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2'-Amino-LNA has the potential to acquire various functions through chemical modification at the 2'-nitrogen atom. This study focused on 2'-N-alkylaminocarbonyl 2'-amino-LNA, which is a derivative of 2'-amino-LNA. We evaluated its practical usefulness as a chemical modification of anti-miRNA oligonucleotide. The synthesis of phosphoramidites of 2'-N-alkylaminocarbonyl substituted 2'-amino-LNA bearing thymine and 5-methylcytosine proceeded in good yields. Incorporating the 2'-N-alkylaminocarbonyl-2'-amino-LNA monomers into oligonucleotides improved the duplex stability for complementary RNA strands and robust nuclease resistance. Moreover, 2'-N-alkylaminocarbonyl-2'-amino-LNA is a promising scaffold that significantly increases the potency of anti-miRNA oligonucleotides.

Chemical modifications have been extensively used for therapeutic oligonucleotides because they strongly enhance the stability against nucleases, binding affinity to the targets, and efficacy. We previously reported that oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing the thymine (T) nucleobase show excellent biophysical properties for applications in antisense technology. In this paper, we describe the synthesis of GuNA[Me] phosphoramidites bearing other typical nucleobases including adenine (A), guanine (G), and 5-methylcytosine (mC). The phosphoramidites were successfully incorporated into oligonucleotides following the method previously developed for the GuNA[Me]-T-modified oligonucleotides. The binding affinity of the oligonucleotides modified with GuNA[Me]-A, -G, or -mC toward the complementary single-stranded DNAs or RNAs was systematically evaluated. All of the GuNA[Me]-modified oligonucleotides were found to have a strong affinity for RNAs. These data indicate that GuNA[Me] could be a useful modification for therapeutic antisense oligonucleotides.

Ionic liquid monomers with ion pair interaction energies ranging from 73.0 to 101.4 kcal/mol were designed by using the calculated electrostatic potential (ESP) values of the component ions. The io...

We recently designed guanidine-bridged nucleic acids (GuNA), and GuNA bearing a thymine (T) nucleobase was synthesized and successfully incorporated into oligonucleotides. The GuNA-T-modified oligonucleotides possessed high duplex-forming ability towards their complementary single-stranded RNAs and were highly stable against 3'-exonuclease. Therefore, GuNA is a promissing artificial nucleic acid for therapeutic antisense oligonucleotides. We herein report the facile synthesis of GuNA phosphoramidites bearing adenine (A), guanine (G), and 5-methylcytosine (mC) nucleobases and a robust method for the preparation of GuNA-modified oligonucleotides, even with sequences having acid-sensitive purine nucleobases. Oligonucleotides modified with GuNA-A, -G, or -mC possessed high duplex-forming ability, similar to those modified with GuNA-T. Moreover, some of the GuNA-modified oligonucleotides were revealed to have high base discriminating ability compared with that of their natural counterparts. GuNA nucleosides exhibited no genotoxicity in bacterial reverse mutation assays. Thus, all GuNAs (GuNA-T, -A, -G, and -mC) are now available to be examined in therapeutic applications.

Anti-microRNA oligonucleotides (AMOs) are valuable tools for the treatment of diseases caused by the dysregulation of microRNA expression. However, the correlation between chemical modifications in AMO sequences and the microRNA-inhibitory activity has not been fully elucidated. In this study, we synthesized a series of AMOs containing cationic guanidine-bridged nucleic acids (GuNA) and evaluated their activities using a dual luciferase assay. We also optimized the site of GuNA substitution and found an effective design for the inhibition of microRNA-21, which was partially different from that of conventional nucleic acid derivatives. This study showed that GuNA-substituted AMOs are effective in inhibiting the function of microRNA.

AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis.This multicentre, randomised, double-blind, placebo-controlled, phase 3 study consisted of two phases: a treatment phase and an open-label re-treatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6-10, endoscopic subscore of 2 or more, rectal bleeding subscore of 1 or more, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimisation method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥6 to ≤7, ≥8 to ≤10 points), any use of corticosteroid, anti-TNFα antibody, or immunosuppressants during the disease-active period (yes vs no), duration of induction therapy until randomisation (4 weeks vs ≥4 weeks) as the minimisation factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, three times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary endpoint was the proportion of patients with a clinical response at week 8, and was analysed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score of 30% or more and 3 or more, a reduction in rectal bleeding score of 1 or more or rectal bleeding subscore of 1 or less, and an endoscopic subscore of 1 or less at week 8. The study is registered with ClinicalTrials.gov, NCT03531892, and is closed to recruitment.Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n=102) or placebo (n=101). At week 8, 46 (45%) patients in the AJM300 group and 21 (21%) patients in the placebo group had a clinical response (odds ratio 3·30, 95% CI 1·73-6·29; p=0·00028). During the 8-week treatment and 16-week extension treatment periods, adverse events occurred in 39 (39%) of 101 patients in the placebo group and 39 (38%) of 102 patients in the AJM300 group. We found no difference in the incidence of adverse events between groups or after repeated administration of AJM300. The most common adverse event was nasopharyngitis (11 [11%] of 101 patients in the placebo group and ten [10%] of 102 patients in the AJM300 group). The most common treatment-related adverse event was also nasopharyngitis (four [4%] of 101 patients in the placebo group and three [3%] of 102 patients in the AJM300 group). Most adverse events were mild-to-moderate in severity. No deaths were reported. A serious adverse event was reported in the AJM300 group (one patient with anal abscess), but this was judged to be unrelated to study drug.AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis.EA Pharma and Kissei Pharmaceutical.For the Japanese translation of the abstract see Supplementary Materials section.

