Hailan Wang

A survey of semen indices in insecticide sprayers.

A Survey of Semen Indices in Insecticide Sprayers: Michihiro Kamijima, et al. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine—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.

Species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) in several organs of mice, rats, and marmosets

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 α involved in different toxic processes, a possibly major difference in MEHP-formation capacity could be also considered on extrapolation from rodents to humans.

Neurologic Abnormalities in Workers of a 1-Bromopropane Factory

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.

Dose-Dependent Biochemical Changes in Rat Central Nervous System after 12-Week Exposure to 1-Bromopropane

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.

Characterization of Liver Injury Associated with Hypersensitive Skin Reactions Induced by Trichloroethylene in the Guinea Pig Maximization Test

Characterization of Liver Injury Associated with Hypersensitive Skin Reactions Induced by Trichloroethylene in the Guinea Pig Maximization Test: Xiaojiang Tang, et al. Guangdong Poison Control Center, China—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 γ‐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.

Dose-dependent neurologic abnormalities in workers exposed to 1-bromopropane.

Objectives: To investigate the health effects of 1-bromopropane (1-BP) and its dose-dependency in 1-BP production factories in China. Methods: 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. Results: 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. Conclusions: The results indicate that exposure to 1-BP induces dose-dependent neurotoxicity in female workers.

Occupational trichloroethylene hypersensitivity syndrome: Human herpesvirus 6 reactivation and rash phenotypes

BACKGROUND 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). OBJECTIVE This study aimed to clarify HHV6 status, cytokine profiles and their association with rash phenotypes in patients with TCE hypersensitivity syndrome. METHODS 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. RESULTS 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). CONCLUSION 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.

iTRAQ-based proteomic profiling of human serum reveals down-regulation of platelet basic protein and apolipoprotein B100 in patients with hematotoxicity induced by chronic occupational benzene exposure

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.

Sex Differences in Metabolism of Trichloroethylene and Trichloroethanol in Guinea Pigs

Sex Differences in Metabolism of Trichloroethylene and Trichloroethanol in Guinea Pigs: Yui HIBINO, et al. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine—

Exposure reconstruction of trichloroethylene among patients with occupational trichloroethylene hypersensitivity syndrome

Occupational trichloroethylene (TCE) exposure can induce life-threatening generalized dermatitis accompanied by hepatitis: TCE hypersensitivity syndrome (HS). Since the patients’ exposure levels have not been fully clarified, this study estimated end-of-shift urinary concentrations of trichloroacetic acid (TCA) and their lower limit below which the disease occurrence was rare. TCA concentration was measured in 78 TCE HS patients whose urine was collected at admission between 2nd and 14th d after their last shift. Then a linear regression model was used to calculate the mean TCA concentration with 95% confidence interval (95% CI) and 95% prediction interval (95% PI) in the end-of-shift urine. The estimated mean concentration was 83 (95% CI, 49–140) mg/l with 95% PI 9.6–720 mg/l. TCA concentrations were also measured in the end-of-shift urine of 38 healthy workers involved in the same job as were the patients. The geometric mean and its 95% CI were 127 mg/l and 16–984 mg/l, respectively. The exposure levels in HS patients might have thus overlapped with those in workers without HS. Accordingly, it was suggested that HS occurred in the environment where the workers were exposed to the TCE concentration corresponding to the urinary TCA concentration as low as 10 mg/l.