Chronic Exposure to Deoxynivalenol Has No Influence on the Oral Bioavailability of Fumonisin B1 in Broiler Chickens

Both deoxynivalenol (DON) and fumonisin B₁ (FB₁) are common contaminants of feed. Fumonisins (FBs) in general have a very limited oral bioavailability in healthy animals. Previous studies have demonstrated that chronic exposure to DON impairs the intestinal barrier function and integrity, by affecting the intestinal surface area and function of the tight junctions. This might influence the oral bioavailability of FB₁, and possibly lead to altered toxicity of this mycotoxin. A toxicokinetic study was performed with two groups of 6 broiler chickens, which were all administered an oral bolus of 2.5 mg FBs/kg BW after three-week exposure to either uncontaminated feed (group 1) or feed contaminated with 3.12 mg DON/kg feed (group 2). No significant differences in toxicokinetic parameters of FB₁ could be demonstrated between the groups. Also, no increased or decreased body exposure to FB₁ was observed, since the relative oral bioavailability of FB₁ after chronic DON exposure was 92.2%.     

Use of Monoclonal Antibodies in the Sensitive Detection and Neutralization of Botulinum Neurotoxin Serotype B

Botulinum neurotoxins (BoNT) are some of nature’s most potent toxins. Due to potential food contamination, and bioterrorism concerns, the development of detection reagents, therapeutics and countermeasures are of urgent interest. Recently, we have developed a sensitive electrochemiluminescent (ECL) immunoassay for BoNT/B, using monoclonal antibodies (mAbs) MCS6-27 and anti-BoNT/B rabbit polyclonal antibodies as the capture and detector. The ECL assay detected as little as 1 pg/mL BoNT/B in the buffer matrix, surpassing the detection sensitivities of the gold standard mouse bioassays. The ECL assay also allowed detection of BoNT/B in sera matrices of up to 100% sera with negligible matrix effects. This highly-sensitive assay allowed the determination of the biological half-lives of BoNT/B holotoxin in vivo. We further tested the toxin neutralization potential of our monoclonal antibodies using the mouse systemic and oral intoxication models. A combination of mAbs protected mice in both pre- and post-exposure models to lethal doses of BoNT/B. MAbs were capable of increasing survival of animals when administered even 10 h post-intoxication in an oral model, suggesting a likely time for BoNT/B complexes to reach the blood stream. More sensitive detection assays and treatments against BoNT intoxication will greatly enhance efforts to combat botulism.     

Report from the EPAA workshop: In vitro ADME in safety testing used by EPAA industry sectors

There are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritisation, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data.     

UPLC-MS/MS测定大鼠血浆多柔比星浓度方法的建立及毒代动力学应用

目的 建立一种简便、快速、灵敏的测定大鼠多柔比星血药浓度的超高效液相-质谱联用（UPLC-MS/MS）法,并将其应用于注射用盐酸多柔比星大鼠体内毒代动力学实验。方法 采用ACQUITY UPLC^® BEH C₁₈（50 mm×2.1 mm,1.7 μm）色谱柱,流动相为0.1%甲酸（含2 mmol/L甲酸铵）水溶液-乙腈,梯度洗脱。体积流量为0.4 mL/min,进样量为10 μL。采用电喷雾离子源（ESI）,多反应监测（MRM）方式扫描,以正离子方式进行检测,蛋白沉淀法提取样品。用于定量分析的离子对分别为多柔比星m/z 544.43→m/z 397.08,内标地西泮m/z 285.02→154.40。SD大鼠30只,按体质量随机分为3组,分别单次iv 52.2、61.4、72.3 mg/m²盐酸多柔比星后测定血药浓度,并用DAS 3.1.4软件计算毒代参数。结果 血浆中内源性物质不干扰待测物和内标的测定,多柔比星在0.5～100 ng/mL范围内线性关系良好,定量下限为0.5 ng/mL。多柔比星在0.5、1、20、80 ng/mL 4个浓度的批内批间精密度RSD值为3.21%～12.79%。多柔比星在1、80 ng/mL的提取回收率和基质效应分别为102.00%～103.75%和79.27%～89.34%。SD大鼠分别单次iv给予注射用盐酸多柔比星52.2、61.4、72.3 mg/m²后,多柔比星在大鼠体内的AUC_0-t分别为（2 318.78±282.65）、（3 203.11±829.41）和（3 326.96±546.04） ng·h/mL,C_0.083h分别为（1 720.50±851.19）、（3 363.00±1 458.84）和（2 156.50±919.90）ng/mL。结论 建立的UPLC-MS/MS分析方法灵敏度高、样品处理方法简单、样品分析时间短,可以应用于大鼠多柔比星毒代动力学试验中。     

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

The application of chemical-specific toxicokinetic or toxicodynamic data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default or categorically-based uncertainty factors. The present review summarizes the state-of-the-science since the introduction of the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) guidance on chemical-specific adjustment factors (CSAF) in 2005 and the availability of recent applicable guidance including the WHO/IPCS guidance on physiologically-based pharmacokinetic (PBPK) modeling in 2010 as well as the U.S. EPA guidance on data-derived extrapolation factors in 2014. A summary of lessons learned from an analysis of more than 100 case studies from global regulators or published literature illustrates the utility and evolution of CSAF in regulatory decisions. Challenges in CSAF development related to the adequacy of, or confidence in, the supporting data, including verification or validation of PBPK models. The analysis also identified issues related to adequacy of CSAF documentation, such as inconsistent terminology and often limited and/or inconsistent reporting, of both supporting data and/or risk assessment context. Based on this analysis, recommendations for standardized terminology, documentation and relevant interdisciplinary research and engagement are included to facilitate the continuing evolution of CSAF development and guidance.     

