Shinji Kumagai

Cholangiocarcinoma among offset colour proof-printing workers exposed to 1,2-dichloropropane and/or dichloromethane

Objectives The present study was conducted to investigate the relationship between occupational chemical exposure and incidence of cholangiocarcinoma among workers in the offset colour proof-printing section of a small printing company in Osaka, Japan. Methods We identified 51 men who had worked in the proof-printing room, and 11 men who had worked in the front room for at least 1 year between 1991 and 2006. We interviewed them about the chemicals they used, and estimated their levels of exposure to chemicals. We also investigated the medical records of 11 cholangiocarcinoma patients, and calculated the standardised mortality ratio (SMR) from 1991 to 2011. Results Workers used 1,2-dichloropropane (1,2-DCP) from approximately 1985 to 2006, and dichloromethane (DCM) from approximately 1985 to 1997/1998. Exposure concentrations were estimated to be 100–670 ppm for 1,2-DCP and 80–540 ppm for DCM among the proof-printing workers. All 11 patients were pathologically diagnosed with cholangiocarcinoma. Ages at diagnosis were 25–45 years, and ages at death were 27–46 years among the six deceased individuals. The primary cancer site was the intrahepatic bile duct for five patients, and the extrahepatic bile ducts for six. All patients were exposed to 1,2-DCP for 7–17 years and diagnosed with cholangiocarcinoma 7–20 years after their first exposure. Ten patients were also exposed to DCM for 1–13 years. The SMR for cholangiocarcinoma was 2900 (expected deaths: 0.00204, 95% CI 1100 to 6400) for all workers combined. Conclusions These findings suggest that 1,2-DCP and/or DCM may cause cholangiocarcinoma in humans.

Mapping the Risk of Mesothelioma Due to Neighborhood Asbestos Exposure

RATIONALE Little is known about neighborhood exposure to asbestos and mesothelioma risk among residents around an industrial source of asbestos. OBJECTIVES To investigate the magnitude of the risk among residents by asbestos exposure levels and to determine the range of the area affected by asbestos. METHODS 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. MEASUREMENTS AND MAIN RESULTS 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. CONCLUSIONS Neighborhood exposure to asbestos can pose a serious risk to residents across a wide area.

Use of a Closed System Device to Reduce Occupational Contamination and Exposure to Antineoplastic Drugs in the Hospital Work Environment

OBJECTIVES The aim of the preset study was to evaluate the applicability of a closed system device to protect against occupational contamination and exposure to antineoplastic drugs in the work environment of a hospital. METHODS We compared the contamination by and exposure to cyclophosphamide (CPA) between a conventional mixing method and a mixing method using a closed system device. Wipe samples in the preparation room, gloves samples and 24-h urine samples of pharmacists preparing antineoplastic drugs were collected. Working surfaces inside the biological safety cabinet (BSC), front side of the air grilles of the BSC, stainless steel trays, working table and floor were wiped. At first, sample collection was done on 5 days over an interval of 2 weeks using the conventional mixing method. After 2 weeks training for using the closed system device, sample collection was done 5 days over an interval of 2 weeks using the closed system device. RESULTS When pharmacists prepared antineoplastic drugs by the conventional method, CPA was detected from all wipe samples, and the mean and median concentrations of CPA were 1.0 and 0.16 ng cm(-2), respectively (range was from 0.0095 to 27 ng cm(-2)). When pharmacists prepared antineoplastic drugs with a closed system device, CPA was detected from 75% of the wipe samples at mean and median concentrations of 0.18 and 0.0013 ng cm(-2), respectively (the range was from lower than detection limit to 4.4 ng cm(-2)). Using the closed system device significantly reduced the surface contamination of CPA for all wipe sampling points in the preparation room (Mann-Whitneys U-test). The range of CPA of glove samples used in the conventional method and closed system device ranged from lower than detection limit to 3200 ng per glove-pair and from lower than detection limit to 740 ng per glove-pair, respectively. Using the closed system device significantly reduced the gloves contamination of CPA (Mann-Whitneys U-test). The range of urinary CPA of six pharmacists preparing the antineoplastic drugs with the conventional method and closed system device ranged from lower than detection limit to 170 ng day(-1) and from lower than detection limit to 15 ng day(-1), respectively. Using the closed system device significantly reduced the amount of urinary CPA in pharmacists preparing the antineoplastic drugs (Wilcoxons signed ranks test). CONCLUSIONS We concluded that a closed system device can reduce occupational contamination and exposure to antineoplastic drugs in the hospital work environment.

