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QbR Frequently Asked QuestionsDisclaimer: These are general answers and may not be applicable to every product. Each ANDA is reviewed individually. This document represents the Office of Generic Drugs’s (OGD’s) current thinking on these topics.Format and SubmissionHow should QbR ANDAs be submitted?OGD’s QbR was designed with the expectation that ANDA applications would beorganized according to the Common Technical Document (CTD) format, a submissionformat adopted by multiple regulatory bodies including FDA. Generic firms are strongly recommended to submit their ANDAs in the CTD format (either eCTD or paper) tofacilitate implementation of the QbR. The ANDA Checklist for completeness andacceptability of an application for filing can be found on the OGD web page:/cder/ogd/anda_checklist.pdf .What is a QOS?The Quality Overall Summary (QOS) is the part of the CTD format that provides asummary of the CMC aspects of the application. It is an important tool to make the QbR review process more efficient.How long should a QOS be?OGD believes the CTD guidance1 recommendation of 40 pages to be an appropriatecompromise between level of detail and concision. The CTD guidance recommendation does not include tables and figures.The same information should not be included in multiple locations in the QOS. Instead of repeating information, refer to the first location of the original information in the QOS by CTD section number.Should the QOS be submitted electronically?All applications should include an electronic QOS. For paper submissions, it isrecommended that both an electronic QOS and a paper QOS be included.What file format should be used for the QOS?All applications, both eCTD and paper submissions, should have an electronic QOS. The electronic QOS should be contained in one document. Do not provide separate files foreach section or question.The electronic QOS should be provided as both a pdf and a Microsoft Word file. Microsoft Word files should be readable by Word 2003.1 Guidance for Industry M4Q: The CTD – Quality (August 2001) /cder/guidance/4539Q.htmWhat fonts should be used in the QOS?Because of FDA’s internal data management systems, please use only use these TrueType fonts: Times New Roman, Arial, Courier New. Times New Roman is recommended as the main text font.Should the applicable QbR question be presented within the body of Module 2 of the relevant section, followed by sponsor's answer?Yes, include all the QbR questions without deletion in the QOS.Can the granularity of module 3 be used in module 2?Yes, the granularity can be used for section and subsection headings. However, the QOS should always be submitted as a single file.Can color be used in the QOS?Yes, but sponsors should ensure that the QOS is legible when printed in black and white.Colored text should not be used.Is the QOS format available on OGD webpage and questions therein mandatory to be followed?For an efficient review process, OGD desires all applications to be in a consistent format.See the OGD QbR questions and example QOS:/cder/ogd/QbR-Quality_Overall_Summary_Outline.doc/cder/ogd/OGD_Model_Quality_Overall_ Summary.pdf/cder/ogd/OGD_Model_QOS_IR_Product.pdfFor amendments to applications, should the documentation consist of a revision of the QOS? Would new PD reports be required?The QOS should not be updated after submission of the original ANDA. Any additional data (including any new PD reports) should be provided as a stand alone amendment.Responses to deficiencies should be provided in electronic format as both a pdf andMicrosoft Word file.After January 2007, what will happen to an application that does not have a QOS or contains an incomplete QOS?OGD will contact the sponsor and ask them to provide a QOS. If the sponsor provides the QOS before the application comes up for review, OGD will use the sponsor’s QOS.OGD’s QbR questions represent the current thinking about what information is essential to evaluate an ANDA. Reviewers will use deficiency letters to ask ANDA sponsors thequestions that are not answered in the sponsor’s QOS.In February 2007, 75% of ANDAs submitted contained a QOS.If a question is not applicable to a specific formulation or dosage form, should the question be deleted or unanswered?Sponsors should never delete a QbR question, but instead answer as not applicable, with a brief justification. Please answer all parts of multi-part questions.For sterile injectables, to what extent should sterility assurance be covered in QOS?The current QbR was not intended to cover data recommendations for Sterility Assurance information. In the future, other summaries will cover other disciplines.MAPP 5040.1, effective date 5/24/04, specifies location of the microbiology information in the CTD format.Where in the CTD should an applicant provide comparative dissolution data between the generic and RLD?The comparison between the final ANDA formulation and the RLD should be provided in5.3.1, this comparison should be summarized in the QOS. Comparisons with otherformulations conducted during development should be included in 3.P.2.Is it possible to submit an amendment in CTD format for a product that was already submitted in the old ANDA format?No, all amendments to an application under review should use the same format as theoriginal submission.How is a paper CTD to be paginated?“Page numbering in the CTD format should be at the document level and not at the volume or module level. (The entire submission should never be numbered consecutively by page.) In general, all documents should have page numbers. Since the page numbering is at the document level, there should only be one set of page numbers for each document.”2. For paper submission, tabs locating sections and subsections are useful.For the ANDA submitted as in paper CTD format, can we submit the bioequivalence study report electronically? Or does the Agency require paper copy only?The bioequivalence summary tables should always be provided in electronic format.Will QbR lead to longer review times?Many of the current long review times result from applications that do not completelyaddress all of the review issues and OGD must request additional information through the deficiency process. This iterative process will be reduced with the use of the QbR template.Sponsors that provide a QOS that clearly and completely addresses all the questions in the QbR should find a reduction in the overall review time.Will DMFs for the drug substance be required to be in CTD if the ANDA is in CTD format?No. CTD format DMFs are recommended.What should be included in 3.2.R.1.P.2, Information on Components?COA’s for drug substance, excipients and packaging components used to produce theexhibit batch.2 Submitting Marketing Applications According to the ICH/CTD Format: General Considerations/cder/guidance/4707dft.pdfHow should an ANDA sponsor respond to deficiencies?OGD requests that sponsors provide a copy of the response to deficiencies in electronic format as both a pdf file and a Microsoft Word file.QUALITY OVERALL SUMMARY CONTENT QUESTIONS2.3 Introduction to the Quality Overall SummaryWhat information should be provided in the introduction?Proprietary Name of Drug Product:Non-Proprietary Name of Drug Product:Non-Proprietary Name of Drug Substance:Company Name:Dosage Form:Strength(s):Route of Administration:Proposed Indication(s):Maximum Daily Dose:2.3.S DRUG SUBSTANCEWhat if an ANDA contains two or more active ingredients?Prepare separate 2.3.S sections of the QOS for each API. Label them 2.3.S [API 1] and2.3.S [API 2].What if an ANDA contains two or more suppliers of the same active ingredient?Provide one 2.3.S section. Information that is common between suppliers should not be repeated. Information that is not common between suppliers (e.g. different manufacturing processes) should have separate sections and be labeled accordingly (drug substance,manufacturer 1) and (drug substance, manufacturer 2).Can information in this section be provided by reference to a DMF?See individual questions for details. As a general overview:•Information to be referenced to the DMFo Drug substance structure elucidation;o Drug substance manufacturing process and controls;o Container/closure system used for packaging and storage of the drugsubstance;o Drug substance stability.•Information requested from ANDA Sponsoro Physicochemical properties;o Adequate drug substance specification and test methods including structure confirmation;o Impurity profile in drug substance (process impurity or degradant);o Limits for impurity/residual solvent limits;o Method validation/verification;o Reference standard.2.3.S.1 General InformationWhat are the nomenclature, molecular structure, molecular formula, and molecular weight?What format should be used for this information?Chemical Name:CAS #:USAN:Molecular Structure:Molecular Formula:Molecular Weight:What are the physicochemical properties including physical description, pKa, polymorphism, aqueous solubility (as function of pH), hygroscopicity, melting point, and partition coefficient?What format should be used for this information?Physical Description:pKa:Polymorphism:Solubility Characteristics:Hygroscopicity:Melting Point:Partition Coefficient:Should all of these properties be reported? Even if they are not critical?Report ALL physicochemical properties listed in the question even if they are not critical.If a property is not quantified, explain why, for example: “No pKa because there are no ionizable groups in the chemical structure” or “No melting point because compounddegrades on heating”.What solubility data should be provided?The BCS solubility classification3 of the drug substance should be determined for oral dosage forms.Report aqueous solubility as a function of pH at 37º C in tabular form. Provide actualvalues for the solubility and not descriptive phrases such as “slightly soluble”.3 See BCS guidance /cder/guidance/3618fnl.pdf for definitionSolvent Media and pH Solubility Form I(mg/ml) Solubility Form II(mg/ml)Should pH-solubility profiles be provided for all known polymorphic forms?No, it is essential that the pH-solubility profile be provided for the form present in the drug product. The relative solubility (at one pH) should be provided for any other more stable forms.Physicochemical information such as polymorphic form, pKa, solubility, is usually in the confidential section of DMF. Is reference to a DMF acceptable for this type of information?No, knowledge of API physicochemical properties is crucial to the successful development of a robust formulation and manufacturing process. In view of the critical nature of thisinformation, OGD does not consider simple reference to the DMF to be acceptable.The Guidance for Industry: M4Q: The CTD-Quality Questions and Answers/ Location Issues says only the polymorphic form used in the drug product should be described in S.1 and other known polymorphic forms should be described in S.3. OGD’s examples placed information about all known polymorphic forms in S.1. Where does OGD want this information?This information may be included in either S.1 or in S.3. Wherever presented, list allpolymorphic forms reported in literature and provide brief discussion (i.e., which one is the most stable form) and indicate which form is used for this product.Other polymorph information should be presented by the ANDA applicant as follows: • 2.3.S.3 Characterization: Studies performed (if any) and methods used to identify the potential polymorphic forms of the drug substance. (x-ray, DSC, and literature) • 2.3.S.4 Specification: Justification of whether a polymorph specification is needed and the proposed analytical method• 2.3.P.2.1.1 Pharmaceutical Development –Drug Substance: Studies conducted to evaluate if polymorphic form affects drug product propertiesWhy does OGD need to know the partition coefficient and other physicochemical properties?Physical and chemical properties may affect drug product development, manufacture, or performance.2.3.S.2 ManufactureWho manufactures the drug substance?How should this be answered?Provide the name, address, and responsibility of each manufacturer, including contractor, and each proposed production site or facility involved in manufacturing and testing.Include the DMF number, refer to the Letter of Authorization in the body of data, andidentify the US Agent (if applicable)How do the manufacturing processes and controls ensure consistent production of the drug substance?Can this question be answered by reference to a DMF?Yes. It is preferable to mention the source of the material (synthetic or natural) when both sources are available.The DMF holder’s COA for the batch used to manufacture the exhibit batches should be provided in the body of data at 3.2.S.4.4.If there is no DMF, what information should be provided?A complete description of the manufacturing process and controls used to produce the drugsubstance.2.3.S.3 CharacterizationHow was the drug substance structure elucidated and characterized?Can structure elucidation be answered by reference to a DMF?Yes.What information should be provided for chiral drug substances?When the drug substance contains one or more chiral centers, the applicant should indicate whether it is a racemate or a specific enantiomer.When the drug substance is a specific enantiomer, then tests to identify and/or quantify that enantiomer should be included. Discussion of chirality should include the potential forinterconversion between enantiomers (e.g. racemization/epimerization).How were potential impurities identified and characterized?List related compounds potentially present in the drug substance. Identify impurities bynames, structures, or RRT/HPLC. Under origin, classify impurities as process impurities and/or degradants.Structure Origin ID ChemicalName[SpecifiedImpurity]Is identification of potential impurities needed if there is a USP related substances method?Yes.Can this question be answered by reference to a DMF?The ANDA should include a list of potential impurities and their origins. The methodsused to identify and characterize these impurities can be incorporated by reference to the DMF.According to the CTD guidance, section S.3 should contain a list of potential impurities and the basis for the acceptance criteria for impurities, however in the OGD examples this information was in section S.4. Where should it go?This information may be included in either S.3 or in S.4.2.3.S.4 Control of Drug SubstanceWhat is the drug substance specification? Does it include all the critical drug substance attributes that affect the manufacturing and quality of the drug product?What format should be used for presenting the specification?Include a table of specifications. Include the results for the batch(es) of drug substance used to produce the exhibit batch(es). Identify impurities in a footnote. Test results and acceptance criteria should be provided as numerical values with proper units whenapplicable.Tests Acceptancecriteria AnalyticalprocedureTest results for Lot#AppearanceIdentificationA:B:AssayResidualSolventsSpecified ImpuritiesRC1RC2RC3Any UnspecifiedImpurityTotal Impurities[AdditionalSpecification]*RC 1: [impurity identity]RC 2: [impurity identity]RC 3: [impurity identity]What tests should be included in the drug substance specification?USP drugs must meet the USP monograph requirements, but other tests should be included when appropriate. For USP and non USP drugs, other references (EP, BP, JP, the DMF holder’s specifications, and ICH guidances) can be used to help identify appropriate tests.Only relevant tests should be included in the specification. Justify whether specific tests such as optical rotation, water content, impurities, residual solvents; solid state properties(e.g. polymorphic form, particle size distribution, etc) should be included in thespecification of drug substance or not.Does OGD accept foreign pharmacopeia tests and criteria for drug substances?There are several examples where a drug substance is covered by a monograph in EP or JP, but not in the USP. ANDA and DMF holders can obtain information regardingphysicochemical properties, structure of related impurities, storage conditions, analytical test methods, and reference standards from EP or JP to support their submission to OGD.Although the USP remains our official compendium, we usually accept EP when the drug substance is not in USP (However, a complete validation report for EP methods should be provided in the ANDA).For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?What level of detail does OGD expect for the analytical method justifications and validations?Provide a summary of each non-USP method. This can be in a tabular or descriptive form.It should include the critical parameters for the method and system suitability criteria ifapplicable. See an example in section 2.3.P.5 of this document.For each analytical procedure, provide a page number/link to the location of validationinformation in Module 3. For quantitative non-compendial analytical methods, provide a summary table for the method validation. See an example in section 2.3.P.5 of thisdocument.Is validation needed for a USP method?No, but USP methods should be verified and an ANDA sponsor should ensure that theUSP assay method is specific (e.g. main peak can be separated from all process impurities arising from their manufacturing process and from degradation products) and the USPrelated substance method is specific (e.g. all the process impurities and degradants can be separated from each other and also separated from main peak).Is validation needed if the USP method is modified or replaced by an in-house method?Yes. Data supporting the equivalence or superiority of the in-house method should beprovided. In case of a dispute, the USP method will be considered the official method.Is reference to the DMF for drug substance analytical method validations acceptable?No. ANDA sponsors need to either provide full validation reports from the ANDA holder or reference full validation reports from the DMF holder (provided there is a copy of the method validation report in the ANDA and method verification from the ANDA holder). AppearanceIdentityAssayImpurities (Organic impurities)What format should be used for related substances?List related compounds potentially present in the drug substance. (Either here or S.3)Name Structure Origin[SpecifiedImpurity]Provide batch results and justifications for the proposed acceptance criteria. See guidance on ANDA DS impurities4 for acceptable justifications. If the DS is compendial, include the USP limits in the table. If the RLD product is used for justification/qualification, then its results should also be included. If an ICH justification is used, then the calculation of the ICH limits should be explained.To use the ICH limits, determine the Maximum Daily Dose (MDD) indicated in the label and use it to calculate the ICH Thresholds: Reporting Threshold (RT), Identification1. The amount of drug substance administered per day2. Higher reporting thresholds should be scientifically justified3. Lower thresholds can be appropriate if the impurity is unusually toxicSponsors can use the ICH limits to ensure the LOQ for the analytical method is equal or below the RT, establish the limit for “Any Unspecified Impurity” to equal or below the IT, and establish limits for each “Specified Identified Impurity” and each “SpecifiedUnidentified Impurity”5 to equal or below the QT.An impurity must be qualified if a limit is established above the QT. Options forqualification include reference to the specific impurity listed in a USP monograph,comparison to the RLD product, identifying the impurity as a significant metabolite of the drug substance, literature references including other compendial monographs (EP, BP, JP), or conducting a toxicity study.4/cder/guidance/6422dft.pdf5 The ANDA DS guidance states “For unidentified impurities to be listed in the drug substance specification, we recommend that you clearly state the procedure used and assumptions made in establishing the level of the impurity. It is important that unidentified specified impurities be referred to by an appropriate qualitative analytical descriptive label (e.g., unidentified A, unidentified with relative retention of 0.9)”. Q3A(R) states “When identification of an impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful effort should be included in the application.”Name DrugSubstance(Lot #)USPLimit forDrugSubstanceRLDDrugProduct(Lot #)ProposedAcceptancecriteriaJustification[Specified Impurity,Identified][BatchResults][BatchResults][SpecifiedImpurity,Unidentified]Any UnspecifiedImpurityTotalImpuritiesInclude the column for RLD drug product only if that data is used to justify the drugsubstance limit (example a process impurity that is also found in the RLD).What is OGD’s policy on genotoxic impurities?FDA is developing a guidance for genotoxic impurities. According to the ICH Q3A lower thresholds are appropriate for impurities that are unusally toxic.If impurities levels for an approved generic drug are higher than the RLD, can the approved generic drug data be used as justification for a higher impurity specification?According to ANDA DP and DS Impurity guidances, any approved drug product can be used to qualify an impurity level. However, the guidances qualify this by later stating “This approved human drug product is generally the reference listed drug (RLD). However, you may also compare the profile to a different drug product with the same route ofadministration and similar characteristics (e.g. tablet versus capsule) if samples of thereference listed drug are unavailable or in the case of an ANDA submitted pursuant to a suitability petition.”What if there are no impurities’ tests found in the USP monograph for a USP drug substance? What should the ANDA sponsor do?Please work with your supplier (DMF Holder) to ensure that potential synthetic process impurities (e.g. isomers (if any), side reaction products), degradation impurities, metalcatalysts, and residual solvents are adequately captured by your impurities test method.There may be information available in published literature as well, regarding potentialimpurities.Can levels of an impurity found in the RLD and identified by RRT be used for qualification?Qualification of a specified unidentified impurity by means of comparative RRT, UVspectra, and mass spectrometry with the RLD may be acceptable. However, the ANDAsponsor should make every attempt to identify the impurity.If levels are higher than in an approved drug product then the sponsor should provide data for qualification of the safety of this impurity at this level.Can a limit from a USP monograph for “any unspecified impurity” be used to justify a limit for “any unspecified impurity” greater than the ICH Q3 identification threshold?No. Any unspecified impurity (any unknown) limit should not exceed ICH Q3A “IT”based on MDD. Non-specific compendial acceptance criteria (e.g. Any Individual Impurity is NMT 0.5%) should not be used for justification of proposed impurity acceptance criteria.However, if the USP limit is less than the ICH threshold, then the USP limit should be used. Can a limit for an identified impurity in the drug substance be qualified with data obtained from RLD drug product samples treated under the stressed conditions?No. Test various samples of marketed drug product over the span of its shelf life (ideally, near the end of shelf-life). Data generated from accelerated or stressed studies of the RLD is considered inappropriate.Impurities (Residual Solvents)Will OGD base residual solvent acceptance limits on ICH limits or process capability?The ICH guidance on residual solvents6 provides safety limits for residual solvents but also indicates that “residual solvents should be removed to the extent possible”. ANDA residual solvent limits should be within the ICH safety limits, but the review of the ANDA includes both of these considerations.OGD generally accepts the ICH limits when they are applied to the drug product.What about solvents that are not listed in Q3C?Levels should be qualified for safety.Impurities (Inorganic impurities)Polymorphic FormWhen is a specification on polymorphic form necessary?See ANDA polymorphism guidance7 for a detailed discussion.Particle SizeWhen is a drug substance particle size specification necessary?A specification should be included when the particle size is critical to either drug productperformance or manufacturing.For example, in a dry blending process, the particle size distribution of the drug substance and excipients may affect the mixing process. For a low solubility drug, the drug substance particle size may have a critical impact on the dissolution of the drug product. For a high solubility drug, particle size is often not critical to product performance.6 /cder/guidance/Q3Cfnl.pdf7/cder/guidance/6154dft.pdfWhat justification is necessary for drug substance particle size specifications?As for other API properties, the specificity and range of acceptance criteria for particle size, and the justification thereof, could vary from none to very tight limits, depending upon the criticality of this property for that drug product.Particle size specifications should be justified based on whether a change in particle sizewill affect the ability to manufacture the product or the final product performance.In general, a sponsor either should demonstrate through mechanistic understanding orempirical experiments how changes in material characteristics such as particle size affecttheir product.In the absence of pharmaceutical development studies, the particle size specificationshould represent the material used to produce the exhibit batch.When should the particle size be specified as distribution [d90,d50,d10] and when is a single point limit appropriate?When critical, a particle size should be specified by the distribution. There may be othersituations when a single point limit can be justified by pharmaceutical development studies.2.3.S.5 Reference StandardsHow were the primary reference standards certified?For non-compendial, in-house reference standards, what type of qualification data is recommended? Will a COA be sufficient?COA should be included in Module 3, along with details of its preparation, qualification,and characterization. This should be summarized in the QOS.In terms of the qualification data that may be requested, it is expected that these reference standards be of the highest possible purity (e.g. may necessitate an additionalrecrystallization beyond those used in the normal manufacturing process of the activeingredient) and be fully characterized (e.g. may necessitate in the qualification reportadditional characterization information such as proof of structure via NMR) beyond theidentification tests that are typically reported in a drug substance COA. StandardLaboratory Practice for preparation of reference standards entails recrystallization toconstant physical measurements or to literature values for the pure material.2.3.S.6 Container Closure SystemWhat container closure is used for packaging and storage of the drug substance?Can this question be answered by reference to a DMF?Yes.。

