Differential relative effect potencies of some dioxin-like compounds in human peripheral blood lymphocytes and murine splenic cells

Human risk assessment for dioxin-like compounds is typically based on the concentration measured in blood serum multiplied by their assigned toxic equivalency factor (TEF). Consequently, the actual value of the TEF is very important for accurate human risk assessment. In this study we investigated the effect potencies of three polychlorinated dibenzo-p-dioxins (PCDDs), six polychlorinated dibenzofurans (PCDFs) and 10 polychlorinated biphenyls (PCBs) relative to the reference congener 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) in in vitro exposed primary human peripheral blood lymphocytes (PBLs) and mouse splenic cells. REPs were determined based on cytochrome P450 (CYP) 1A1, 1B1 and aryl hydrocarbon receptor repressor (AhRR) gene expression as well as CYP1A1 activity in human PBLs and Cyp1a1 gene expression in murine splenic cells. Estimated median human REPs for 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (1234678-HpCDD), 2,3,4,7,8,-pentachlorodibenzofuran (23478-PeCDF), 1,2,3,4,7,8-hexachlorodibenzofuran (123478-HxCDF) and 1,2,3,4,7,8,9-heptachlorodibenzofuran (1234789-HpCDF) were with 0.1, 1.1, 1 and 0.09, respectively, significantly higher compared to those estimated for mouse with REPs of 0.05, 0.45, 0.09 and 0.04, respectively. Opposite to these results, the estimated median human REP of 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), was with 0.001 30-fold lower compared to the mouse REP of 0.03. Furthermore, human REPs for 1234678-HpCDD, 23478-PeCDF, 123478-HxCDF, 1234789-HpCDF and PCB 126 were all outside the ± half log uncertainty range that is taken into account in the WHO-assigned TEFs. Together, these data show congener- and species-specific differences in REPs for some, but not all dioxin-like congeners tested. This suggests that, more emphasis should be placed on human-tissue derived REPs in the establishment of a TEF for human risk assessment.     

经典名方竹叶石膏汤的物质基准量值传递分析

目的建立竹叶石膏汤(Zhuye Shigao Decoction,ZSD)物质基准的HPLC特征图谱及指标成分含量测定方法,并结合化学模式识别法进行评价,探寻其质量传递规律。方法制备20批ZSD物质基准,建立HPLC特征图谱,明确共有峰归属,测定全方出膏率、指标成分异荭草苷、人参皂苷Rg1、人参皂苷Re、人参皂苷Rb1、甘草苷和甘草酸的含量及转移率,对物质基准进行量值传递分析。结果 20批ZSD物质基准特征图谱的相似度均大于0.90,共确定了21个特征峰,分别来自方中淡竹叶(6个峰)、麦冬(6个峰)、半夏(3个峰)、甘草(6个峰)4个药味;化学模式识别法将20批样品分为4类;各指标成分从饮片到物质基准的转移率分别为异荭草苷31.94%～50.91%,甘草苷35.77%～62.55%,甘草酸13.09%～22.63%,人参皂苷Rg1 57.28%～83.95%,人参皂苷Re 42.21%～72.27%,人参皂苷Rb1 38.19%～64.57%;出膏率为16.99%～27.06%。结论采用特征图谱、多指标含量测定以及化学模式识别法对ZSD物质基准进行量值传递分析,该方法科学合理,可为后续制剂开发提供参考。     

Carcinogenicity of glycidamide in B6C3F1 mice and F344/N rats from a two-year drinking water exposure

Acrylamide is a contaminant in baked and fried starchy foods, roasted coffee, and cigarette smoke. Previously we reported that acrylamide is a multi-organ carcinogen in B6C3F₁ mice and F344/N rats, and hypothesized that acrylamide is activated to an ultimate carcinogen through metabolism to the epoxide glycidamide. We have now examined the carcinogenic effects of glycidamide administered at 0, 0.0875, 0.175, 0.35 and 0.70 mM in drinking water to the same strains of rodents for two years. In male and female mice, there were significant increases in tumors of the Harderian gland, lung, forestomach, and skin. Female mice also had an increased incidence of tumors of the mammary gland and ovary. In male and female rats, there were significant increases in thyroid gland and oral cavity neoplasms and mononuclear cell leukemia. Male rats also had increases in tumors of the epididymis/testes and heart, while female rats demonstrated increases in tumors of the mammary gland, clitoral gland, and forestomach. A similar spectrum of tumors was obtained in mice and rats administered acrylamide. These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to glycidamide and that the carcinogenic activity of acrylamide is due to its conversion into glycidamide.     

