Application of Benchmark Dose (BMD) in Estimating Biological Exposure Limit (BEL) to Cadmium

Objective To estimate the biological exposure limit （BEL） using benchmark dose （BMD） based on two sets of data from occupational epidemiology. Methods Cadmium-exposed workers were selected from a cadmium smelting factory and a zinc product factory. Doctors, nurses or shop assistants living in the same area served as a control group. Urinary cadmium （UCd） was used as an exposure biomarker and urinary D2-microgloburin （B2M）, N-acetyl-D-D-glucosaminidase （NAG） and albumin （ALB） as effect biomarkers. All urine parameters were adjusted by urinary creatinine. Software of BMDS （Version 1.3.2, EPA.U.S.A） was used to calculate BMD. Results The cut-off point （abnormal values） was determined based on the upper limit of 95% of effect biomarkers in control group. There was a significant dose response relationship between the effect biomarkers （urinary B2M, NAG9 and ALB） and exposure biomarker （UCd）. BEL value was 5 μg/g creatinine for UB2M as an effect biomarker, consistent with the recommendation of WHO. BEL could be estimated by using the method of BMD. BEL value was 3 μg/g creafinine for UNAG as an effect biomarker. The more sensitive the used biomarker is, the more occupational population will be protected. Conclusion BMD can be used in estimating the biological exposure limit （BEL）. UNAG is a sensitive biomarker for estimating BEL after cadmium exposure.

Benchmark Dose Assessment for Coke Oven Emissions-Induced Mitochondrial DNA Copy Number Damage Effects

Objective The study aimed to estimate the benchmark dose(BMD)of coke oven emissions(COEs)exposure based on mitochondrial damage with the mitochondrial DNA copy number(mtDNAcn)as a biomarker.Methods A total of 782 subjects were recruited,including 238 controls and 544 exposed workers.The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction.Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95%confidence lower limit(BMDL).Results The mtDNAcn of the exposure group was lower than that of the control group(0.60±0.29 vs.1.03±0.31;P<0.001).A dose-response relationship was shown between the mtDNAcn damage and COEs.Using the Benchmark Dose Software,the occupational exposure limits(OELs)for COEs exposure in males was 0.00190 mg/m^(3).The OELs for COEs exposure using the BBMD were 0.00170 mg/m^(3)for the total population,0.00158 mg/m^(3)for males,and 0.00174 mg/m^(3)for females.In possible risk obtained from animal studies(PROAST),the OELs of the total population,males,and females were 0.00184,0.00178,and 0.00192 mg/m^(3),respectively.Conclusion Based on our conservative estimate,the BMDL of mitochondrial damage caused by COEs is0.002 mg/m^(3).This value will provide a benchmark for determining possible OELs.

Benchmark Dose Estimation for Cadmium-Induced Renal Effects Based on a Large Sample Population from Five Chinese Provinces

A survey involving 6103 participants from five Chinese provinces was conducted to evaluate the threshold value of urinary cadmium （UCd） for renal dysfunction as benchmark dose low （BMDL）. The urinary N-acetyl-13-D-glucosaminidase （UNAG） was chosen as an effect biomarker. The UCd BMDLs for UNAG ranged from 2.18μg/g creatinine （cr） to 4.26μg/g cr in the populations of different provinces. The selection of the sample population and area affect the evaluation of the BMDL. The reference level of UCd for renal effects was further evaluated based on the data of all 6103 subjects. With benchmark responses （BMR） of 10%/5%, the overall UCd BMDLs for males in the total population were 3.73/2.08 μg/g cr. The BMD was slightly lower in females, thereby indicating that females may be relatively more sensitive to Cd exposure than are males.

