小川 真規

Aim: Exposure assessment of lead (Pb) and Arsenic (As) from food, water, and house dust intake were assessed among pregnant women, their children and fetuses in Pakistan and Japan, as well as their body burden of the metals in their blood. Method: Fifty families which included a pregnant woman, a fetus and the 1-3-year-old siblings were recruited in Karachi and Khairpur in Pakistan, and Shimotsuke and Asahikawa in Japan, respectively. Their dietary exposure to Pb and As was measured in 3-day food duplicates and drinking water by ICP-MP. Pb in house dust and respirable dust was evaluated with an energy dispersive X-ray fluorescence spectrometry. Nonradioactive isotope Pb profiles of blood specimens will be compared with those of the exposure origins, such as food duplicates, respirable house dust, the soils nearby, and gasoline. Results: Judging from the data collected and analyzed so far, contribution from dietary intake is highly correlated to higher body burden of Pb among Pakistani mothers. Additional data analyses will reveal the status of Pb and As body burden in Pakistani mothers, fetuses and their siblings, and causal sources of high body burden is delineated by Pb isotope profile analysis of different sources of Pb exposure.

Background: Aluminum is considered to be a relatively safe metal for humans. However, there are some reports that aluminum can be toxic to humans and animals. In order to estimate the toxicity of aluminum with respect to humans, we measured the aluminum concentration in urine of aluminum-handling and non-handling workers and investigated the relationships between their urinary aluminum concentrations and pre-clinical findings. Methods: Twenty-three healthy aluminum-handling workers and 10 healthy non-aluminum-handling workers participated in this study. Their medical examinations, which were otherwise unremarkable, included the collection of urine and blood. Urinary aluminum levels were analyzed using ICP analysis. As pre-clinical tests, we measured KL-6, SP-D, TRCP-5b, IL-6, and IL-8 in blood and delta-ALA and beta 2-microglobulin in urine. These were considered to be lung, bone, kidney and inflammation markers. Moreover, we measured 8-OHdG in urine as an oxidative DNA damage marker. Results: The aluminum concentration in urine ranged from 6.9 to 55.1 mu g/g cre (median: 20.1 mu g/g cre) in the aluminum-handling workers and from 5.6 to 15.6 mu g/g cre (median: 8.8 mu g/g cre) in the non-aluminum-handling workers, with a significant difference between them. In the pre-clinical findings, there were no significant differences between these two groups except in the case of delta-ALA. However, there were no significant relationships between aluminum concentration and the pre-clinical findings, work years, age or 8-OHdG in the aluminum-handling workers. Conclusions: While the excretion of aluminum in urine was elevated in aluminum-handling workers, our findings suggest that low-dose aluminum is not directly harmful to humans, at least when workers' urinary aluminum concentration is below 55 mu g/g cre.

To measure current Hg, Cd, and Pb exposure in Japanese children, and to estimate dietary intakes of foods responsible for high body burden. Blood, hair, and urine samples were collected from 9 to 10-year-old 229 children in Asahikawa and measured for Hg, Cd, and Pb in these matrices. Diet history questionnaire was used to estimate intake of marine foods and other food items. Hg level was measured by cold vapor atomic absorption spectrometry. Cd and Pb levels were determined with inductively coupled plasma mass spectrometry. Geometric mean (GM) of blood Hg, Cd, and Pb was 4.55 mu g/L, 0.34 mu g/L, and 0.96 mu g/dL, respectively. Urinary Cd level was 0.34 mu g/g creatinine (GM) and hair Hg was 1.31 mu g/g (GM). Approximately one-third (35 %) of blood samples had Hg level above the U.S. EPA reference dose (RfD; 5.8 mu g/L). Hair Hg level exceeded U.S. EPA RfD (1.2 mu g/g) in 59 % samples. Children in the upper quartile of blood Hg level had significantly higher intake of large predatory fish species compared to those in the lower quartile of blood Hg. Those with high blood Hg level may be explained by more frequent intake of big predatory fish. Cd and Pb exposure is generally low among Japanese children. As no safety margin exists for Pb exposure and high exposure to MeHg is noted in Japanese population; periodic biomonitoring and potential health risk assessment should continue in high-risk populations, notably among children.

