Comparative PBT screening using (Q)SAR tools within REACH legislation

Small to medium sized enterprises (SMEs) in the EU are facing challenges due to the introduction of new legislation designed to protect consumers and the environment, REACH (Registration, Evaluation, Authorisation and Restriction of CHemicals). There can be high costs associated with implementing REACH because data on mammalian toxicity, environmental toxicity and environmental fate properties is required and if this data is obtained experimentally the cost is significant. These costs can be reduced if reliable quantitative structure–activity relationships ((Q)SAR) models are instead used to obtain the required information. In this paper we investigate how easily freely available (Q)SAR models can be applied for persistent, bioaccumulative and toxic (PBT) screening of 17 chemicals of interest to SMEs. In this study the PBT predictions obtained from the more user-friendly PBT Profiler and the Danish(Q)SAR database for the chemicals were compared with the results taken directly from the EPI Suite software. It was found that these widely used (Q)SAR databases might have some errors and examples are provided. It was concluded that extra care must be taken when considering the use of these databases for PBT screening. In addition, to increase the likelihood of a correct prediction, data estimates from various (Q)SAR models relevant to the PBT endpoints must be compared.     

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Abstract

The availability of validated and characterized SAR models of toxicological phenomena provides a method to apply SAR technology to a variety of environmental, public health and industrial situations. These include (i) the prioritization of environmental pollutants for control and or regulation, (ii) the design of multi-action optimized therapeutics from which the potential for unwanted side-effects have been engineered out, (iii) the development of SAR-based computer-driven screening procedure to identify candidate therapeutics based upon combinatorial chemistry or compilations of molecular structures, (iv) the generation of toxicological profiles to be used in the selection of benign chemicals in the early stages of product development.     

Validity and validation of expert (Q)SAR systems

At a recent workshop in Setubal (Portugal) principles were drafted to assess the suitability of (quantitative) structure–activity relationships ((Q)SARs) for assessing the hazards and risks of chemicals. In the present study we applied some of the Setubal principles to test the validity of three (Q)SAR expert systems and validate the results. These principles include a mechanistic basis, the availability of a training set and validation. ECOSAR, BIOWIN and DEREK for Windows have a mechanistic or empirical basis. ECOSAR has a training set for each QSAR. For half of the structural fragments the number of chemicals in the training set is >4. Based on structural fragments and log Kow, ECOSAR uses linear regression to predict ecotoxicity. Validating ECOSAR for three ‘valid’ classes results in predictivity of ?≥?64%. BIOWIN uses (non-)linear regressions to predict the probability of biodegradability based on fragments and molecular weight. It has a large training set and predicts non-ready biodegradability well. DEREK for Windows predictions are supported by a mechanistic rationale and literature references. The structural alerts in this program have been developed with a training set of positive and negative toxicity data. However, to support the prediction only a limited number of chemicals in the training set is presented to the user. DEREK for Windows predicts effects by ‘if-then’ reasoning. The program predicts best for mutagenicity and carcinogenicity. Each structural fragment in ECOSAR and DEREK for Windows needs to be evaluated and validated separately.     

Structure-Activity Relationships for Non-Congeneric Structures. Application of Substructural Balance Method for Antiallergic Activity

Abstract

This paper presents a new research method of structure-activity relationships (SAR) based on the concept of substructural balance. By using antiallergic activity (PCA, rat, iv) of a non-congeneri set of 267 structures, the structural feature of active group is expressed in terms of substructural balanance. Each structure was expressed with 100 new substructures and the number of each substructure in a molecule was counted. The substructural balance was expressed as their ratio. Structures were classified into three groups based on their potencies (ED₅₀), active (44), median (33) and inactactive (190) group. Using two substructural ratios, 80.53% of inactive and 57.58% of median structures were excluded from those that were active. Common features of active structures were shown as a zone indicating the optimal ranges of two substructural ratios. Two substructural ratios were determined out of 4950 substructural ratios, all possible combinations of 100 substructures (₁₀₀C₂), by selecting the greatest discriminatory power of inactive from active structures. The substructures used in this work include: the number of bonds comprising of the longest conjugate system, the number of skeletal atoms and the numbers of electron-donor pairs at certain distances in the molecule.     