Development of A Reference Dose for BDE-47,99,and 209 Using Benchmark Dose Methods

Eleven recently completed toxicological studies were critically reviewed to identify toxicologically significant endpoints and dose-response information. Dose-response data were compiled and entered into the USEPA＇s benchmark dose software （BMDS） for calculation of a benchmark dose （BMD） and a benchmark dose low （BMDL）. After assessing 91 endpoints across the nine studies, a total of 23 of these endpoints were identified for BMD modeling, and BMDL estimates corresponding to various dose-response models were compiled for these separate endpoints. Thyroid, neurobehavior and reproductive endpoints for BDE-47, -99, -209 were quantitatively evaluated. According to methods and feature of each study, different uncertainty factor （UF） value was decided and subsequently reference doses （RfDs） were proposed. Consistent with USEPA, the lowest BMDLs of 2.10, 81.77, and 1698 I^g/kg were used to develop RfDs for BDE-47, -99, and -209, respectively. RfDs for BDE-99 and BDE-209 were comparable to EPA results, and however, RfD of BDE-47 was much lower than that of EPA, which may result from that reproductive/developmental proves to be more sensitive than neurobehavior for BDE-47 and the principal study uses very-low-dose exposure.

Benchmark Dose for Dioxin Based on Gestational Diabetes Mellitus Using Coexposure Statistical Methods and an Optimized Physiologically Based Toxicokinetic Model

Dioxins are ubiquitous endocrine-disrupting substances,but determining the effects and benchmark doses in situations of coexposure is highly challenging.The objective of this study was to assess the relationship between dioxin andgestational diabetes mellitus(GDM),calculate the benchmark dose(BMD)of dioxin in coexposure scenarios,and derive a daily exposure threshold using an optimized physiologically based toxicokinetic(PBTK)model.Based on a nested casecontrol study including 77 cases with GDM and 154 controls,serum levels of 29 dioxin-like compounds(DLCs)along with 10 perfluoroalkyl acids(PFAAs),seven polybrominated diphenyl ethers(PBDEs),and five non-dioxin-like polychlorinated biphenyls(ndl-PCBs)were measured at 9−16 weeks of gestation.Bayesian machine kernel regression(BKMR)was employed to identify significant chemicals,and probit and logistic models were used to calculate BMD adjusted for significant chemicals.A physiologically based toxicokinetic(PBTK)model was optimized using polyfluorinated dibenzo-p-dioxins and dibenzofurans(PFDD/Fs)data by the Bayesian−Monte Carlo Markov chain method and was used to determine the daily dietary exposure threshold.The median serum level of total dioxin toxic equivalent(TEQ)was 7.72 pg TEQ/g fat.Logistic regression analysis revealed that individuals in the fifth quantile of total TEQ level had significantly higher odds of developing GDM compared to those in the first quantile(OR,8.87;95%CI 3.19,27.58).The BKMR analysis identified dioxin TEQ and BDE-153 as the compounds with the greatest influence.The binary logistic and probit models showed that the BMD10(benchmark dose corresponding to a 10%extra risk)and BMDL_(10)(lower bound on the BMD_(10))were 3.71 and 3.46 pg TEQ/g fat,respectively,when accounting for coexposure to BDE-153 up to the 80%level.Using the optimized PBTK model and modifying factor,it was estimated that daily exposure should be below 4.34 pg TEQ kg^(−1)bw week^(−1)in order to not reach a harmful serum concentration for GDM.Further studies should utilize coexposure statistical methods and physiologically based pharmacokinetic(PBTK)models in reference dose calculation.

基于基准剂量方法的动物替代策略及其应用

剂量-反应评估作为风险评估中的关键定量步骤,其作用是确定安全剂量水平。与传统最大无害剂量方法相比,基准剂量(BMD)法促进了3R原则(减少、替代和优化)在毒理试验中的使用。本文综述了BMD法特性,包括对研究设计的依赖性较小、在起始点中更好地量化不确定性及整合额外信息能力等;总结了BMD法基于剂量-反应评估和数据整合在减少动物使用方面的作用。

Subchronic Oral Toxicity Evaluation of Lanthanum： A 90-day, Repeated Dose Study in Rats

Objective The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level（NOAEL）,which is a critical factor in the establishment of an acceptable dietary intake（ADI）.Methods In accordance with the Organization for Economic Co-operation and Development（OECD） testing guidelines,lanthanum nitrate was administered once daily by gavage to Sprague-Dawley（SD） rats at dose levels of 0,1.5,6.0,24.0,and 144.0 mg/kg body weight（BW） per day for 90 days,followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups.Outcome parameters were mortality,clinical symptoms,body and organ weights,serum chemistry,and food consumption,as well as ophthalmic,urinary,hematologic,and histopathologic indicators.The benchmark dose（BMD） approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum.Results Significant decreases were found in the 144.0 mg/kg BW group in the growth index,including body weight,organ weights,and food consumption.This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day.Importantly,the 95% lower confidence value of the benchmark dose（BMDL） was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males.Conclusion The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements（REEs）.