Background: Although a causal relationship between mesothelioma and asbestos exposure is well known, few studies have shown a relationship to non-occupational exposure, including neighborhood exposure, most likely because of the large effect size of occupational exposure. The aim of this study was to quantify the risk of malignant mesothelioma death associated with neighborhood asbestos exposure due to a large-scale asbestos-cement (AC) plant in Amagasaki, Japan, by properly adjusting for occupational exposure. Methods: We conducted a nested case-control study in which a fixed population of 143,929 residents who had been living in Amagasaki City between 1975 and 2002 were followed from 2002 to 2015. All 133 cases and 403 matched controls were interviewed about their occupational, domestic, household, and neighborhood asbestos exposures. Odds ratios (ORs) for mesothelioma death associated with neighborhood exposure were estimated by a conditional logistic-regression model that adjusted for other asbestos exposures. We adopted cumulative indices that considered residence-specific asbestos (crocidolite) concentrations and durations during the potential exposure period of 1957-1975 to evaluate individual neighborhood exposures.Results: There was an increasing, dose-dependent risk of mesothelioma death associated with neighborhood exposure, demonstrated by ORs in the highest quintile category that were 21.4 (95% CI: 5.8 - 79.2) for all, 23.7 (95% CI: 3.8 -147.2) for males, and 26.0 (95% CI: 2.8 - 237.5) for females, compared to the lowest quintile, respectively. These results clearly demonstrated no substantial differences between males and females in relation to the magnitude of risk from neighborhood exposure.Conclusions: By adjusting for occupational and other asbestos exposures, a dose-dependent relationship was demonstrated between mesothelioma death and neighborhood asbestos exposure from a large-scale AC plant. Our findings suggest that the risk of mesothelioma death associated with neighborhood exposure persists and will not be diminished for many years, even though it has been decades since the AC plant closed.

This Document, "Guidelines for personal exposure monitoring of chemicals" ("this Guideline"), has been prepared by "The Committee for Personal Exposure Monitoring" ("the Committee") of the Expert Division of Occupational Hygiene & Ergonomics, Japan Society for Occupational Health. Considering the background of the growing importance of personal exposure monitoring in risk assessment and the need to prepare for the introduction of monitoring using personal samplers from an administrative perspective in recent years, the Committee was organized in November 2012. The Committee has prepared this Guideline as a "practical guideline" for personal exposure monitoring, so as to offer proposals and recommendations to the members of the Japan Society for Occupational Health and to society in general. The scope of this Guideline covers all chemical substances and all related workplaces regarded as targets for general assessment and the management of risk. It thus is not to be considered to comment on legal regulations and methodology. The main text provides the basic methods and concepts of personal exposure monitoring, while 31 "Appendices" are provided in this Guideline throughout the series; technical descriptions, statistical bases, and actual workplace examples are provided in these appendices, to assist better understanding. The personal exposure monitoring described as per this Guideline is equivalent to an "expert-centered basic method to reasonably proceed with the assessment and management of risk at workplaces." It is considered that practicing and expanding on this method will significantly contribute in reforming the overall framework of occupational hygiene management in Japan.

1,2-Dichloropropane (1,2-DCP) has been used as a paint remover in the industry. The International Agency for Research on Cancer reclassified this compound recently to group 1 (carcinogenic to humans) based on epidemiological studies of cholangiocarcinoma among offset-color proof-printing workers exposed to 1,2-DCP in Japan. Two-year rodent carcinogenicity bioassays demonstrated that 1,2-DCP induced tumors in liver and lung, but not in bile duct. The present study was designed to assess the toxic effects of 1,2-DCP on proliferation and apoptosis in mice bile duct and the role of cytochrome P450 (CYP450) in any such effect. Male C57BL/6JJcl mice were cotreated or untreated with 1-aminobenzotriazole (1-ABT), a CYP450 inhibitor, and exposed to inhalation of 1,2-DCP at 0, 50, or 250 ppm alone, or at 0, 50, 250, or 1250 ppm 8 h/day for 4 weeks. Exposure to 1,2-DCP increased proliferation and apoptosis of cholangiocytes and induced severe hepatic damage, but had no effect on the lungs. Cotreatment with 1-ABT abrogated the effects of 1,2-DCP on proliferation and apoptosis of cholangiocytes. The results revealed that 1,2-DCP induces proliferation and apoptosis of cholangiocytes and that this effect is mediated through CYP450.

