Hailan Wang

Nagoya City University, Nagoya, Aichi, Japan

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Publications (21)55.55 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Trichloroethylene (TRI) has the potential to cause generalized dermatitis complicated with hepatitis. The guinea pig maximization test (GPMT) also suggests that both TRI and its metabolite trichloroethanol (TCE) exhibit immunogenicity and possible sex differences in guinea pigs. However, TRI and TCE metabolisms in guinea pigs have not been elucidated in detail. The first issue to clarify may be the sex differences in relation to the immunogenicity. Methods: We collected urine from Hartley male and female guinea pigs 24 hours after intracutaneous injection of TRI, TCE or trichloroacetic acid (TCA) during a GPMT and measured the urinary metabolites by gas chromatography-mass spectrometry. Results: After TRI treatment, the amount of TCA was significantly greater in females than males, while there was no sex difference in the total amount (TCA + TCE). TCA was only detected in urine after TCA treatment. Interestingly, not only TCE but also TCA was detected in urine of both sexes after TCE treatment, and the amount of TCA was also greater in females than males. An additional experiment showed that TCE treatment did not result in the detection of urinary TCA in cytochrome P450 (CYP)2E1-null mice but did in wild-type mice, suggesting the involvement of CYP2E1 in the metabolism from TCE to TCA. The constitutive expression of CYP2E1 in the liver of guinea pigs was greater in females than males. Conclusion: The sex difference in urinary TCA excretion after TRI and TCE treatments may be due to variation of the constitutive expression of CYP2E1.
    Journal of Occupational Health 09/2013; · 1.63 Impact Factor
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    ABSTRACT: Trichloroethylene (TCE) is an industrial solvent which can cause severe generalized dermatitis, i.e., occupational TCE hypersensitivity syndrome. Reactivation of latent human herpesvirus 6 (HHV6) can occur in such patients, which has made TCE known as a causative chemical of drug-induced hypersensitivity syndrome (DIHS). This study aimed to clarify HHV6 status, cytokine profiles and their association with rash phenotypes in patients with TCE hypersensitivity syndrome. HHV6 DNA copy numbers, anti-HHV6 antibody titers, and cytokines were measured in blood prospectively sampled 5-7 times from 28 hospitalized patients with the disease. The patients (19 had exfoliative dermatitis (ED) and 9 had non-ED type rash) generally met the diagnostic criteria for DIHS. Viral reactivation defined as increases in either HHV6 DNA (≥100 genomic copies/10(6) peripheral blood mononuclear cells) or antibody titers was identified in 24 (89%) patients. HHV6 DNA, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-5, IL-6 and IL-10 concentrations were remarkably higher in the patients than in the healthy workers (p<0.01). Positive correlations between HHV6 DNA, TNF-α, IFN-γ, IL-6 and IL-10 were significant (p<0.05) except for that between HHV6 DNA and IFN-γ. An increase in HHV6 DNA was positively associated with an increase in TNF-α on admission (p<0.01). HHV6 DNA, the antibody titers, TNF-α and IL-10 concentrations were significantly higher in ED than in the non-ED type (p<0.05). Reactivated HHV6 and the increased cytokines could be biomarkers of TCE hypersensitivity syndrome. The higher-level reactivation and stronger humoral responses were associated with ED-type rash.