Genetic toxicology of thallium: a review

This review summarizes the current knowledge about the general toxicity of thallium (Tl) and its environmental sources, with special emphasis placed on its potential mutagenic, genotoxic, and cytotoxic effects on both eukaryotic and prokaryotic cells. Tl is a nonessential heavy metal that poses environmental and occupational threats as well as therapeutic hazards because of its use in medicine. It is found in two oxidation states, thallous (Tl⁺) and thallic (Tl³⁺), both of which are considered highly toxic to human beings and domestic and wild organisms. Many Tl compounds are colorless, odorless and tasteless, and these characteristics, combined with the high toxicity of TI compounds, have led to their use as poisons. Because of its similarity to potassium ions (K⁺), plants and mammals readily absorb Tl⁺ through the skin and digestive and respiratory systems. In mammals, it can cross the placental, hematoencephalic, and gonadal barriers. Inside cells, Tl can accumulate and interfere with the metabolism of potassium and other metal cations, mimicking or inhibiting their action. The effects of Tl on genetic material have not yet been thoroughly explored, and few existing studies have focused exclusively on Tl⁺. Both in vivo and in vitro studies indicate that Tl compounds can have a weak mutagenic effect, but no definitive effect on the induction of primary DNA damage or chromosomal damage has been shown. These studies have demonstrated that Tl compounds are highly toxic and lead to changes in cell-cycle progression.     

Pulmonary clearance kinetics and extrapulmonary translocation of seven titanium dioxide nano- and submicron materials following intratracheal administration in rats

Abstract

We evaluated and compared the pulmonary clearance kinetics and extrapulmonary translocations of seven titanium dioxide (TiO₂) nano- and submicron particles with different characteristics, including size, shape and surface coating. Varying doses of TiO₂ nano- and submicron particles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats. The rats were euthanized under anesthesia for 3, 28 and 91 days after administration. Ti levels in pulmonary and various extrapulmonary organs were determined using inductively coupled plasma-sector field mass spectrometry (ICP-SFMS). The lungs, including bronchoalveolar lavage fluid (BALF), contained 55–89% of the administered TiO₂ dose at 3 days after administration. The pulmonary clearance rate constants, estimated using a one-compartment model, were higher after administration of 0.375–2.0?mg/kg body weight (bw) (0.016–0.020/day) than after administration of 3.0–6.0?mg/kg bw (0.0073–0.013/day) for six uncoated TiO₂. In contrast, the clearance rate constant was 0.011, 0.0046 and 0.00018/day following administration of 0.67, 2.0 and 6.0?mg/kg bw TiO₂ nanoparticle with Al(OH)₃ coating, respectively. Translocation of TiO₂ from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner. Furthermore, the translocation of TiO₂ from the lungs to the thoracic lymph nodes after 91 days was higher when Al(OH)₃ coated TiO₂ was administered (0.93–6.4%), as compared to uncoated TiO₂ (0.016–1.8%). Slight liver translocation was observed (<0.11%), although there was no clear trend related to dose or elapsed time. No significant translocation was observed in other organs including the kidney, spleen and brain.     

Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se

The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General’s 2014 report on the health consequences of nicotine exposure.     

聚乙二醇化重组人胰岛素注射液Beagle犬毒动学研究

目的 研究毒性剂量暴露下聚乙二醇化重组人胰岛素注射液（PEG-Det）的毒动学（TK）,以评价系统暴露与剂量、时间及毒性结果之间的关系,通过重复给药分析药物在体内是否存在蓄积及代谢方式是否改变等特性。方法 32只健康Beagle犬随机分为4组,每组8只,雌雄各半,分别sc低、中、高剂量（37.5、75.0、150.0 μg/kg）PEG-Det及溶媒,每周给药2次,重复给药9个月。分别于首次（d1）、中期（d89）和末期（d260）给药后采用放射免疫分析（RIA）法检测不同时间血药浓度,采用罗氏血糖仪同步测定动物血糖水平。试验数据采用DAS 3.0药动程序拟合分析并计算TK参数。结果 各剂量组动物sc给药后,随血药浓度升高伴随血糖降低,且与给药剂量呈正相关;随给药频率增加,血糖降低幅度减小;单次和多次给药后,PEG-Det的C_max和AUC与剂量均呈正相关;随给药频率增加,各剂量组的C_max和AUC_ss降低,且给药末期（9个月）的蓄积指数（R_Cmax和R_AUC）均小于1;各剂量组在给药不同阶段的消除半衰期t_1/2z为20~30 h;达峰时间T_max和清除率CL_z/F均在一定范围内波动,不与剂量相关。结论 Beagle犬重复sc给予PEG-Det 37.5、75.0、150.0 μg/kg,随给药剂量增加,药物暴露量增大;经多次给药后,血浆中胰岛素浓度趋于平稳,体内无药物蓄积;且血糖降低幅度减少,在维持有效浓度和药效的基础上,降低了由低血糖带来的安全性风险。     

甲基异柳磷毒性研究

甲基异柳磷是我国新发展的一种以防治地下害虫为主、兼治地面害虫的新型有机磷农药。本研究包括一系列毒性试验;并从亚细胞水平上对该农药中毒机理进行了探讨。研究结果表明甲基异柳磷杀虫效果显著,在体内代谢迅速,无明显蓄积毒性,未发现致畸性、致突变性、生殖毒性及迟发神经毒性,对人、畜比较安全。目前,已列入国家作为取代六六六的重点推广品种。