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Morimoto Y.,University of Occupational and Environmental Health Japan | Horie M.,University of Occupational and Environmental Health Japan | Kobayashi N.,Japan National Institute of Health Sciences | Shinohara N.,Japan National Institute of Advanced Industrial Science and Technology | Shimada M.,Hiroshima University
Accounts of Chemical Research | Year: 2013

Although the demand for nanomaterials has grown, researchers have not conclusively determined the effects of nanomaterials on the human body. To understand the effects of nanomaterials on occupational health, we need to estimate the respiratory toxicity of nanomaterials through inhalation studies, intratracheal instillation studies, and pharyngeal aspiration studies. The discrepancies observed among these studies tend to result from differences in the physiochemical properties of nanomaterials, such as aggregation and dispersion. Therefore, in all toxicity studies, identification of the physicochemical properties of nanomaterials is essential.This Account reviews the inhalation toxicity of manufactured nanomaterials and compares them with inhalation and intratracheal instillation studies of well-characterized fullerene and carbon nanotubes. In many reports, pulmonary inflammation and injury served as pulmonary endpoints for the inhalation toxicity. To assess pulmonary inflammation, we examined neutrophil and macrophage infiltration in the alveolar and/or interstitial space, and the expression of the neutrophil and/or monocyte chemokines. We also reported the release of lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) in the bronchoalveolar lavage fluid (BALF), the expression of oxidative stress-related genes characteristic of lung injury, and the presence of granulomatous lesion and pulmonary fibrosis.In the inhalation and intratracheal instillation studies of well-characterized fullerenes, exposure to fullerene did not induce pulmonary inflammation or transient inflammation. By contrast, in an inhalation study, a high concentration of multiwall carbon nanotubes (MWCNTs) and single-wall carbon nanotubes (SWCNTs) induced neutrophil inflammation or granulomatous formations in the lung, and intratracheal instillation of MWCNTs and SWCNTs induced persistent inflammation in the lung.Among the physicochemical properties of carbon nanotubes, the increased surface area is associated with inflammatory activity as measured by the increase in the rate of neutrophils measured in bronchoalveolar lavage fluid. Metal impurities such as iron and nickel enhanced the pulmonary toxicity of carbon nanotubes, and SWCNTs that included an amorphous carbon induced multifocal granulomas in the lung while purer SWCNTs did not. The aggregation state also affects pulmonary response: Exposure to well-dispersed carbon nanotubes led to the thickening of the alveolar wall and fewer granulomatous lesions in the lung, while agglomerated carbon nanotubes produced granulomatous inflammation.The values of the acceptable exposure concentration in some countries were based on the data of subacute and subchronic inhalation and intratracheal instillation studies of well-characterized fullerene and carbon nanotubes. In Japan, the acceptable exposure concentration of fullerene is 0.39 mg/m3. In Europe, the proposal concentration is 44.4 μg/m3 for acute toxicity and 0.27 μg/m3 for chronic toxicity. The proposal acceptable exposure concentrations of carbon nanotubes are 0.03, 0.05, and 0.007 mg/m3 in Japan, Europe, and the United States, respectively. © 2012 American Chemical Society.

Suzuki H.,Japan National Institute of Health Sciences
Archives of Gerontology and Geriatrics | Year: 2012

We previously reported the regional differences in the IELs present in the proximal (P), middle (M), and distal (D) parts of the small intestine, cecum (Ce), and colon (Co) of mice. In this study, we investigated the age-dependent changes in the regional differences of IELs from young adult to aged mice. In this experiment, 3-, 6-, 12-, 18-, and 24-month-old mice were examined. IELs were separately isolated from 5 parts of the intestines and analyzed by flow cytometry. Regional differences in the number and phenotype of IELs showed the same trends in all age groups. The number of IELs was highest in 6-month-old mice and then gradually decreased with age. As to IEL subsets, age-related changes were not seen except for a few subsets among the age groups. We conclude that age-related decreases in IELs in mouse small intestine may be one of the aging phenomena of the intestinal immune system. Such age-related decreases in IELs may be concerned with the increased liability to intestinal infections in the elderly. © 2011 Elsevier Ireland Ltd.