    Journal of dermatological science 07/2013; · 3.71 Impact Factor
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    ABSTRACT: Benzene is an important industrial chemical and an environmental contaminant, but the pathogenesis of hematotoxicity induced by chronic occupational benzene exposure (HCOBE) remains to be elucidated. To gain an insight into the molecular mechanisms and developmental biomarkers for HCOBE, isobaric tags for relative and absolute quantitation (iTRAQ) combined with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) were utilized. Identification and quantitation of differentially expressed proteins between HCOBE cases and healthy control were thus made. Expressions of selected proteins were confirmed by western blot and further validated by ELISA. A total of 159 unique proteins were identified (≥95% confidence), and relative expression data were obtained for 141 of these in 3 iTRAQ experiments, with fifty proteins found to be in common among 3 iTRAQ experiments. Plasminogen (PLG) was found to be significantly up-regulated, whereas platelet basic protein (PBP) and apolipoprotein B100 (APOB100) were significantly down-regulated in the serum of HCOBE cases. Additionally, the altered proteins were associated with the molecular functions of binding, catalytic activity, enzyme regulator activity and transporter activity, and involved in biological processes of apoptosis, developmental and immune system process, as well as response to stimulus. Furthermore, differential expressions of PLG, PBP and APOB100 were confirmed by western blot, and the clinical relevance of PBP and APOB100 with HCOBE was validated by ELISA. Overall, our results showed that lowered expression of PBP and APOB100 proteins served as potential biomarkers of HCOBE, and may play roles in the benzene-induced immunosuppressive effects and disorders in lipid metabolism.
    Toxicology 11/2011; 291(1-3):56-64. · 4.02 Impact Factor
  • Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 09/2011; 53(10):1095-8. · 1.88 Impact Factor
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    ABSTRACT: To investigate the health effects of 1-bromopropane (1-BP) and its dose-dependency in 1-BP production factories in China. Data of 60 female and 26 male workers in three 1-BP factories and the same number of age-, sex-, and region-matched controls were interviewed and examined. The time-weighed average exposure levels of individual workers were estimated. Regression analysis on exposure level showed dose-dependent increase in the distal latency of tibial nerve, threshold for vibration sense in toes, lactate dehydrogenase, thyroid stimulating hormone, and follicle stimulating hormone in female workers. The analysis also showed dose-dependent decrease in sensory nerve conduction velocity of the sural nerve, red blood cell, and hematocrit in female workers. The results indicate that exposure to 1-BP induces dose-dependent neurotoxicity in female workers.
    Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 08/2010; 52(8):769-77. · 1.88 Impact Factor
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    ABSTRACT: To study the 1-bromopropane (1-BP)-induced altered gene expression profiles in rat gonad, and explore its male reproductive toxicity-related mRNA changes. Twelve F344/NSIc male rats were randomly divided into two groups of 6 each. Rats were exposed to either fresh air or 5030 mg/m3 1-BP through inhalation for 8 h. Rats were sacrificed and testes were removed at 16 h after exposure. Global changes in gene expression were determined by microarray analysis using rat genital chip followed by Real-time PCR validation. Among the 5082 genes and ESTs in the genital chip, 62 genes were down-regulated and 3 genes were up-regulated by 1-BP, which include synthetic sex hormone-related genes cytochrome P450 aromatase (CYP19a), glutathione S-transferase (GSTT1), creatine kinase (Ckb), myelin and lymphocyte protein (Mal) and S100 calcium-binding protein (S100a4). Classification analysis revealed that the majority of gene changes was involved protein/lipid metabolism, followed by the stress-associated defense response. Real-time PCR confirmed the down-regulation of CYP19a, GSTT1, Mal and S100a4 genes. Acute high-dose exposure to 1-BP causes the down-regulation of testicular CYP19a, S100a4, GSTT1 and Mal. This altered gene profiles might reflect the toxic mechanism which suggested that 1-BP disrupt the metabolics and endocrine balance.
    Wei sheng yan jiu = Journal of hygiene research 03/2010; 39(2):191-6.