Background: Biological monitoring is used to assess toluene exposure in medical examinations. The American Conference of Industrial Hygienists, Japanese Society for Occupational Health and Deutsche Forschungsgemeinschaft have proposed various biological exposure determinants, such as toluene in blood and urine, and o-cresol in urine. Toluene in blood is a common biomarker among them. Toluene is a volatile organic solvent; therefore, sample preservation under appropriate conditions before measurement is necessary. However, little study has been done on the stability of toluene in workers' blood samples under conditions simulating those of a medical examination. Finding: We carried out a pilot study on the stability of toluene in blood from humans, according to different methods of sample preservation. Toluene in blood was analyzed by head space-gas chromatography/mass spectrometry. The sealing performance of the vial was examined by using toluene-added blood and the stability of toluene in blood according to the preservation period was examined by using blood from toluene-handling workers, which was collected with vacuum blood tubes. The sealing performance of the headspace vial used in this study was good for three days and toluene in blood in tubes from workers was stable at least within 8 hours up to blood packing at 4 degrees C. Conclusion: We could propose that the collected blood need only be transferred into headspace vials on the collection day and analyzed within a few days, if the samples are preserved at 4 degrees C. Our data size is limited; however, it may be considered basic information for biological monitoring in medical examinations.

Intake of foods and drinks containing benzoic acid influences the urinary hippuric acid (HA) concentration, which is used to monitor toluene exposure in Japan. Therefore, it is necessary to control the intake of benzoic acid before urine collection. Recently, some reports have suggested that components of coffee, such as chlorogenic, caffeic, and quinic acids are metabolized to HA. In this study, we evaluated the influence of coffee intake on the urinary HA concentration in toluene-nonexposed workers who had controlled their benzoic acid intake, and investigated which components of coffee influenced the urinary HA concentration. We collected urine from IS healthy men who did not handle toluene during working hours, after they had consumed coffee, and we measured their urinary HA concentrations; the benzoic acid intake was controlled in these participants during the study period. The levels of chlorogenic, caffeic, and quinic acids in coffee were analyzed by LC-MS/MS. Urinary HA concentration increased significantly with increasing coffee consumption. Spectrophotometric LC-MS/MS analysis of coffee indicated that it contained chlorogenic and quinic acids at relatively high concentrations but did not contain benzoic acid. Our findings suggest that toluene exposure in coffee-consuming workers may be overestimated.

シックビル症候群患者の臨床所見並びに環境測定結果について：吉田辰夫ほか．関西労災病院環境医学研究センター―目的：シックハウス症候群の調査報告は数多くあるが，日本における職業性シックビルディング症候群（SBS）の症例報告は限られている．われわれは集団発生事例において臨床的な観察と環境濃度測定を実施した． 対象と方法：オフィス内に新設した耐火金庫室内部の塗装工事後に体調不良を訴え，当科を受診した事務職員11名（男性2名と女性9名）に問診，血液一般および生化学検査，免疫学的検査，肺機能検査，神経眼科的検査および精神心理検査を実施し，事務所内環境測定を塗装後27日後，55日後，132日後の3回実施した．非受診者（男性21名と女性1名）においては自記式質問紙調査を実施した． 結果：事務職員は工事終了9日後に仕事を始めたが，その直後に大半の従業員が異臭を感じ，頭痛，倦怠感，集中力の低下や眼の刺激を訴えた．塗装に使用された塗料はアクリル樹脂塗料で，金庫室内のトルエン，キシレン，総揮発性有機化合物（T-VOC）の27日後の濃度は2,972，2,610，7,100 μg/m³であったが，132日後には，78，113，261 μg/m³に低下していた．結論：自覚症状，アレルギー等の他の器質的疾患の検査は否定的なこと，環境測定結果から，受診者11名のうち女性7名をSBSと診断した．非受診者（男性22名と女性1名）における質問紙の回答でも，異臭や不快感などの訴えの出現と消滅の時期が金庫内のトルエンなどの濃度推移と一致していたことから，SBS診断の妥当性が確認された．<br> （産衛誌2011; 53: 25-32）<br>

