第一节设计安全无毒化学品的一般原则.ppt

1、Chapter 3,Designing Safer Chemicals,General Principles for Designing Safer Chemicals,Methods for Designing Safer Chemicals,Chapter 3 Designing Safer Chemicals,3.1 General Principles for Designing Safer Chemicals,3.1.1 General Principles for Designing Safer Chemicals,Two main ways to avoid Hazard and

2、 Toxicity: 1：make it not possible to enter the body, 2：make it not possible to affect the bio-chemical and physiological processes(生物化学和生理过程) hazardously.to human beings, to environment Direct hazard & Indirect hazard,General Principles for Designing Safer Chemicals,External considerations： Reductio

3、n of exposure or accessibility 减少化学品与生物机体接触的可能性Internal considerations： Prevention of toxic effects 预防化学品的毒性,They refer to the reduction of exposure by designing chemicals to improve the important physical and chemical properties related to environmental distribution and the up-take of the chemicals

4、 by man and other living organisms.,External considerations：,General Principles for Designing Safer Chemicals,External considerations: Reduction of exposure or accessibility,A. Properties related to environmental distribution/dispersion 1. Volatility/density/melting point 2. Water solubility 3. Pers

5、istence/biodegradation (生物降解性) a. oxidation, b. hydrolysis, c. microbial degradation（微生物降解性） 4. Conversion to biologically active substances 5. Conversion to biologically inactive substances,B. Properties related to uptake by organisms 1. Volatility （挥发性） 2. Lipophilicity（亲油性） 3. Molecular size 4. D

6、egradation （降解性） a. hydrolysis（水解）, b. Effect of pH, c. susceptibility to digestive enzymes （敏感性） （消化酶）,External considerations: Reduction of exposure or accessibility,Structural designs or redesigns: increase degradation rates, reduce volatility（挥发性）, reduce persistence time in the environment and

7、possibility of conversion to biologically active substances in the environment.,External considerations,Molecular designs : reduce or impede（妨碍） absorption by man, animals and aquatic life（水生生物）.,C. Consideration of routes of absorption by man, animals or aquatic life 1. Skin/eyes 2. Lungs 3. Gastro

8、intestinal tract（消化系统） 4. Gills(鳃) or other specific routes,External considerations: Reduction of exposure or accessibility,Bio-accumulation（生物聚集）or Bio-magnification （生物放大）:It refers to the increase of tissue concentration of a chemical as it progresses up the food chain.生物放大：指食物链向上一级进展，化学物质在组织中的浓度

9、增大的现象。,External considerations: Reduction of exposure or accessibility,Certain chemicals, for example chlorinated pesticides and other chlorinated hydrocarbons, will be stored in the tissues (组织) of a wide range of living organisms and may accumulate to toxic level (致毒水平).This phenomenon is exacerba

10、ted (恶化) by the fact that the lower forms of life or the organism at lower trophic (营养的) stages are subsequently consumed as food by fish, mammals and birds.These species in turn may be consumed by human.,External considerations:,Bio-magnification Food chain Hence, the substances of concerns may bot

11、h bio-accumulate in lower life forms and bio-magnify or increase their concentration in higher life forms by orders of magnitude as they accumulate and migrate up the food chain. 毒物可在低级生命形式中聚集，并会随着食物链在更高一级的生命形式中被生物放大到更大的数量级，如此由低级生命形式传递到更高级的生命形式。,External considerations: Reduction of exposure or acce

12、ssibility,D. Reduction/elimination of impurities 1. Generation of impurities of different chemical classes （不同化学类别的不纯物） 2. Presence of toxic homologs（同系物） 3. Presence of geometric, conformational or stereoisomers (几何、构象及光学异构体),External considerations: Reduction of exposure or accessibility,They gene

13、rally include approaches using molecular manipulations to : Facilitate bio-detoxication (生物解毒性) Avoid direct toxicity Avoid indirect bio-toxicity or bio-activation,Internal considerations: Prevention of toxic effects (预防毒性),Internal considerations-Prevention of toxic effects,A. Facilitation of de-to

14、xication （促进生物解毒性） 1. Facilitation of excretion（排泄） a. selection of hydrophilic(亲水的) compounds b. facilitation of conjugation/acetylation(乙酰化) conjugated with: glucuronic acid(葡萄糖醛酸) sulfate(硫酸盐), amino acid to accelerate urinary（泌尿器的） or biliary (胆汁的) excretion c. other considerations,2. Facilitati

