lesions, such as squamous cell hyperplasia with atypia, squamous cell metaplasia and the inflammation of the respiratory region and atrophy of the olfactory epithelium were increased in both sexes in a dose-dependent manner. In mice, the incidences of histiocytic sarcomas of the uterus in female mice were increased in a dose-dependent manner and the incidences of nasal hemangiomas in both sexes were increased in a dose-dependent manner. Nasal squamous cell carcinoma, a rare tumor, was observed, although not statistically significant, in both sexes. Non-neoplastic lesions such as nodular hyperplasia of the transitional epithelium and cuboidal changes of the respiratory epithelium in the nasal cavity, were increased both in males and females in a dose-dependent manner. The present study demonstrated clear evidence of carcinogenicity of BGE in both rats and mice by the 2-year whole body inhalation exposure.

Carcinogenicity of multi-walled carbon nanotubes: challenging issue on hazard assessment.

OBJECTIVES: This report reviews the carcinogenicity of multi-walled carbon nanotubes (MWCNTs) in experimental animals, concentrating on MWNT-7, a straight fibrous MWCNT. METHODS: MWCNTs were administered to mice and rats by intraperitoneal injection, intrascrotal injection, subcutaneous injection, intratracheal instillation and inhalation. RESULTS: Intraperitoneal injection of MWNT-7 induced peritoneal mesothelioma in mice and rats. Intrascrotal injection induced peritoneal mesothelioma in rats. Intratracheal instillation of MWCNT-N (another straight fibrous MWCNT) induced both lung carcinoma and pleural mesothelioma in rats. In the whole body inhalation studies, in mice MWNT-7 promoted methylcholanthrene-initiated lung carcinogenesis. In rats, inhalation of MWNT-7 induced lung carcinoma and lung burdens of MWNT-7 increased with increasing concentration of airborne MWNT-7 and increasing duration of exposure. CONCLUSIONS: Straight, fibrous MWCNTs exerted carcinogenicity in experimental animals. Phagocytosis of MWCNT fibers by macrophages was very likely to be a principle factor in MWCNT lung carcinogenesis. Using no-observed-adverse-effect level-based approach, we calculated that the occupational exposure limit (OEL) of MWNT-7 for cancer protection is 0.15 µg/m3 for a human worker. Further studies on the effects of the shape and size of MWCNT fibers and mode of action on the carcinogenicity are required.

In vitro chromosomal aberrations induced by various shapes of multi-walled carbon nanotubes (MWCNTs).

OBJECTIVES: IARC has classified one type of multi-walled carbon nanotubes (MWCNTs), MWNT-7, as possibly carcinogenic to humans (Group 2B); however, other types of MWCNT were categorized as not classifiable as to their carcinogenicity to humans (Group 3). In vitro chromosomal aberration assays of MWNT-7 showed polyploid formation but not structural abnormalities. This study investigated the influence of the shape and size of MWCNT on in vitro induction of chromosomal aberrations. METHODS: Microscopic analysis and viable cell counting were used to assay for chromosomal aberrations and cytotoxicity induced in a Chinese hamster lung cell line (CHL/IU) exposed to different MWCNTs. RESULTS: Using scanning electron microscopy, seven MWCNTs were classified into three types: straight fibrous, curved fibrous, and tangled. The straight fibrous MWCNTs were the strongest inducers of polyploidy and the most cytotoxic among the three types of MWCNTs. The curved fibrous MWCNTs induced more polyploidy than the tangled MWCNTs, and the cytotoxicity of both types seemed to be a reflection of their induction of polyploidy. None of the seven MWCNTs induced structural chromosomal aberrations. CONCLUSION: The non-clastogenicity of the MWCNTs indicates that the MWCNTs may not interact directly with DNA. Since the straight fibrous MWCNTs, which exhibit a structure similar to asbestos, were the strongest inducers of polyploidy, MWCNT shape may be an important factor in induction of polyploidy. We hypothesize that CHL/IU cells endocytosed MWCNTs and formed endosomes with shapes corresponding to those of the endocytosed MWCNTs, and that the long axis diameter of the endosome is important in the capability of MWCNTs to induce polyploidy.

Lung carcinogenicity of inhaled multi-walled carbon nanotube in rats.