Polychlorinated dibenzo-p-dioxin and dibenzofuran concentrations in the serum samples of workers at continuously burning municipal waste incinerators in Japan

OBJECTIVES To find whether concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in serum increased in workers at municipal incinerators that burn continuously. METHODS 30 Workers employed at three municipal waste incineration plants (incinerator workers) and 30 control workers were studied. The incinerator workers had worn dust masks or airline masks during the periodic repair work inside the incinerators. Previous job, dietary habit, smoking habit, distance from residence to the incineration plant, and body weight and height were obtained from a questionnaire survey. Concentrations of PCDDs/PCDFs were measured in the serum of the workers and the dust deposited in the plants. The influence of various factors on serum concentrations of PCDDs/PCDFs was examined by multiple regression analysis. RESULTS Dust analysis showed the greatest amount of octachlorodibenzo-p-dioxin (OCDD), followed by 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), 1,2,3,4,6,7,8-heptachlorodibenzofuran (HpCDF), and octachlorodibenzofuran (OCDF). The toxicity equivalents (TEQs) of PCDDs and PCDFs in the deposited dust were 4.8, 1.0, and 6.4 ng TEQs/g, respectively, for plants A, B, and C. The mean serum TEQs of PCDDs and PCDFs in the incinerator workers and control workers were 19.2 and 22.9 pg TEQs/g lipid, respectively, for area A, 28.8 and 24.5 pg TEQs/g lipid for area B, and 23.4 and 23.6 pg TEQs/g lipid for area C. No significant differences were found between the incinerator workers and the controls for TEQs of PCDDs and PCDFs separately, and TEQs of PCDDs and PCDFs together. However, the serum 1,2,3,4,6,7,8-HpCDF concentration was significantly higher in the incinerator workers than in the controls for all the three areas. When the exposure index to 1,2,3,4,6,7,8-HpCDF is defined as the product of the concentration of 1,2,3,4,6,7,8-HpCDF in the deposited dust and duration of employment, the concentration of 1,2,3,4,6,7,8-HpCDF in serum increased as the exposure index increased. Multivariate analysis suggested that the serum concentration of HpCDF increased with duration of employment at the incineration plants and OCDF increased with employment of ⩾21 years. The other significant variables (p<0.01 or p<0.001) were area for hexachlorodibenzo-p-dioxin (HxCDD) and tetrachlorodibenzofuran (TCDF), Brinkman index for HpCDD, and body mass index (BMI) for tetrachlorodibenzo-p-dioxin (TCDD), HpCDD, and TEQs of PCDDs. CONCLUSION The serum TEQs of PCDDs and PCDFs was not significantly higher among the incinerator workers, but the serum concentration of 1,2,3,4,6,7,8-HpCDF was. This suggests that the incinerator workers had inhaled dust containing PCDDs and PCDFs while working in plants equipped with incinerators that burn continuously.

Association between occupational exposure levels of antineoplastic drugs and work environment in five hospitals in Japan

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.

Genotoxic Risks to Nurses from Contamination of the Work Environment with Antineoplastic Drugs in Japan

Genotoxic Risks to Nurses from Contamination of the Work Environment with Antineoplastic Drugs in Japan: Jin Yoshida, et al. Department of Environmental Health, Osaka Prefectural Institute of Public Health—The aims of the present study were to clarify the work environment contamination by antineoplastic drugs in a hospital ward and to assess the genotoxic risks to nurses who routinely handle antineoplastic drugs in Japan. The exposed group consisted of 19 female nurses who routinely handled antineoplastic drugs. The control group consisted of 18 female nurses who did not handle antineoplastic drugs in the same hospital as the exposed group. The genotoxicity of the 19 antineoplastic drugs used in the hospital ward and 8 wipe samples of the workbench after handling of antineoplastic drugs were measured using the umu assay. Lymphocyte DNA damage (tail length) was measured with alkaline methods of the single cell gel electrophoresis assay (comet assay). Of the 19 antineoplastic drugs, dacarbazine, bleomycin, daunorubicin, doxorubicin, pirarubicin, carboplatin, cisplatin and etoposide induced genotoxicity. Of the 8 sampling d, the umu activity of the wipe sample was positive on 3 d. Contamination of the workbench was found when the nurses handled more drugs than on other days. The medians of the tail length in the comet assay were 8.5 and 5.1 μm, respectively, for the exposed and control groups, with a significant difference (p=0.004 by Mann‐Whitneys U‐test). In the present study, the nurses of the exposed group were considered to have been exposed to antineoplastic drugs and lymphocyte DNA damage of the exposed group was suggested to be induced by antineoplastic drugs.