Subchronic Oral Toxicity Evaluation of Sodium Dehydroacetate: A 90-day Repeated Dose Study in Rats

Objective The present study was undertaken to evaluate the subchronic oral toxicity of sodium dehydroacetate(DHA-Na)and to determine the point of departure(POD),which is a critical factor in the establishment of an acceptable dietary intake.Methods DHA-Na was administered once daily by gavage to Sprague–Dawley rats at dose levels of 0.0,31.0,62.0,and 124.0 mg/kg BW per day for 90 days,followed by a recovery period of 4 weeks in the control and 124.0 mg/kg BW per day groups.The outcome parameters were mortality,clinical observations,body weights,food consumption,hematology and clinical biochemistry,endocrine hormone levels,and ophthalmic,urinary,and histopathologic indicators.The benchmark dose(BMD)approach was applied to estimate the POD.Results Significant decreases were found in the 62.0 and 124.0 mg/kg BW groups in terms of the body weight and food utilization rate,whereas a significant increase was found in the thyroid stimulating hormone levels of the 124.0 mg/kg BW group.Importantly,the 95%lower confidence limit on the BMD of 51.7 mg/kg BW was modeled for a reduction in body weight.Conclusion The repeated-dose study indicated the slight systemic toxicity of DHA-Na at certain levels(62.0 and 124.0 mg/kg BW)after a 90-day oral exposure.

磷酸三苯酯经口参考剂量(RfD)的推导

磷酸三苯酯(TPHP)是一种有机磷酸酯阻燃剂,作为溴系阻燃剂的替代品被大量生产和使用,近年来在环境及生物体中频繁被检出。已有研究表明TPHP主要经口暴露,引起人体不良健康结局。目前国际上还缺乏非致癌经口暴露参考剂量(RfD),严重制约了TPHP的环境健康风险评估工作。该文综合现有文献报道,提取相关剂量效应数据,为TPHP开发了非致癌经口参考剂量(RfD)。现有TPHP流行病学、毒理学等相关研究表明,大鼠/小鼠经口暴露于TPHP产生的毒性效应包括肾脏毒性、肝脏毒性、神经毒性、内分泌毒性、发育毒性以及生殖毒性。针对不同毒性效应,使用贝叶斯BMD在线系统(BBMD)从哺乳动物毒性研究中得出相应起算点(POD),依据保守性原则,关键效应为10周龄雄性后代小鼠体重增加,POD为0.01 mg/(kg·d)。总不确定系数为1000,包括种间(10)、种内(10)、亚慢性外推至慢性毒性(3)和完整数据库(3),最终推导得出TPHP的参考剂量RfD为1×10^(-5)mg/(kg·d)。该文阐明了TPHP毒性文献收集、危害识别、剂量效应建模和RfD推导的详细过程,为环境污染物人体健康毒性参数推导提供具体可操作的规范指导,获得的RfD值可为TPHP的环境健康风险评估管理提供重要信息。