BACKGROUND: Multi-walled carbon nanotubes (MWCNTs) constitute one of the most promising types of nanomaterials in industry today. With their increasing use, the potential toxicity and carcinogenicity of MWCNT needs to be evaluated in bioassay studies using rodents. Since humans are mainly exposed to MWCNT by inhalation, we performed a 104-week carcinogenicity study using whole-body inhalation exposure chambers with a fibrous straight type of MWCNT at concentrations of 0, 0.02, 0.2, and 2 mg/m3 using male and female F344 rats. RESULTS: Lung carcinomas, mainly bronchiolo-alveolar carcinoma, and combined carcinomas and adenomas were significantly increased in males exposed to 0.2 and 2 mg/m3 MWNT-7 and in females exposed to 2 mg/m3 MWNT-7 compared to the clean air control group. However, no development of pleural mesothelioma was observed. Concentration-dependent toxic effects in the lung such as epithelial hyperplasia, granulomatous change, localized fibrosis, and alteration in BALF parameters were found in MWNT-7 treatment groups of both sexes. There were no MWNT-7-specific macroscopic findings in the other organs, including the pleura and peritoneum. Absolute and relative lung weights were significantly elevated in male rats exposed to 0.2 and 2 mg/m3 MWNT-7 and in all exposed female groups. The lung burdens of MWNT-7 were clearly increased in a concentration-dependent as well as a duration-dependent manner. CONCLUSION: There is clear evidence that MWNT-7 is carcinogenic to the lungs of male and female F344 rats, however no plural mesothelioma was observed.

Improved method for measurement of multi-walled carbon nanotubes in rat lung.

BACKGROUND: Previously, we have developed and reported the method of measuring multi-walled carbon nanotube (MWCNT) in the lung from rats exposed to MWCNT intratracheally. The present research was performed to improve the analytical method of MWCNT to measure multiple samples in a short period of time. For the xanalysis of MWCNTs from tissues, the existence of carbon black may interfere. Therefore, it was examined whether or not carbon black interfere the determination of MWCNT in the standard solutions. Then, MWCNTs were administered to rats and the MWCNTs were determined in the rats by the new method and the recovery rates and time for determination were calculated. The standard solutions for MWCNTs and carbon black were prepared, and the concentrations in the solutions were determined by HPLC with checking their linearity between the concentrations and signal intensities. The reproducibility of the determination was also checked. METHODS: The concentrations of MWCMTs in the standard solutions were determined by HPLC with a fluorescent detector. Those of carbon black were also determined using the same method. The MWCNTs were administered to rats intratracheally. The MWCNTs in the lung were determined in a newly modified method including digestion of lung tissues by strong alkali solution and marking MWCNTs by benzo[ghi]perylene. The time for the determinations was recorded and the recovery rate of MWVNTs was calculated. RESULTS: MWCNT showed linearity in a range of 0.2 to 1.0 µg/mL. In contrast, carbon black demonstrated a very low slope, showing flat pattern. Regarding the reproducibility of the analysis, the coefficient of variation was lower than 10 %. The analysis of 20 samples were completed in 1.5 h. The recovery rates of MWCNT from the lung of rats receiving intratracheal MWCNT administration were 101 to 102 %. CONCLUSIONS: The improved method for measuring MWCNT allows an efficient MWCNT quantitation in a short period of time. Also, a small amount of MWCNTs can be measured without influence of carbon black.

Thirteen-week study of toxicity of fiber-like multi-walled carbon nanotubes with whole-body inhalation exposure in rats.

Cancer development due to fiber-like straight type of multi-walled carbon nanotubes (MWCNTs) has raised concerns for human safety because of its shape similar to asbestos. To set concentrations of MWCNT for a rat carcinogenicity study, we conducted a 13-week whole body inhalation study. F344 male and female rats, 6-week-old at the commencement of the study, were exposed by whole-body inhalation to MWCNT at concentrations of 0, 0.2, 1 and 5 mg/m(3) with a generation and exposure system utilizing the cyclone sieve method. Measured concentrations in the exposure chambers were 0.20 ± 0.02, 1.01 ± 0.11 and 5.02 ± 0.25 mg/m(3) for 13 weeks. The MMAD (GSD) of MWCNT were 1.4-1.6 µm (2.3-3.0), and mean width and length were 94.1-98.0 nm and 5.53-6.19 µm, respectively, for each target concentration. Lung weights were increased 1.2-fold with 1 mg/m(3) and 1.3-fold with 5 mg/m(3) in both sexes compared to the controls. In the bronchoalveolar lavage fluid (BALF) analyses, inflammatory parameters were increased concentration-dependently in both sexes from 0.2 mg/m(3). Granulomatous changes in the lung were induced at 1 and 5 mg/m(3) in females and even at 0.2 mg/m(3) in males. Focal fibrosis of the alveolar wall was observed in both sexes at 1 mg/m(3) or higher. Inflammatory infiltration in the visceral pleural and subpleural areas was induced only at 5 mg/m(3). In conclusion, we determined 0.2 mg/m(3) as the low-observed-adverse-effect level (LOAEL) for respiratory tract toxicity in the present inhalation exposure study of rats.

The increases in relative mRNA expressions of inflammatory cytokines and chemokines in splenic macrophages from rats exposed to multi-walled carbon nanotubes by whole-body inhalation for 13 weeks.

