| ObjectiveThe 1-bromopropane(1-BP)is a liquid bromide with a strong smell and non-coloring to a light yellow color.It has been identified as one of the main substitute chemicals for ozone-depleting solvents on account of its non-destructive properties to the atmospheric ozone layer,and is widely used as the cleaning agents of precision instrument,spray adhesives and degreasing agents,China has become one of the major 1-BP producers in the world currently.Only in one year of 2008 the national production has reached 20,000 tons.As its production and usage increasing with the time past,the numbers of workers exposed to 1-BP are increasing accordingly,and more attention has been paid to the health hazards induced by 1-BP.Occupational exposure to 1-BP mainly affects the nervous and reproductive systems and the liver.Neurotoxicity is one of the most serious adverse effects induced by 1-BP.The group of biomarkers including exposure,effect and susceptibility markers not only reveals the process and path of 1-BP health injury,but also advances the time nodes of prevention and intervention.This project studied on both the animal experiments and the epidemiological survey of occupational population.The signs of poisoning,changing of specific indexes(Neuron Specific Enolase,NSE;S-100βproteinS-100β,Cyclooxygenase-2,COX-2)of nerve injury in cerebral cortex and serum,the contact signs changes in urine such as 1-BP prototype and N-Acetyl-S-(n-Propyl)-L-Cysteine(AcPrCys)were observed in Wistar male rats exposed to 1-BP.On the basis of the results of the animal experiments,the population research was carried out.The representative 1-BP production and using companies were chosen for the epidemiological study,which included current epidemiological investigation,detection of 1-BP exposure concentration in the workshops and measurement of the specific indexes of nerve injury and the contact signs changes in the urine.Based on the results obtained,the analysis of the trends of the same indicators in both the experimental animals and occupational exposure populations were performed to provide the possible clues for the exposure and effect biomarkers of 1-BP.Methods1.Experimental animal research:Fifty-four Wistar male rats were randomly divided into the 0(control group),500 and the 1000ppm 1-BP treatment group,18 rats were in each group.The three groups of rats were exposed to 1-BP in inhalation with nose-only exposure system for 6h/d(8:00am-2:00pm)for 21 days.The concentrations of 1-BP were monitored at three time points(10:00 am,12:00 am and 2:00 pm)every day.Rats were weighed and recorded every other day after the start of the experiment.After exposure to 1-BP for 7,14 and 21 days,six rats were sacrificed at each time point,the brain tissue,blood(separating serum)and urine were collected using metabolism cage on the day before the death.Two of six rats were chosen to separate the brain,hypophysis,spinal cord,ischiadic nerve and tibiofibular nerve tissues for histopathological examination.Changes of NSE,S-100β and COX-2 in the rat cerebral cortex and serum were measured by ELISA kits.Changes of 1-BP and AcPrCys in rat urine were measured by GC-MS and LC-MS/MS methods.2.Epidemiological investigation:There was an epidemiological survey on three 1-BP production enterprises and three 1-BP use enterprises and the total number of 1-BP exposure people was 71.The subjects working in the fields of food,clothing and other non-chemical contact industry were chosen as the control population.The total number of control workers was 71.The technical process of the production data,the concentrations of both 1-BP exposed individuals and the environments were collected.The questionnaire survey on exposure and control group was performed to contain information about basic situation,occupation history and health status.Blood(separating serum)and urine were collected,as well as neurobehavioral manifestation was observed for the exposure group.Results1.Construction of 1-BP induced nerve injury model in rats:After 21 days exposure,the weight of rats treated with 500 and 1000ppm 1-BP were decreased significantly compared with the control group(P<0.05).The main adverse effect in the histopathological examination included cerebellar local Purkinje cell atrophy,lumbar gray matter vacuolar degeneration,tibiofibular nerve fibers swelling and thickening.2.Effects of 1-BP on the typical biomarkers of effect on nerve injury in rats:a)NSE:After exposure to 1000ppm 1-BP from 1 to 3 weeks,NSE was increased significantly compared with the control and 500ppm group in the cerebral cortex of the rats(P<0.05).NSE was increased significantly on the 7th,14th and 21th days in the 500ppm group,compared with the control and 1000ppm group in the serum(P<0.05);b)S-100β:After exposure to 1000ppm 1-BP from 1 to 3 weeks,S-100β was increased significantly compared with the control and 500ppm group in the cerebral cortex of the rats(P<0.05).S-100β was increased significantly in the serum on the 21th days in the 1000ppm group,compared with the control and 500ppm group(P<0.05);c)COX-2:After exposure to 500 and 1000ppm 1-BP from 1 to 3 weeks,COX-2 was increased significantly compared with the control group in the cerebral cortex of the rats(P<0.05).COX-2 was increased significantly in the cerebral cortex on the 14th and 21th days in the 500ppm group compared with the 1000ppm group(P<0.05).COX-2 was increased significantly in the serum on the 14th days in the 500ppm group,compared with the control group(P<0.05).COX-2 was increased significantly in the serum on the 7th and 14th days in the 1000ppm group,compared with the control group(P<0.05).A correlation between the changes of COX-2 in the cerebral cortex and serum was found3.Screening the biomarker of exposure on 1-BP through the detection of urine 1-BP prototype and metabolite AcPrCys,both of them were the contact signs of 1-BP in the urine.There was a correlation between the changes of NSE and COX-2 in the serum and AcPrCys in the urine was found.4.Epidemiological investigation:There was no significant difference in NSE,S-100βand COX-2 between the occupational exposure group and the control group.The exposure concentration of 1-BP in the use enterprises was generally higher than that of the production enterprises,and especially some superindex of exposure concentration was found in the use enterprises.The negative emotional score and the total score of mind in the use enterprises were generally higher than that of the production enterprises(P<0.05).1-BP was detected in some of urine samples and AcPrCys was detected in all urine samples,but none of them were detected in the control group.AcPrCys has a good correlation with the exposure concentration and might be used as a 1-BP occupational exposure biomarker.Conclusion1.Comprehensive analysis the results of NSE,S-100β and COX-2 in the cerebral cortex and serum of rats and the results of histopathological examination,it can be preliminary determined that 1-BP induced subacute nerve injury in the experimental rats.There was a correlation between cerebral cortex and serum on COX-2.2.The changes of NSE,S-100β and COX-2 in occupational exposure group were not significant and none association was found with the health hazard in the 1-BP exposed population.3.The 1-BP prototypes and the metabolites AcPrCys were detected in the urine of both experimental and occupational exposure groups,and a good correlation between AcPrCys and exposure concentration was found.The results suggested that AcPrCys was more suitable as a 1-BP exposure biomarker than the 1-BP prototype. |
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