Benchmark dose approach for renal dysfunction in workers exposed to lead

Benchmark dose (BMD) and the lower confidence limit on the benchmark dose (BMDL) of blood lead were estimated to explore the biologic exposure limits for renal dysfunction caused by lead. One hundred thirty-five workers from one storage battery plant were selected as lead exposure group while 143 mechanics as the control. The relationship between the blood lead concentration and the urinary excretion of total protein (TP), beta2-microglobulin (beta2-MG), and N-acetyl-beta-D-glucosaminidase (NAG) was studied. The quantal linear logistic regression model (BMDS Version 1.3.1) was used to calculate BMD and BMDL of blood lead. The results showed that the levels of NAG, beta2-MG, and TP in lead-exposed workers were higher than those of control group and elevated along with rising length of employment. The levels of three indices for renal dysfunction increased with the elevated blood lead. The BMD and BMDL of blood lead for renal dysfunction were from 299.4 to 588.7 microg/L and from 253.4 to 402.3 microg/L, respectively. The BMDL of blood lead was ranged from high to low as TP, beta2-MG, and NAG. It is suggested that the urinary NAG activity could be a sensitive and early biomarker of renal tubular dysfunction induced by lead. When assessing renal function in workers occupationally exposed to lead, a blood lead level of 250 microg/L could serve as a warning signal.     

Estimation of safe dietary intake levels of acrylamide for humans

Acrylamide (AA), a human neurotoxicant and rat tumorigen, is produced in starchy foods when cooked. AA is also an industrial chemical used in polyacrylamide production. A safety evaluation of ingested AA by humans was conducted using a newly developed, state-of-the-art physiologically-based toxicokinetic (PBPK or PBTK) model to compare internal doses of AA and its metabolite glycidamide (GA) in humans and rats. Based on modes of action (MoA), a nonlinear dose–response approach was applied for neurotoxicity (non-genotoxicity) and carcinogenicity (mixed: genotoxicity and epigenetic MoA). Tolerable daily intake (TDI) for neurotoxicity from AA was estimated to be 40 μg/kg-day; TDIs for cancer were estimated to be 2.6 and 16 μg/kg-day based on AA or GA, respectively. Margins of exposure (MoE) were calculated for average AA consumers to be 300 and 500 based on AA and GA, respectively; for cancer, the MoE for average AA consumers was estimated to be 200 and 1200 based on AA and GA, respectively. For high consumers of AA, MoEs were somewhat less.     

Pharmacy curriculum outcomes assessment for individual student assessment and curricular evaluation

The Pharmacy Curriculum Outcomes Assessment (PCOA) is a standardized examination for assessing academic progress of pharmacy students. Although no other national benchmarking tool is available on a national level, the PCOA has not been adopted by all colleges and schools of pharmacy. Palm Beach Atlantic University (PBAU) compared 2008-2010 PCOA results of its P1, P2, and P3 students to their current grade point average (GPA) and to results of a national cohort. The reliability coefficient of PCOA was 0.91, 0.90, and 0.93 for the 3 years, respectively. PBAU results showed a positive correlation between GPA and PCOA scale score. A comparison of subtopic results helped to identify areas of strengths and weaknesses of the curriculum. PCOA provides useful comparative data that can facilitate individual student assessment as well as programmatic evaluation. There are no other standardized assessment tools available. Despite limitations, PCOA warrants consideration by colleges and schools of pharmacy. Expanded participation could enhance its utility as a meaningful benchmark.     