Background Rabeprazole at 10 or 20 mg twice daily (b.i.d.) has been reported to be highly effective in the treatment of proton pump inhibitor (PPI)-resistant reflux esophagitis (RE) that is refractory to the standard once-daily PPI regimen. We evaluated the efficacy and safety of rabeprazole maintenance therapy at 10 mg once daily (q.d.) or b.i.d. for longer than 8 weeks. Methods Patients with RE refractory to standard PPI regimens for at least 8 weeks were enrolled. They were treated with rabeprazole at 10 or 20 mg b.i.d. for 8 weeks during the open-label treatment period. After endoscopic examination, those with confirmed healing entered the subsequent double-blind maintenance therapy. During this period, the subjects were randomized to receive rabeprazole 10 mg q.d. (control) or 10 mg b.i.d. The primary endpoint was the endoscopic no-recurrence rate at Week 52. Results In total, 517 subjects entered the treatment, and 359 subjects continued on maintenance therapy. The full analysis set for central assessment included 343 subjects. The no-recurrence rate at Week 52 was significantly higher in the b.i.d. group (73.9%; p 2 test) than in the q.d. group (44.8%). In particular, the b.i.d. regimen was more effective in all subgroups with Los Angeles Classification Grade B to D at treatment entry. Conclusions In the maintenance treatment of PPI-resistant RE, rabeprazole at 10 mg b.i.d. exerted a stronger recurrence-preventing effect than 10 mg q.d. over 52 weeks. No particular safety issues were noted during long-term administration. ClinicalTrials.gov number: NCT02135107.

This Document, "Guidelines for personal exposure monitoring of chemicals" ("this Guideline"), has been prepared by "The Committee for Personal Exposure Monitoring" ("the Committee") of the Expert Division of Occupational Hygiene & Ergonomics, Japan Society for Occupational Health. Considering the background of the growing importance of personal exposure monitoring in risk assessment and the need to prepare for the introduction of monitoring using personal samplers from an administrative perspective in recent years, the Committee was organized in November 2012. The Committee has prepared this Guideline as a "practical guideline" for personal exposure monitoring, so as to offer proposals and recommendations to the members of the Japan Society for Occupational Health and to society in general. The scope of this Guideline covers all chemical substances and all related workplaces regarded as targets for general assessment and the management of risk. It thus is not to be considered to comment on legal regulations and methodology. The main text provides the basic methods and concepts of personal exposure monitoring, while 31 "Appendices" are provided in this Guideline throughout the series; technical descriptions, statistical bases, and actual workplace examples are provided in these appendices, to assist better understanding. The personal exposure monitoring described as per this Guideline is equivalent to an "expert-centered basic method to reasonably proceed with the assessment and management of risk at workplaces." It is considered that practicing and expanding on this method will significantly contribute in reforming the overall framework of occupational hygiene management in Japan.

An N-methylguanidine-bridged nucleic acid (GuNA[NMe]), a guanidine-bridged nucleic acid (GuNA) bearing a methyl substituent at the bridge, was successfully synthesised and incorporated into oligonucleotides. By employing an acetyl protecting group, GuNA[NMe]-modified oligonucleotides bearing acid-sensitive purine nucleobases were successfully prepared. The obtained GuNA[NMe]-modified oligonucleotides exhibit excellent binding affinity towards the complementary single-stranded RNA and DNA. Furthermore, even a single GuNA[NMe] modification provides robust enzymatic stability, similar to that achieved by the well-established phosphorothioate backbone modification. These data indicate that such a GuNA[NMe] represents a valuable modification for the development of therapeutic oligonucleotides.

This Document, "Guidelines for personal exposure monitoring of chemicals" ("this Guideline"), has been prepared by "The Committee for Personal Exposure Monitoring" ("the Committee") of the Expert Division of Occupational Hygiene & Ergonomics, Japan Society for Occupational Health. Considering the background of the growing importance of personal exposure monitoring in risk assessment and the need to prepare for the introduction of monitoring using personal samplers from an administrative perspective in recent years, the Committee was organized in November 2012. The Committee has prepared this Guideline as a "practical guideline" for personal exposure monitoring, so as to offer proposals and recommendations to the members of the Japan Society for Occupational Health and to society in general. The scope of this Guideline covers all chemical substances and all related workplaces regarded as targets for general assessment and the management of risk. It thus is not to be considered to comment on legal regulations and methodology. The main text provides the basic methods and concepts of personal exposure monitoring, while 31 "Appendices" are provided in this Guideline throughout the series; technical descriptions, statistical bases, and actual workplace examples are provided in these appendices, to assist better understanding. The personal exposure monitoring described as per this Guideline is equivalent to an "expert-centered basic method to reasonably proceed with the assessment and management of risk at workplaces." It is considered that practicing and expanding on this method will significantly contribute in reforming the overall framework of occupational hygiene management in Japan.