DEVELOPMENT REPORT – July 29, 2002: Tools for DevelopmentBy Jill MossThis is the VOA Special English Development Report. Building things or making clothes can be difficult in developing countries, especially without the correct tools. However, an international humanitarian organization called CARE is trying to change this. CARE runs a special program called Tools for Development to help workers in developing countries.The Tools for Development program sells used tools and equipment at low cost to people who have small businesses. The tools are priced low enough so that poor people can buy them.Roy Megarry (Ma-GARY) started Tools for Development fifteen years ago. At thetime, he was the publisher of the Globe and Mail, a Canadian newspaper. MisterMegarry got the idea for the program while visiting a technical training school forboys in Lima, Peru.The Catholic priest who operated the school told Mister Megarry that the schoolneeded equipment for its training program. Mister Megarry sent a letter to thepresident of Sears Company in Canada requesting help. The company gaveequipment to the school in exchange for advertising in the newspaper. Today, Tools for Development receives free equipment and gifts from companies and organizations all over the world. Since the program began, more than two -thousand people have purchased more than six-thousand tools andequipment. They paid a total cost of one -million -two-hundred-thousand dollars. Mister Megarry says at least ten-thousand jobs have been saved or created because of the program. Money gained from the sale of the tools is used for loans, training and shipping costs.People can buy many kinds of equipment through Tools for Development. For example, there are tools for metal workers, shoemakers, pipe builders, clothing makers and people who fix vehicles. Some computers are also sold. Tools for Development is currently operating in Ecuador, Costa Rica and Jamaica. However, CARE is hoping to expand the program to other developing nations. You can learn more about Tools for Development. Write to CARE Canada, the Globe and Mail newspaper, four-four-four Front Street West, Toronto, Ontario, M-five -V, two-S-nine, Canada. Or you can visit the CARE Canada Internet Web site at w-w-w-dot-c-a-r-e-dot-c-a. This VOA Special English Development Report was written by Jill Moss.Email this article to a friendPrinter Friendly Version (Photo - CARE)。

