Chapter 3 Designing Safer Chemicals. General Principles General Principles for Designing for Designing Safer Chemicals Safer ChemicalsMethods for Designing

Chapter 3Chapter 3

Designing Designing Safer Safer

ChemicalChemicalss

General Principles General Principles for Designing for Designing Safer ChemicalsSafer Chemicals

Methods Methods for Designingfor Designing Safer ChemicalsSafer Chemicals

Chapter 3 Chapter 3 Designing Safer ChemicalsDesigning Safer Chemicals

3.1 General Principles for 3.1 General Principles for

Designing Safer ChemicalsDesigning Safer Chemicals

3.2. Techniques 3.2. Techniques

in designing of safer in designing of safer

chemicalschemicals

3.1.1 General Principles for 3.1.1 General Principles for Designing Safer ChemicalsDesigning 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

Including Direct hazard & Indirect hazard

General Principles for Designing General Principles for Designing Safer ChemicalsSafer Chemicals

External considerationsExternal considerations ：：

Reduction of exposure or accessibilityReduction of exposure or accessibility

减少化学品与生物机体接触的可能性减少化学品与生物机体接触的可能性

Internal considerationsInternal considerations ：：

Prevention of toxic effectsPrevention of toxic effects

预防化学品的毒性预防化学品的毒性

These considerations 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 considerationsExternal considerations ：：

General Principles for Designing General Principles for Designing Safer ChemicalsSafer Chemicals

External considerations:External considerations: Reduction of exposure or Reduction of exposure or

accessibilityaccessibility A. Properties related to environmental

distribution/dispersion 1. Volatility （挥发性） /density/melting point 2. Water solubility 3. Persistence( 持久性 )/biodegradation ( 生物降解性 )

a. oxidation, b. hydrolysis （水解） ,

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. Degradation （降解性） a. hydrolysis （水解） , b. Effect of pH,

c. susceptibility to digestive enzymes

（敏感性）（消化酶）


accessibilityaccessibility

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.

External considerationsExternal 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. Gastrointestinal tract （消化系统）

4. Gills( 鳃 ) or other specific routes



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。

External considerations:External considerations: Reduction of exposure or accessibility 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 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.

External considerations:External considerations:

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。

External considerations: Reduction of External considerations: Reduction of exposure exposure

or accessibility or accessibility

Bioaccumulation efficiency

BCF= cb/ce

cb: the concentration of a hazardous

material in the tissue of organic system

ce: the concentration of the hazardous

material in the environment


or accessibility or accessibility


or accessibility or accessibility Different kinds of living creature have

different accumulation ability to different

hazardous materials. Rainbow trout （虹鳟鱼） :

BCF: 2,2’,4,4’-biphenyl 12400

CCl4 17.7 Tunny ( 金枪鱼 ) ： BCF ： copper 100 Sponse ( 海绵 ) ： BCF ： copper 1400

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 )



They generally include approaches using They generally include approaches using

molecular manipulations to :molecular manipulations to :

Facilitate bio-detoxication (Facilitate bio-detoxication ( 生物解毒性生物解毒性 ))

Avoid direct toxicityAvoid direct toxicity

Avoid indirect bio-toxicity or bio-activationAvoid indirect bio-toxicity or bio-activation

InternalInternal considerations: considerations: Prevention of toxic effects (Prevention of toxic effects ( 预防毒性预防毒性 ))

Internal considerations-PreventionInternal considerations-Prevention of toxic effects 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

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.


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.


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


Opportunities for the synthetic chemistOpportunities 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.

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.

Opportunities for the synthetic chemistOpportunities for the synthetic chemist

3.1.2. Building the foundation for 3.1.2. Building the foundation for designing safer chemicalsdesigning 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

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

3.1.2. Building the foundation for 3.1.2. Building the foundation for designing safer chemicalsdesigning safer chemicals

1. Awareness of the concept1. 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.

2. Scientific and economic credibility2. 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.

3. Focus on chemicals of concern3. 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 ( 反作用 ). 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 research4. 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.

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.


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 efficacious and

safe will be severely limited.


5. Revision of chemical education5. 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.

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 )

5. Revision of chemical education5. 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.


Industrial Industrial efficacy efficacy

of chemicalsof chemicals

Industrial Industrial efficacy efficacy

of chemicalsof chemicals

Industrial Industrial synthesis synthesis

chemistchemist

Industrial Industrial synthesis synthesis

chemistchemist

Traditional

Industrial educational mode

Medical and Medical and pesticide pesticide chemistschemists

Medical and Medical and pesticide pesticide chemistschemists

Pharmacological,Pharmacological,Biochemical,Biochemical,Toxicological effectsToxicological effects(SAR(SAR ））

Pharmacological,Pharmacological,Biochemical,Biochemical,Toxicological effectsToxicological effects(SAR(SAR ））

Traditional

Pharmacological educational

mode

New hybrid New hybrid Green chemistGreen chemist

A comparison of the traditional educational A comparison of the traditional educational mode andmode and

the new mode needed for cultivation of hybrid the new mode needed for cultivation of hybrid chemistchemist


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.

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.

6. Chemical industry involvements6. 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.

Documents

Chapter 3 Designing Safer Chemicals. General Principles General Principles for Designing for Designing Safer Chemicals Safer ChemicalsMethods for Designing