Chemical exposure levels in printing and coating workers with cholangiocarcinoma (third report): Kenichi Yamada, et al. Occupational Health Research and Development Center, Japan Industrial Safety and Health Association OBJECTIVE: This study aimed to identify the chemicals used by five printing workers and one coating worker who developed cholangiocarcinoma and estimate the workers’ levels of chemical exposure. METHODS: We obtained information on chemicals from the Ministry of Health, Labour and Welfare, Japan, and estimated working environment concentrations of the chemicals in printing and coating rooms and exposure concentrations during the ink and dirt removal processes. We also calculated shift time‐weighted averages of exposure concentrations. RESULTS: All five printing workers were exposed to both 1,2‐dichloropropane (1,2‐DCP) and dichloromethane (DCM). The estimated maximum exposure concentrations for each of the five workers were 190 to 560 ppm for 1,2‐DCP and 300 to 980 ppm for DCM, and the estimated shift average exposure concentrations were 0 to 230 ppm for 1,2‐DCP and 20 to 470 ppm for DCM. The coating worker was exposed to 1,2‐DCP, but not DCM. He did not use ink, and thus was subjected to different conditions than the printing workers. The estimated maximum exposure concentration of 1,2‐DCP was 150 ppm, and the estimated shift time‐weighted average exposure concentration was 5 to 19 ppm. CONCLUSIONS: Our findings support the notion that 1,2‐DCP contributes to the development of cholangiocarcinoma in humans and the notion that DCM may also be a contributing factor. The finding that the coating worker was exposed to 1,2‐DCP at a lower exposure concentration is important for determining the occupational exposure limit. Furthermore, the subject did not use ink, which suggests that ink did not contribute to the development of cholangiocarcinoma.

Objectives: N,N-Dimethylacetamide (DMAC) is widely used in industry as a solvent. It can be absorbed through human skin. Therefore, it is necessary to determine exposure to DMAC via biological monitoring. However, the precision of traditional gas chromatography (GC) is low due to the thermal decomposition of metabolites in the high-temperature GC injection port. To overcome this problem, we have developed a new method for the simultaneous separation and quantification of urinary DMAC metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Methods: Urine samples were diluted 10-fold in formic acid, and 1-μl aliquots were injected into the LC-MS/MS equipment. A C18 reverse-phase Octa Decyl Silyl (ODS) column was used as the analytical column, and the mobile phase consisted of a mixture of methanol and aqueous formic acid solution. Results: Urinary concentrations of DMAC and its known metabolites (N-hydroxymethyl-N-methylacetamide (DMAC-OH), N-methylacetamide (NMAC), and S- (acetamidomethyl) mercapturic acid (AMMA) ) were determined in a single run. The dynamic ranges of the calibration curves were 0.05-5 mg/l (r≥0.999) for all four compounds. The limits of detection for DMAC, DMAC-OH, NMAC, and AMMA in urine were 0.04, 0.02, 0.05, and 0.02 mg/l, respectively. Within-run accuracies were 96.5%-109.6% with relative standard deviations of precision being 3.43%-10.31%. Conclusions: The results demonstrated that the proposed method could successfully quantify low concentrations of DMAC and its metabolites with high precision. Hence, this method is useful for evaluating DMAC exposure. In addition, this method can be used to examine metabolite behaviors in human bodies after exposure and to select appropriate biomarkers.

Objectives: We previously reported a cluster of cholangiocarcinoma patients among proof-printing workers who were exposed to 1,2-DCP for a long term. The present study was conducted to evaluate blood parameters in these proof-printing workers during and after exposure. Methods: Health examination records during employment and after retirement were obtained for ten cholangiocarcinoma patients to analyze their blood parameters. The patients and/or their relatives were also interviewed about lifestyle and occupational history. Results: All study patients were exposed to 1,2-DCP for 6–17 years. Red blood cells, hemoglobin, hematocrit, total cholesterol, triglycerides, and fasting plasma glucose were within the standard ranges for almost all patients, but the γ-glutamyl transpeptidase (γ-GTP) levels exceeded the standard range during 1,2-DCP exposure for six patients. Two of the six patients were diagnosed with cholangiocarcinoma during 1,2-DCP exposure, and the other four patients were diagnosed 1–9 years after termination of exposure. The remaining four patients had γ-GTP levels within the standard range during 1,2-DCP exposure, but had increased γ-GTP levels thereafter, and were diagnosed with cholangiocarcinoma 4–10 years after termination of exposure. Aspartate aminotransferase and alanine aminotransferase levels started to increase following the increase in γ-GTP levels. Conclusions: Workers exposed to 1,2-DCP should be provided with periodic health examinations during and after exposure. In the examination, even small increases in γ-GTP levels should be considered a signal of early development of cholangiocarcinoma.(J Occup Health 2014; 56: 279-284)