Evaluation of SARs for the prediction of eye irritation/corrosion potential–structural inclusion rules in the BfR decision support system†

The proposed REACH regulation within the European Union (EU) aims to minimise the number of laboratory animals used for human hazard and risk assessment while ensuring adequate protection of human health and the environment. One way to achieve this goal is to develop non-testing methods, such as (quantitative) structure–activity relationships ([Q]SARs), suitable for identifying toxicological hazard from chemical structure and physicochemical properties alone. A database containing data submitted within the EU New Chemicals Notification procedure was compiled by the German Bundesinstitut für Risikobewertung (BfR). On the basis of these data, the BfR built a decision support system (DSS) for the prediction of several toxicological endpoints. For the prediction of eye irritation and corrosion potential, the DSS contains 31 physicochemical exclusion rules evaluated previously by the European Chemicals Bureau (ECB), and 27 inclusion rules that define structural alerts potentially responsible for eye irritation and/or corrosion. This work summarises the results of a study carried out by the ECB to assess the performance of the BfR structural rulebase. The assessment included: (a) evaluation of the structural alerts by using the training set of 1341 substances with experimental data for eye irritation and corrosion; and (b) external validation by using an independent test set of 199 chemicals. Recommendations are made for the further development of the structural rules in order to increase the overall predictivity of the DSS.     

Endocrine disruption profile analysis of 11,416 chemicals from chemometrical tools⊥

A number of chemicals released into the environment have the potential to disturb the normal functioning of the endocrine system. These chemicals termed endocrine disruptors (EDs) act by mimicking or antagonizing the normal functions of natural hormones and may pose serious threats to the reproductive capability and development of living species. Batteries of laboratory bioassays exist for detecting these chemicals. However, due to time and cost limitations, they cannot be used for all the chemicals which can be found in the ecosystems. SAR and QSAR models are particularly suited to overcome this problem but they only deal with specific targets/endpoints. The interest to account for profiles of endocrine activities instead of unique endpoints to better gauge the complexity of endocrine disruption is discussed through a SAR study performed on 11,416 chemicals retrieved from the US-NCI database and for which 13 different PASS (Prediction of Activity Spectra for Substances) endocrine activities were available. Various multivariate analyses and graphical displays were used for deriving structure-activity relationships based on specific structural features.     

Spaceborne SAR real-time echo simulation platform based on VPX

To perform the ground test of a spaceborne Synthetic Aperture Radar （SAR） system, an echo simulator with the characteristics of multimode, multi-assemblage, and real time is proposed in this paper. A hardware platform of the real-time echo simulator based on the VPX bus is designed. With this platform, real-time multi-point echo generation and scenario targets echo generation can be achieved by the real-time signal processing in Field Programmable Gate Array （FPGA）, utilizing the parameters calculated by the industry computers. Fklrthermore, this platform can output different signals if it is expanded to multi-channels, making it possible for the assignment of echo generation and test in different spaceborne SAR modes. The test results with the actual SAR system show that this platform can satisfy the system requirements and is now used in practice.     

一般构型机载双站SAR回波信号特性分析

一般构型机载双站合成孔径雷达(SAR)的成像结构与系统参数使其回波信号具有新的特性,文中从残余距离徙动、多普勒参数、回波频谱三个方面对信号特性进行分析。研究结果表明,残余距离走动与残余距离弯曲具有方位向非对称性,宽场景成像中需按照残余距离徙动与二阶相位误差对观测场景进行成像区分块;多普勒质心具有二维扩散性,多普勒调频率与多普勒带宽具有二维扩展性;在距离频域-方位时域校正距离走动可削弱因双站斜视带来的回波信号距离-方位向二维强耦合,推导了距离走动校正后的回波频谱公式。仿真验证了一般构型机载双站SAR的信号特性与距离走动校正方法的有效性。     

超宽带纽扣式天线与人体之间的相互影响研究

提出了一种新型的纽扣式超宽带天线,在给出其辐射性能的基础上,研究了天线与人体之间的相互影响,在不同工作频率下分析了天线安装在人体不同部位时天线性能的变化规律,仿真了人体大脑和躯干对天线辐射场的吸收辐射率情况,仿真和实测结果表明:设计天线在人体附近工作时,辐射性能受到人体影响较小,同时天线辐射对人体的影响符合国际非电离辐射防护委员会的标准,适用于以人体为中心的通信系统.     

BAN电磁辐射比吸收率SAR的研究

体域网（BAN）的研究在远程医疗及远程医疗服务方面起着重要的作用,由于无线传感器节点附着在人体表面,人体不可避免地会吸收可能有害的电磁波,因此,对人体处于BAN网络下的SAR值的研究变得格外重要.而由于BAN中通信距离很短,电磁波沿身体表面传播的通道与普通的无线信道不同,需要建立适用于BAN网络环境的计算模型.以FDTD有限时域差分法为依托,建立三维矩形人体组织网格模型以及三维站立式人体网格模型,采用半波偶极子天线在贴近人体皮肤表面处对矩形人体组织模型与站立式人体模型在不同频率下的SAR值进行仿真,得到了在0.9 GHz,2.4 GHz,5 GHz 3种频率下人体SAR值.