pesticides and by jWH4u22

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									Chapter 3

 Designing
   Safer
 Chemicals
               Chapter 3
       Designing Safer Chemicals



General Principles      Methods
for Designing           for Designing
Safer Chemicals          Safer Chemicals
    3.1 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
    General Principles for Designing Safer
                 Chemicals
External considerations
   They refer to the reduction in exposure by
    designing chemicals that influence important
    physical and chemical properties related to
    environmental distribution and the up-take of
    the chemical by man and other living organisms.
           External considerations
 Structural designs or redesigns:

 increase degradation rates and those that
  reduce volatility(挥发性), persistence in the
  environment or conversion in the environment to
  biologically active substances
   Molecular designs :
    reduce or impede(妨碍) absorption by man,
    animals and aquatic life(水生生物) also
    represent important external considerations.
              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
         a. oxidation, b. hydrolysis,
         c. microbial degradation
    4. Conversion to biologically active substances
    5. Conversion to biologically inactive substances
              External considerations:
          Reduction of exposure or accessibility
   B. Properties related to uptake by organisms
    1. Volatility
    2. Lipophilicity(亲油性)
    3. Molecular size
    4. Degradation
        a. hydrolysis(水解), b. Effect of pH,
        c. susceptibility to digestive enzymes
                                 (消化酶)
             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
             External considerations:
         Reduction of exposure or accessibility

   D. Reduction/elimination of impurities
     1. Generation of impurities of different
    chemical classes
     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:
   Bioaccumulation(生物集聚)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.
                 External considerations:
   It is well known that 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.

   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:

   Hence, the substances of concern may both bio-
    accumulate in lower life forms and biomagnify or
    increase their concentration in higher life forms
    by orders of magnitude as they accumulate and
    migrate up the food chain.
               internal considerations:

   They generally include approaches using molecular
    manipulations to facilitate:
     Biodetoxication
     The avoidance of direct toxicity
     The avoidance of indirect bio-toxicity or
    bio-activation
         Internal considerations-Prevention
                    of toxic effects
   A. Facilitation of detoxication
    1. Facilitation of excretion(排泄)
       a. selection of hydrophilic(亲水的) compounds
       b. facilitation of conjugation/acetylation
         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
        Internal considerations-Prevention
                   of toxic effects
   2. Facilitation of biodegradation

       a. oxidation
       b. reduction
       c. hydrolysis
           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 of the organism or
    strategic molecular relocation of the toxic group
      c. structural blocking of toxic groups
      d. alternative molecular sites for toxic groups
         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.
           Internal considerations-Prevention
                      of toxic effects
   C. Avoidance of indirect biotoxication (bioactiovation)

   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 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.

   e.g. both properties that reduce exposure and one or more
    properties that facilitate excretion or metabolic deactivation.
        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
    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
     3.1.2. Building the foundation for designing
                   safer chemicals

   Increased awareness of the concept of designing
    safer chemicals
   Establishing the scientific, technical, and economic
    credibility of the concept
   Effecting a sharper focus on chemicals of concern
   Greater emphasis on mechanistic and SAR research
    in toxicity
   Revision in the concepts and practice in chemical
    education
   Major participation by the chemical industry
                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
        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.
            Focus on chemicals of concern
   There must be a sharper focus on, and the
    establishment of properties for, those chemicals and
    chemical classes of great concern to human and
    environment.
   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 th
    environment.
    Factors such as production volume, use and physico-
    chemical properties
         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.
            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.
A comparison of the traditional educational mode and
the new mode needed for cultivation of hybrid chemist

 Industrial             Traditional         Industrial
  efficacy                                   synthesis
of chemicals            Industrial            chemist
                        educational
                        mode
Pharmacological,          Traditional       Medical and
Biochemical,
Toxicological effects
                                             pesticide
                          Pharmacological
(SAR)                                        chemists
                            educational
                               mode
                           New hybrid
                          Green chemist
           Revision of chemical education

   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.
          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.
        3.2. Techniques
in designing of safer chemicals
    Techniques in designing of safer chemicals

   To reduce the toxicity of a chemical substance
    or to make a safer chemical than a similar
    chemical substance requires an understanding
    of the basic toxicity.
    Techniques in designing of safer chemicals