OBJECTIVES Previously, the author reported a cluster of 11 cholangiocarcinoma cases exposed to 1,2-dichloropropane (1,2-DCP) and/or dichloromethane (DCM) in an offset proof-printing company. Before that report, the association between the two chemicals and cholangiocarcinoma had not been known. The current study describes two cholangiocarcinoma patients exposed to 1,2-DCP or DCM in different offset printing companies. METHODS The author obtained medical records for the patients, and interviewed the surviving patient and a relative of the deceased patient about their occupational history. RESULTS Case 1 was a man born in 1950. He worked in the printing section in a proof-printing company for 26 years. He was diagnosed as cholangiocarcinoma in 1998 and died in 2000. In proof-printing operations, he used gasoline for 14 years and 1,2-DCP for 11 years to remove ink from a rubber transcription roller (blanket). The exposure concentration of 1,2-DCP was estimated to be between 72 and 5,200 ppm. Case 2 was a man born in 1963. He worked in the printing section in a general offset printing company for 11 years. He was diagnosed with cholangiocarcinoma in 2007. In printing operations, he used both kerosene and a mixture of 50% DCM and 50% 1,1,1-trichloroethane (1,1,1-TCE) for 11 years to remove ink from a blanket. The exposure concentration of DCM was estimated to be between 240 and 6,100 ppm. He was simultaneously exposed to similar levels of 1,1,1-TCE. CONCLUSIONS Because the offset printing process may cause cholangiocarcinoma, occupational history should be examined for patients with this cancer.

This study was conducted to develop a tool for evaluating the work environment for the preparation of antineoplasticdrugs and identify issues in safety assessment.We prepared a checklist for the safe handling of antineoplastic drugs,whichincluded the following items : A) safety equipment and its maintenance,B) training and training documentation,C) devicesfor ensuring safety,D) personal protective equipment and E) emergency care.Further,we examined relationships betweenattainment levels for checklist items and occupational contamination levels for cyclophosphamide (CPA),fluorouracil (5FU),gemcitabine (GEM) and platinum-containing drugs (Pt) based on wipe samples from equipment in the preparationroom (wipe test).Next,pharmacists in a particular hospital were asked to improve their work environment using the checklist.To evaluate their improvements,we collected wipe samples and one-day urine samples from them,before and afterthey took improvement measures.The results showed that an increase in safety attainment scores was reflected in a decrease in CPA,GEM and Pt contaminationlevels in the wipe test,as well as one in urinary levels of CPA.However,the 5FU level in the wipe test increased,probably due to a 6-fold increase in the amount of 5FU prepared,compared to before the improvement measures weretaken.From these findings,we concluded that the checklist would be useful for improving the hospital work environment.

Purpose. The aim of the present study was to evaluate the measurement of contamination by antineoplastic drugs for safer handling of such drugs by medical workers. We investigated the relationship between the contamination level of antineoplastic drugs and the conditions of their handling. Methods. Air samples and wipe samples were collected from equipment in the preparation rooms of five hospitals (hospitals A—E). These samples were subjected to measurement of the amounts of cyclophosphamide (CPA), fluorouracil (5FU), gemcitabine (GEM), and platinum-containing drugs (Pt). Twenty-four-hour urine samples were collected from the pharmacists who handled or audited, the antineoplastic drugs were analyzed for CPA and Pt. Results. Pt was detected from air samples inside BSC in hospital B. Antineoplastic drugs were detected from wipe samples of the BSC in hospitals A, B, D, and E and of other equipment in the preparation rooms in hospitals A, B, C, and D. Cyclophosphamide and 5FU were detected from wipe samples of the air-conditioner filter in hospital A, and CPA was detected from that in hospital D. Cyclophosphamide was detected from urine samples of workers in hospitals B, D, and E. Conclusion. The contamination level of antineoplastic drugs was suggested to be related with the amount of drugs handled, cleaning methods of the equipment, and the skill level of the technique of maintaining negative pressure inside a vial. In order to reduce the contamination and exposure to antineoplastic drugs in the hospital work environment very close to zero, comprehensive safety precautions, including adequate mixing and cleaning methods was required in addition to BSC and closed system device.

石綿は20世紀初頭から世界各地で大量に使用されてきたため，石綿または石綿製品の取扱い事業場は現在も含め数多くある．それ故，石綿が近隣に及ぼす影響範囲の検討は，一般住民に発見される中皮腫の石綿曝露源を考える上でも，地域全体を石綿関連疾患から予防するためにも重要である．本稿ではその影響範囲に関する文献的解説を試みた．事業場活動を原因とする石綿曝露源と周辺住民の中皮腫による死亡リスク上昇との関連を検討した研究は実は極めて少ない．しかし，それらの研究によれば，英国ロンドンの石綿製造工場の場合は800 m以内で，南アフリカとヨーロッパ諸国の石綿鉱山や石綿製品製造工場，さらには造船所の場合はそれぞれ1,000 mと2,000 m以内で，またイタリアの石綿セメント工場の場合には2,500 mを超えても，中皮腫死亡の有意なリスク上昇が認められている．著者らが検討した旧石綿セメント管製造工場近隣住民の中皮腫死亡リスクも，工場から1,500 m離れた所まで有意な上昇を認めた．公衆衛生担当者と医療関係者そして企業は，石綿の近隣曝露が広い範囲にわたって中皮腫の重大なリスク上昇をもたらすことを十分認識する必要がある．