常见国际英文缩写词汇常见国际组织英文缩写UN ( United Ntions) 联合国UNSC（Security Council）联合国安全理事会FO (Food nd griculture Orgniztion of the United Ntions) (联合国)粮食及农业组织UNESCO (United Ntions Eductionl, Scientific nd Culturl Orgniztion) 联合国教科文组织UNCF (United Ntions Children's Fund,其前身是United Ntions Interntionl Children's Emergency Fund) 联合国儿童基金会UNIDO (United Ntions Industril Development Orgniztion)联合国工业进展组织UNDP (United Ntions Development Progrmme)联合国开发计划署UNEP (United Ntions Environment Progrmme)联合国环境署UNCDF(United Ntions Cpitl Development Fund)联合国资本开发基金会UNCTD (United Ntions Conference on Trde nd Development) 联合国贸易与进展会议WHO (World Helth Orgniztion) 世界卫生组织WMO (World Meteorologicl Orgniztion) 世界气象组织WTO (World Trde Orgniztion) 世界贸易组织GTT (Generl greement on Triffs nd Trde) 关税及贸易组织WIPO (World Intellectul Property Orgniztion)世界知识产权组织WPC (World Pece Council) 世界和平理事会ILO (Interntionl Lbour Orgniztion) 国际劳工组织IMF (Interntionl Monetry Fund) 国际货币基金组织IOC (Interntionl Olympic Committee) 国际奥林匹克委员会UPU (Universl Postl Union) 万国邮政联盟ITU (Interntionl Telecommuniction Union) 国际电信联盟IFC(Interntionl Finnce Corportion) 国际金融公司IMO (Interntionl Mritime Orgniztion) 国际海事组织ISO (Interntionl Stndrd Orgniztion) 国际标准化组织ICO (Interntionl Civil vition Orgniztion) 国际民用航空组织ID (Interntionl Development ssocition) 国际开发协会IFD (Interntionl Fund for griculturl Development) 国际农业进展基金会IOJ (Interntionl Orgniztion of Journlists) 国际新闻工协会ICC(Interntionl Chmber of Commerce)国际商会UE(Universl Espernto ssocition)国际世界语协会INTELST (Interntionl telecommunictions Stellitic)国际通信卫星机构IRTO (Interntionl Rdio nd Television Orgniztion)国际广播电视组织IE (Interntionl tomic Energy gency) 国际原子能机构NTO (North tlntic Trety Orgniztion)北大西洋公约组织OPEC(Orgniztion of Petroleum Exporting Countries) 石油输出国组织OECD (Orgniztion for Economic Coopertion nd Development)经济合作与进展组织CME(Council for Mutul Economic ssistnce)经济互助委员会(经互会)PEC (si nd Pcific Economic Coopertion) 亚洲太平洋经济合作组织SEN (ssocition of Southest sin Ntions)东南亚GJ联盟OU (Orgniztion of fricn Unity) 非洲统一组织OIC (Orgniztion of the Islmic Conference) 伊斯兰会议组织CIS (Commonwelth of Independent Sttes) 独立GJ联合体EU (Europen Union) 欧洲联盟IPU (Inter-Prlimentry Union) 各国议会联盟OSCE (Orgniztion for Security nd Coopertion in Europe)欧洲安全与合作组织EEC (Europen Economic Communities) 欧洲经济共同体OEEC (Orgniztion for Europen Economic Coopertion)欧洲经济合作组织NM (the Non-ligned Movement) 不结盟运动NC (fricn Ntionl Congress) 非洲RM大会PLO (Plestine Libertion Orgniztion)XX勒斯坦解放组织ICRC (Interntionl Committee of the Red Cross) 红十字国际委员会NS（Ntionl eronutics nd Spce dministrtion）美国航天太空总署。