Hirabayashi Y.,Japan National Institute of Health Sciences
Annals of the New York Academy of Sciences | Year: 2014

This paper reviews quantitative and qualitative studies conducted to identify changes in the characteristics of hematopoietic stem/progenitor cells (HSCs/HPCs) with or without radiation exposure. The numerical recovery of HSCs/HPCs after radiation exposure is lower than for other types of cells, an effect that may depend on hierarchical ordering of generation age during blood cell differentiation, from primitive HSCs to various differentiated HPCs. Studies are in progress to evaluate gene expression in bone marrow cells and cells in the lineage-negative, c-Kit+, stem cell antigen+ (LKS) fraction from 21-month-old mice, with or without radiation exposure. Preliminary data suggest that cell cycle-related genes, that is, cyclin D1 (Ccnd1), phosphatidylinositol 3 kinase regulatory subunit polypeptide 1 (PiK3r1), and Fyn, are upregulated solely in the LKS fraction from 21-month-old mice irradiated at 6 weeks of age, compared with the LKS fraction from age-matched nonirradiated control mice. Additional studies may provide evidence that the aging phenotype is exaggerated following exposure to ionizing radiation, specifically in the LKS fraction. © 2014 New York Academy of Sciences.

Suzuki H.,Japan National Institute of Health Sciences
Food Additives and Contaminants - Part A Chemistry, Analysis, Control, Exposure and Risk Assessment | Year: 2012

The mouse bioassay is widely used to detect diarrhetic shellfish poisoning (DSP) toxins. To the best of our knowledge, however, there have been no reports specifically on strain differences in susceptibility to DSP toxins. In this study, we investigated the susceptibility of different mice strains to okadaic acid (OA), one of the representative DSP toxins. A lethal dose of OA was injected intraperitoneally (i.p.) into mice. The mice were observed until 24 h after injection. Five inbred strains (A/J, BALB/c, C3H/He, C57BL/6, and DBA/2) and two non-inbred strains (ddY, and ICR) of mice were compared. All the mice were male, weighed 16-20 g, and were 4-5 weeks old. The lethality was 90-100% in the A/J, BALB/c, ddY, and ICR strains, 70-80% in the C3H/He and C57BL/6 strains, and 40% in DBA/2 strain. Survival analysis showed that the BALB/c, C57BL/6, ddY, and ICR strains died earlier and the A/J, C3H/He and DBA/2 strains survived longer. These results indicate that significant differences may exist in the susceptibility of mice strains to OA. © 2012 Copyright Taylor and Francis Group, LLC.

Azuma Y.,Japan National Institute of Health Sciences
Biological & pharmaceutical bulletin | Year: 2012

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is a promising treatment for colorectal, breast and gastric cancers, but often causes hand-foot syndrome (HFS), the most common dose-limiting toxicity. The current study was conducted to investigate the relationship between HFS and efficacy of capecitabine in 98 patients with metastatic breast cancer. Possible associations between HFS and efficacy endpoints, including time-to-treatment failure (TTF), tumor response in metastatic lesions and changes in tumor markers, were investigated retrospectively using electronic medical records. The TTF of group with HFS of grade 1 and ≥2 was significantly longer than that of group with no HFS, respectively (hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.18-0.87 for group with grade 1; HR, 0.42, 95% CI, 0.19-0.90 for group with grade ≥2). Significantly higher disease control rates for the liver metastasis were observed in patients with HFS (grade 1 and greater) than in those without HFS (92.9 vs. 42.9%, p=0.009). Furthermore, prevention of increases in tumor marker levels (carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA15-3) and National Cancer Center-Stomach-439 (NCC-ST439)) was evident in patients with HFS. This study clearly showed a significant correlation between HFS and some efficacy markers of capecitabine therapy in patients with metastatic breast cancer, and suggests that early dose adjustment based on severity of HFS might improve efficacy. Studies are needed to explore predictive biomarkers for HFS/efficacy, so that capecitabine therapy can be further tailored to patient response.

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