Little is known about neighborhood exposure to asbestos and mesothelioma risk among residents around an industrial source of asbestos.To investigate the magnitude of the risk among residents by asbestos exposure levels and to determine the range of the area affected by asbestos.We calculated standardized mortality ratios of mesothelioma from 1995 to 2006 among the estimated population at risk that lived around a former large asbestos cement pipe plant in Amagasaki City, Japan, between 1957 and 1975, the time when the plant had used crocidolite and chrysotile. The distance between the plant and homes and relative asbestos concentrations obtained by diffusion equations involving meteorological conditions were used to determine asbestos exposure levels among residents.We identified 73 mesothelioma deaths of 35 men and 38 women who had no occupational exposure to asbestos. Among persons who had lived within a 300-m radius of the plant, the standardized mortality ratio of mesothelioma was 13.9 (95% confidence interval, 5.6-28.7) for men and 41.1 (95% confidence interval, 15.2-90.1) for women. When the study area was divided into five regions by relative asbestos concentration, standardized mortality ratios of mesothelioma declined, for both sexes, in a linear dose-dependent manner with concentration. The regions with a significantly elevated standardized mortality ratio reached 2,200 m from the plant in the same direction in which the wind predominantly blew.Neighborhood exposure to asbestos can pose a serious risk to residents across a wide area.

FIA combustion chambers have been used broadly for the testing of the combustibility of various bunker fuel oils. Their ultimate goal is, of course, discriminating good fuels from trouble inducing fuels, but so far not very successfully. There is a lack of a quantitative evaluation method for the combustion process inside them. In this study, multivariate analysis was applied to the heat release curves. For the first time we can characterize the minute differences between the trouble inducing fuel and the normal one. As a result, with 10 variables, much more precise discrimination of good fuels was realized. The reliability high was 95%. However, this figure cannot be trusted fully owing to insufficient samples.

A trial to find appropriate animal models of dichloropropane‐induced cholangiocarcinoma based on the hepatic distribution of glutathione Stransferases: Lingyi Zhang, et al. Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science OBJECTIVE: It has been reported that 1,2‐Dichloropropane (DCP) induced cholangiocarcinoma (CCA) in offset color proof‐printing workers. However, exposure to DCP by inhalation or gavage for 2 year did not induce CCA in mice and rats. The present study mapped the hepatic distribution of GST, which is known to activate dihalogenated alkanes, and proliferative and fibrotic changes in bile ducts in various species to find the most appropriate animal model of DCP‐induced CCA. METHODS: First, 12 each of C57BL/6J mice, Balb/cA mice, F344 rats, Syrian hamsters, and guinea pigs were divided into four equal groups and exposed to DCP at 0, 300, 1,000, or 3,000 ppm 8 hours/day for 7 days. Second, 32 Balb/cA mice and 32 Syrian hamsters were each divided into four equal groups and exposed to DCP at 0, 200, 400, and 800 ppm 6 hours/ day for 14 days. After the last exposure, the animals were decapitated, and the livers were dissected out for histopathological evaluation. Immunostaining was conducted to determine the distribution of GSTT1, GSTM1, and GSTPi, as well as the expression of proliferation marker Ki67. RESULTS: GSTT1, GSTM1, and GSTPi were expressed in both hepatocytes and bile duct cells in all control and exposed animals. There was no clear difference in the expression of Ki67 between the exposed groups and the control. No fibrotic changes were observed in any species or strains examined. CONCLUSIONS: Expression of GSTT1 or other GST isozymes might not explain the difference in sensitivity of hepatocytes and the bile duct to DCP between humans and rodents

Objectives This study aimed to evaluate the relationship between cumulative exposure to 1,2-dichloropropane (1,2-DCP) and incidence risk of cholangiocarcinoma among workers in the offset proof-printing section of a small printing company in Osaka, Japan. Methods We identified 95 workers of a printing company (78 men and 17 women) who had been exposed to 1,2-DCP between 1987 and 2006, and calculated the standardised incidence ratio (SIR) of cholangiocarcinoma from 1987 to 2012. We estimated cumulative exposure to 1,2-DCP and calculated SIRs in four exposure categories. We also calculated incidence rate ratios (RRs) adjusted by sex, age, calendar year and dichloromethane (DCM) exposure for three exposure categories using Poisson regression analysis. Results Cumulative exposures to 1,2-DCP ranged from 32 to 3433 ppm-years (mean, 851 ppm-years) and the SIR was 1171 (95% CI 682 to 1875). In the analysis of the four exposure categories, SIRs increased significantly in the three highest exposure categories, but not in the lowest category. Adjusted RRs in the middle and high exposure categories were 14.9 (95% CI 4.1 to 54.3) and 17.1 (95% CI 3.8 to 76.2), respectively, in the analysis without lag time, and were 11.4 (95% CI 3.3 to 39.6) and 32.4 (95% CI 6.4 to 163.9), respectively, in the analysis with a 5-year lag. The trend analysis revealed a significant increase in RR in association with increasing cumulative exposure to 1,2-DCP. DCM exposure was not significantly associated with the development of cholangiocarcinoma. Conclusions The present study demonstrated an exposure–response relationship between exposure to 1,2-DCP and the development of cholangiocarcinoma.