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    ABSTRACT: To study the reproductive toxicity of male rats exposed to 1-bromopropane and 2-bromopropane and to explore the toxic mechanism of two isomers. 18 SPF SD male rats were randomly divided into 3 groups of 6 each, respectively. The groups were exposed to corn oil, 1-BP (1 g/kg) and 2-BP (1 g/ kg) for 7 days by intraperitoneally injection. Trait of reproductive organs, sperm characteristics, testicular histological and apoptotic findings and the lipid peroxidation in the testicular and epididymal tissue were determined. Results showed that treatment with bromopropanes induced reduction in sperm concentration and increments in abnormalities of sperm injuries to sperm quality. In addition, 1-BP increased GR activity (7. 42 +/- 2.98 vs. 4.25 +/- 1.18, P < 0.05) in testis, and SOD activity (91.87 +/- 3.93 vs. 80.59 +/- 9.92, P < 0.05) and MDA level (0.49 -/+ 0.20 vs. 0.39 +/- 0.08, P < 0.05) in epididymis. 2-BP decreased the GSH lever (6.35 +/- 1.86 vs. 10.89 +/- 3.69, P < 0.05) and increased the MDA level (0.42 +/- 0.07 vs. 0.24 +/- 0. 11, P < 0.05; 0.48 +/- 0.08 vs. 0.39 +/- 0.08, P < 0.05) in epididymis and testis, decreased GST ( 53.21 +/- 9.60 vs. 61.98 +/- 10.41, P < 0.05) and GR activity (2.48 +/- 1.21 vs. 7.75 +/- 8.56, P < 0.05) in epididymis. There were no histopathological changes in treatment with 1-BP rats, except that retained and elongated spermatids near basement membrane at the spermatogenesis cycle were found. Whereas, treatment with 2-BP induced vacuolation, degeneration and necrosis in seminiferous tubules. Paralleling with testicular lesion, treatment with 2-BP increased the total apoptotic cells per tubule, the percentage of apoptotic cells and apoptotic index significantly, comparing with control (17.72 +/- 4.59 vs. 5.92 +/- 1.05, P < 0.05; 0.34 +/- 0.14 vs. 0.10 +/- 0.02, P < 0.05; 6.64 +/- 3.40 vs. 0.59 +/- 0.20, P < 0.01). As compring with 1-BP group, exposed to 2-BP increased the percentages of TUNEL-positive tubules and apoptotic cellindex (0.34 +/- 0. 14 vs. 0.12 +/- 0. 03, P < 0.05; 6.64 +/- 3.40 vs. 0.76 +/- 0.21, P < 0.01). In addition, 2-BP group increased the proportion of apoptotic germ cells and the number of active caspase-3-positive cells per tubule, compared with 1-BP and control (P < 0.01, P < 0.01; P < 0.01, P < 0.01). This study indicates that bromopropanes can cause reproductive disorder in male rats, the rats treatment with 2-BP had more toxicity than that with 1-BP, and it might have different toxic mechanism between two isomers.
    Wei sheng yan jiu = Journal of hygiene research 01/2010; 39(1):4-8.
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    ABSTRACT: Idiosyncratic generalized skin disorders complicated by hepatitis, which resemble severe drug hypersensitivities, occur sporadically in workers exposed to trichloroethylene (TCE) in China. However, it has been a matter of controversy whether the solvent itself, not its impurities or stabilizers, can cause hypersensitivity reactions or not. This study aimed to characterize the exposure of hospitalized patients and their healthy colleagues. TCE metabolites were measured in urine of 19 hospitalized patients suffering from the disorders. To assess the exposure of patients' healthy colleagues, on-site surveys were conducted in 6 factories where the disorders occurred and in 2 control factories without such occurrences despite TCE use. Urinalysis of the patients detected trichloroacetic acid (TCA) in all of them. Its average concentration in the end-of-shift urine was estimated to be 206 mg/l. On-site survey of healthy exposed workers revealed that the maximum urinary TCA concentrations and the maximum time-weighted average concentrations of personal TCE exposure were 318-1,617 mg/l and 164-2,330 mg/m(3), respectively. There was no common impurity in TCE used in the factories. These results suggested that TCE itself caused the skin hypersensitivity disorders, and that the disorders occurred in factories where TCE metabolites could be extensively accumulated, possibly due to long working hours. Since the lowest TCA concentration in the end-of-shift urine of the patients was estimated to be 72-80 mg/l, it is recommended to control TCE exposure to keep the urinary TCA concentration below 50 mg/l to reduce the disease risk.