N-Methyl-2-pyrrolidone (NMP) has been used in many industries and biological monitoring of NMP exposure is preferred to atmospheric monitoring in Occupational health. We developed an analytical method that did not include solid phase extraction (SPE) but utilized deuterium-labeled compounds as internal standard for high-performance liquid chromatography-electrospray ionization-mass spectrometry using a C30 column. Urinary concentrations of NMP and its known metabolites 5-hydoxy-N-methyl-2-pyrrolidone (5-HNMP), N-methyl-succinimide (MSI), and 2-hydroxy-N-methylsuccinimide (2-HMSI) were determined in a single run. The method provided baseline separation of these compounds. Their limits of detection in 10-fold diluted urine were 0.0001, 0.006, 0.008, and 0.03 mg/L, respectively. Linear calibration covered a biological exposure index (BEI) for urinary concentration. The within-run and total precisions (CV, %) were 5.6% and 9.2% for NMP, 3.4% and 4.2% for 5-HNMP, 3.7% and 6.0% for MSI, and 6.5% and 6.9% for 2-HMSI. The method was evaluated using international external quality assessment samples, and urine samples from workers exposed to NMP in an occupational area. (C) 2009 Elsevier B.V. All rights reserved.

Acetaldehyde is an intermediate of ethanol oxidation. It covalently binds to DNA, and is known as a carcinogen. Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals have the inactive ALDH2 genotypes (ALDH2* 2/*2 and ALDH2* 1/*2), and Aldh2 knockout mice appear to be a valid animal model for humans with inactive ALDH2. This review gives an over view of published studies on Aldh2 knockout mice, which were treated with ethanol or acetaldehyde. According to these studies, it was found that Aldh2 -/- mice (Aldh2 knockout mice) are more susceptible to ethanol and acetaldehyde-induced toxicity than Aldh2 +/+ mice (wild type mice). When mice were fed with ethanol, the mortality was increased. When they were exposed to atmospheres containing acetaldehyde, the Aldh2 -/- mice showed more severe toxic symptoms, like weight loss and higher blood acetaldehyde levels, as compared with the Aldh2 +/+ mice. Thus, ethanol and acetaldehyde treatment affects Aldh2 knockout mice more than wild type mice. Based on these findings, it is suggested that ethanol consumption and acetaldehyde inhalation are inferred to pose a higher risk to ALDH2-inactive humans. These results also support that ALDH2-deficient humans who habitually consume alcohol have a higher rate of cancer than humans with functional ALDH2.

In order to determine low levels of Cd in urine samples, we tried to remove Mo interference using ICP-MS with a dynamic reaction-cell technique, but failed due to the low sensitivity and the variance with the standards. We then performed solid-phase extraction (SPE) before the ICP-MS measurement. A commercially available chelating resin, NOBIAS PA-1, was used for SPE, and could effectively remove Mo from urine samples, permitting the accurate determination of Cd by ICP-MS. This SPE-ICP-MS method gave 0.012 mu g Cd L-1 as the method limit of quantification, and the mean recovery of Cd spiked with 0.0505 and 5.05 mu g L-1 was 93.1 and 97.6%, respectively.

Dimethyltin dichloride (DMTC) is widely used as a heat stabilizer in manufacturing the polyvinyl chloride. We previously reported a case of acute DMTC poisoning with neurological manifestations very similar to trimethylated tin JMT) encephalopathy, based on results of speciation analysis of methylated tins in the patient's urine with use of a combination of high performance liquid chromatography and inductively coupled plasma-mass spectrometry (HPLC-ICP-MS), which yielded peaks corresponding to DMT and TMT. In this study, we developed an analytical method to confirm TMT in urine using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and found TMT molecular ion in the patient's urine. (c) 2008 Elsevier B.V. All rights reserved.

Organotins are widely used as stabilizers of polyvinyl chloride and as catalysts or biocides. It is well known that dimethyltin (DMT) is less neurotoxic than trimethyltin (TMT). A Korean worker who was exposed to DMT compounds showed neurological symptoms similar to those of TMT encephalopathy, in association with high levels of both DMT and TMT in the urine and blood. The case suggested the possibility of the methylation of DMT in humans. Here, we investigated whether TMT is detected in the urine of mice and rats exposed only to DMT dichloride (DMTC). Three Slc:ICR mice and three Slc:Wistar rats were placed in individual metabolic cages, and one day later, they were injected intraperitoneally with DMTC (10 mg/kg body weight (wt); 5.4 mgSn/kg body wt; 45.5 micromol/kg body wt) over 4 consecutive days. Twenty-four hour urine samples were collected every evening for 11 consecutive days starting at baseline (before treatment). Speciation analyses of methyltin compounds in urine were performed using a combination of high performance liquid chromatograph-inductively coupled plasma mass spectrometry. High concentrations of DMT and time-dependent increase in TMT concentrations were found in both mice and rats during the 4-day treatment, and their concentrations decreased gradually after the cessation of treatment. The chemical compound of the detected peak was confirmed to be TMT by liquid chromatography-tandem mass spectrometry. Neither DMT nor TMT was detected in the samples collected at baseline. Our results indicate urinary excretion of TMT in mice and rats injected with DMTC, confirming the production of TMT in vivo, probably through methylation of DMT.

Aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde produced from ethanol into acetate and plays a major role in the oxidation of acetaldehyde in vivo. About half of all Japanese people have inactive ALDH2. We generated homozygous Aldh2 null (Aldh2-/-) mice by gene targeting knockout as a model of ALDH2-deficient humans. To investigate the mutagenicity of acetaldehyde, a micronucleus assay and a T-cell receptor (TCR) gene mutation assay were performed in Aldh2-/- mice and wild-type (Aldh2+/+) mice exposed to acetaldehyde. The mice were continuously exposed to 125 and 500 ppm of acetaldehyde vapor for 2 weeks. Another group was orally administered 100 mg/k once a day for 2 weeks continuously. The mice were killed after 2 weeks of exposure to acetaldehyde, and the frequency of micronucleated reticulocytes was measured by flow cytometry. We also observed the incidence of TCR gene mutations in T-lymphocytes by measuring the variant CD3(-)CD4(+) expression by flow cytometry. The frequency of micronucleated reticulocytes induced by acetaldehyde was significantly increased in Aldh2-/- mice, but not in Aldh2+/+ mice. TCR mutant frequency was also associated with acetaldehyde exposure in Aldh2-/- mice, especially after oral administration however, it was not associated with acetaldehyde exposure in Aldh2+/+ mice. In conclusion, Aldh2-/- mice showed high sensitivity in the micronuclei and TCR mutation assays compared with Aldh2+/+ mice after exposure to acetaldehyde.

Case Reports. We experienced two cases of acute lead poisoning due to occupational exposure to lead. The patients were engaged in stripping off antirust compounds including Pb from a bridge and re-painting it at the same work place. Both patients exhibited colic, arthralgia, and anemia. Blood lead levels were 73.1 mu g/dl and 96.3 mu g/dl. Intravenous CaEDTA chelation therapy was therefore performed. After chelation, blood lead levels decreased and symptoms gradually disappeared. Discussion. Although the patients were working with protective equipment, the workplace was in the mountains and there was no water for washing. The patients were thus unable to washing their hands and faces. We assume that they swallowed lead dust left on their hands and faces when they removed their clothing, and believe that this poisoning occurred due to lack of knowledge sufficient for protection.

Aldh (aldehyde dehydrogenase) 2 knockout (KO) mice have been generated in our laboratory. We evaluated the effects of subacute ethanol treatment on the survival rate, expression of Aldh1, Aldh2, Cytochrome P450 (Cyp) 1A1, Cyp2e1 and Cyp4b1 in wild (Aldh2 +/+) mice (C57BL/6) and Aldh2 knock out (Aldh2 ?/?) mice. Physiological saline (0.3 mL/day) was administered to 4 Aldh2 +/+ and 4 Aldh2 ?/? mice for 8 days as a control. Forty percent ethanol (0.3 mL/day ethanol 2 g/kg/day) was then administered to 5 Aldh2 +/+ and 9 Aldh2 ?/? mice for 8 days. Three mice of the ethanol administered Aldh2 +/+ group and eight mice of the ethanol administered Aldh2 ?/? group died during the 8 days. The weights of mice were decreased by ethanol exposure to 85% and 74% in Aldh2 +/+ and Aldh2 ?/? group, respectively. The survival rates of the ethanol administered Aldh2 +/+ and Aldh2 ?/? group were 40 and 11%. Liver and pancreas disorder was revealed in the ethanol administered Aldh2 +/+ and Aldh2 ?/? group in the results of serum chemical examination, immunohistochemical staining and western blot analysis. Cyp2e1 is more inducible to ethanol toxicity in Aldh2 ?/? mice compared with Aldh2 +/+ mice when ethanol is administered according to the results of quantitative PCR.