Objective In several Japanese printing plants, printing workers have suffered from cholangiocarcinoma. 1,2-dichloropropane (1,2-DCP) is considered to be a causative agent, and whether or not other chemicals also contribute to the development of this disease has not been conclusively determined. This study aimed to identify the chemicals used by seven printing workers who developed cholangiocarcinoma, as well as to estimate the levels of chemical exposure among them. Methods Information was obtained from the Ministry of Health, Labour and Welfare, Japan, to identify chemicals used by printing workers who developed cholangiocarcinoma and to estimate chemical exposure concentrations. Working environment concentrations of the chemicals in the printing rooms were estimated using a well-mixed model, and exposure concentrations during the ink removal operation were estimated using a near-field and far-field model. Shift time-weighted averages of exposure concentrations were also calculated. Results Four of the seven printing workers were exposed to both 1,2-DCP and dichloromethane (DCM). The estimated maximum exposure concentrations for each of the four workers were 230 to 420 ppm for 1,2-DCP and 58 to 720 ppm for DCM, and the estimated shift average exposure concentrations were 0 to 210 ppm for 1,2-DCP and 15 to 270 ppm for DCM. The remaining three workers were exposed to DCM but not 1,2-DCP. The estimated maximum exposure concentrations of DCM for each of the three workers were 600 to 1,300 ppm, and the estimated shift average exposure concentrations were 84 to 440 ppm. Conclusions Our findings suggest that DCM may contribute to the development of cholangiocarcinoma in humans.

Air pollution in the cabins of 101 Japanese cars due to organic compounds diffusing from the interior materials has been described in our previous report. In the present study, the influence of the manufacturer, specifications and usage status of these cars on the interior air pollution was evaluated by covariance analysis. Also, the levels of air pollution in the initial phases of delivery as a new car were estimated using previous data for the time-courses of interior concentrations of organic compounds measured in another new car. The findings showed greater air pollution in the cabins of luxury cars, with leather seats or leather steering wheels, or high-end catalogue prices. Differences in the specifications contributed more markedly to interior air pollution than differences in manufacturers. Also, usage status, such as everyday ventilation affected the long-term interior air quality. The sum values of interior concentrations of 154 compounds, for which there were time-course data, were estimated to be approximately 1700 μg·m-3 as a median (max. 11,000 μg·m-3) at 1 month from delivery (interior temperature, 32°C; interior humidity, 45%).

The types and concentrations of organic compounds in the interior air of 101 different types of Japanese domestically produced private-use cars were examined. All the vehicles had been registered in the summer season as new cars and were less than 3 years old. The airborne compounds in the cabins were collected for 24h under static condition with the engine stopped and the windows, doors and vents closed. A total of 275 organic compounds, including many aliphatic hydrocarbons and aromatic hydrocarbons, were identified, and 242 of them could be quantitated for each cabin. The sum of the concentrations of 241 compounds excluding formaldehyde was approximately 600 g·m-3 as a median, ranging from 136 to 3968 g·m-3 for the tested cars. The findings demonstrated that the air in the cabin of these cars was contaminated by high concentrations of a large variety of organic compound diffusing from the interior materials.