    Journal of Occupational Health 07/2008; 50(4):328-38. · 1.63 Impact Factor
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    ABSTRACT: Trichloroethylene (TCE) can induce non-dose-related hepatitis, possibly classified as delayed-type hypersensitivity (immune-mediated hepatitis), as well as dose-related toxic liver injury. However, the difference in pathophysiology between the two kinds of hepatitis remains unknown. This study aimed to characterize the liver injury associated with hypersensitive skin reactions induced by TCE in guinea pigs. As a model of dose-related acute toxic liver injury, the animals were treated with intradermal injection (ii) (0, 167, 500, 1500 or 4500 mg/kg of TCE) or dermal patch (dp) (0 or 900 mg/kg of TCE). The guinea pig maximization test (GPMT) was also carried out as a model of immune-mediated liver injury, in which the total TCE dosage was below 340 mg/kg. In the group of TCE 4500 mg/kg (ii), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased (p<0.01), while total protein and globulin decreased (p<0.05). Evident fatty degeneration, hepatic sinusoid dilation and inflammatory cell infiltration were observed. No significant change was found in animals treated with TCE of doses below 500 mg/kg (ii) or 900 mg/kg (dp). In the GPMT, sensitization rates of TCE-induced dermal allergy were 66%. ALT, AST, lactate dehydrogenase and the relative liver weight increased significantly (p<0.05) while albumin, IgA and gamma-glutamyl transpeptidase decreased significantly (p<0.05). Lesions of ballooning changes were observed in liver pathology. Thus, TCE could cause both acute-type toxic liver injury and immune-mediated liver injury, the so-called delayed-type hypersensitivity at doses below the dosage for toxic liver injury. Interestingly, the histopathological features were quite different: fatty degeneration was most prominent in the former, and ballooning in the latter.
    Journal of Occupational Health 04/2008; 50(2):114-21. · 1.63 Impact Factor
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    ABSTRACT: Workers exposed to trichloroethylene (TCE) rarely show severe generalized skin disorders and accompanying hepatitis which resemble drug hypersensitivities. The disorders are completely different from solvent-induced irritating contact dermatitis, and their serious consequences have become one of the critical occupational health issues recently in Asia. The present review sheds light on the analogous relationship between the reported patients' clinical manifestations and those of severe drug rash, and provides a comprehensive picture of the disorder occurrences among TCE-exposed workers to date. All literature published in English and ad hoc publications in local languages were reviewed. The patients typically showed rash on the extremities, face, neck or trunk with/without fever 2 weeks to 2 months after commencement of occupational TCE exposure. Reported cutaneous manifestations were classified into two hypersensitivity categories, i.e. hypersensitivity syndrome and erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis. Based on this categorization, 124 (52%) cases were classified as the former and 115 (48%) as the latter. According to the two spectra, the prevalence of each clinical finding of TCE-related skin disorders was close to that in drug hypersensitivities except for disease incidence and the prevalence of fever, hepatitis, and lymphadenopathy. Occurrences of the disorders have been reported from the USA, Japan, Spain, Singapore, China, Korea, Thailand, and the Philippines. The case reports from industrialized countries were mostly published up to 1990, whereas cases from Asian industrializing countries appeared thereafter. The TCE-related generalized skin disorders are important not only in terms of the number of disease occurrences and severity but from the viewpoint of drug hypersensitivity. Systematic collection of clinical information is necessary in cases diagnosed by the same criteria as those used for drug hypersensitivities. Detailed exposure assessments are also required to establish preventive strategies in these countries.
