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Designing Safer Chemicals: Methods and Principles

This chapter explores the methods and principles for designing safer chemicals, focusing on the reduction of hazard and toxicity. It discusses both external considerations (reducing exposure/accessibility) and internal considerations (prevention of toxic effects).

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Designing Safer Chemicals: Methods and Principles

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  1. Designing Safer Chemicals Chapter 3

  2. Chapter 3 Designing Safer Chemicals Methods for Designing Safer Chemicals General Principles for Designing Safer Chemicals

  3. 3.1 General Principles for Designing Safer Chemicals

  4. 3.1.1 General Principles for Designing Safer Chemicals • Two main ways to avoid Hazard and 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

  5. General Principles for Designing Safer Chemicals • External considerations: Reduction 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

  6. General Principles for Designing Safer Chemicals • 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 by man and other living organisms. External considerations:

  7. External considerations: Reduction of exposure or accessibility • A. Properties related to environmental distribution/dispersion • 1. Volatility/density/melting point • 2. Water solubility • 3. Persistence/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

  8. External considerations: Reduction of exposure or accessibility • B. Properties related to uptake by organisms • 1. Volatility (挥发性) • 2. Lipophilicity(亲油性) • 3. Molecular size • 4. Degradation (降解性) a. hydrolysis(水解), b. Effect of pH, c. susceptibility to digestive enzymes (敏感性) (消化酶)

  9. External considerations • Structural designs or redesigns: increase degradation rates, reduce volatility(挥发性), reduce persistence time in the environment and possibility of conversion to biologically active substances in the environment. • Molecular designs : reduce or impede(妨碍) absorption by man, animals and aquatic life(水生生物).

  10. External considerations: Reduction of exposure or accessibility • C. Consideration of routes of absorption by man, animals or aquatic life • 1. Skin/eyes • 2. Lungs • 3. Gastrointestinal tract(消化系统) • 4. Gills(鳃) or other specific routes

  11. 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增大的现象。

  12. External considerations: • 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 exacerbated (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.

  13. External considerations: Reduction of exposure or accessibility • Bio-magnification  Food chain • Hence, the substances of concerns may both 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。

  14. External considerations: Reduction of exposure or accessibility • 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)

  15. Internal considerations: Prevention of toxic effects (预防毒性) • They generally include approaches using molecular manipulations to : • Facilitate bio-detoxication (生物解毒性) • Avoid direct toxicity • Avoid indirect bio-toxicity or bio-activation

  16. Internal considerations-Prevention of toxic effects • A. Facilitation of de-toxication (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.Facilitation of biodegradation (可生物降解性) a. oxidation; b. reduction; c. hydrolysis

  17. Internal considerations-Prevention of toxic effects • B. Avoidance of direct toxication • 1. Selection of non-toxic chemical classes or parent compounds • 2. Selection of non-toxic functional groups a. avoidance of toxic groups; b. planned biochemical elimination of toxic structure through 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.

  18. Internal considerations-Prevention of toxic effects • Indirect biotoxication—bioactivation • It describes the circumstances 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.

  19. Internal considerations-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 structural modifications that prevent bioactivation

  20. 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 structures 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 excretion (排泄) or metabolic (代谢)deactivation.

  21. Opportunities for the synthetic chemist • 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 efficacy. • Data and information on the structure-biological activity relationship of these same chemicals at molecular level.

  22. 3.1.2. Building the foundation for designing safer chemicals • Academia • Industry • To bring about a universal practice of the design of safer chemicals, substantial changes must take place in both academia and industry

  23. 3.1.2. Building the foundation for designing safer chemicals • 1、Increased awareness of the concept of designing safer chemicals • 2、Establishing the scientific, technical, and economic credibility of the concept • 3、Effecting a sharper focus on chemicals of concern • 4、Greater emphasis on mechanistic and SAR research in toxicity • 5、Revision in the concepts and practice in chemical education • 6、Major participation by the chemical industry

  24. 1. Awareness of the concept • Strict environmental control:already but the origin of the environmental 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: misleading reports still exist and what is really needed does not appear. • Industry: Although some ideas are accepted, it is far from practice.