Case: 72-yr-old manChief complaint: Breathing difficulty with wheezingwhen cutting Falcata.Personal medical history: Eczema since infancy.Tubercular pleurisy at the age of 28.Family medical history: Nothing of special note.Occupational history: Worker in wood furnitureproduction. Had been working with wood sincegraduation from junior high school.Working inpresent position since the age of 18.Smoking status: Nonsmoker, both present and past.Alcohol consumption: One bottle of beer and twoglasses of brandy every day.Pets: None.History of present illness: The patient had bronchialasthma at the age of 17. The main symptom was coughingwith slight breathing difficulty. At 30 yr of age, he wasstruck by a severe asthma attack, and was unconsciousovernight. From that time, his asthma attacks appearedonly at the turn of the season. Control by drug therapywas excellent for about ten years from when he was 60yr old, and there were no asthma attacks. The patientbecame conscious of breathing difficulty with wheezingafter entering the factory at the age of 70 yr. He began toregularly visit a local doctor’s office once a week. Hedid not have the complaint of itchy eyes. Theophyllinetablets were prescribed three times a day after each meal.Becromesazon inhalation medicine and Predonizorontablets were prescribed for use during an attack. Recently,he noticed that the symptoms appeared when cuttingFalcata with a circular saw. He could not enter the factorywhen Falcata was being cut. His symptoms appearedeven if he entered the factory without knowing thatFalcata had been cut. The severity of his symptomsgradually decreased when he left the factory and did notappear with wood other than Falcata. His symptomsdisappeared after the processing of Falcata wasdiscontinued.Two other employees also complained of sneezing,runny nose and voice change after cutting Falcata.However, they did not suffer from breathing difficultywith wheezing. Employees at other factories have alsocomplained of sneezing and runny nose after handlingFalcata.To confirm the diagnosis of occupational asthma (OA)induced by Falcata, the patient was hospitalized at theOsaka Prefectural Medical Center for Respiratory andAllergic Diseases on September 12, 2005. Signedinformed consent was obtained from the patient for thisstudy and the bronchial provocation test. This study andthe bronchial provocation test were approved by theHospital Ethics Committee. Findings on admission: Height 160.8 cm, weight 60Kg, temperature 36.5 °C, pulse 76 beats per minute, bloodpressure 140/75 mmHg, SpO

In order to evaluate the load on the low back of care workers in nursing homes for the elderly, basic activities and working postures were analyzed for six care workers using the 30-s snap reading method. The trunk inclination angle (TIA) was also measured continuously using an inclination monitor. The analysis of basic activities showed that 22.5% and 21.1% of the workshift were spent on 'bathing and ablution' and 'meal', respectively, and 9.3%, 8.7% and 8.3% were spent on 'assistance with elimination', 'assistance with moving and repositioning' and 'exchange of bed sheet', respectively. Total of the assistance activity was 43.7% of the workshift. The analysis of working posture showed that 'standing' and 'standing bent forward' accounted for 36.1% and 29.5%, respectively, of the workshift. Total of three postures loading the low back ('standing bent forward', 'squatting', 'kneeling') accounted for 39.0%. The time spent in TIA of 20 degrees or more was 45.7%. The postures loading the low back during 'bathing and ablution', 'exchange of bed sheet' and 'assistance with elimination' account for 68.3%, 58.2% and 49.6%, respectively, which suggests that these activities load the low back of the care workers considerably.

Experimental studies are conducted to clarify the relationship between the flow structure and the cutting capability of abrasive water injection jets (AWIJs). The water velocity is obtained by the PIV method. It is shown that the water velocity decreases steeply with slight addition of abrasive. When the abrasive flow rate is relatively large, the water velocity is 0.25 to 0.35 times fo the theoretical velocity calculated by Bernoulli's equation. Cutting tests conducted with specimens of aluminum plate show the existence of the optimum abrasive-mass flow rate, which gives minimum taper of the cut and narrow initial damage zone.

Inhalation toxicokinetics of p-dichlorobenzene ( p-DCB) in humans was evaluated, and the amounts of daily absorption and internal accumulation were estimated in order to obtain fundamental data for the risk assessment of chronic low-level exposure in the general population. Seven male subjects continuously inhaled about 2.5 ppm of p-DCB vapor for 1 h, and the concentration-time courses of p-DCB in their exhaled air and serum and of urinary 2,5-dichlorophenol (2,5-DCP), a major metabolite of p-DCB, were examined. The toxicokinetics of p-DCB was evaluated on the basis of the time courses using a linear two-compartment model. The amounts of p-DCB absorbed daily and the internal accumulation in chronic low-level exposure were extrapolated using the estimated toxicokinetic parameters. p-DCB was transferred from inhaled air to the body with a constant high absorption rate during exposure. The major route for elimination from the body was urinary excretion followed by metabolism, not exhalation. However, during 9-11 h after the start of exposure, the fraction of p-DCB excreted in urine was only 5-16% of the amount absorbed. Furthermore, most of the absorbed p-DCB seemed to be distributed rapidly to the tissues, such as fat, according to toxicokinetic analysis. Consequently, p-DCB seems to require a long time to be completely eliminated from the body. The amounts of daily absorption and internal accumulation were extrapolated to average 0.27 mg/day and 2.9 mg, respectively, in the subjects exposed chronically to 1 ppb of p-DCB. The amount absorbed daily agreed approximately with that extrapolated from rats which inhaled p-DCB in our previous study.

In order to evaluate occupational exposure conditions, it is necessary to determine the 8-hr time-weighted average (8-hr TWA) of exposure concentrations and compare the 8-hr TWA value with the permissible exposure limit, but 8-hr sampling is difficult for the outside laboratories because of trip time. For working environment measurement, because sampling duration in a unit work area may be one hour, the measurement can be conducted in several work areas in a day. If exposure conditions can be evaluated with the 1-hr TWA values, sampling to determine the exposure concentration would be efficient and able to be completed during the work area sampling. From this point of view, methods for evaluating exposure conditions with 1-hr or more TWA values are proposed in this paper.