   Once toxicity is understood, strategic structural
    modifications can be made that directly or
    indirectly attenuate 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.
      Techniques in designing of safer chemicals
   Toxicological mechanism

             structural modifications of the molecule

   Reducing Absorption
   Use of toxic mechanism
   Use of structure-activity
              (toxicity) relationships
   Use of isosteric replacement(等电排置换)
   Use of retrometabolic (soft chemical) design
   Identification of equally efficacious,
                         less toxic chemical substitutes
   Elimination of the need for associated toxic substances
  3.2.1.Toxicity of chemicals


 There  three fundamental requirements
  for chemical toxicity:
 Exposure to the chemical substance

 the contact of the substance with the
  skin, mouth 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: the interrelationship of
  absorption, distribution, metabolism and
  excretion.

           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 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, in that they
    yield a toxicophore subsequent to metabolism.
               Aspects of chemical toxicity
                Exposure

Absorption                        Chemical-
Distribution                      biomolecular
Metabolism                        interaction in
Excretion                         target tissue


                   Toxic effect
                   1:Absorption
   It refers to the entrance of the substance into the
    bloodstream form 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 are circulated
    throughout the body, and again cross many
    cellular membranes to gain entrance into the
    cells of organs and tissues.
                   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.
                    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, absorption 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) and water solubility.
                   Absorption

   Anatomical(解剖的) and biological factors
    are also important in absorption.

   These include surface area, thickness of the
    membrane barrier, and blood flow.
        Physicochemical and biological factors
  influencing membrane permeation and absorption

Physicochemical factors
 Molecular size,
 molecular weight,
 dissociation constant,
 aqueous solubility,
 lipophilicity
      (octanol/water partition coefficient, i.e., log P),
 physical state(solid, liquid, gas),
 particle size
         Physicochemical and biological factors
   influencing membrane permeation and absorption

Biological factors

Route of           Surface       Thickness of         Blood flow
exposure            area(m2)   absorption barrier(µm) (L/min.)

 Skin               1.8           100-1000              0.5

Gastrointestinal     200            8-12                1.4
 tract
Lung                140            0.2-0.4              5.8
      Absorption by Gastrointestinal tract

   The gastrointestinal tract is a major site from
    which chemical substances are absorbed.

   Many environmental toxicants enter the food
    chain and are absorbed together with food from
    the gastrointestinal tract.
       Absorption by Gastrointestinal tract

   In occupational settings, for example, airborne
    toxic substances enter the mouth from
    breathing and, if not inhaled, can be swallowed
    and absorbed from the gastrointestinal tract.
       Absorption by Gastrointestinal tract

   The major physiological factors governing the
    absorption from gastrointestinal tract are surface
    area and blood flow.

   The largest absorbing surface area and the
    second greatest blood flow.
         Absorption by Gastrointestinal tract
   The majority of absorption from the
    gastrointestinal tract occurs from the small
    intestines.

   The pH of the gastrointestinal tract ranges from
    about 1-2 in the small intestines, and gradually
    increases to about 8 in the large intestines.
         Absorption by Gastrointestinal tract
   This variation in influences the extent to which
    acidic or basic chemical substances are ionized,
    which influence the extent of absorption.
   Acidic substances are absorbed more readily from
    the small intestines (pH=1-2) than the large
    intestines, because they are less dissociated in
    the small intestines.
   The opposite is true for basic substances.pH=8,
    absorbed in large intestines.
         Absorption by Gastrointestinal tract
   The physicochemical properties that most
    significantly affect the extent to which a substance
    is adsorbed from the gastrointestinal tract include:

    Physical state
    Particle size(for solid)
    The relative lipid to water partition
    Dissociation constant
    Molecular weight
    Molecular size
          Absorption by Gastrointestinal tract
   A substance must be sufficiently water soluble such
    that it can undergo requisite dissociation to its free
    molecular from.
   Substances that are liquid in their neat form, or are
    already dissolved in a solvent, are generally absorbed
    more quickly from the gastrointestinal tract than a
    substance that is a solid.
   Generally, substances that are in the form of salts
    (e.g., hydrochloride salts, sodium salts, etc.) undergo
    dissolution more quickly than their un-ionized(neutral)
    form, and are absorbed more quickly.
         Absorption by Gastrointestinal tract
   For solid, particle size also affects the rate of
    dissolution and thus, overall absorption.