BACKGROUND: The toxicity of multi-walled carbon nanotubes (MWCNT) may be related to the immune system. The objective of this study was to obtain information for immunotoxic mechanisms of MWCNT in situ. METHODS: Using whole-body inhalation, male and female rats were exposed to 0, 0.2, 1 or 5 mg MWCNT/m³ for 13 weeks. Thereafter, spleens were recovered from the rats. Real-time PCR was done to assess expression of TNFα, IL-1ß, IL-6, IL-10, MCP-1 and MIP-1α mRNA in the splenic macrophages; splenic T-lymphocytes were examined for IL-2 and TGF-ß1 mRNA expression. RESULTS: The relative expression of IL-1ß mRNA in the cells from female rats exposed to 5 mg MWCNT/m³ was significantly higher than that in control cells. For IL-6 and IL-10, cells from rats in the 0.2 and 5 mg MWCNT/m³ had significantly higher mRNA expressions than did cells from controls. Expression of IL-1ß, IL-6 and TNFα genes in cells from males in all exposure groups were higher than in control cells. Expression of MIP-1α in the cells from female 5-mg group was significantly higher than that in cells in the control. Only IL-2 was expression reduced, i.e. cells from male and female rats in all MWCNT groups had significantly lower mRNA expressions than control cells. CONCLUSIONS: Systemic inflammation would likely occur in rats (or other hosts) exposed to MWCNT via inhalation due to increases in the expression of inflammatory cytokines in splenic macrophages. Moreover, decreases in IL-2 expression in T-lymphocytes may be critical to the potential reductions in anti-tumor responses in MWCNT-exposed hosts.

Inhalation carcinogenicity of dichloromethane in rats and mice.

The carcinogenicity of inhaled dichloromethane (DCM) was examined by exposing groups of 50 F344/DuCrj rats and 50 Crj: BDF1 mice of both sexes to 0, 1000, 2000, or 4000 ppm (w/w) DCM-containing aerosol for 2 years. Inhalation of DCM resulted in increased incidences of subcutis fibromas, mammary gland fibroadenoma, and peritoneum mesotheliomas in male rats; mammary gland fibroadenomas in female rats; and bronchiolar-alveolar adenomas and carcinomas in the lung and hepatocellular adenomas and carcinomas in male and female mice. These results clearly indicate that inhaled DCM is carcinogenic in F344/DuCrj (SPF) rats and Crj: BDF1 (SPF) mice.

Unilateral imagined movement increases interhemispheric inhibition from the contralateral to ipsilateral motor cortex.

Whether a cortical drive to one limb modulates interhemispheric inhibition (IHI) from the active targeting to the non-active motor cortex (M1) remained unclear. The present study using a conditioning-test transcranial magnetic stimulation (TMS) paradigm aimed to directly demonstrate the modulation of IHI during unilateral voluntary or imagined movement in humans. Subjects were asked to actually perform right index-finger abduction (10-70% of the maximum voluntary contraction) or to imagine the movement. Conditioning and test TMS with an interstimulus interval of 5, 10, and 15 ms were applied over the left and right M1, respectively, and the test motor evoked potential (MEP) was recorded from the left first dorsal interosseous (FDI) muscle. The conditioning TMS intensity was adjusted ranging from 0.6 to 1.4 (in 0.2 steps) times the resting motor threshold (rMT). With test TMS alone, MEP in the left FDI muscle significantly increased during voluntary or imagined movement of the right index-finger. MEP amplitude was significantly reduced in proportion to increments of the conditioning TMS intensity at rest (1.2 and 1.4 times the rMT, P < 0.05, respectively). Importantly, the MEP inhibition was markedly enhanced during voluntary or imagined movement in comparison with that at rest. The regression analysis revealed that IHI varied depending on the intensity of the impulses conveyed from left to right M1, but not on the corticospinal excitability of the active right hand. Our results suggest that IHI from the active to non-active M1 is enhanced during unilateral volitional motor activity.

Development of a new multi-walled carbon nanotube (MWCNT) aerosol generation and exposure system and confirmation of suitability for conducting a single-exposure inhalation study of MWCNT in rats.

Because the primary route of human exposure to multi-walled carbon nanotube (MWCNT) is via inhalation, a new dry MWCNT aerosol generation and exposure system for whole-body inhalation exposure using a cyclone and sieve has been developed. The system was tested for operational performance at 0.2, 1 and 5 mg/m(3). Additionally, it was examined whether this system can be employed in animal whole-body inhalation studies by exposing rats to MWCNT aerosol for 6 h at 5 mg/m(3). The system could consistently provide aerosols with a similar particle size distribution and configuration at all the target exposure concentrations. Almost all MWCNTs were fibrous, and the presence of many well-dispersed, nano-sized particles was confirmed. Additionally, the animal study revealed that large amounts of MWCNTs were inhaled into the lung, resulting in an inflammatory response, with increased LDH and albumin levels, and granulomatous change. Therefore, the aerosol generation and exposure system appears useful for MWCNT inhalation studies using rats.