专题05中国迈入智能网驾驶新时代【原文·外刊阅读】China's intelligent connected driving industry enters new stage with faster pace（文章来源：Global Times）China's intelligent connected vehicle industry,which strives to integrate vehicles with road andcloud computing, has moved to a new stage featuringrapid technological and ecological development,instead of a small-scale testing stage, according towhite paper released by the National InnovationCenter of Intelligent and Connected Vehicles (CICV).It added that a technology roadmap for top-level design is needed at the seventh World Intelligence Congress (WIC) held in north China's Tianjin Municipality from Thursday to Saturday.China is promoting the commercial application of its intelligent connected vehicles. Till now, the country has built seven pilot zones of the Internet of vehicles, 16 pilot cities for coordinated development of smart city infrastructure and smart connected vehicles, and 17 national-level demonstration base to test intelligent connected cars.Miao Changxing, an official from the Ministry of Industry and Information, said on Tuesday in Beijing that over 2,000 road test and demonstration application licenses have been issued and 10,000 kilometers road opened to test driverless vehicles.New output value of the intelligent connected vehicle industry will reach 1.06 trillion yuan (about $151 billion) by 2025, and 2.8 trillion yuan (about $398.5 billion) by 2030, said Zheng Jihu, director of the CICV.Zheng added that developing the industry takes a very complicated process, which requires the integrated and coordinated advance of vehicles, roadside infrastructure, cloud control platforms, telecommunication networks, maps for high-precision positioning and security protection systems.China is leading the world in telecommunications and new energy vehicles, and the application in the intelligent connected vehicle industry will boost the development of vehicle, transport, communication and cloud computing, said Zheng.Autonomous driving in ChinaBloomberg anticipated in April that Elon Musk wants to test its full self-driving technology in China, as the country's artificial intelligence-powered autonomous-vehicle market is "showing serious promise."Accelerating the large-scale application of Level 4 autonomous driving – with Level 6 the highest – will be important in leading the development of the automobile industry and build a new competitive advantage of the country, according to a report issued by the China Academy of Information and Communications Technology during the WIC.However, there are still many challenges autonomous driving have to overcome. The report urged to provide safety guarantees for automatic driving and integrate it into transportation system;It added that the use of unmanned driving should be expanded, and a commercial closed loop of research and development, testing and operation created, it said.In addition, it advocated that policies and regulations be iterated and innovated to get autonomous driving protected by the law, and a positive and inclusive social environment built to accelerate commercial operation of autonomous driving service.【原创·语法填空】China is promoting the commercial 1 (apply) of intelligent connected vehicles. As of now, the country 2 (establish) 7 pilot areas for the Internet of Vehicles, 16 pilot cities for the coordinated3 (develop) of smart city infrastructure and intelligent connected vehicles, and 17 national level intelligent connected vehicle test and demonstration bases. Bloomberg predicted in April4 Elon Musk would like to test its fully automated driving technology in China, because China's artificial intelligence driven autonomous vehicle market "shows great prospects".According to a report 5 (release) by the China Institute of Information and Communication Technology during the WIC period, accelerating the large-scale application of Level 4 autonomous driving, with Level 6 being the highest, 6 (be) of great significance in leading the development of the automotive industry and establishing new national competitive advantages. 7 , there are still many challenges toovercome for autonomous driving. The report urges providing safety guarantees for autonomous driving and integrating it 8 the transportation system; It added that the use of unmanned driving should be expanded and a commercial closed-loop for research and development, testing, and operation should be established. In addition, 9 advocates for iterative and innovative policies and regulations to ensure legal protection for autonomous driving and establish 10 positive and inclusive social environment to accelerate the commercial operation of autonomous driving services.【答案】1. application2. has established3. development4. that5. released6. will be7. However8. into9. it 10. a【原创·阅读理解】1. What is the main meaning of the sixth paragraph?A. High precision positioning is extremely important.B. The promotion of new energy vehicles is very smooth.C. The development of the intelligent connected vehicle industry is complex.D. The application of fully autonomous driving technology is challenging.【答案】C【解析】细节理解题。

DEVELOPMENT REPORT - U.N. Report Warns of Risk to Goal to Cut Poverty by 2015By Jill MossBroadcast: Monday, September 12, 2005I'm Barbara Klein with the VOA Special English Development Report.The United Nations has released its two thousand five Human Development Report. The report shows that eighteen countries have moved down the list in terms of conditions for their people. Twelve are in central and southern Africa. The others are former Soviet republics.But the U.N. report says many other nations have made progress. It says people in developing countries are generally healthier, wealthier and better educated than they were fifteen years ago. And they are also more likely to live in a democratic system.The report says one hundred thirty million people escaped extreme poverty during the nineteen nineties. And more than one thousand million gained access to clean water. But the study says two and one-half thousand million people still live on less than two dollars a day. And around half as many still do not have safe water.The U.N. Development Program has published the yearly report sincenineteen ninety. This year's came out last week. Later this week is the WorldSummit in New York. Leaders will mark the sixtieth anniversary of the UnitedNations. They also will discuss progress over the past five years toward theU.N.'s Millennium Development Goals.One goal is to cut the number of people living in extreme poverty by fiftypercent by two thousand fifteen. Other goals are to reduce child deaths bytwo-thirds and to provide basic education for all children in the next ten years. The new Human Development Report warns that the goals are at risk. It says that without more money for development, there will be millions of deaths that could have been prevented. And, it says, more than eight hundred million people will still be living in extreme poverty. The number is almost four hundred million higher than the target for two thousand fifteen.The U.N. report says developing nations must seek investment and fight dishonesty. But it says economic growth alone will not help most countries reach the goal to reduce poverty. It says they must also fight social inequalities and respect human rights.Finally, the report calls for major changes to international policies on aid, trade and security. It United Nationssays the world has the resources to end poverty, but must also have the political will.This VOA Special English Development Report was written by Jill Moss. Our reports are on the Internet at . I'm Barbara Klein.。

Unit 1 EnvironmentEarth’s Health in Sharp Decline, Massive Study Finds大规模研究发现：地球的“健康”每况愈下The report card has arrived from the largest ever scientific Earth analysis, and many of the planet’s ecosystems are simply not making the grade.有史以来对地球进行的最大规模的科学分析结果表明，地球上的许多生态系统都达不到标准。

The UN-backed Millennium Ecosystem Assessment Synthesis Report found that nearly two-thirds of Earth’s life-supporting ecosystems, including clean water, pure air, and stable climate, are being degraded by unsustainable use.由联合国主持的《千年生态系统评估综合报告》指出，由于不可持续的使用，地球上将近三分之二的用来维持生命的生态系统（包括干净的水源、纯净的空气以及稳定的气候）正遭受破坏。

Human has caused much of this damage during the past half century. Soaring demand for food, fresh water, timber, fiber and fuel have led to dramatic environmental changes, from deforestation to chemical pollution, the report says. The already grim situation may worsen dramatically during the first half of the 21st century, the report’s authors warn.以上大部分的破坏都是人类在过去的半个世纪里造成的。