   The smaller the particle size, the larger the
    surface area and the faster the dissolution and
    absorption of the substance.

   Larger particle size means less surface area and
    therefore a slower dissolution in the gastric fluids,
    and slower or even less absorption.
          Absorption by Gastrointestinal tract
   Lipid solubility is more important than water solubility
    in regard to absorption from gastrointestinal tract.
   The more lipid soluble a substance is, thee better it is
    absorbed.
   Highly lipophilic substances (log P >5) ,however, are
    usually very poorly water soluble and generally are not
    well absorbed because of their poor dissolution in the
    gastric juice.
   On the other hand chemical substances with extreme
    water solubility and very low lipid solubility are also not
    readily absorbed.
         Absorption by Gastrointestinal tract
   The higher the molecular weight the less a
    substance is absorbed from the gastrointestinal
    tract. Assuming sufficient aqueous and lipid
    solubility, a general guide is:
   Substances with molecular weights less than 300
    Daltons are typically well absorbed.
   Substances with molecular weights ranging over
    300-500 are not readily absorbed.
   Substances with molecular weights in the
    thousands are sparingly absorbed.
          Absorption by Gastrointestinal tract
   The function of the lung: exchange oxygen for carbon
    dioxide.
   The continuous, repetitive branching of the airways from
    the trachea(支气管)to the terminal alveoli(肺气泡)(where
    gas exchange takes place) create an enormous surface
    area.
   The lungs also receive 100% of the blood pumped from the
    heart.
   The thickness of the alveola cellular membrane (the
    absorption barrier of the lung ) is only 0.2~0.4μm.
              Absorption from the lung
   These      anatomical       and     physiological
    characteristics of the lung enable the rapid and
    efficient absorption of oxygen and favor the
    absorption of other substances as well.

   Because the cellular membranes of the
    alveoli( 肺 气 泡 ) are very thin(0.2∼0.4µm), so
    that the distance a substance has to traverse
    the alveolar membrane is very short. Chemicals
    absorbed through the lung can enter the flood
    within seconds. In fact, water solubility, rather
    than lipid solubility , is the more important factor.
                Absorption from the lung
   For solid substances,
   Particles of 1μm.and smaller may be particularly well
    absorbed from the lung because they have a large
    surface area and can also penetrate deep in the narrow
    alveolar sacs of the lung(肺气囊).
   Particles of 2 to 5μm are mainly deposited into the
    tracheobronchiolar(支气管) regions of the lung, from
    where they are cleaned by retrograde( 倒 退 的 )
    movement of the mucus(粘液) layer in the ciliated(有纤
    毛的) portions of the respiratory tract.
   Particles of 5μm or larger are usually deposited in the
    nasopharyngeal( 鼻 咽 ) region and are too large for
    absorption from the lung, but also may be swallowed
    and absorbed from the gastrointestinal tract
                Skin (Dermal) Absorption

       Unlike the lung and the gastrointestinal tract, the
    primary purpose of the skin is not for the absorption
    of substances essential to life, but rather protection
    against the external environment.
      Compared to the lung and gastrointestinal tract, the
    skin has much less surface area and blood flow, as
    well as a considerably thicker absorption barrier.
      Nonetheless, the skin represents a significant
    organ of exposure and absorption.
                Skin (Dermal) Absorption
      For chemicals to be absorbed from the skin, they
    must pass through the 7 cell layers of the
    epidermis(表皮) before entering the blood and lymph
    capillaries( 毛 细 血 管 )in the dermis( 皮 肤 ). This
    absorption barrier ranges from 100 to 1000μm. The
    rate determining step is diffussion through the stratum
    corneum (horny layer, 角 质 层 ), which is the
    uppermost layer of the epidermis. Passage through
    the 6 other layer is much more rapid.
                 Skin (Dermal) Absorption
      Substances that are liquid in their neat(纯的) form
    tend to be absorbed more readily than solid, because
    liquids cover more dermal surface area and are nearer
    to their free molecular state than are solid.
   Solid with higher melting points (>125℃) and
    substances (particularly solids) that are ionic or highly
    polar are generally not well absorbed from the skin.
       Substances with greater lipophilicity ( 油 溶 性 )
    (higher log P) are absorbed more readily from the skin
    than are less lipophilic substances.
               Skin (Dermal) Absorption