15、on of biodegradation (可生物降解性) a. oxidation； b. reduction； c. hydrolysis,B. Avoidance of direct toxication 1. Selection of non-toxic chemical classes or parent compounds2. Selection of non-toxic functional groups a. avoidance of toxic groups; b. planned biochemical elimination of toxic structure thro

16、ugh the normal metabolism (新陈代谢) of the organism or strategic molecular relocation of the toxic groups; c. structural blocking of toxic groups; d. alternate molecular sites for toxic groups.,Internal considerations-Prevention of toxic effects,Indirect biotoxicationbioactivationIt describes the circu

17、mstances where a chemical is not toxic in its original structural form but becomes toxic after in vivo transformation to a toxic metabolite （代谢物）.Bioactivation represents a characteristic mechanism for the toxicity of many carcinogenic(致癌的), mutagenic（诱变的）, and teratogenic（畸胎的） chemicals.,Internal c

18、onsiderations-Prevention of toxic effects,C. Avoidance of indirect biotoxication (bioactivation)1. Avoiding chemicals with known activation routes a. highly electrophilic or nucleophilic groups b. unsaturated bonds c. other structural features 2. Structural blocking of bioactivation Incorporation of

19、 structural modifications that prevent bioactivation,Internal considerations-Prevention of toxic effects,Opportunities for the synthetic chemist,Both the external and internal considerations provide a wide range of opportunities and approaches to the synthetic chemist for designing chemical structur

20、es that reduce or eliminate the toxicity of industrial and commercial chemicals.The opportunities and approaches are expanded further by the possibility of factoring more than one approach into the molecular design.e.g. both properties that reduce exposure and one or more properties that facilitate

21、excretion （排泄） or metabolic （代谢）deactivation.,The effective harmonization（一致） of the safety considerations and of complex living organisms with the efficacy considerations of chemical structures for industrial and commercial purposes is expected to achieve.Delicate（精巧的） balance between safety and ef

22、ficacy.Data and information on the structure-biological activity relationship of these same chemicals at molecular level.,Opportunities for the synthetic chemist,3.1.2. Building the foundation for designing safer chemicals,Academia Industry To bring about a universal practice of the design of safer

23、chemicals, substantial changes must take place in both academia and industry,1、Increased awareness of the concept of designing safer chemicals2、Establishing the scientific, technical, and economic credibility of the concept3、Effecting a sharper focus on chemicals of concern4、Greater emphasis on mech

24、anistic and SAR research in toxicity5、Revision in the concepts and practice in chemical education6、Major participation by the chemical industry,3.1.2. Building the foundation for designing safer chemicals,1. Awareness of the concept,Strict environmental control： already but the origin of the environ

25、mental pollution has not yet been understood. Green chemistry: Scientific activities and educational activities have been carried out, however, vague(含糊的) or blurred（模糊不清的） understanding or even misunderstandings still generally exist in both academia and industry as well as other area.The media: mi

26、sleading reports still exist and what is really needed does not appear. Industry: Although some ideas are accepted, it is far from practice.,2. Scientific and economic credibility,The scientific credibility of the concept with respect to academia and the funding institutions must be established.The

27、technical and economic feasibility from the standpoint of industry (even private industry) must be demonstrated by real examples.,3. Focus on chemicals of concern,Both industry and academia should focus their attention on those commercial chemicals and chemical classes that have the greatest potenti

28、al for adverse effects. This involves not only an assessment of the toxicological properties per se（本身）, but also the extent of the potential exposure to human and the environment. Factors such as production volume, use and physicochemical properties.,4. Mechanistic toxicological research,Research i

29、n toxicology must shift its emphasis to mechanistic research, or basic understanding of how a specific chemical or chemical class exerts its toxicological effect on living organisms at the molecular level.It is only with the accumulation of substantial data and information of this nature that the ex

30、isting principles and concepts of structure-activity relationship (SAR) can be developed further.,The SAR of a chemical may involve one or more functional groups, the parents compounds or a combination of functional groups and the parent chemical or chemical class.The elucidation of toxicological me

31、chanisms on a chemical specific or class specific basis and the systematic compilation of this data will provide the necessary foundation and guidance for the molecular manipulation by synthetic chemists to develop safer chemicals.,4. Mechanistic toxicological research,To stimulate interest and prov