EUR 23844 EN -2009Development of structural alerts for the in vivo micronucleus assay inrodentsRomualdo Benigni a , Cecilia Bossa a , Olga Tcheremenskaia aand Andrew Worthb aIstituto Superiore di Sanita’, Environment and Health Department,Rome, Italy b Institute for Health & Consumer Protection, European Commission -Joint Research Centre, Ispra, ItalyThe mission of the IHCP is to provide scientific support to the development and implementation of EU policies related to health and consumer protection.The IHCP carries out research to improve the understanding of potential health risks posed by chemical, physical and biological agents from various sources to which consumers are exposed.European CommissionJoint Research CentreInstitute for Health and Consumer ProtectionContact informationAddress: TP 582E-mail: andrew.worth@ec.europa.euTel.: +39 0332 789566Fax: +39 0332 786717http://http://ecb.jrc.ec.europa.eu/qsar/http://ec.europa.eu/dgs/jrc/Legal NoticeNeither the European Commission nor any person acting on behalf of the Commission is responsible for the use which might be made of this publication.A great deal of additional information on the European Union is available on the Internet.It can be accessed through the Europa serverhttp://europa.eu/JRC 52274EUR23844 ENISSN 1018-5593Luxembourg: Office for Official Publications of the European Communities© European Communities, 2009Reproduction is authorised provided the source is acknowledgedPrinted in ItalyABSTRACTIn vivo mutagenicity and carcinogenicity studies are posing a high demand for test-related resources. Among these studies, the micronucleus test in rodents is the most widely used, as follow up to positive in vitro mutagenicity results. A recent survey of the (Q)SAR models for mutagenicity and carcinogenicity has indicated that no (Q)SAR models for in vivo micronucleus are available in the public domain. Therefore, the development and extensive use of estimation techniques such as (Q)SARs, read-across and grouping of chemicals, promises to have a huge animal saving potential for this endpoint. In this report, we describe the identification of structural alerts for the in vivo micronucleus assay, and provide the list of underlying chemical structures. These structural alerts provide a coarse-grain filter for the preliminary screening of potential in vivo mutagens.LIST OF ABBREVIATIONSEPA Environmental Protection AgencyEU European UnionFDA Food and Drug AdministrationHOMO Highest Occupied Molecular OrbitalISS Istituto Superiore di Sanita’JRC Joint Research CentreLUMO Lowest Unccupied Molecular OrbitalOECD Organisation for Economic Cooperation and Development(Q)SAR(Quantitative)Structure-Activity RelationshipREACH Registration Evaluation and Authorisation of CHemicalsROC Receiver Operating CurveSA Structural AlertSA_BB Benigni-Bossa structural alerts for mutagnicity /carcinogenicity in ToxtreeSA_Mic Structural alerts refers for the in vivo micronucleus assay inToxtreeSA_Prot Structural alerts for protein binding in the OECD QSAR ToolboxCONTENTS1.Introduction (6)2.Structural alerts (8)3.Development of structural alerts for the in vivo micronucleus assay (10)4. Final considerations (20)5.References (21)Appendix 1 (23)1.IntroductionMutagenicity testing is an important part of the regulatory hazard assessment of chemicals. It is undertaken for two main reasons: a) to detect chemicals that might cause genetic damage in germ cells, and thus increase the burden of heritable (genetic) disease in the human population; and b) to detect chemicals that might be carcinogenic (based on the assumption that mutagenesis, for example in somatic cells, is a key event in the process of carcinogenesis). Since no method is able alone to detect all possible genotoxic events, a wide array of test systems has been developed and accepted internationally in regulatory schemes.Most often, these methods are used within a 2-tiered integrated testing approach: Tier 1 includes in vivo assays, and Tier 2 includes in vivo assays. As a matter of fact, mutagenicity testing was the first toxicity endpoint for which in vivo assays were accepted for regulatory testing, some 25 years ago. The latter usually comprise bacterial mutagenicity and cytogenetics tests, although gene mutation testing in cultured mammalian cells is sometimes also undertaken.Tier 2 of the testing strategy involves the use of short-term in vivo studies (usually a bone-marrow cytogenetics assay) to assess whether any potential for genotoxicity detected at the Tier 1 in vivo stage is actually expressed in the whole animal. Thus, negative results in vivo are usually considered sufficient to indicate lack of mutagenicity, whereas a positive result is not considered sufficient to indicate that the chemical represents a mutagenic hazard (i.e. it could be a false positive). The above approach to genotoxicity testing has been adopted throughout the EU1,and has been recommended internationally as part of the strategy for predicting and quantifying mutagenic and carcinogenic hazard (Ashby et al.,1996; Combes et al.,2007; Kirkland and Speit,2008; Lilienblum et al.,2008).1http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_r7a_en.p df?vers=20_08_08According to an assessment carried out by the former European Chemicals Bureau (ECB), the in vivo mutagenicity studies, shortly followed by carcinogenicity, are posing high demand for test-related recourses (Pedersen et al.,2003; Van der Jagt et al.,2004). Among those, the micronucleus test in rodents is the most widely used, as follow up to positive in vivo mutagenicity results. A recent survey of the (Q)SAR models for mutagenicity and carcinogenicity (performed jointly by ISS and the JRC) has indicated that no (Q)SAR models for in vivo micronucleus are available in the public domain (Benigni et al.,2007): therefore, the development and extensive use of estimation techniques such as (Q)SARs, read-across and grouping of chemicals, might have a huge saving potential for this endpoint.In this report, we describe: a) the collection of data on chemicals tested with the in vivo micronucleus assay; b) preliminary analyses of the data; c) the identification of Structural Alerts (SA) proper to this toxicological endpoint. First, some background information on the concept of SA is provided.2.Structural alertsThe SAs for a toxicological endpoint are molecular functional groups or substructures known to be linked to that type of toxicity.The SAs are a coarse-grained approach to the use of Structure-Activity Relationships (SAR) to understand the toxicity mechanisms and to predict the toxic activity of chemicals. Because of their nature, the SAs have the role of pointing to chemicals potentially toxic, whereas no conclusions or indications about nontoxic chemicals are possible (except by exclusion) (Benigni and Bossa,2006; Benigni and Bossa,2008).A set of chemicals characterized by the same SA constitute a family (class) of compounds that share the same mechanism of action. The reactivity of a SA can be modulated or abolished by the remaining part of the molecule in which the SA is embedded. At a coarse-grain level, such modulating effects can be represented by other molecular substructures (e.g., bulky groups ortho to an aromatic amine group) that are known to have an influence on the reactivity of the SA. Usually, the knowledge on the modulating substructures is quite limited for most of the SAs, thus it provides limited help in deciding which chemicals in a class will actually be toxic and viceversa. A powerful generalization of the Structure-Activity Relationships is provided by the Quantitative Structure-Activity Relationship (QSAR) analysis, which produces a mathematical model that links the biological activity to a limited number of physical chemical or other molecular properties (descriptors) with general relevance. Since most of the descriptors have continuous values, the QSARs provide fine-tuned models of the biological activity,and can give account of subtle differences. General introductions on QSAR are given elsewhere (Hansch and Leo, 1995, Hansch et al.,2002). Thus the SAs are not a discriminant model on the same ground of the QSAR models: the latter produce estimates for both positive and negative chemicals, as well as for the gradation of toxic potency.The main role of the SAs is that of preliminary, or large-scale screenings. They are excellent tools for coarse-grain characterization of chemicals, including: description of sets of chemicals, preliminary hazard characterization, category formation and priority setting (enrichment). Since fine-tuned QSARs do not exist for many types of chemicals, the models based on SAs hold a special place in predictive toxicology. Theknowledge on the action mechanisms as exemplified by the SAs is routinely used in SAR assessment in the regulatory context (see, for example, the mechanistically-based reasoning as presented in Woo et al. (2002). In addition, the SAs are at the basis of popular commercial (e.g., DEREK, by Lhasa Ltd.2) and non-commercial software systems (e.g., Oncologic, by US Environmental Protection Agency[EPA]3).Recently, as follow-up of the collaboration between ISS and JRC,a rulebase for mutagens and carcinogens has been designed and implemented in the software Toxtree 1.51. It uses a structure-based approach consisting of a new compilation of SAs for carcinogenicity and mutagenicity. It also offers three mechanistically based QSARs for congeneric classes (aromatic amines and aldehydes) (Benigni et al., 2008a). Toxtree 1.51 is freely available from the JRC website.42/3/oppt/newchems/tools/oncologic.htm4http://ecb.jrc.ec.europa.eu/qsar/qsar-tools/index.php?c=TOXTREE3.Development of structural alerts for the in vivomicronucleus assay3.1 DataThe compilation of SAs for the in vivo micronucleus assay in rodents provided here, is based on both the existing knowledge on the mechanisms of toxic action and a structural analysis of the chemicals tested in the assay.The in vivo micronucleus data in the public domain is quite limited. A search of the Chemical Carcinogenesis Research Information System(CCRIS) at the Toxnet website with the query: “in vivo micronucleus” points only to 240 chemicals.5For this work, the remarkably larger commercial database by Leadscope Inc., called “FDA SAR Genetox Database” was used.6This database contains more than 700 chemicals tested in in vivo micronucleus with rodents, and includes data from both the public domain and the US Food and Drug Administration (FDA) files. A large majority of data were based on the analysis of micronuclei in bone marrow cells; for details on the technique, see for example, Krishna and Hayashi (2000).3.1 Preliminary analysesSince the main role of the in vivo micronucleus assay in regulatory schemes is that of confirming (or disproving) the positive in vitro results, it is of interest to check how the in vivo micronucleus results relate to the rodent carcinogenicity data and to the primary in vitro prediction test, i.e., the Salmonella typhimurium(Ames) test.Tables I and II display the relationships between the in vivo micronucleus ad the two reference tests. The results for rodent carcinogenicity and the Ames test were retrieved from the freely available ISSCAN v3a database,7which is characterized by:5/cgi-bin/sis/search6/product_info.php?products_id=777http://www.iss.it/ampp/dati/cont.php?id=233&lang=1&tipo=7a) the high quality of both chemical and biological information; b) the QSAR-ready format (Benigni et al.,2008b). Obviously, the total numbers of chemicals in the two tables are relative only to those chemicals tested in both systems.Table I. Contingency table comparing the results of the rodent carcinogenicity testwith the micronucleus testTable II:Contingency table comparing the results of the Salmonella typhimuriumassay with the micronucleus testTable I shows that is the in vivo micronucleus assay is poorly sensitive to the rodent carcinogens: about 60% of the rodent carcinogens are not detected by the micronucleus. The poor sensitivity of the micronucleus assay to potential genotoxins is also apparent from Table II.It should be emphasized that the present results obtained with the large Leadscope micronucleus database are in agreement with previous analyses based on smaller datasets in the public domain (Benigni,1995).In a second round of analyses, the extent to which the micronucleus data are related to well established indicators of DNA and protein binding was checked. This in view of the plethora of the reported mechanisms of micronucleus induction. As a matter of fact, micronuclei are markers of both aneugenic (change in the chromosomes number, usually by loss) and clastogenic (chromosome breakage) effects. It is generally assumed that such effects are generated through a range of different pathways. Evidence (mainly gathered from in vitro studies) indicates that micronuclei can be induced e.g., by typical DNA-attacking agents (e.g., alkylating agents like methylmethane sulfonate), by mitotic spindle poisons (e.g., colcemide, vincristine), or by inhibitors of cytokinesis (e.g., cytochalasin B). The latter effects are probably due to interference with proteins. Other chemicals are thought to be clastogenic through aspecific disturbance of cytokinesis due to lipophilicity (Dorn et al.,2007).The relative influence of DNA and protein binding on micronucleus generation was checked by recording the distribution of structural alerts for the two effects in the Leadscope in vivo micronucleus database. As probes for DNA binding, we used the structural alerts for carcinogenicity / mutagenicity implemented in Toxtree 1.51. As a matter of fact, the large majority of these alerts refer to genotoxic carcinogenicity, which is assumed to be caused through direct interaction with DNA (Benigni and Bossa, 2008). As probes for protein binding, we used the alerts implemented in the Organisation for Economic Cooperation and Development (OECD) QSAR Toolbox.8 These alerts were mainly developed from the mechanistic knowledge on skin sensitization, and model the covalent binding to proteins.The results of the above analysis is displayed in Figure 1 as a ROC graph. It appears that the structural alerts for carcinogenicity /mutagenicity correlate to some extent with the induction of micronuclei, whereas those for protein covalent binding show no correlation (in the graph, they are on the diagonal line which represents random results).8/document/23/0,3343,en_2649_34379_33957015_1_1_1_1,00.htmlFigure 1. Receiver Operating Curve showing the concordance of two sets of structural alerts with the results of the in vivo micronucleus assay(SA_BB refers to the Benigni-Bossa alerts in Toxtree; SA_Prot refers to the alerts for proteinbinding in the OECD QSAR Toolbox)3.3 Structural Alerts for in vivo micronucleus assaySince the above analyses pointed to genotoxic effects as an important determinant of micronuclei induction, we developed the list of Structural alerts for in vivo micronucleus using the carcinogenicity / mutagenicity alerts in Toxtree as a core , and then searching for additional substructures specific to the micronucleus-positive chemicals. From the Toxtree alerts for carcinogenicity / mutagenicity,we excluded four alerts specific for non-genotoxic mechanisms of carcinogenicity.Using linear discriminant analysis as an analytical tool and ROC plots as a graphical tool, a series of additional substructures were added / removed to / from the Toxtreealerts in order to increase sensitivity and specificity.In these exploratory analyses, wescreened the very large collection of substructural patterns and functional groups (more than 27,000) contained in the software Leadscope Enteprise 2.4.15-6. We also re-checked the Toolbox protein binding alerts for individual substructures related with micronucleus induction.The result is the optimized list of alerts in Appendix 1. Together with the Toxtree alerts, it contains five additional substructures identified in the course of this research. For the sake of clarity,the codes of the alerts in Toxtree are maintained, whereas the five additional alerts have new codes.Figure 2 displays the agreement between the alerts for in vivo micronucleus, and the experimental results for this endpoint. Out of 547 negatives, the specificity of the SAs is 0.57. The sensitivity is 0.65 out of 182 positives. The overall accuracy is 0.59. For a comparison, the ROC graph shows the newly developed alerts for micronucleus together with those for DNA and protein binding. It appears that the performance of the final list of alerts is considerably higher than that of the DNA binding and Protein binding alerts.Table III gives the true positive rate for the individual alerts.Figure 2 Receiver Operating Curve showing the concordance of structural alerts for the in vivo micronucleus assay with the experiemtnal results for this assay(SA_Mic refers to the in vivo micronucleus alerts in Toxtree)Table III: Characterisation of Structural Alerts.3.4 Further analyses on the alerts for micronucleusA striking evidence in Table III is the relatively low percentage of true positives identified by many SAs. In other words, often the toxic potential of the alerts is not translated into actual toxicity in the experimental system. For a comparison, the True Positive Rate of the various alerts for mutagenicity /carcinogenicity in Toxtree is remarkably higher, ranging from 70 to 100% (Benigni and Bossa,2008).The above result contributes to better understand the evidence in Tables I and II, where it appears that the micronucleus assay has many more negatives than the carcinogenicity bioassay and the Salmonella mutagenicity test. Table III indicates that the low sensitivity of the micronucleus assay is largely due to the fact that often,chemical functionalities and substructures which are supposed to be reactive do not exert their potential reactivity in this experimental system.The issue of the low sensitivity of the micronucleus assay has been recognized by scientists involved in research aimed at improving the available short-term mutagenicity assays; as a matter of fact, validation of further, more sensitive in vivo assays (e.g., in vivo Comet assay) is presently in progress (Kirkland and Speit,2008).In the context of this research, we investigated if a general effect of bioavailability on the limited sensitivity of micronucleus was apparent. To this aim, we considered two chemical descriptors well known as to be linked to bioavailability: logP (hydrophobicity) and Molar Refractivity (MR) (Hansch and Leo,1995). The two descriptors were calculated with the C-QSAR software (Daylight, Inc.)9for all the chemicals in the micronucleus database. For the two parameters, Table IV reports the ranges of values for positive and negative micronucleus results.Table IV: Ranges of C-logP and C-MR in chemicals assayed withthe micronucleus testIt appears that the micronucleus positives cover a more limited range of logP values than the micronucleus negatives; however, the consideration of exclusion values for logP in combination with the SAs did not improve the overall performance (results not shown).Whereas no general effect of logP (or MR) was found, analyses on the individual chemical classes showed that logP cut-offs can be identified for the classes of Nitroaromatics (Negatives at logP > 0.0), Aromatic Diazo (Negatives at logP < 3.7),9/about/index.htmland Oxolanes (Negatives at logP > 1.5). The consideration of these cut-offs increases the specificity of the SAs from0.57 to 0.60.The above result suggests a possible strategy to understand and modeling the many negative results observed with the micronucleus. Since the bone marrow (main target of the test) is an organ easily accessible by the blood stream, it can be hypothesized that the lack of effect shown by several chemicals with SAs (hence potentially reactive) is due to the many possible targets for reaction encountered in the in vivo situation; this diminishes the probability for the chemicals of reaching, and interacting with the molecular target(s) of the micronucleus test. For example, highly reactive chemicals will probably react with any target encountered in their way (e.g., proteins, water)before reaching the bone marrow. Thus it can be envisaged that QSARs for individual chemical classes should be developed, and that they should consider parameters linked to chemical reactivity(such as HOMO and LUMO energies). It can be hypothesized that the models derived from these QSARs will contribute to modulate the individual SAs.4. Final considerationsStructural alerts point to classes of chemicals with the potential to cause toxic effects (here, in vivo micronucleus). Since this potential is modulated in each molecule by the rest of the structure (e.g., other functional groups, electronic structure, bulky groups), not all chemicals in a class are equally toxic. In the case of the SAs identified in the present study for the in vivo micronucleus test, the percentage of chemicals that have SAs but are not active in the test system is particularly high. This evidence agrees with, and rationalizes the notion that this test system is sensitive to genotoxins to a limited extent, and does not respond to a large number of recognized carcinogens and mutagens. For this reason, a positive in vivo micronucleus result adds a strong weight to an in vivo positive mutagenicity result, whereas a negative in vivo micronucleus result has a much lower relevance. The availability of a wider range of in vivo mutagenicity assays is a priority for the present regulatory strategies.Within the above perspective, the SAs identified in this study provide a coarse-grain filter for a preliminary screening of potentially in vivo mutagens. In a risk assessment process, further information(e.g., QSARs for individual classes, experiments) is necessary to complete this initial screening step.5.ReferencesAshby,J., M.D.Waters, J.Preston, I.D.Adler, G.R.Douglas, R.Fielder, M.D.Shelby,D.Anderson, T.Sofuni, H.N.B.Gopalan, G.Becking and C.Sonich-Mullin(1996). IPCS harmonization of methods for the prediction and quantification of human carcinogenic/mutagenic hazard, and for indicating the probable mechanism of action of carcinogens. Mutat.Res./Fundamental and Molecular Mechanisms of Mutagenesis. 352:153-157.Benigni,R. (1995). Mouse bone marrow micronucleus assay: relationships with in Vitro mutagenicity and rodent carcinogenicity. J.Toxicol.Environ.Health.45:337-347.Benigni,R. and C.Bossa(2006). Structural alerts of mutagens and carcinogens.put.-Aid.Drug Des.2:169-176.Benigni,R. and C.Bossa(2008). Structure Alerts for carcinogenicity,and the Salmonella assay system: a novel insight through the chemical relational databases technology. Mutat.Res.Revs.659:248-261.Benigni,R., C.Bossa, N.G.Jeliazkova, zeva and A.P.Worth(2008a). The Benigni / Bossa rulebase for mutagenicity and carcinogenicity -a module of Toxtree. JRC Report EUR 23241 EN. European Commission Joint Research Centre, Ispra, Italy.http://ecb.jrc.ec.europa.eu/DOCUMENTS/QSAR/EUR_23241_EN.pdfBenigni,R., C.Bossa, A.M.Richard, and C.Yang (2008b). A novel approach: chemical relational databases, and the role of the ISSCAN database on assessing chemical carcinogenicity.Ann.Ist.Super.Sanità. 44:48-56.Benigni,R., C.Bossa, zeva and A.P.Worth(2007).Collection and evaluation of (Q)SAR models for mutagenicity and carcinogenicity. JRC Report EUR 22772 EN. European Commission Joint Research Centre, Ispra, Italy.http://ecb.jrc.ec.europa.eu /documents/QSAR/EUR_22772_EN.pdfCombes,R., C.Grindon, M.T.D.Cronin, D.W.Roberts and J.Garrod(2007). Proposed integrated decision-tree testing strategies for mutagenicity and carcinogenicity in relation to the EU REACH legislation.ATLA. 35:267-287.Dorn,S.B., G.H.Degen, T.Müller, D.Bonacker, H.F.P.Joosten, J.van der Louw,F.A.A.van Acker and H.M.Bolt(2007). Proposed criteria for specific and non-specific chromosomal genotoxicity based on hydrophobic interactions.Mutat.Res./Genetic Toxicology and Environmental Mutagenesis. 628:67-75. Hansch,C., D.Hoekman, A.Leo, D.Weininger and C.D.Selassie(2002).Chem-bioinformatics: comparative QSAR at the interface between chemistry and biology.Chem.Revs.102:783-812.Hansch,C. and A.Leo (1995). Exploring QSAR. 1. Fundamentals and applications in chemistry and biology.American Chemical Society. Washington, D.C.Kirkland,D. and G.Speit(2008). Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens III.Appropriate follow-up testing in vivo.Mutat.Res.654:114-132.Krishna,G. and M.Hayashi(2000). In vivo rodent micronucleus assay: protocol, conduct and data interpretation.Mutat.Res.455:155-166.Lilienblum,W., W.Dekant, H.Foth, T.Gebel, J.G.Hengstler, R.Kahl, P.J.Kramer,H.Schweinfurth and K.M.Wollin(2008). Alternative methods to safety studiesin experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH).Regulat.Toxicol.82:211-236.Pedersen,F., J.de Brujin, S.J.Munn and K.Van Leeuwen(2003).Assessment of additional testing needs under REACH. Effects of (Q)SARs, risk based testing and voluntary industry initiatives. JRC report EUR 20863 EN. European Commission Joint Research Centre, Ispra, Italy.http://ecb.jrc.ec.europa.eu/home.php?CONTENU=/DOCUMENTS/REACH/PUBLICATIONS/ Van der Jagt,K., S.J.Munn, J.Torslov and J.de Brujin (2004).Alternative approaches can reduce the use of test animals under REACH. Addendum to the Report "Assessment of addtional testing needs under REACH. Effects of (Q)SARs, risk based testing and voluntary industry initiatives. JRC Report EUR 21405 EN.European Commission Joint Research Centre, Ispra, Italy.http://ecb.jrc.ec.europa.eu/home.php?CONTENU=/DOCUMENTS/REACH/PUBLICATIONS/ Woo,Y.T., i, J.L.McLain, M.Ko Manibusan and V.Dellarco(2002). Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products. Environ.Health Perspect.110:75-87.Appendix 1European CommissionEUR 23844 EN–Joint Research Centre –Institute for Health and Consumer ProtectionTitle: Development of Structural alerts for the in vivo micronucleus assay in rodentsAuthor(s): Benigni R, Bossa C, Tcheremenskaia O and Worth A Luxembourg: Office for Official Publications of the European Communities 2009–42pp. –21x 29.7cmEUR –Scientific and Technical Research series –ISSN 1018-5593AbstractIn vivo mutagenicity and carcinogenicity studies are posing a high demand for test-related resources. Among these studies, the micronucleus test in rodents is the most widely used, as follow up to positive in vitro mutagenicity results. A recent survey of the (Q)SAR models for mutagenicity and carcinogenicity has indicated that no (Q)SAR models for in vivo micronucleus are available in the public domain. Therefore, the development and extensive use of estimation techniques such as (Q)SARs, read-across and grouping of chemicals, promises to have a huge animal saving potential for this endpoint. In this report, we describe the identification of structural alerts for the in vivo micronucleus assay, and provide the list of underlying chemical structures. These structural alerts provide a coarse-grain filter for the preliminary screening of potential in vivo mutagens.。