   Highly lipophilic substances(log P > 5), however,
    can pass through the stratum corneum but are
    generally too water insoluble to pass through the
    remaining layers and enter the bloodstream.
    These substances are poorly absorbed from the
    skin.
                    2:Distribution
   Distribution refers to the movement of a chemical
    through the living system from its sites of entry into
    the bloodstream following absorption from the skin,
    gastrointestinal tract, or lung. Distribution usually
    occurs rapidly.
   The rate of distribution of organs or tissues is
    primarily determined by blood flow and the rate of
    diffusion out of the capillaries into the cells of a
    particular organ.
   Following absorption, many substances distribute
    to the heart, liver, kidney, brain, and other well-
    perfused(灌注) organs.
                   2:Distribution
Where a substance is distributed?
 (1)largely dependent upon its Physicochemical
 Characteristics.
   lipophilic substances: enter the brain.
   plasma proteins: accumulations in fatty tissues

 (2)Target Organs of a particular substance
 The toxicity of a substance is usually elicited in only one
 or two organs. These sites are referred to as the
 TARGET ORGANS of a particular substance.
                     3:Metabolism
   The body has the ability to distinguish between
    non-food chemical and nutritional substances.
   nutritional substances → non-nutritional substances
   non-nutritional substances : the body will try to eliminate
    as quickly as possible.
    urine(尿) and feces(粪): requires greater water solubility

   The body has enzyme-mediated mechanisms for
    converting substances into more water soluble
    substances that are easier to excrete. (metabolism or
    biotransformation).
                 3:Metabolism
 The purpose of metabolism
  detoxication: a defense mechanism to convert
  potentially toxic chemical substances to other
  substances (metabolites) that are readily
  excreted.
 The chemical reactions involve

 phase-Ⅰor phase-Ⅱreactions
       3:Metabolism Phase-Ⅰ reactions
    Phase-Ⅰreactions convert the chemical substances
    into a more polar metabolite by oxidation, reduction,
    or hydrolysis.
   The enzyme systems responsible for Phase-
    Ⅰreactions are located predominately in the smooth
    endoplasmic(肉质网) reticulum(网状组织) of the liver.
    These enzymes are also present in other organs,
    including the kidney, lung, and gastrointestinal
    epithelium(上皮细胞).
   Reaction type of metabolism: oxidation catalyzed by
    the cytochrome P450
                  Phase-Ⅱ Reactions
   Phase-Ⅱ reactions involve coupling (conjugation) of the
    chemical substance or its polar (Phase-Ⅰ) metabolite
    with an endogenous(内生的) substrate such as
    glucuronate(葡萄糖酸), sulfate, acetate, or an amino acid,
    which further increases water solubility and promote
    excretion.
                   Phase-Ⅱ Reactions
   The enzyme systems responsible for Phase-Ⅱreactions
    are also located predominately in the smooth endoplasmic
    reticulum of the liver. These enzymes are also present in
    other organs, including the kidney, lung, and
    gastrointestinal epithelium.
   Reaction type of metabolism: oxidation catalyzed by the
    cytochrome P450
                    Metabolism
   Note: Metabolism of certain chemical substances
    does not result in detoxication.
   In fact, it is the metabolites of many toxic
    chemical substances that, ironically, are
    responsible for the toxicity.
   What does this is referred to as ???
          4:Toxicodynamics(毒物动态学)
   The toxicodynamic phase comprises the processes
    involved in the molecular interaction between the
    toxic substance and its bio-molecular sites of action
    and the resultant sequence of biochemical and
    biophysical events that finally result in the observed
    toxic effect.
   Receptors(受体): for reversible-acting agents
   Sites of induction of chemical lesions(诱导化学伤
    害位): for irreversible-acting agents.
              4:Toxicodynamics

   In general, a toxic substance exerts its toxicity by
    the interaction of a particular portion of the
    molecule or a metabolite thereof with a cellular
    macromolecule (enzymes, nuclei acids, or protein,
    to name just a few), which disrupts normal
    biochemical function of the macromolecule and
    ultimately results in the toxicity.