A LUNG MODEL DESCRIBING UPTAKE OF ORGANIC SOLVENTS AND ROLES OF MUCOSAL BLOOD FLOW AND METABOLISM IN THE BRONCHIOLES

A simple lung model (mucosal blood flow and metabolism model, MBM model) was developed to describe the uptake of organic solvents and investigate the role of mucosal blood flow and metabolism. The model separates the lung into four compartments, the peripheral bronchial tract (gas phase), the mucus layer lining the wall surface of the tract, the alveolar space (gas phase), and the alveolar blood. Solvent molecules are absorbed in the mucus layer during inhalation and released during exhalation. The deposited solvent diffuses radially into the mucosal tissue of the respiratory tract and transfers to the mucosal blood flow. To describe this behavior, a hypothetical mucosal blood flow throughout the mucus layer was used. The solvent in the mucosal tissue may be also metabolized, and a hypothetical metabolism in the mucus layer was used. The rate of the hypothetical mucosal blood flow was determined to be 5.2 ml/min based on the best fitting of previously obtained data for seven polar organic solvents. The MBM model predicts that as the blood? air partition coefficient (lB) increases from 0.1 to 20, the relative end-exhalation (E end) will decrease from 0.89 to 0.07, and as l B increases to 500, Eend will increase to 0.33. After l B = 500, E end is predicted to decrease again, and at l B = 10000, E end is 0.09. The model also predicts that as l B increases from 0.1 to 10, the relative uptake (U) increases from 0.08 to 0.61, and as l B increases to 150, U decreases to 0.50. After l B = 150, U increases again, and at l B = 10,000, U is 0.8. The predictions show good agreement with values observed in human experimental studies. The MBM model predicts that uptake by the mucosal blood (U Al) would be equal to uptake by the alveolar blood (U Mu) at l B of 1000 and UAl is more than 90% of total uptake at l B > 10,000. The model also shows that U is significantly increased by the mucosal metabolism at l B between 50 and 5000. Especially, U in the case of CLMu = 100 ml/min is higher by 0.3 than that in the nonmucosal metabolism.

Interior Air Pollution in Automotive Cabins by Volatile Organic Compounds Diffusing from Interior Materials: I. Survey of 101 Types of Japanese Domestically Produced Cars for Private Use

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.

Association between Occupational Exposure and Control Measures for Antineoplastic Drugs in a Pharmacy of a Hospital

OBJECTIVES To investigate the association between occupational contamination and exposure levels to antineoplastic drugs and the application of control measures in a hospital work environment. METHODS Wipe samples of equipments were collected at a hospital in Osaka Prefecture, Japan, from 2007 to 2011. These samples were subjected to measurements of cyclophosphamide (CP), gemcitabine (GEM), platinum-containing drugs (Pt), and fluorouracil (5FU). Additionally, 24-h urine samples were collected from pharmacists who handled antineoplastic drugs, which were analyzed for CP and alpha-fluoro-beta-alanine (AFBA). The application of control measures was scored according to a checklist, which consisted of the following five items: safety equipment and maintenance, training and documentation, devices for safe handling, personal protective equipment, and emergency care. The aim was to obtain a score of 80%. RESULTS The median CP, GEM, and 5FU concentrations of all wipe samples were significantly lower during the period when the mean score was >80% (attainment period) versus when the mean score was ≤80% (nonattainment period; all P < 0.001, Mann-Whitneys U-test). Additionally, the median urinary CP and AFBA concentrations of pharmacists during the attainment period tended to be lower than that of those during the nonattainment period (P = 0.061 and 0.061, respectively, using Mann-Whitneys U-test). CONCLUSIONS Contamination and levels of exposure to antineoplastic drugs decreased with a score higher than 80%. The scores of the items on the checklist appeared to adequately reflect the condition of the control measures, as increases in all five items were associated with reductions in the contamination by and levels of exposure to all drugs.

APPLICATION OF INVERSE GAUSSIAN DISTRIBUTION TO OCCUPATIONAL EXPOSURE DATA

Abstract Occupational exposure concentrations are generally assumed to vary in a log-normal manner. However, because the mean of random samples from a log-normal distribution is not lognormally distributed, it cannot, in theory, deal with the changes in the distribution of timeweighted average (TWA) values when the averaging time varies. On the other hand, inverse Gaussian distribution, which is similar to a log-normal one, offers the advantage of reproducibility. This paper proposes the application of inverse Gaussian distribution to occupational exposure data. First, inverse Gaussian distribution was compared with the log-normal one. Second, in order to simplify the application, the percentiles of inverse Gaussian distribution with CV = 0.25 to 4 were calculated. Finally, this distribution was applied to occupational exposure data.