BIC与MCMC基准剂量估计模型的比较研究

目的比较BIC估计法与MCMC近似法两种后验概率法在贝叶斯基准剂量估计中的稳健性,并为山西省洪洞县儿童羟基代谢物可接受剂量的制定提供参考建议。方法首先介绍基于BIC估计法和MCMC近似法计算后验权重的原理,模拟研究选用Integrated Risk Information System数据库中不同剂量-反应数据集共30个,分析比较两种方法的优劣,并在实例研究中采用权重法进行数据整合。结果模拟研究结果显示在所研究的30个数据集中BIC估计法在BMR为0.01时有4个数据集出现BMDL预测失败的情况,在BMR为0.001时有1个数据集出现BMD预测失败的情况,以及6个数据集出现BMDL预测失败的情况。MCMC近似法计算的BMD/BMDL在每一种模型都有70%以上的数据集高于BIC估计法得到的BMD/BMDL。实例分析表明符合洪洞县儿童体内羟基代谢物剂量-反应关系的模型有linear(P=0.13,β=14.3%)、logistic(P=0.06,β=9.5%)、Weibull(P=0.14,β=10.6%)、multistage(P=0.15,β=31.1%)、Hill(P=0.21,β=34.6%)。在BMR为0.001的情况下,洪洞县儿童体内八种羟基代谢物(2-OHN、1-OHN、9-OHF、2-OHF、2-OHphe、1-OHphe、1-OHBaP、3-OHBaP)的可接受剂量(μmol/mol)依次为0.577μmol/mol、1.546μmol/mol、8.135μmol/mol、0.359μmol/mol、0.120μmol/mol、0.098μmol/mol、0.044μmol/mol、0.003μmol/mol。结论MCMC近似法在BMD估计中具有较好的稳定性和鲁棒性。

基准剂量在氟接触人群骨效应评价中的应用

[目的]将基准剂量(BMD)法应用于氟接触人群,通过比较,寻找有意义的监测氟对人群骨骼损伤的指标。[方法]测定氟中毒病区人群的骨密度及尿氟(UF)、尿肌酐(UCr)、尿羟脯氨酸(HYP)、血氟(BF)、血清中骨钙素(BGP)、碱性磷酸酶(AKP)、骨特异性碱性磷酸酶(BAKP)等指标并计算Z评分(Zscore),计算各效应指标的尿氟基准剂量下限(BMDL)值。[结果]与对照组比,氟接触组的UF、BF、BGP、HYP、BAKP及骨密度差异均有显著性,P<0.05。按尿氟分组后,骨密度随尿氟浓度的升高而逐渐降低,尿氟最高组骨密度显著低于最低组,P<0.01;而各组BGP、HYP水平与最低组比显著上升,P<0.01。AKP与BAKP的变化趋势不明显。BGP、HYP、Zscore、BAKP、AKP的尿氟BMDL值分别为0.31、2.75、4.36、4.06及5.09mg/L。[结论]内剂量能更好地反映人群对氟的接触水平。通过各指标尿氟BMDL值的相互比较,本研究认为Zscore是相对特异而敏感地反映氟接触人群骨损伤的效应指标,而BGP与HYP可作为十分敏感的氟接触高危人群的筛选指标。

应用基准剂量法探讨氯蜱硫磷的参考剂量

目的应用基准剂量(BMD)法探讨氯蜱硫磷(毒死蜱)的参考剂量。方法 80只清洁级成年雌性SD大鼠,ig给予氯蜱硫磷0.25,0.5,1,2,4,8和16 mg.kg-1,每天1次,连续21 d。21 d后处死大鼠测定大鼠大脑皮质、海马和血清中乙酰胆碱酯酶(AChE)活性,观察氯蜱硫磷的未观察到损害作用剂量。采用R语言的PROAST28.1软件包计算BMD及其下限值,将BMD下限值除以安全系数100得到氯蜱硫磷的参考剂量。结果 与正常对照组相比,氯蜱硫磷4,8和16 mg.kg-1使大鼠海马中AChE活性明显降低(P<0.01);氯蜱硫磷2,4,8和16 mg.kg-1使大鼠皮质中AChE活性明显降低(P<0.01);而氯蜱硫磷1,2,4,8和16 mg.kg-1使大鼠血清中AChE活性明显降低(P<0.01)。随着氯蜱硫磷染毒剂量的增加,大鼠海马、皮质和血清中的AChE活性表现出下降趋势。以AChE活性作为指标,海马、皮质和血清中氯蜱硫磷的未观察到损害作用剂量分别为低于2.0,1.0,0.5 mg.kg-1的剂量,BMD分别为0.81,0.90和0.41 mg.kg-1,参考剂量分别为5.5,4.6和3.6μg.kg-1;为人类膳食安全,将氯蜱硫磷的参考剂量定为3.6μg.kg-1。结论 BMD法可制定比未观察到损害作用剂量法更加安全的参考剂量,并可以进一步应用于膳食暴露风险评估。