What the particular portion is called as ???
             Figure 3-2
     Aspect of chemical toxicity
                       Absorption,
Exposure               Distribution,
 Exposure              Metabolism,
 phase                   Excretion
                    Toxicokinetic phase


                     Chemical-biological
 Toxic
                        Interaction
 Effect               in target tissues
                       Toxicodynamics
                   5: Excretion
   Substances are eliminated from the body
    urine, feces, or breath, bile(胆汁) duct(排泄
    管),
    The kidney and bile duct eliminate polar
    (more water soluble) substances more
    efficiently than substances with high lipid
    solubility.

   The kidney is the most important organ for
    eliminating substances or their metablites
    from the body.
                   5: Excretion
   Substances excreted in the feces are
    typically the metabolites of absorbed
    substances, which enter the gastrointestinal
    tract through the bile duct.


   Excretion from the lung occurs mainly with
    volatile substances.
          3.3
Molecular modification
that reduce absorption
          Reducing Absorption From the
             Gastrointestinal Tract
   If oral exposure is expected to be significant, the
    chemical should be modified to reduce absorption
    from the gastrointestinal tract. Modifications such
    as:
   Increasing particle size or keeping the substance in
    an un-inonized form (i.e., free base, free acid)
       Log P > 5 (not water soluble)
       > 500 daltons molecular weight
       Melting point > 150℃
       Being solid rather than liquid
       Incorporation of several substitutes (e.g., -SO3-) that
    remain strongly ionized at a pH of 2 or below
      Containing sulfonates
       Reducing absorption from the lung
   Less volatile
        low vapor pressure
        higher boiling point
   Low water solubility
   High melting point ( > 150℃)
   Particle size: > 5µm
    Reducing Absorption From the Skin

   To be solid
   To be polar or ionized
     sodium salt of an acid,
     hydrochloride salt of an amine
   To be water soluble
   To be of low lipophilicity
   Increasing particle size
   Increasing molecular eight
           3.4
Designing safer chemicals
from an under standing of
    toxic mechanism
              1: Toxic Mechanisms Involving
                Electrophiles(亲电性物质)
   Chemical substances that are electrophilic or are
    metabolized to electrophilic species are capable of
    reacting covalently with nucleophilic substituents of
    cellular macromolecules such as DNA, RNA,
    enzymes, proteins, and others.

   Examples of nucleophilic substituents :
     thiolgroups(巯基)of cysteinyl(半酰氨酸) residues in protein
     sulfur atoms of methionyl(甲硫氨酸) residues in protein
     primary amino groups of arginine(精氨酸) and lysine(赖氨酸)
     residues
     secondary amino groups (e.g., histidine,组氨酸) in protein
     amino groups of purine(嘌呤) bases in RNA and DNA
      oxygen atoms of purines and pyrimidines(嘧啶)
     and, phosphate oxygens (P=O) of RNA and DNA
          1: Toxic Mechanisms Involving
            Electrophiles(亲电性物质)
   These irreversible covalent interactions can lead to a
    variety of toxic effects including cancer, hepatotoxicity
    (肝中毒), hematotoxicity(血液中毒), nephrotoxicity(肾中
    毒), reproductive toxicity, and developmental toxicity.


   Fortunately, the mammalian(哺乳动物) body has several
    defense systems that offer “sacrificial” nucleophiles
    that can react with foreign electrophiles.
   Such as the glutathione(股胱甘肽) transferase system
    and the epoxide hydratase system
 Electrophilic       Non-electrophilic
  chemical              Chemical
 substances            substances

                                          Metabolism
                        Electrophilic
                         chemical
                        substances


   Reaction with nucleophiles within            Reaction with nucleophiles
                                                      of non-defense
       Natural defense systems                   Cellular macromolecules


      Non-toxic,
Water soluble adducts

                              Excretion              Toxicity
                                  Figure 3-3
    Detoxification of electrophilic substances or electrophilic metapolites
 1: Toxic Mechanisms Involving Electrophiles

Examples of electrophilic substituents
  commonly encountered in
  commercial substances, the reaction
  they undergo with biological
  neucleophiles, and the resulting
  toxicity
 Table    3-4
  Table 3-4 Examples of electrophilic substituents Commonly encountered in commercial
substances, the reaction they undergo with biological neucleophiles, and the resulting toxicity