    International Archives of Occupational and Environmental Health 05/2007; 80(5):357-70. · 2.10 Impact Factor
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    ABSTRACT: Idiosyncratic generalized skin disorders resembling serious drug hypersensitivities have reportedly occurred after occupational exposure to trichloroethylene. However, factors associated with the disorders remain unknown except for trichloroethylene exposure. This study aimed at clarifying whether infectious diseases contributed to the development of rash or hepatitis in patients with trichloroethylene-related generalized skin disorders. Fifty-nine patients consecutively hospitalized between March 2002 and December 2003 and 59 healthy exposed workers selected on an age-matched basis in the patients' factories were enrolled in the study. Information on possible risk factors for rash and hepatitis was collected with structured checklists. Antibody titers were measured for hepatitis A, B and C viruses, Mycoplasma pneumoniae, herpes simplex viruses 1 and 2, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, measles and rubella virus. Thirty-six cases (59%) showed exfoliative dermatitis, 17 (28%) erythema multiforme, 4 (7%) Stevens-Johnson syndrome, and 4 (7%) toxic epidermal necrolysis. Before the onset of rash, 16 (27%) cases had received medication prescribed for the preceding fever, a main first symptom of the disorders. Marked increases in anti-human herpesvirus 6 IgG titer (> or =256), which indicated viral reactivation, were noted in 14 (25%) patients, while no abnormal increase was detected in the controls (p<0.001). Anti-measles IgM titer was positive in 2 (7%) cases but not in the controls (p=0.49). The involvement of other known risk factors of rash or hepatitis was ruled out. These results suggest that part of trichloroethylene-related generalized cutaneous disorders occurring in China and drug-induced hypersensitivity syndrome overlap in terms of human herpesvirus 6 reactivation.
    Journal of Occupational Health 11/2006; 48(6):417-23. · 1.63 Impact Factor
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    ABSTRACT: 1-Bromopropane (1-BP) exhibits neuroreproductive toxicities in adult rats and humans. Here, we determined the effects of exposure of rat dams to 1-BP during pregnancy and lactation on the growth and sexual maturation of their offspring. In Experiment 1, 40 rats were exposed to 0, 100, 400 and 800ppm 1-BP during pregnancy and lactation for 8h/day. Ten rats that were not placed in chambers throughout the experiment served to observe the effect of separation of dams from offspring. In Experiment 2, three groups of 10 pregnant rats each were exposed to fresh air in three chambers and 10 other rats were exposed to 800ppm 1-BP during pregnancy and lactation for 8h/day. After delivery, offspring of the exposed and non-exposed dams were swapped so that they were nursed by the opposite dams. In Experiment 1, the survival rate and body weight of offspring were lower than the non-exposed in 1-BP dose-dependent manner. In Experiment 2, the survival rate and body weight of offspring (Group A) nursed by exposed dams and those (Group B) of exposed dams were significantly lower than non-exposed groups. The body weight of Group A was lower than that of Group B, although the two groups showed a significant equal decrease in the survival rate. The number of dead offspring from Group A was significantly higher. Our results indicate that exposure to 1-BP during pregnancy and lactation has comparable effects on survival rate, but exposure during lactation has a more adverse effect on growth of offspring than that during pregnancy. Moreover, exposure during lactation is associated with reduced early survival of third generation (F2) rats.