Comparing BMD‐derived genotoxic potency estimations across variants of the transgenic rodent gene mutation assay

There is growing interest in quantitative analysis of in vivo genetic toxicity dose‐response data, and use of point‐of‐departure (PoD) metrics such as the benchmark dose (BMD) for human health risk assessment (HHRA). Currently, multiple transgenic rodent (TGR) assay variants, employing different rodent strains and reporter transgenes, are used for the assessment of chemically‐induced genotoxic effects in vivo . However, regulatory issues arise when different PoD values (e.g., lower BMD confidence intervals or BMDLs) are obtained for the same compound across different TGR assay variants. This study therefore employed the BMD approach to examine the ability of different TGR variants to yield comparable genotoxic potency estimates. Review of over 2000 dose‐response datasets identified suitably‐matched dose‐response data for three compounds (ethyl methanesulfonate or EMS, N‐ethyl‐N‐nitrosourea or ENU, and dimethylnitrosamine or DMN) across four commonly‐used murine TGR variants (Muta™Mouse lacZ , Muta™Mouse cII , gpt delta and BigBlue® lacI ). Dose‐response analyses provided no conclusive evidence that TGR variant choice significantly influences the derived genotoxic potency estimate. This conclusion was reliant upon taking into account the importance of comparing BMD confidence intervals as opposed to directly comparing PoD values (e.g., comparing BMDLs). Comparisons with earlier works suggested that with respect to potency determination, tissue choice is potentially more important than choice of TGR assay variant. Scoring multiple tissues selected on the basis of supporting toxicokinetic information is therefore recommended. Finally, we used typical within‐group variances to estimate preliminary endpoint‐specific benchmark response (BMR) values across several TGR variants/tissues. We discuss why such values are required for routine use of genetic toxicity PoDs for HHRA. Environ. Mol. Mutagen. 58:632–643, 2017. © 2017 Her Majesty the Queen in Right of Canada. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.     

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     

经典名方当归四逆汤物质基准指纹图谱及关键质量属性量值传递规律研究

目的 建立经典名方当归四逆汤（Danggui Sini Decoction,DSD）指纹图谱并结合化学模式识别进行分析,建立多成分含量测定的方法,明确关键质量属性的传递规律。方法 采用HPLC法,乙腈-0.2%乙酸水溶液为流动相,建立指纹图谱,采用中药色谱指纹图谱相似度评价软件（2012年版）,结合层次聚类分析（hierarchical cluster analysis,HCA）、主成分分析（principal component analysis,PCA）与正交偏最小二乘法-判别分析（orthogonal partial least squares-discriminant analysis,OPLS-DA）,寻找造成不同批次DSD物质基准质量差异的主要化学成分。制备15批物质基准,测定其指纹图谱相似度、指标性成分含量及干膏率。结果 建立了当归四逆汤指纹图谱,确定了16个共有峰,15批DSD物质基准相似度大于0.90,3种化学识别模式均将样品分为3类,造成主要差异的质量差异物来源于甘草苷。所建立的多成分含量测定方法耐用性良好。饮片-物质基准芍药苷、甘草苷、甘草酸的平均转移率分别为52.94%、48.79%、47.39%,干膏率平均传递率为86.40%。结论 建立了经典名方当归四逆汤指纹图谱,寻找出了造成批次差异的标志物及含量测定的方法,DSD物质基准的关键质量属性均可在饮片-水煎液-物质基准中稳定传递,初步构建DSD全过程质量控制体系,为后续制剂研究提供参考。     

经典名方阳和汤基准样品量值传递分析

目的 建立经典名方阳和汤基准样品HPLC指纹图谱并对其指标性成分（5-羟甲基糠醛、桂皮醛、肉桂酸、芥子碱硫氰酸盐、甘草酸）进行含量测定,研究阳和汤基准样品量值传递规律,为复方制剂研制奠定基础。方法 制备15批阳和汤基准样品,建立HPLC指纹图谱,明确并归属特征峰;对阳和汤基准样品中指标性成分进行含量测定,分析指标性成分从饮片-基准样品的传递规律。结果 15批阳和汤基准样品指纹图谱相似度>0.83,标定了13个共有峰,并对各共有峰进行药材归属,其中2、8号峰来自熟地黄;10、11号峰来自肉桂;1、3～6号峰来自炒白芥子;13号峰来自麻黄;7、9、12号峰来自甘草。指标性成分5-羟甲基糠醛、桂皮醛、肉桂酸、芥子碱硫氰酸盐、甘草酸质量分数分别为0.028%～0.508%、0.076%～0.244%、0.006%～0.018%、0.430%～0.677%、0.100%～0.335%,转移率分别为1.21%～10.74%、2.68%～12.76%、11.46%～31.43%、39.61%～60.30%、4.90%～18.69%;基准样品出膏率为27.38%～40.73%。结论 采用指纹图谱...