   Electrophile            Characteristic          Neucliophi
                             Structure                                  Toxic Effect
                                                   lic reaction
                                                                   Various, e.g. Cancer,
                              R-X                  Substitutio
  Alkyl halides                                                    granulocytopenia(粒性白
                          X=Cl、Br、I、F              n               细胞减少症)
                                                                   Various,e.g.    Cancer,
        α-β-                 C=C—C=O                               mutations,
                                                                   Hepatotoxicities ( 肝 中
    unsaturated              C≡C-C=0                Michael
                                                                   毒), nephrotoxicity (肾中
   carbonyl and              C=C-C≡N                addition       毒), hematotoxicity (血液
  related groups               C=C-S-                              中毒), neurotoxicity (神
                                                                   经中毒)
                                                   Schiff base
   γ-diketones         R1COCH2CH2COR2                              Neurotoxicity
                                                   formation
 Epoxides                                                          Mutagenicity( 变 种 ) ,
 (Terminal)                                                        Testicular leisions( 睾 丸
                           CH           CH 2       Addition        损伤)
                                   O
                                                                   Cancer (癌症),
   Isocyanates                —N=C=O               Addition        Mutagenicity(变种),
   (异氰酸酯)                     —N=C=S                               Immunotoxicity
                                                                   (免疫系统中毒)
1. Toxic Mechanisms Involving Electrophiles
   In fact:
         electrophilic substituent ≠ toxic.

   Its toxicity depends on factors

      Overall bioavailability;
      Metabolism;

      Presence of other substituents that may
      attenuate the reactivity of the electrophilic
      substituent.
    2:Designing Safer Electrophilic Substances

   Ideally, electrophilic substituents should never be
    incorporated into a substance.
   However the electrophilic group is often necessary
    for the intended commercial use of the substance.
   This poses a dilemma for the chemist who wishes
    to design an electrophile to react with a nucleophile
    necessary for intended commercial use but not with
    biological nucleophiles in individuals exposed to the
    substance.
   As impossible as this may seem, there are
    approaches that chemists can use to design safer,
    commercially-useful electrophilic substances.
2:Designing Safer Electrophilic Substances

    (1)Decreasing the electrophilicity of
     the molecules

  Avoiding the interaction of the
  molecule with the cellular
  macromolecule in the tissues, thus
  reducing the toxicity
    Example
   Acrylates(丙烯酸酯), for example, contain an
    α,β-unsaturated carbonyl system
   Incorporation of a methyl (-CH3) group onto the α-
    carbon (to provide a methacrylate) decreases the
    electrophilicity (i.e., reactivity) of the β-carbon and,
    hence, methacrylates (甲基丙烯酸酯) do not undergo
    1,4-Michael addition reactions as readily.
    Methacrylates often have commercial efficacy
    similar to acrylates in many applications, but are
    less likely to cause cancer because they are less
    reactive.
    Acrylates(丙烯酸酯)
     β       α
                           Carcinogenic (致癌)
    CH2=CHCOOCH2CH3

    Methacrylates (甲基丙烯酸酯)

β        α
CH2=C(CH3)-COOCH3

                  Non-carcinogenic
    Example

 This point can be demonstrated by
  comparing ethyl acrylate, which causes
  cancer in experimental animals, to methyl
  methacrylate, which does not cause
  cancer in a similar assay.
 It seems logical that placement of a methyl
  group onto the α-carbon of similar α, β-
  unsaturated systems may also decrease
  toxicity without sacrificing commercial
  utility.
 (2) electrophilic-masking approach
  Reactants for the
                           Masking agents
  production of the
  product

                        The product is
  Removing the          regenerated in
  masking agent         situ for use

in the production, transportation, and storage
   The hazardousness is eliminated
3:Toxic Mechanisms Involving Bioactivation to
Electrophiles and the design of related molecule.

      The  majority of biochemical reactions that
      lead to formation of electrophilic metabolites
      involve cytochrome(细胞色素)P450-
      catalyzed oxidations .
      In these reactions a particular portion of
      the molecule is bioactivated to become an
      electrophile.
Examples

 4-Alkyl-Phenol(4-烷基酚)
  Allyl Alcohols(烯醇)
  Propargl Archohols(炔丙基醇)

 Alkens(烯烃)   and Alkynes(炔烃)
3.2 Designing Safer Chemicals
             Using
  Structure-Activity (Toxicity)
         Relationships
As discussed earlier, substances that are capable
of producing a biological effect (pharmacological
or toxicological) contain a structural feature that
bestows the intrinsic biological property.