the sustainable developmentgoals reportThe Sustainable Development Goals (SDGs) are a set of 17 goals established by the United Nationsin 2015 to address global challenges such as poverty, inequality, climate change and peace. The goals are a roadmap for a sustainable future, and are designed to ensure that no one is left behindin the progress towards global development.The Sustainable Development Goals Report is a document produced by the United Nations that tracks global progress towards achieving the SDGs. The report is released every year, and provides an overview of the successes and challenges of the previous year, as well as identifying areas where more progress is needed.The 2021 Sustainable Development Goals Report highlights the impact of the COVID-19 pandemic on the progress towards achieving the SDGs. The report notes that the pandemic has caused significant setbacks in the progress towards the goals,particularly in areas such as poverty, education, and health. The report states that the pandemic has pushed an additional 120 million people into extreme poverty, and has disrupted education for over 1.6 billion students worldwide.Despite these setbacks, the report also highlights areas of progress. The report notes that significant progress has been made towards reducing maternal and child mortality rates, and that the number of people without access to electricity has continued to decline. The report also notes that progress has been made towards reducing greenhouse gas emissions, although more action is needed to meet global climate targets.The report also highlights the importance of partnerships in achieving the SDGs. The report notes that progress towards the SDGs can only be achieved through collaborative action across all sectors and stakeholders, including governments, civil society, and the private sector. The report calls for increased investment in sustainabledevelopment and for the establishment of effective partnerships to achieve the SDGs.The Sustainable Development Goals Report is an important document that provides an overview of global progress towards achieving the SDGs. The report highlights the successes and challenges of the previous year, and identifies areas where more progress is needed. The report also emphasizes the importance of partnerships in achieving the SDGs, and calls for increased investment in sustainable development. The SDGs are a roadmap for a sustainable future, and the Sustainable Development Goals Report plays a critical role in tracking progress towards this goal.。