    Toxicology 08/2006; 224(3):219-28. · 4.02 Impact Factor
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    ABSTRACT: Assessments of the reproductive toxicity of organophosphorus insecticides are important public health issues. This study aimed at defining the testicular toxicity of dichlorvos (DDVP) since this toxicity was suspected by our previous survey on pesticide sprayers and in some earlier publications during the 1970s. Ten-week-old Wistar rats were divided into four groups (n=8 or 9) and were injected subcutaneously with DDVP (0, 1, 2 or 4 mg/kg) 6 days a week for 9 weeks. After that period, erythrocyte cholinesterase (ChE) activities decreased dose-dependently, showing 44-55% inhibition among the treated groups. No significant difference was observed in the reproductive organ weights in any treated groups compared with the control group. Sperm motility decreased slightly but significantly in the 1 and 4 mg/kg groups, and significant regressions were observed between sperm motility and both blood ChE activity and urinary concentration of dimethyl phosphate (DMP), a urine metabolite of DDVP. However, sperm counts and sperm morphology in the cauda epididymidis, plasma testosterone concentrations, and histopathology in the testes in all the treated groups were not significantly different from those of the control group. Since only the sperm motility deteriorated by DDVP exposure at doses inducing marked inhibition of cholinesterase activities in the rats, it was suggested that the risk of testicular dysfunction posed to occupationally exposed humans would be small in terms of the effect of DDVP exposure alone. This conclusion was also supported by an estimate of the decrease in human sperm motility based on the urinary DMP concentrations observed in actual occupational settings.
    Toxicology 10/2005; 213(1-2):129-37. · 4.02 Impact Factor
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    ABSTRACT: To clarify species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) we measured the activity of four DEHP-metabolizing enzymes (lipase, UDP-glucuronyltransferase (UGT), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH)) in several organs (the liver, lungs, kidneys, and small intestine) of mice (CD-1), rats (Sprague-Dawley), and marmosets (Callithrix jacchus). Lipase activity, measured by the rate of formation of mono(2-ethylhexyl) phthalate (MEHP) from DEHP, differed by 27- to 357-fold among species; the activity was highest in the small intestines of mice and lowest in the lungs of marmosets. This might be because of the significant differences between Vmax/Km values of lipase for DEHP among the species. UGT activity for MEHP in the liver microsomes was highest in mice, followed by rats and marmosets. These differences, however, were only marginal compared with those for lipase activity. ADH and ALDH activity also differed among species; the activity of the former in the livers of marmosets was 1.6-3.9 times greater than in those of rats or mice; the activity of the latter was higher in rats and marmosets (2-14 times) than in mice. These results were quite different from those for lipase or UGT activity. Because MEHP is considered to be the more potent ligand to peroxisome proliferator-activated receptor alpha involved in different toxic processes, a possibly major difference in MEHP-formation capacity could be also considered on extrapolation from rodents to humans.
    Archive für Toxikologie 04/2005; 79(3):147-54. · 5.22 Impact Factor
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    ABSTRACT: We reported recently that 1-bromopropane (1-BP; n-propylbromide, CAS Registry no. 106-94-5), an alternative to ozone-depleting solvents, is neurotoxic and exhibits reproductive toxicity in rats. The four most recent case reports suggested possible neurotoxicity of 1-BP in workers. The aim of the present study was to establish the neurologic effects of 1-BP in workers and examine the relationship with exposure levels. We surveyed 27 female workers in a 1-BP production factory and compared 23 of them with 23 age-matched workers in a beer factory as controls. The workers were interviewed and examined by neurologic, electrophysiologic, hematologic, biochemical, neurobehavioral, and postural sway tests. 1-BP exposure levels were estimated with passive samplers. Tests with a tuning fork showed diminished vibration sensation of the foot in 15 workers exposed to 1-BP but in none of the controls. 1-BP factory workers showed significantly longer distal latency in the tibial nerve than did the controls but no significant changes in motor nerve conduction velocity. Workers also displayed lower values in sensory nerve conduction velocity in the sural nerve, backward recalled digits, Benton visual memory test scores, pursuit aiming test scores, and five items of the Profile of Mood States (POMS) test (tension, depression, anxiety, fatigue, and confusion) compared with controls matched for age and education. Workers hired after May 1999, who were exposed to 1-BP only (workers hired before 1999 could have also been exposed to 2-BP), showed similar changes in vibration sense, distal latency, Benton test scores, and depression and fatigue in the POMS test. Time-weighted average exposure levels in the workers were 0.34-49.19 ppm. Exposure to 1-BP could adversely affect peripheral nerves or/and the central nervous system.