Excessive alcohol consumption is associated with increased risks of many diseases including cancer. We evaluated oxidative DNA damage in Aldh2 +/+ and Aldh2 -/- mice after they had been subjected to acute ethanol exposure. Olive tail moment, which was measured using a comet assay, was not increased by ethanol treatment in both Aldh2 +/+ and Aldh2 -/- mice. However, after controlling for the effect of ethanol exposure, the Aldh2 genotype was a significant determinant for Olive tail moments. Although the ethanol treatment significantly increased the hepatic 8-OHdG generation in only Aldh2 +/+ mice, the level of 8-OHdG was the highest in Aldh2 -/- ethanol treated mice. The increase in the level of 8-OHdG was associated with hepatic expression of cytochrome P450 2E1 (CYP2E1). The levels of Olive tail moment and the hepatic 8-OHdG in the Aldh2 -/- control group were significantly higher than those of the Aldh2 +/+ control group. The level of CYP2E1 in liver tissue showed a similar pattern to those of the oxidative DNA damage markers. This study shows that acute ethanol consumption increases oxidative DNA damage and that expression of CYP2E1 protein may play a pivotal role in the induction of oxidative DNA damage. The finding that oxidative DNA damage was more intense in Aldh2 -/- mice than in Aldh2 +/+ mice suggests that ALDH2-deficient individuals may be more susceptible than wild-type ALDH2 individuals to ethanol-mediated liver disease, including cancer.

Acetaldehyde production during ethanol metabolism has been implicated as an important link between oxidative stress and cell damage, which suggests that oxidative stress caused by ethanol exposure may be more severe in aldehyde dehydrogenase 2 (ALDH2)-deficient individuals than in those with wild-type ALDH2. We evaluated the activities of the major antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), in liver tissue isolated from Aldh2 +/+ and Aldh2 -/- mice that were exposed to ethanol. The activities of CAT and GPx were significantly increased by ethanol treatment in A1dh2 +/+ mice (3.33-fold and 1.65-fold, respectively). The mean activity of SOD in A1dh2 +/+ mice was 1.46-fold that in the A1dh2 +/+ control group, but the difference was not statistically significant. In Aldh2 -/- mice, the activities of SOD and CAT were decreased and that of GPx was slightly increased after ethanol exposure, but the differences were not significant. We postulate that antioxidant enzyme expression after ethanol consumption may differ according to the intracellular level of acetaldehyde or free radicals, which in turn depends on the activity of ALDH2. These results suggest that the greater toxicity of ethanol in Aldh2 -/- mice than in Aldh2 +/+ mice may be due to decreased antioxidant enzyme expression.

An analytical method using a combination of solid-phase extraction (SPE) and gas chromatography with a flame thermionic detector (GC/FTD) was developed for determination of N-methyl-2-pyrrolidone (NMP), N-methylsuccinimide (NISI), and 2-hydroxy-N-methylsuccinimide (2-HMSI) in human urine. The SPE cartridge of poly(divinylbenzene/hydroxymethacrylate) used was directly loaded with urine sample, followed by elution with methyl isobutyl ketone (MIBK) and subsequent centrifugation, and the supernatant was injected into the capillary GC using a DB 1701. This method allowed efficient separation of NMP, MSI, and 2-HMSI, which were nearly free of interference by other GC peaks arising from urine. Recoveries of NMP, MSI, and 2-HMSI from the SPE cartridge were about 98, 101, and 67%, respectively, with limits of detection of 0.04, 0.02, and 0.06 mg/L, respectively, which met the regulatory requirements. The present method was used for assay in biological monitoring of workers exposed to NMP in their occupational environment. (C) 2007 Elsevier B.V. All rights reserved.

