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1、Chapter 3,Designing Safer Chemicals,3.1 General Principles for Designing Safer Chemicals 3.2. Techniques in designing of safer chemicals,3.2.1 Understanding of the basic toxicity and corresponding molecular design (毒理学分析及相关分子设计) 3.2.2 The use of SARs to design safer chemicals (利用构效关系设计安全的化学品) 3.2.3
2、The use of Group Contribution Method to construct SARs (利用基团贡献法构筑构效关系) 3.2.4 The use of isosteric replacement to design safer chemicals (利用等电排置换设计更加安全的化学品) 3.2.5 soft chemical design (“软”化学设计) 3.2.6 The use of another kind of material to replace the hazardous one (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 Elim
3、ination the need of hazardous associated materials (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 un
4、derstanding of the basic toxicity is required.,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 app
5、roaches that provide the framework for molecular modification needed for the rational design of safer chemicals.,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 s
6、tructure-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,Techniques in designing of safe
7、r chemicals,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),Exposure to the chemical substance: The contact of the substance with the skin, mou
8、th or nostrils(鼻孔),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): t
9、he 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.,Aspects of chemical
10、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 stru
11、ctural features are toxicogenic (产毒的), in that they yield a toxicophore subsequent to metabolism.,Toxicokinetics phase (毒性动力学相) The absorption, distribution, metabolization and excretion of chemicals in organic body ( 化学品在生命机体内吸收、分布、代谢和排泄的内在关系) Toxicodynamics（毒性动态学相） The interaction between the toxi
12、cophore of the chemical with the cell molecule of the body resulting in toxicity (化学品毒性载体与生物分子活性位的致毒相互作用),Aspects of chemical toxicity,Aspects of chemical toxicity,Exposure,Absorption Distribution Metabolism Excretion,Chemical and biomolecular interaction in target tissue,Toxic effect,毒性动力学相,毒性动态学相,
13、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 must pass through numerous cellular membranes and enter the bloodstream (which is mostly aqueous) where they
14、 are circulated throughout the body, and again cross many cellular membranes to gain entrance into the cells of organs and tissues.,This means that the substance must have the necessary physicochemical properties that enable the molecules comprising the substance to reach their free molecular form,
15、cross biological membranes and enter the blood.,1：Absorption,The membranes of essentially all cells of the body, particularly those of the skin, the epithelial(上皮的) lining(衬) of the lung, the gastrointestinal tract, capillaries（毛细血管）, and organs, are composed chiefly of lipids(脂肪). Therefore, absorp
16、tion of a chemical substance into the body and its ability to travel through the bloodstream(distribution) to the area of the body where the toxic response is elicited requires that the substance has a certain amount of both lipid solubility (lipophilicity 酯溶性) and water solubility.,1：Absorption,Physicochemical and biological factors influencing membrane permeation and absorption,Physicochemical factors,Molecular size, molecular weight, dissociation constant, aqueous solubility, lipophilic