    Environmental Health Perspectives 10/2004; 112(13):1319-25. · 7.26 Impact Factor
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    ABSTRACT: This study aims at clarifying the semen indices of insecticide sprayers who are exposed mainly to organophosphorus and pyrethroid insecticides. Eighteen male sprayers out of 54 working for 9 companies in central Japan and 18 age-matched students or medical doctors as unexposed controls participated in detailed reproductive check-ups conducted in summer and the following winter. The sprayers were exposed to insecticides more in summer, the busiest season, than winter, the off-season (p<0.05). Erythrocyte true cholinesterase activities in the sprayers were lower than in the controls in summer (p<0.05), and decreased in significant association with the increase in exposure frequency. Testicular volumes in the sprayers tended to be smaller than in the controls (p=0.06). The serum testosterone concentration in winter in the sprayers was higher than in the controls (p<0.05), though luteinizing hormone and follicle stimulating hormone concentrations were not significantly different. The sperm counts and vitality were comparable between the groups, but detailed sperm motility analysis in summer revealed that the percentages of slow progressive and nonprogressive motile sperm were twice as high in the sprayers (p<0.05), and that of rapid progressive sperm tended to be lower (p=0.06). Such differences were not observed in winter. Differential sperm morphology counts showed that interaction of group and abstinence effects were significant in sperm with normal morphology and with head deformity only in the summer check-up. Despite possible inherent differences between the groups, the above season-dependent differences suggested that the observed lower semen quality in the sprayers was associated with pesticide spraying work.
    Journal of Occupational Health 03/2004; 46(2):109-18. · 1.63 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the health effects of exposure mainly to 1-bromopropane, which is an alternative to ozone-depleting solvents, and to establish biomarkers for assessing 1-bromopropane exposure. Twenty-four female and 13 male workers of a 1-bromopropane-factory were interviewed, and their urine and blood samples were collected. Measured parameters included 1-bromopropane levels in the factory, as well as individual exposure levels, urinary 1-bromopropane levels, enzymatic activity and M subunit's concentration of serum creatine kinase (CK). Frequent symptoms reported by workers exposed to 1-bromopropane were nose, throat, and eyes irritation or malaise and/or headache. Urinary 1-bromopropane levels correlated significantly with individual exposure levels, but enzymatic activity or CK-M subunit did not. The symptoms suggested irritation of the mucous membrane and possible adverse effects on the central nervous system. There were no severe chronic symptoms suggestive of neurological damage in workers exposed to less than 170 ppm. Urinary 1-bromopropane level may be a good indicator of exposure. Am. J. Ind. Med. 45:63-75, 2004.
    American Journal of Industrial Medicine 02/2004; 45(1):63-75. · 1.97 Impact Factor
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    ABSTRACT: 1-Bromopropane is used as a cleaning agent or adhesive solvent in the workplace. The present study investigated the long-term effects of exposure to 1-bromopropane on biochemical components in the central nervous system (CNS) of rats. Four groups, each of nine male Wistar rats, were exposed to 200, 400, or 800 ppm 1-bromopropane or fresh air only, 8h per day, 7 days a week for 12 weeks. We measured the levels of neuron-specific gamma-enolase, glia-specific beta-S100 protein, creatine kinase (CK) subunits B and M, heat shock protein Hsp27 (by enzyme immunoassay), enzymatic activity of CK and levels of glutathione (GSH), oxidized glutathione (GSSG) and sulfhydrul (SH) base in the cerebrum, cerebellum, brainstem and spinal cord. gamma-Enolase decreased dose-dependently in the cerebrum, which showed a decrease in wet weight, at 400 ppm or over, but no change was noted in beta-S100 protein in any brain region or spinal cord. Hsp27 decreased in the cerebellum, brainstem and spinal cord. Protein-bound SH base, non-protein SH base and total glutathione decreased in every brain region. CK activity decreased dose-dependently at 200 ppm or over, and the ratio of CK activity to CK-B concentration tended to decrease in all regions. The decrease in gamma-enolase in the cerebrum suggests the involvement of biochemical changes in neurons with decrease in the wet weight of the cerebrum. Glutathione depletion and changes in proteins containing SH base as a critical site might be the underlying neurotoxic mechanism of 1-bromopropane. The biochemical changes in the cerebrum indicate that long-term exposure to 1-bromopropane has effects on the CNS.