儿童尿氟的基准剂量及其与氟斑牙相关关系的研究

目的 探讨尿氟的基准剂量及其在地方性氟中毒防治中的应用。方法 选择江苏省某县瓦庙村(地方性氟中毒重病区村)和新淮村(非病区村)的所有在校8～13岁儿童为调查对象,根据儿童尿氟含量及肌酐校正后的尿氟含量把两村儿童分为不同的接触组,即:尿氟含量<1.0 0mg/L(A组)、1.0 0～mg/L(B组)、2 .0 0～mg/L(C组)、3 .0 0～mg/L(D组)、4.0 0～mg/L(E组)、5 .0 0～mg/L(F组)及 6.0 0mg/L(G组)共7组和肌酐校正后的尿氟含量<0 .2 0mg/mmolCr(A1组)、0 .2 0～mg/mmolCr(B1组)、0 .40～mg/mmolCr(C1组)、0 .60～mg/mmolCr(D1组)、及 0 .80mg/mmolCr(E1组)共5组,分别统计各组儿童的氟斑牙和缺损型氟斑牙的患病率及氟斑牙指数。结果 随着儿童尿氟及肌酐校正后尿氟含量的增加儿童氟斑牙患病率和缺损型氟斑牙患病率逐渐增加,呈显著的剂量-反应关系。根据尿氟含量及肌酐校正后尿氟含量与儿童氟斑牙及缺损型氟斑牙患病率的剂量-反应关系计算的尿氟含量和肌酐校正后尿氟含量的BMDL分别为:1.5 5、1.88mg/L和0 .43、0 .49mg/mmolCr。由此计算的儿童尿氟和肌酐校正后尿氟含量的参考剂量(RfD ,Refer enceDose)分别为:1.5 5、1.88mg/L和0 .43、0 .49mg/mmolCr。结论 根据本次调查结果并结合同类研究成果,建议8～13岁非病区儿?

慢性铅接触者肾损害早期监测指标的研究

[目的]估算引起肾功能损害的血铅的基准剂量 (BMD)和基准剂量可信区间下限 (LBMD) ,探索铅接触引起肾损害的生物接触限值。[方法]选择某蓄电池厂的工人135名为铅接触组 ,以机械工人和学生为对照。观察了血铅含量与尿总蛋白 (TP)、尿β2_微球蛋白 ( β2_MG)和尿N_乙酰_β_D_氨基葡萄糖苷酶 (NAG)的关系。用BMDSVersion1.3.1软件的logis tic模型进行基准剂量估算。[结果]引起肾损害的血铅BMD和LBMD分别为299.4～588.7μg/L和253.4～402.3μg/L,引起肾损害血铅LBMD大小依次为TP、β2_MG和NAG。[结论]尿NAG是监测肾功能损害最敏感的指标 。

基准剂量法在咪鲜胺锰盐亚慢性毒性研究中的应用

[目的 ]应用基准剂量法分析咪鲜胺锰盐 (tetrakis[N propyl N [2 ( 2 ,4,6 trichlorophenoxy)ethyl]imiazole 1 car boxamide]manganese(Ⅱ )chloridecomplex)原药亚慢性毒性试验结果 ,估算其基准剂量。 [方法 ]SD大鼠咪鲜胺锰盐亚慢性喂饲毒性试验 ( 90d) ,设对照、低、中、高剂量组 ( 0、111、3 3 3、10 0 0mg/kg饲料 )。观察指标有 :大鼠中毒症状及死亡情况、体重及摄食量变化、血液常规和生化及病理组织学变化。基准剂量计算采用EPA的BMDS软件。 [结果 ]雄性大鼠高剂量组肝体比、肾体比、睾体比及中剂量组肾体比 ,与对照组相比 ,差异有统计学意义 ;雌性大鼠高剂量组肝体比、肾体比及中剂量组肝体比 ,与对照组相比 ,差异有统计学意义 ;中、高剂量组少数动物出现肝脏、肾脏炎症小灶 ;低剂量组雌、雄性大鼠均未见明显异常。 [结论 ]咪鲜胺锰盐原药的无明显损害剂量 (NOAEL)雌、雄均为 111mg/kg饲料 ,按每日每千克体重摄入量计算 ,雌、雄大鼠NOAEL分别为 ( 9.0 7± 0 .2 7)、( 10 .3 2± 0 .66)mg/(kg·d)。咪鲜胺锰盐原药的基准剂量的 95 %可信限下限 (BMDL)值 ,雌、雄性大鼠分别为 12 1.0 6、13 4.5 1mg/kg饲料 ,按每日每千克体重摄入量计算BMDL值雌、雄性大鼠分别为 11.83、11.0 2mg/(kg·d) ,均略?