The toxicity and carcinogenicity of arsenic depend on its species. Individuals living in Japan consume much seafood that contains high levels of organoarsenics. Speciation analysis of urinary arsenic is required to clarify the health risks of arsenic intake. There has been no report of urinary arsenic analysis in Japan using high performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). We performed speciation analysis of urinary arsenic for 210 Japanese male subjects without occupational exposure using HPLC-ICP-MS. The median values of urinary arsenics were as follows: sodium arsenite (AsIII), 3.5; sodium arsenate (AsV), 0.1; monomethylarsonic acid (MMA), 3.1; dimethylarsinic acid (DMA), 42.6; arsenobetaine (AsBe), 61.3; arsenocholine, trimethylarsine oxide, and unidentified arsenics (others), 5.2; and total arsenic (total As), 141.3 mu gAs/1. The median creatinine-adjusted values were as follows: AsIII, 3.0; AsV, 0.1; MMA, 2.6; DMA, 35.9; AsBe, 52.1; others 3.5; and total As, 114.9 mu gAs/g creatinine. Our findings indicate that DMA and AsBe levels in Japan are much higher than those found in Italian and American studies. It appears that the high levels of DMA and AsBe observed in Japan may be due in part to seafood intake. ACGIH and DFG set the BEI and BAT values for occupational arsenic exposure as 35 mu gAs/l and 50 mu gAs/l, respectively, using the sum of inorganic arsenic (iAs), MMA, and DMA. In the general Japanese population, the sums of these were above 50 mu gAs/l in 115 (55%) samples. We therefore recommend excluding DMA concentration in monitoring of iAs exposure.

In this study, we evaluated the inhalation toxicity of acetaldehyde in Aldh2 KO ( Aldh-/-) mice, using pathological method. Male C57BL/6 ( Aldh+/+) mice and Aldh -/- mice were exposed to atmospheres containing acetaldehyde at levels of 0, 125, and 500 ppm for 24 h/day during 14 days. Although the average blood acetaldehyde concentration of Aldh -/- mice was higher than that of Aldh2+/+ mice in the acetaldehyde exposure group, observable effects by the acetaldehyde exposure on the lung and liver were not different between wild type and ALDH2 null mice. In Aldh2-/- mice, the levels of 1) erosion of respiratory epithelium and the subepithelial hemorrhage in nose, 2) hemorrhage in nasal cavity, 3) degeneration of respiratory epithelium in larynx, pharynx and trachea, and 4) degeneration of dorsal skin were higher compared with Aldh2+/+ mice, indicating that Aldh2-/- mice are more acetaldehyde-sensitive than Aldh2+/+ mice. This is the first example for studying pathological effects of Aldh2 deficiency using Aldh-/- mice exposed to a low level of acetaldehyde.

In order to clarify the effects of ALDH2 polymorphism on the carcinogenicity and organ damage caused by ethanol consumption, labeled ethanol was administered to wild-type (C57BL/6, Aldh2+/+) and Aldh2 knock-out (Aldh2-/-) mice, and DNA adduct levels of organs were compared according to Aldh2 genotype. Aldh2-/- mice, which have the same genetic background as C57BL/6 mice except in the Aldh2 gene, were used as a model of lack of ALDH2 activity in humans. The DNA adduct levels in liver, stomach, and kidney and radioactivity in liver, stomach, kidney, and serum were measured by liquid scintillation counting 6, 12, and 24 It after administration. Though radioactivity levels in all organs decreased over time, there were no significant differences in radioactivity between Aldh2+/+ and Aldh2-/- mice. On the other hand, the DNA radioactivity in each organ tested differed significantly between Aldh2+/+ and Aldh2-/- mice 24h after administration. These findings show that ethanol consumption affects DNA in Aldh2-/- mice much more strongly than in Aldh2+/+ mice. According to the IARC document, ethanol consumption is carcinogenic to humans (Group 1). Moreover, several studies have shown that ALDH2-deficient humans who habitually consume ethanol have higher rates of cancer than humans with ALDH2. Our results support these findings of epidemiological studies. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Around three million Japanese are persistently infected with HBV or HCV. Though most of them work in various industries, little is known about the actual conditions in their workplaces. To clarify the workplace conditions of workers with hepatitis, three kinds of questionnaire surveys, answered by occupational health physicians and workers with hepatitis, were carried out. The rates of workers recognized as workers with hepatitis B or C by occupational health physicians were 0.82% and 0.48% of 130,092 workers, respectively. About 30% of workers with hepatitis were engaged in "hazardous work". The percentage of workers engaged in various types of hazardous work among workers with hepatitis was nearly the same as that among all Japanese workers. About 30% of occupational health physicians witnessed exacerbation of hepatitis in the workers at their workplaces, and 22% of workers with hepatitis experienced exacerbation of hepatitis. The rate of workers with hepatitis who had experienced exacerbation was not significantly different between workers with and without hazardous work. Workers with hepatitis have strong, concerns about the relationship between work and exacerbation. As causes of exacerbation, occupational health physicians cited "unknown", "drinking" and "quit treatment" while workers with hepatitis answered "work-related causes", besides "unknown" and "drinking."