1In Developing World, Health Services May Be Just a Phone Call AwayMonday, May 03, 2010This is the VOA Special English Development Report.Sending and receiving money by text message. Sharing crop prices. Just talking to a loved one far from home. These are some of the ways that mobile phones have changed lives in developing countries. Another way is through e-health, electronic health services.One example is a telephone hotline in the Democratic Republic of Congo. Callers can receive information about family planning and the prevention of unwanted pregnancies. They are able to speak privately with trained operators about contraceptive methods andabout health clinics.Photo: APMicheline Kapinga makes a call on a cell phone in the village of Kamponde in central CongoThe nonprofit group Population Services International and its partner Association de Sante Familiale launched the service in two thousand five. The United States Agency for International Development finances the program. And an agreement with the Vodacom company makes the service free to callers.We talked with Jamaica Corker, on her cell phone, at the Population Services International office in the D.R.C.JAMAICA CORKER: "The hotline has given us an opportunity to take advantage of cell phone technology, to reach people outside of our intervention zone with family planning messaging. In a country the size of western Europe, we can't be everywhere at the same time, and the hotline allows them to call in no matter where they are and to ask us the information that we can provide -- even if we're not necessarily able to provide the services directly."Jamaica Corker says more than twenty thousand people called the hotline in two thousand eight, the latest year available. More than eighty percent were men. She says this is mainly because men own most of the phones.The group also has family planning hotlines in Benin and Pakistan. And it is launching a mobile phone program to gather records on condom sales around Tanzania.The journal Health Affairs recently published an issue on "E-Health in the Developing World." Editor Susan Dentzer says e-health is improving lives in different ways.SUSAN DENTZER: "For example in Rwanda, where cellphone-based technologies are being used to keep track of dispensation of drugs to patients with H.I.V. And Rwanda is actually at the leading edge of developing nations in tapping these technologies to advance health and health care."In South Africa, a campaign of text messages about H.I.V. led to aVOA Special English2large increase in calls to the national AIDS helpline. And a program in Peru sends text messages to patients with H.I.V., reminding them to take their medicines.And that's the VOA Special English Development Report, written by June Simms. Tell us about e-health services where you are. You can share ideas and find our programs at and on Facebook at VOA Learning English. That's also our address on Twitter, YouTube and iTunes. I'm Steve Ember. 3。