燃煤型砷中毒大鼠肾损伤特点及其生物学标志的基准剂量分析

目的观察燃煤型砷中毒大鼠肾毒性作用,应用基准剂量(BMD)法探讨肾功能效应标志改变的尿砷(UAs)的基准剂量。方法 Wistar大鼠连续90 d喂饲砷25,50,100 mg·kg-1污染饲料。检测大鼠UAs、肾砷(KAs)及肾功能指标并观察肾常规病理学及其纤维化改变。以UAs为暴露标志,尿β2-微球蛋白微球蛋白(Uβ2-MG)、尿N-乙酰-β-D-氨基葡萄糖苷酶(UNAG)及尿白蛋白(UALB)为效应标志,运用BMD法计算各效应标志对应的UAs的BMD及其基准剂量95%可信限下限BMDL。结果砷100 mg·kg-1组大鼠UAs,KAs,UALB,UNAG,Uβ2-MG含量均高于正常对照组(P<0.05);光镜下各染砷组大鼠肾HE染色可见炎性细胞浸润、肾小管上皮细胞肿胀、肾间质毛细管扩张、充血等不同程度的病理学改变,Masson染色可见肾小管间质不同程度的纤维化;以UAs为暴露标志,Uβ2-MG,UNAG,UALB为效应标志,计算得出各效应标志UAs的BMD分别为998.9,1213.5和1386.9μg·g-1Cr,BMDL分别为660.5,803.6和909.4μg·g-1Cr。燃煤型砷中毒大鼠肾功能早期改变的尿砷的BMD及BMDL分别为998.9和660.5μg·g-1Cr。结论微小病变型肾病可能是燃煤砷污染对肾损害的主要病理类型,推荐使用较为敏感的生物学标志Uβ2-MG来估算砷致肾损伤的生物暴露限值。

燃煤砷污染地区砷中毒患者的肾功能损害

[目的]探讨燃煤砷污染对人群肾脏的损害作用、剂量-反应关系以及砷致肾功能损害的生物接触限值。[方法]以临床诊断并复查的燃煤型砷中毒患者122例为调查对象,无砷污染区居民123例为对照。检测尿砷(uAs)作为砷接触剂量,以尿β_2-微球蛋白(uβ_2-MG)、尿白蛋白(uALB)、尿N-乙酰-β-D葡萄糖苷酶(uNAG)为肾损害的效应指标,并计算uAs的基准剂量(BMD)及其下限值(BMDL)。[结果]①砷中毒患者uAs、uβ_2-MG、uNAG、uALB含量均高于对照组(P<0.01),uAs与各肾功能指标间呈正相关,存在明显剂量一反应关系。②以uβ_2-MG、uNAG和uALB为效应指标时,uAs的BMD与BMDL分别为11.45μg/mmol Cr与8.90μg/mmol Cr、13.26μg/mmol Cr与10.43μg/mmol Cr、9.54μg/mmol Cr与7.48μg/mmol Cr。[结论]长期砷接触可引起人体肾小球和肾小管的混合性损伤;砷接触与肾损害问存在明显剂量-反应关系;砷致肾功能损害的uALB生物接触限值为7.48μg/mmolCr;uALB可作为评价砷接触人群肾功能改变的敏感生物指标。