In this study, we aim to compare the criteria for sensitizers among national organizations in various countries and international organizations, and to specify whether each Pollutant Release and Transfer Register (PRTR)-designated chemical substance is a sensitizer by each organization. The definition of sensitizing chemicals and the designation of respective sensitizers according to the PRTR law, Japan Society for Occupational Health (JSOH), American Conference of Governmental Industrial Hygienists (ACGIH), European Union (EU), and Deutsche Forschungsgemeinshaft (DFG) were studied. Of the 435 PRTR-designated chemical substances, 15 are listed as sensitizers according to the PRTR law, 16 as sensitizers of the airway and 21 as sensitizers of the skin by JSOH, 12 as sensitizers (no discrimination) by ACGIH, 19 (airway) and 85 (skin) by EU, and 15 (airway) and 43 (skin) by DFG. Only 9 substances were designated as sensitizers by all these organizations. The variation in the designation of sensitizers is accounted for by the differences in the classification criteria and grouping of chemical substances. JSOH limits the definition of sensitizers to substances that induce allergic reactions in humans and uses only human data. Other organizations utilize not only human evidence but also appropriate animal tests. In addition, EU designates an isocyanate as a sensitizer except those for which there is evidence showing that they do not cause respiratory sensitivity. The worldwide enforcement of the globally harmonized system (GHS) of classification and labeling of chemicals could promote not only the consistent designation of sensitizers among national and international organizations, but also the development of testing guidelines and classification criteria for mixtures.

Health-Many new biomarkers are being studied, in addition to classical biomarkers, such as chemical substances and their metabolites in blood and urine and modified enzymes. Among these new biomarkers, hemoglobin adducts are thought to be especially useful for the estimation of chemical exposures. We review here the use of biomarkers for monitoring exposures to nine substances, mainly focusing on PRTR class I designated chemical substances, styrene, phenyloxirane (styrene oxide), 4,4'-methylendiphenyl diisocyanate (MDI), 4,4'-methylendianiline (MDA), 1,3-butadiene, ethylene oxide, propylene oxide, acrylamicle and acrylonitrile. Hemoglobin adduct levels were elevated after exposures to styrene, MDI, MDA, 1, 3-butadiene ethylene oxide, acrylamide and acrylonitrile. Moreover: hemoglobin adducts of butadiene, ethylene oxide, acrylamide and acrylonitrile have several useful advantages. For example, the hemoglobin adduct of 1,3-butadiene is an even more useful biomarker of exposure than urinary metabolites, and in the case of ethylene oxide, even though the concentration of ethylene oxide-Hb in the blood of workers did not exceed the value of the German exposure equivalent, a significant difference in it was found between workers and a control group. Also hemoglobin adducts of acrylamide and acrylonitrile can reflect their exposures because there are no urinary metabolites of acrylamide and acrylonitrile that are useful for exposure assessment. In addition to these advantages, hemoglobin adducts are superior to DNA adducts with respect to the availability of large amounts, availability of methods for chemical identification, and well-defined life spans due to the absence of repair. Hemoglobin adducts can be effective biomarkers for assessing exposure to and the effects of chemicals.

The number of fatalities in Japan attributable to lung cancer exceeded 50000 in 2001. It is socially desirable that various markers, which can be utilized for the prevention of lung cancer, be established. We believe that smoking or exposure to carcinogens in air induces mutations in bronchial and alveolar epithelia, leading to the development of lung cancer. It would be useful to have markers of individual differences in susceptibility to chemical carcinogen-induced lung cancer 1) to identify genetic polymorphisms of enzymes metabolizing chemical carcinogens and 2) to investigate the expression of enzymes metabolizing chemical carcinogens. In this paper, we review CYP expression in the bronchial epithelium. CYP1, CYP2 and CYP3 are expressed in the bronchial epithelium. We also show the relationship between the genetic polymorphisms of cytochrome P450 (CYP) and a person's susceptibility to chemical carcinogen-induced lung cancer. We demonstrate the relationship between cigarette consumption and the CYP expression profile in the bronchial epithelium. To maintain and promote public health, we must apply evidence, such as CYP polymorphisms and CYP profiles to disease prevention and also to aggressively advance evidence-based prevention (EBP) of lung cancer.