OBJECTIVE To develop and validate a physiologically based toxicokinetics and toxico?dynamics(PBTK/TD)model for chlorpyrifos(CPF)in rats following both oral and subcutaneous expo?sures to CPF. METHODS ①A PBTK/TD model was established with toxicokinetics and toxicodynam?ics data in literature,which was used for predicting contents of CPF and 3,5,6-trichloro-2-pyridinol (TCP)in blood and activities of acetylcholine esterase(AChE)in the plasma and brain of rats exposed to CPF.②Rats were given 50 mg · kg-1 CPF oral and 50 mg · kg-1 CPF sc simultaneously. Blood and brain samples were collected at 0,1,2,4,6,8,12,24 and 48 h,respectively,after CPF administration (n=5). CPF And TCP contents in plasma,activities of AChE in the plasma and brain were deter?mined,and compared with the simulation values by PBTK/TD model in order to validate the accuracy of the model. RESULTS It was predicted by the PBTK/TD model that after the administration (oral+sc) of CPF 20+20,10+30 and (30+10)mg · kg-1,the concentrations of CPF and TCP in plasma increased and then decreased with time in each group. The inhibitory level of AChE activity in the plasma was orally dose-dependent,while AChE activity of the brain was more sensitive to CPF subcutaneous exposure. The simulation values obtained by the PBTK/TD model were not significantly different from the experimental values obtained by co-administered CPF at(50+50)mg · kg-1. CONCLUSION This CPF PBTK/TD model can quantitatively estimate target tissue dosimetry and AChE inhibition.

Objective To evaluate the role of transient receptor potential channel 8 (TRPM8) in the development and maintenance of neuropathic pain and the relationship with nuclear factor kappa B (NF-κB) in the dorsal root ganglion of rats.Methods Thirty-six pathogen-free healthy adult male SpragueDawley rats,weighing 180-200 g,aged 6-8 weeks,were divided into 3 groups (n=12 each) using a random number table:sham opeation group (group S),neuropathic pain group (group NP) and TRPM8 bocker BCTC group (group BCTC).Neuropathic pain was induced by ligation of the right sciatic nerve in anesthetized rats.BCTC 20 nmol was intrathecally injected once a day on preoperative day 1 and postoperative days 1,3,7 and 10 in group BCTC.The thermal,mechanical and cold pain thresholds were measured on preoperative day 1 and postoperative days 1,3,7,10 and 14.The dorsal root ganglions of the lumbar segment (L4-6) were removed on postoperative days 7 and 14 for determination of the expression of TRPM8 and NF-κB p65 by Western blot.Results Compared with group S,the thermal and mechanical thresholds were significantly decreased on postoperative days 1-14,and the cold pain threshold was decreased on postoperative days 3-14 in NP and BCTC groups,the expression of TRPM8 and NF-κB p65 in dorsal root ganglions was up-regulated on postoperative days 7 and 14 in group NP (P＜0.05),and no significant change was found in the expression of TRPM8 and NF-κB p65 in dorsal root ganglions in group BCTC (P＞0.05).Compared with group NP,the thermal pain threshold was significantly decreased and the cold pain threshold was increased on postoperative days 3-14,the expression of TRPM8 and NF-κB p65 in dorsal root ganglions was up-regulated on postoperative days 7 and 14,and no significant change was found in the mechanical pain threshold in group BCTC (P＞0.05).Conclusion NF-κB activation after opening of TR-PM8 in dorsal root ganglion neurons is involved in the development and maintenance of neuropathie pain in rats.

Objective To evaluate the role of P2X3 receptors in the development and mnaintenance of neuropathic pain (NP) and the relationship with nuclear factor kappa B (NF-κB) in dorsal root ganglia of rats.Methods Thirty-six SPF healthy male Sprague-Dawley rats,weighing 180-200 g,aged 4-6 weeks,in which intrathecal catheters were successfully implanted,were divided into 3 groups (n =12 each) using a random number table:sham operation group (group S),NP group and P2X3 receptor antagonist A-317491 group (group A).At 3 days after intrathecal catheters were successfully implanted,NP was induced by chronic constriction injury to the sciatic nerve.The sciatic nerve was only exposed but not occluded in group S.Intrathecal injection was performed twice a day for 14 consecutive days starting from 1 day after operation.Normal saline 20 μ l was intrathecally injected in group S and group NP,and A-317491 100 nmol/10 μ1 and normal saline 10 μ l were intrathecally injected in group A.Thermal paw withdrawal threshold (TWT) and mechanical paw withdrawal threshold (MWT) were measured on day 1 before operation and at 30 min after intrathecal injection on days 1,3,7,10 and 14 after operation.On days 7 and 14 after operation,the rats were sacrificed and the dorsal root ganglia of the lumbar segment were removed for determination of the expression of P2X3 receptors and NF-κB p65 by Western blot.Results Compared with group S,TWT and MWT were significantly decreased at each time point after operation,and thc expression of P2X3 receptors andi NF-κB p65 in dorsal root ganglia was up-regulated on days 7 and [4 after operation in group NP (P＜0.05 or 0.01).Compared with group NP,TWT was significantly increased at each time point after operation,MWT was increased on days 3,7,10 and 14 after operation,anl the expression of P2X3 receptors and NF-κB p65 in dorsal root ganglia was down-regulated on days 7 and 14 after operation in group A (P＜0.05).Conclusion The mechanism underlying the development and maintenance of NP is related to the up-regulation of P2X3 receptor expression and promotion of the expression of NF-κB in dorsal root ganglia of rats.

OBJECTIVE Calculate the dietary exposure and exposure risk of Chinese consumers to acephate,using the margin of exposure method.METHODS Determine the bench mark dose of acephate by 21 -day gavage experiment of rats.According to the data from the 2002 National Diet and Nutrition Survey,the 2000 -2006 national food conta mination monitoring program,the 2005 -2006 export monitoring data of customs,calculate the dietary exposure of Chinese consumers to acephate by probabilistic assessment.Estimate the exposure risk by co mparing the margin of exposure with 100. RESULTS The bench mark dose of acephate was 0.75 mg·kg -1 ,the BMDL was 0.51 mg·kg -1 .The exposure of children was higher than that of adults.The proportion at risk of group 1 -6 y,7 -17 y and 18 y or higher was 5%,1 % and 0.1 %,respectively.CONCLUSION So me consumers was of dietary exposure risk to acephate.The high exposure of children should be of great concern.