32、ide academia with the means to undertake more basic research in toxicology, the appropriate institutions must accept the concept and actively participate by making funds available in this specific area of research.Without financial support for conduct of more basic mechanistic research, the opportun

33、ities for new, creative molecular structures that are both efficatious and safe will be severely limited.,4. Mechanistic toxicological research,5. Revision of chemical education,The revision of the existing concepts and practices of chemical education at both undergraduate and graduate level is need

34、ed.Separated mode of education traditionally Although the function of designing safer chemicals can be accomplished through multi-disciplinary collaboration among chemists, toxicologists, pharmacologists, bio-chemists and others, it is believed that individuals with a combined knowledge of chemical

35、structure, industrial application and biological activity at the molecular level will perform more efficiently and effectively.,To provide adequate training of synthetic chemists interested in designing safer chemicals and destined for careers in both academia and industry, it is believed that new c

36、urricula (课程) should be developed to provide firm groundings in biochemistry, pharmacology and toxicology. (药理学) (毒物学),5. Revision of chemical education,At the graduate level this may be best accomplished through joint appointments and multi-disciplinary graduate committees comprised of the appropri

37、ate fields of study to oversee curricula(课程) and graduate research efforts directly related to the chemistry/biology relationships involved in designing safer chemicals.,5. Revision of chemical education,A comparison of the traditional educational mode and the new mode needed for cultivation of hybr

38、id chemist,5. Revision of chemical education,The new hybrid synthetic chemist will evolve from the current subspecialities in synthetic chemistry.The new hybrid chemist or the toxicological chemist or simply green chemist must consider both the function of the chemical in its industrial or commercia

39、l application and its toxicological effects in humans and the environment.,In most respects achieving the delicate balance between safety and efficacy will undoubtedly prove to be the most difficult and challenging effort in the history of synthetic chemistry. However, with the appropriate resolve a

40、nd focus, the development of such chemicals can be achieved.,6. Chemical industry involvements,Major support and participation by the chemical industry is essential. Industry must take steps to increase the awareness of the concept among its scientists and management. Industry must encourage its peo

41、ple to approach the concept with open minds and to carefully evaluate its potential in terms of economic and technical feasibility.,3.2. Techniques in designing of safer chemicals,3.2.1 毒理学分析及相关分子设计3.2.2 利用构效关系设计安全的化学品3.2.3 利用基团贡献法构筑构效关系3.2.4 利用等电排置换设计更加安全的化学品3.2.5“软”化学设计3.2.6 用另一类有相同功效而无毒的物质替代有 毒有害

42、物质3.2.7 消除有毒辅助物品的使用,Techniques in designing of safer chemicals,3.2.1 Understanding of the basic toxicity and corresponding molecular design,To reduce the toxicity of a chemical substance or to make a safer chemical than a similar chemical substance, an understanding of the basic toxicity is required

43、.,Techniques in designing of safer chemicals,Once toxicity is understood, strategic structural modifications can be made that directly or indirectly attenuate (削弱) toxicity but do not reduce the commercial usefulness of the chemical.There are several approaches that provide the framework for molecul

44、ar modification needed for the rational design of safer chemicals.,Techniques in designing of safer chemicals,Toxicological mechanism structural modifications of the molecule1、Reducing Absorption2、Use of toxic mechanism to eliminate toxicity3、Use of structure-activity (toxicity) relationships4、Use o

45、f isosteric replacement（等电排置换）5、Use of retrometabolic (后代谢) (soft chemical 软化学) design6、Identification of equally efficacious, less toxic chemical substitutes7、Elimination of the need for associated toxic substances,Techniques in designing of safer chemicals,3.2.1.1 Toxicity of chemicals,There are t

46、hree fundamental requirements for chemical toxicity (致毒三要素):1. Exposure to the chemical substance (接触致毒)2. Bio-availability (生物吸收致毒)3. Intrinsic toxicity (固有毒性),Exposure to the chemical substance: The contact of the substance with the skin, mouth or nostrils(鼻孔),Aspects of chemical toxicity,Bio-avai

47、lability: The ability of a substance to be absorbed into and distributed within a living organism (e.g., humans, fish) to areas where toxic effects are exerted and is a function of the toxicokinetics of the substance. Toxicokinetics (毒性动力学相): the interrelationship (内在关系) of absorption, distribution, metabolism and excretion.,Aspects of chemical toxicity,Aspects of chemical toxicity,Intrinsic toxicity: The ability of a substance to cause an alteration in normal cellular biochemistry and physiology following absorption.,