  25. 2. Scientific and economic credibility • The scientific credibility of the concept with respect to academia and the funding institutions must be established. • The technical and economic feasibility from the standpoint of industry (even private industry) must be demonstrated by real examples.

  26. 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 potential 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.

  27. 4. Mechanistic toxicological research • Research in 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 existing principles and concepts of structure-activity relationship (SAR) can be developed further.

  28. 4. Mechanistic toxicological research • 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 mechanisms 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.

  29. 4. Mechanistic toxicological research • To stimulate interest and provide 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 opportunities for new, creative molecular structures that are both efficatious and safe will be severely limited.

  30. 5. Revision of chemical education • The revision of the existing concepts and practices of chemical education at both undergraduate and graduate level is needed. • 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 structure, industrial application and biological activity at the molecular level will perform more efficiently and effectively.

  31. 5. Revision of chemical education • 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 curricula (课程) should be developed to provide firm groundings in biochemistry, pharmacology and toxicology. (药理学) (毒物学)

  32. 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 appropriate fields of study to oversee curricula(课程) and graduate research efforts directly related to the chemistry/biology relationships involved in designing safer chemicals.

  33. Industrial efficacy of chemicals Traditional Industrial synthesis chemist Industrial educational mode Traditional Pharmacological, Biochemical, Toxicological effects (SAR) Medical and pesticide chemists Pharmacological educational mode New hybrid Green chemist A comparison of the traditional educational mode and the new mode needed for cultivation of hybrid chemist

  34. 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 commercial application and its toxicological effects in humans and the environment.

  35. 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 and focus, the development of such chemicals can be achieved.

  36. 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 people to approach the concept with open minds and to carefully evaluate its potential in terms of economic and technical feasibility.

  37. 3.2. Techniques in designing of safer chemicals

  38. 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 毒有害物质 • 3.2.7 消除有毒辅助物品的使用

  39. 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.

  40. 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 molecular modification needed for the rational design of safer chemicals.

  41. Techniques in designing of safer chemicals • Toxicological mechanism structural modifications of the molecule • 1、Reducing Absorption • 2、Use of toxic mechanism to eliminate toxicity • 3、Use of structure-activity (toxicity) relationships • 4、Use of isosteric replacement(等电排置换) • 5、Use of retrometabolic (后代谢) (soft chemical 软化学) design • 6、Identification of equally efficacious, less toxic chemical substitutes • 7、Elimination of the need for associated toxic substances

  42. 3.2.1.1 Toxicity of chemicals • There are three 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)

  43. Aspects of chemical toxicity • Exposure to the chemical substance: The contact of the substance with the skin, mouth or nostrils(鼻孔)

  44. Aspects of chemical toxicity • Bio-availability: 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.

  45. Aspects of chemical toxicity • Intrinsic toxicity: The ability of a substance to cause an alteration in normal cellular biochemistry and physiology following absorption.

  46. Aspects of chemical toxicity • Toxicophore (毒性载体): a particular structural portion of the substance to which the toxicity is generally attributed. • Toxicogenic (产毒结构): Some substances contain structural features that are not directly toxic but undergo metabolic conversion (bioactivation) to yield a toxicophore. These structural features are toxicogenic (产毒的), in that they yield a toxicophore subsequent to metabolism.

  47. Aspects of chemical toxicity • 毒性动力学相: 化学品在生命机体内吸收、分布、代谢和排泄的内在关系。 • 毒性动态学相: 化学品毒性载体与生物分子活性位的致毒相互作用。

  48. Aspects of chemical toxicity Exposure 毒性动态学相 Absorption Distribution Metabolism Excretion Chemical and biomolecular interaction in target tissue 毒性动力学相 Toxic effect

  49. 1:Absorption • It refers to the entrance of the substance into the bloodstream from the site of exposure. • For a substance to be absorbed and become bio-available, the molecules of the substance mustpass throughnumerous cellular membranesand enter the bloodstream(which is mostly aqueous)where they are circulated throughout the body, and againcrossmany cellular membranesto gain entrance into the cells of organs and tissues.

  50. 1:Absorption • This means that the substance must have the necessary physicochemical properties that enable the molecules comprising the substance to reach their free molecular form, cross biological membranes and enter the blood.

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