    NeuroToxicology 04/2003; 24(2):199-206. · 2.65 Impact Factor
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    ABSTRACT: Although 1-bromopropane has been used in chemical and electronic industries as an alternative to ozone layer-depleting solvents, its toxicity on female reproductive organs has not been fully elucidated. The aim of this experiment was to determine the effect of 1-bromopropane on female reproductive function in rats. Forty female Wistar rats were divided into four equal groups. Each group was exposed daily to 0, 200, 400, or 800 ppm of 1-bromopropane for eight h a day. After exposure for 7 weeks, all rats in the 800-ppm group became seriously ill and were sacrificed during the 8th week. The other dose groups were exposed for 12 weeks. In the 800-ppm group, but not in the other two exposed groups, body weight was significantly less than the control at each time point from 2 to 7 weeks after the beginning of exposure. Tests of vaginal smears showed a significant increase in the number of irregular estrous cycles with extended diestrus in the 400- and 800-ppm groups. Histopathological examination of the ovary showed a significant dose-dependent reduction of the number of normal antral follicles and a decrease in the number of normal growing follicles in the 400-ppm group. No significant change was found in plasma concentrations of LH or FSH in any group when compared with the control. Our results indicate that 1-bromopropane can induce a dose-dependent ovarian dysfunction in nonpregnant female rats associated with disruption in follicular growth process.
    Toxicological Sciences 02/2003; 71(1):96-103. · 4.33 Impact Factor
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    ABSTRACT: 1-Bromopropane is used widely as an alternative to ozone-depleting solvents. The neurotoxic effects of this agent have been described in humans and experimental animals. Here we investigated the underlying mechanisms of the neurotoxic effects of 1-bromopropane by examining the initial biochemical changes in the central nervous system. Four groups of 9 Wistar male rats each were exposed to 200, 400, or 800 ppm 1-bromopropane or only fresh air, 8 h per day for 7 days. At the end of the experiment, the cerebrum, cerebellum, brain stem and lumbar enlargement of the spinal cord were dissected out from each rat (n = 8) for biochemical analyses. Morphological examinations of the nervous system were performed in the remaining rat of each group. 1-Bromopropane dose-dependently decreased neurospecific gamma-enolase, total glutathione, and nonprotein sulfhydryl groups in the cerebrum and cerebellum. Creatine kinase activity decreased dose-dependently in the brain and spinal cord. Histopathological examination showed swelling of preterminal axons in gracile nucleus and degeneration of myelin in peripheral nerves. Our results of low levels of gamma-enolase suggested that 1-bromopropane might primarily cause functional or cellular loss of neurons in the cerebrum and cerebellum. Glutathione depletion or modification to functional proteins containing a sulfhydryl base as a critical site might be the underlying mechanism of 1-bromopropane neurotoxicity.
    Toxicological Sciences 06/2002; 67(1):114-20. · 4.33 Impact Factor

Publication Stats

320 Citations
55.55 Total Impact Points

Institutions

  • 2013
    • Nagoya City University
      Nagoya, Aichi, Japan
  • 2003–2013
    • University of Occupational and Environmental Health
      • Department of Occupational and Environmental Health
      Kitakyūshū, Fukuoka, Japan
  • 2002–2008
    • Nagoya University
      • • Department of Occupational and Environmental Health
      • • Division of Social Life Science
      Nagoya, Aichi, Japan