基准剂量在镉接触环境流行病学研究中的应用

[目的]通过环境流行病学研究 ,估测环境镉接触引起肾功能不全的基准剂量。[方法]镉污染区居住的居民为接触组 ,非污染区居民为对照组。尿镉 (UCd)为接触生物标记物 ;β 微球蛋白(UBM)、尿N_乙酰_β_D_氨基葡萄糖苷酶(UNAG)、尿视黄醇结合蛋白 (URBP)和尿白蛋白 (UALB)为效应生物标记物 ,并均用尿肌酐校正。[结果]长期接触镉可引起肾脏的损害。本次调查β2 微球蛋白、视黄醇结合蛋白、尿NAG酶和尿白蛋白重污染区显著高于对照区 ,与尿镉的增长呈明显的剂量效应关系。计算得基准剂量 (BMD) ,推出基准剂量的95 %低限水平 (LBMD)。镉所引起的各肾脏损伤指标的LBMD值是不同的 ,大小依次为尿NAG同功酶B(NAG_B)、NAG、UBM和UALB。[结论]镉引起的肾小球损害晚于肾小管损害;而NAGB的基准剂量值最低 。

空气花粉浓度与变应性鼻炎就医人次的暴露-反应关系初探

目的研究北京市海淀区夏秋季空气花粉浓度与变应性鼻炎就医人次的暴露-反应关系,对空气花粉浓度进行危险度分级,评价人群花粉暴露的致敏危险度。方法以周为单位研究北京市海淀区2000—2002年4—9月空气花粉浓度和同期公费医疗病例资料中变应性鼻炎就医人次随时间变化的趋势.对变应性鼻炎就医人次和空气花粉浓度、空气总悬浮颗粒物(TSP)浓度、6种气象因素(日均气温、日最高气温、日最低气温、日均气压、24 h 降水量、日均相对湿度)以及年份哑变量 A_1、A_2进行多重线性回归分析。采用美国环境保护局(EPA)的基准剂量计算软件(BMDS V1.4.1C)计算空气花粉浓度对人群变应性鼻炎致敏基准剂量的95%可信下限(BMDL)值。以变应性鼻炎就医人次为效应终点,用基准剂量(BMD)法进行日花粉浓度分级。结果仅空气花粉浓度和年份哑变量进入了变应性鼻炎就医人次的回归方程.空气花粉浓度与变应性鼻炎就医人次的暴露.反应关系为线性,呈正相关(P<0.001)。空气花粉浓度对人群变应性鼻炎致敏基准剂量的95%可信下限值为21.38粒/1 000 mm^2。以变应性鼻炎就医人次为效应终点,应用 BMD 法进行花粉浓度分级,可初步评估花粉致敏危险度。结论北京市海淀区夏秋季花粉浓度与变应性鼻炎就医人次有一定暴露-反应关系.以 BMD 法进行花粉浓度分级评估花粉致敏危险度有较大的可行性和可信度。

十三吗啉原药的安全性评价

目的研究十三吗啉原药的急性和亚慢性毒性及致突变性,对其进行安全性评价。方法按照GB15670-1995《农药登记毒理学实验方法》进行实验。结果雌性大鼠急性经口LD50为562mg/kg,雄性大鼠为68lmg/kg,雌雄性大鼠急性经皮LD50均大于2000mg/kg。小鼠骨髓多染红细胞微核试验、小鼠睾丸精母细胞染色体畸变试验和Ames试验均为阴性。大鼠亚慢性经口毒性试验雌雄性大鼠的未见有害作用量(NOAEL)值分别为(7.47±0.61)mg/(kg·d)和(20.27±1.06)mg/(kg·d);雌雄性大鼠的基准剂量可信限下限(BMDL)值分别为25.58、35.57mg/(kg·d)。结论十三吗啉急性经口、经皮毒性均属低毒级,无致突变性。大鼠亚慢性经口毒性NOAEL值,雌雄结果差异较大,为克服其方法在评价中的不足,结果大鼠亚慢性经口毒性阈值采用BMDL值。