Association of mesothelioma deaths with neighborhood asbestos exposure due to a large-scale asbestos-cement plant.

A causal relationship between mesothelioma and occupational asbestos exposure is well known, while some studies have shown a relationship to non-occupational exposures. The aim of this study was to quantify the risk of mesothelioma death associated with neighborhood asbestos exposure due to a large-scale asbestos-cement (AC) plant in Amagasaki, Japan, adjusting properly risk factors including occupational exposures. 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 the neighborhood exposure were estimated by a conditional logistic-regression model. For quantitative assessments for neighborhood exposure, we adopted cumulative indices for individuals' residential histories at each residence-specific asbestos concentration multiplied by the duration during the potential exposure period of 1957-1975 (crocidolite). We observed an increasing, dose-dependent risk of mesothelioma death associated with neighborhood exposure, demonstrating that ORs in the highest quintile category were 21.4 (95% confidence interval [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. A quantitative assessment for risk of mesothelioma deaths, adjusting for occupational and non-occupational exposures separately, showed a dose-dependent association with neighborhood exposure and no substantial gender differences in magnitude.

Efficacy and safety of twice-daily rabeprazole maintenance therapy for patients with reflux esophagitis refractory to standard once-daily proton pump inhibitor: the Japan-based EXTEND study.

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 < 0.001, χ2 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.

Concentration determination of urinary metabolites of N,N-dimethylacetamide by high-performance liquid chromatography-tandem mass spectrometry.

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.

Exposure of Mice to 1,2-Dichloropropane Induces CYP450-Dependent Proliferation and Apoptosis of Cholangiocytes.

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.

Relationship between cumulative exposure to 1,2-dichloropropane and incidence risk of cholangiocarcinoma among offset printing workers.

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.

Screening and surveillance for occupational cholangiocarcinoma in workers exposed to organic solvents.

PURPOSE: This study aimed to establish an efficient strategy for screening and surveillance for occupational cholangiocarcinoma. METHODS: We evaluated the consecutive changes in laboratory findings during regular health examinations and in abdominal ultrasonography findings before the diagnosis of occupational cholangiocarcinoma in nine patients. The results of laboratory tests and abdominal ultrasonography at the time of diagnosis were also examined. RESULTS: In all patients, the serum γ-glutamyl transpeptidase (γ-GTP) activity increased several years before the diagnosis of cholangiocarcinoma. The serum alanine aminotransferase (ALT) activity also increased several years before the diagnosis, following an increase in the serum aspartate aminotransferase (AST) activity in most patients. Abdominal ultrasonography before the diagnosis revealed regional dilatation of the bile ducts, which continued to enlarge. At the time of diagnosis, the γ-GTP, AST, and ALT activities were increased in nine, seven, and seven patients, respectively. The regional dilatation of bile ducts without tumor-induced stenosis, dilated bile ducts due to tumor-induced stenosis, space-occupying lesions, and/or lymph node swelling were observed. The serum concentrations of carbohydrate antigen 19-9 (CA 19-9) and/or carcinoembryonic antigen (CEA) were increased in all patients. CONCLUSIONS: Regular health examinations with a combination of ultrasonography and laboratory tests including the γ-GTP, AST, ALT, CA 19-9, and CEA levels are useful for screening and surveillance for occupational cholangiocarcinoma.

A trial to find appropriate animal models of dichloropropane-induced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases.

OBJECTIVES: 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.

Chemical exposure levels in printing and coating workers with cholangiocarcinoma (third report).

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.

Chemical exposure levels in printing workers with cholangiocarcinoma (second report).

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.

Severe acute hepatitis in a printing company worker: a case study.

OBJECTIVES: It has been reported that chlorinated organic solvent is a cause of hepatitis. METHODS: we investigate clinical and pathological findings of a patient with severe acute hepatitis who was exposed to chlorinated organic solvents. RESULTS: A 34-year-old man who was exposed to chlorinated organic solvents including dichloromethane, 1,2-dichloropropane, and trichloroethylene, presented with general fatigue, vomiting, and diarrhea. At admission, his laboratory test results showed extremely elevated aspartate aminotransferase (4,872 IU/l), alanine aminotransferase (3,000 IU/l), and lactate dehydrogenase (11,600 IU/l) levels and a prothrombin level below normal (41%). No encephalopathy was noted. These findings were indicative of severe acute hepatitis. Viral hepatitis, autoimmune hepatitis, alcoholic disease, bile duct disease, and viral infection were excluded as causes of hepatitis by clinical, laboratory, and imaging findings. After diagnosis, the patient was administered fresh frozen plasma and glucagon-insulin therapy. Liver function recovered within a few weeks, and a liver biopsy performed 25 days after admission showed the recovery phase after acute liver damage. CONCLUSIONS: These clinical and pathological findings indicate that exposure to chlorinated organic solvents may have induced severe acute hepatitis in this patient.

Chemical exposure levels in printing workers with cholangiocarcinoma.

OBJECTIVE: This study aimed to identify chemicals used by printing workers with cholangiocarcinoma, as well as the levels of exposure to the chemicals. METHODS: Information necessary to identify chemicals used by printing workers with cholangiocarcinoma and to estimate chemical exposure concentrations was obtained from the Ministry of Health, Labour and Welfare, Japan. 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 (TWA) of exposure concentrations were also calculated. RESULTS: Two workers from each of three small printing plants examined suffered from cholangiocarcinoma, and all six of these workers had been exposed to 1,2-dichloropropane (1,2-DCP) for 10-16 years. The estimated working environment concentrations of 1,2-DCP in the printing rooms were 17-180 ppm and estimated exposure concentrations during the ink removal operation were 150-620 ppm. Shift TWA values were estimated to be 62-240 ppm. Four of the six workers had also been exposed to dichloromethane (DCM) at estimated working environment concentrations of 0-98 ppm and estimated exposure concentrations during the ink removal operation of 0-560 ppm. Shift TWA values were estimated to be 0-180 ppm. Other chlorinated organic solvents (1,1,1-trichloroethane, 1,1-dichloro-1-fluoroethane) and petroleum solvents (gasoline, naphtha, mineral spirit, mineral oil, kerosene) were also used in the ink removal operation. CONCLUSIONS: All six printing workers with cholangiocarcinoma were exposed to very high levels of 1,2-DCP for a long term.

Time course of blood parameters in printing workers with cholangiocarcinoma.

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.