The United Nations Sustainable Development GoalsIntroductionThe United Nations Sustainable Development Goals (SDGs) are a set of 17 global goals adopted by all United Nations Member States in 2015. These goals, also known as the Global Goals, aim to address the most pressing social, economic, and environmental challenges of our time and promote sustainable development worldwide. In this article, we will dive into each of the SDGs, discussing their significance and exploring how they contribute to a more inclusive, equitable, and sustainable future.Goal 1: No Poverty•Target 1.1: By 2030, eradicate extreme poverty for all people everywhere.•Target 1.2: Implement social protection systems and measures to ensure no one is left behind.Goal 2: Zero Hunger•Target 2.1: By 2030, end hunger and ensure access to safe, nutritious, and sufficient food for all.•Target 2.2: Improve agricultural productivity and the incomes of small-scale farmers.Goal 3: Good Health and Well-being•Target 3.1: By 2030, reduce the global maternal mortality ratio and end preventable deaths of newborns and children under 5.•Target 3.2: Ensure universal access to affordable and quality healthcare services.Goal 4: Quality Education•Target 4.1: By 2030, ensure that all girls and boys complete free, equitable, and quality primary and secondary education.•Target 4.2: Ensure equal access to affordable vocational training and tertiary education.Goal 5: Gender Equality•Target 5.1: End all forms of discrimination against women and girls.•Target 5.2: Eliminate all forms of violence against women and girls.Goal 6: Clean Water and Sanitation•Target 6.1: Achieve universal and equitable access to safe and affordable drinking water for all.•Target 6.2: Ensure access to adequate and equitable sanitation and hygiene for all.Goal 7: Affordable and Clean Energy•Target 7.1: By 2030, ensure universal access to affordable, reliable, and modern energy services.•Target 7.2: Increase the share of renewable energy in the global energy mix.Goal 8: Decent Work and Economic Growth•Target 8.1: Sustain per capita economic growth in accordance with national circumstances and, in particular, at least 7% annual GDP growth in the least developed countries.•Target 8.2: Promote inclusive and sustainable economic growth, full and productive employment, and decent work for all.Goal 9: Industry, Innovation, and Infrastructure•Target 9.1: Develop quality, reliable, sustainable, and resilient infrastructure, including regional and transborder infrastructure, to support economic development and human well-being.•Target 9.2: Promote inclusive and sustainable industrialization and foster innovation.Goal 10: Reduced Inequalities•Target 10.1: By 2030, progressively achieve and sustain income growth for the bottom 40% of the population at a rate higher than the national average.•Target 10.2: Empower and promote the social, economic, and political inclusion of all.Goal 11: Sustainable Cities and Communities•Target 11.1: Ensure access for all to adequate, safe, and affordable housing and basic services.•Target 11.2: Provide access to safe, affordable, accessible, and sustainable transport systems for all.Goal 12: Responsible Consumption and Production•Target 12.1: Implement the 10-year framework of programs on sustainable consumption and production, all countries takingaction.•Target 12.2: Achieve sustainable management and efficient use of natural resources.Goal 13: Climate Action•Target 13.1: Strengthen resilience and adaptive capacity to climate-related hazards and natural disasters.•Target 13.2: Integrate climate change measures into national policies, strategies, and planning.Goal 14: Life Below Water•Target 14.1: By 2025, prevent and significantly reduce marine pollution of all kinds.•Target 14.2: Sustainably manage and protect marine and coastal ecosystems to avoid significant adverse impacts.Goal 15: Life on Land•Target 15.1: By 2020, ensure the conservation, restoration, and sustainable use of terrestrial and inland freshwater ecosystems.•Target 15.2: Promote the implementation of sustainable management of all types of forests.Goal 16: Peace, Justice, and Strong Institutions•Target 16.1: Significantly reduce all forms of violence and related death rates everywhere.•Target 16.2: End abuse, exploitation, trafficking, and all forms of violence against and torture of children.Goal 17: Partnerships for the Goals•Target 17.1: Strengthen domestic resource mobilization, including through international support to developing countries, to improvedomestic capacity for tax and other revenue collection.•Target 17.2: Enhance global macroeconomic stability, including through policy coordination and coherence.ConclusionThe United Nations Sustainable Development Goals provide a comprehensive framework for addressing the world’s most critical challenges. From eradicating poverty and hunger to promoting gender equality and sustainable development, these goals guide global efforts towards abetter future for all. Achieving the SDGs requires collaborative action and strong partnerships at all levels, involving governments, businesses, civil society, and individuals. By working together, we can create a more sustainable and inclusive world for present and future generations.。

new report英语作文Title: A Groundbreaking Report on the Future of Sustainable Development.In today's rapidly changing world, the quest for sustainable development has become a paramount concern for individuals, communities, and nations alike. As we face the challenges of climate change, resource scarcity, and social inequality, the need for innovative and comprehensive solutions is more urgent than ever. This groundbreaking report aims to provide a comprehensive analysis of the current state of sustainable development and offer insights into the future directions and potential impact of sustainable practices.The report begins by examining the concept of sustainable development in detail. It highlights the three pillars of sustainability economic, social, and environmental and explains how they interconnect and influence each other. It emphasizes the importance ofbalancing these three aspects to ensure that development is not only profitable but also equitable and environmentally responsible.Turning to the current state of affairs, the report presents a mixed picture. On the one hand, there has been significant progress in some areas of sustainable development. Renewable energy sources are becoming more widely adopted, and there has been a growing focus on waste reduction and recycling. On the other hand, however, the report also points to significant challenges that remain. Climate change continues to pose a major threat, with global warming and extreme weather events becoming more frequent and severe. Additionally, social inequality and poverty persist in many regions, hindering the ability of these communities to participate fully in the benefits of sustainable development.The report goes on to explore the potential impact of sustainable practices on various sectors. In the economic realm, sustainable development can lead to more efficient resource utilization, reduced waste, and the creation ofnew green jobs. Environmentally friendly practices can also enhance the competitiveness of businesses and countries by reducing operational costs and capitalizing on the growing demand for sustainable products and services.In the social domain, sustainable development can promote inclusive growth and reduce disparities. By ensuring that all members of society have access to basic needs such as clean water, education, and healthcare, sustainable practices can foster a more equitable and harmonious society. This, in turn, can lead to improved social well-being and increased stability.The environmental implications of sustainable development are also profound. By reducing greenhouse gas emissions, promoting renewable energy, and conserving natural resources, sustainable practices can help mitigate the worst effects of climate change. They can also protect biodiversity, preserve ecosystems, and ensure the long-term sustainability of our planet.The report concludes by offering a series ofrecommendations and action plans for achieving sustainable development in the future. It calls for a global effort to prioritize sustainable practices across all sectors and levels of society. It also urges governments, businesses, and individuals to collaborate and innovate to find new solutions that address the challenges of sustainability ina comprehensive and integrated manner.In conclusion, this groundbreaking report provides a valuable roadmap for sustainable development in the future. By examining the current state of affairs and offering insights into the potential impact of sustainable practices, it aims to inspire and guide individuals, communities, and nations on the path to a more sustainable and prosperous future.。

united nations sustainable developmentgoalsThe United Nations Sustainable Development Goals (SDGs) are a set of 17 goals adopted by the United Nations General Assembly in 2015, with the aim of creating a sustainable future for all by 2030. The goals address global challenges such as poverty, inequality, climate change, and sustainable development.The 17 SDGs are as follows:1. No Poverty: End poverty in all forms everywhere.2. Zero Hunger: End hunger, achieve food security and improved nutrition, and promote sustainable agriculture.3. Good Health and Well-being: Ensure healthy lives and promote well-being for all at all ages.4. Quality Education: Ensure inclusive and quality education for all and promote lifelong learning.5. Gender Equality: Achieve gender equality and empower all women and girls.6. Clean Water and Sanitation: Ensure availability and sustainable management of water and sanitation for all.7. Affordable and Clean Energy: Ensure access to affordable, reliable, sustainable and modern energy for all.8. Decent Work and Economic Growth: Promote sustained, inclusive and sustainable economic growth, full andproductive employment and decent work for all.9. Industry, Innovation and Infrastructure: Build resilientinfrastructure, promote inclusive and sustainable industrialization and foster innovation.10. Reduced Inequalities: Reduce inequality within and among countries.11. Sustainable Cities and Communities: Make cities and human settlements inclusive, safe, resilient and sustainable.12. Responsible Consumption and Production: Ensuresustainable consumption and production patterns.13. Climate Action: Take urgent action to combat climate change and its impacts.14. Life Below Water: Conserve and sustainably use the oceans, seas and marine resources for sustainable development.15. Life on Land: Protect, restore and promote sustainableuse of terrestrial ecosystems, sustainably manage forests, combat desertification, and halt and reverse land degradation and halt biodiversity loss.16. Peace, Justice and Strong Institutions: Promote peaceful and inclusive societies for sustainable development, provide access to justice for all and build effective, accountableand inclusive institutions at all levels.17. Partnerships for the Goals: Strengthen the means of implementation and revitalize the global partnership for sustainable development.The SDGs are interconnected and require collectiveactions and partnerships among governments, civil society, private sector, and individuals to achieve the ambitious agenda.。

3.csrd欧洲可持续发展报告准则-回复CSRD（Corporate Sustainable Development Reporting）欧洲可持续发展报告准则在企业社会责任报告领域具有重要的指导意义。

CSRD准则旨在规范企业的可持续发展报告，促进企业在经济、环境和社会层面的持续改善。

本文将分为三个部分，逐步回答有关CSRD欧洲可持续发展报告准则的问题。

第一部分：CSRD欧洲可持续发展报告准则的概述首先，我们来了解一下CSRD准则的背景和目标。

CSRD是欧洲委员会于2001年提出的一项倡议，旨在鼓励企业以可持续发展为导向，通过透明、全面的报告来展示其自身经济、环境和社会责任的表现。

CSRD准则将企业的报告要求分为基本要求和细节要求两个层次，旨在提高企业的报告质量和透明度。

接下来，我们来详细了解CSRD准则的主要内容。

CSRD准则要求企业在报告中清晰地呈现其可持续发展战略、目标和绩效，并强调持续改善的重要性。

企业需要向利益相关者提供详尽的信息，包括其经济绩效、环境影响和社会责任履行情况。

此外，企业还需报告有关治理结构、可持续性风险管理和利益相关者参与等方面的信息。

CSRD准则还强调了报告的质量和透明度。

企业需确保报告信息真实准确，不得故意隐瞒或歪曲事实。

此外，企业还需遵守国际准则和标准，如全球报告倡议（GRI）指南和国际一体化报告框架（IIRC），以确保报告内容的可比性和可理解性。

第二部分：CSRD欧洲可持续发展报告准则的价值和意义CSRD欧洲可持续发展报告准则具有以下几个方面的价值和意义。

首先，CSRD准则促进了企业的可持续发展。

通过要求企业报告其可持续发展战略和绩效，CSRD准则鼓励了企业在经济、环境和社会层面的持续改善，并提高了企业的社会责任意识。

其次，CSRD准则增加了企业的透明度和可信度。

企业通过依照CSRD准则进行报告，向利益相关者提供了更全面、准确的信息，增强了外界对企业的信任和认可。