Qualitative                Quantitative
 Structure-                Structure-Activity
 Activity                  Relationships
 Relationships
                           (QSARs)
           pharmacophore / toxicophore
   In the case of drugs, in which the biological
    response is desired, this structural feature is
    referred to genetically as the pharmacophore.
   In the case of commercial chemical
    substances, in which the biological effect is
    undesired (toxic), the structural feature is
    referred to genetically as the toxicophore.
    In either case, the structural feature elicits(引
    起) its biological effect through interaction with
    a specific biomolecular site of action to cause
    changes in cellular biochemistry.
   Substances that contain the same pharmacophore
    or toxicophore are therefore likely to exhibit the
    same pharmacological or toxicological properties.
   The relative potency( 力 量 ) amongst the
    substances in their ability to cause the biological
    effect may vary substantially.
   The relative potency is directly related to the
    specific or incremental( 增 量 的 ) structural
    differences between the substances and the
    influence these differences have on the ability of
    the toxicophore (or pharmacophore) to interact
    with its biomolecular site of action.
             General Principle

Definition:
The ability of substances belonging to
 the same chemical class to a cause a
 particular biological effect and the
 influence     that   their  structural
 differences have on potency are
 referred to as structure-activity
 relationships (SARS).
        General Principle

 The relationship between structure and
  activity for a given group of substances
  becomes much clearer when the
  mechanism of biological action is known.
 Structure-activity relationships are
  useful for several reasons.
               General Principle

   First, a series of structurally-similar
    chemicals with a measured
    pharmacological or toxicological
    response may allow one to infer
    similar pharmacological or toxic
    effects for ananalogous untested
    substance.
           General Principle

   Second,             structure-activity
    relationships can be used to design
    new, analogous substances such that
    the biological activity is either
    maximized (in the case of drug
    substances) or minimized (in the case
    of commercial chemical substances).
              General Principle

 History:
 Structure-activity relationships have been
  used for decades
 by medicinal chemists in the design of
  highly efficacious drug substances,
 by the U.S. Environmental Protection
  Agency for assessing the toxicity of new,
  untested commercial chemicals prior to
  commercialization.
              General Principle

   Despite the structure-activity data
    available for many classes of commercial
    chemical substances, however, the use of
    structure-activity relationships has been
    given little attention by chemists as a
    rational approach for designing new, less
    toxic commercial chemical substances.
               3.2.1 Qualitative
       Structure-Activity Relationships

   With qualitative structure-activity relationships,
    the correlation of toxic effect with structure is
    made by visual comparison of the structures of
    the substances in the series and the
    corresponding effects on the toxicity.
    From qualitative examination of structure-
    activity data the chemist may be able to see a
    relationship between structure and toxicity, and
    identify the least toxic members of the class as
    possible commercial alternatives to the more
    toxic members.
                 Qualitative
       Structure-Activity Relationships
 In addition the chemist may infer from
  the relationship the structural
  characteristics that reduce toxic
  potency, thereby providing a rational
  basis to design new, less toxic
  analogous substances.
                   Qualitative
         Structure-Activity Relationships
   The larger the data set the more apparent
    the relationship between structure and
    activity becomes, but small data sets can
    nonetheless be quite useful.
   The application of qualitative structure-
    activity relationships for the design of safer
    chemicals is demonstrated below using
    several classes of important commercial
    chemical substances.
Examples of Designing Safer Chemicals
       using Qualitative SARS


       Polyethoxylated Nonylphenols
                (聚乙氧基壬酚)
       Glycidyl Ethers(缩水甘油醚)
       1,2,4-Triazole-3-thione
                 ( 1,2,4-三唑-3-硫酮)
       Carboxylic Acids (羧酸)
Polyethoxylated Nonylphenols(聚乙氧基壬酚)
      used as emulsifiers/surfactants,
predominately in detergents and inks
C9H19—C6H4—O(CH2CH2O)nCH2CH2OH
 It has been observed that these substances
cause an intense myocardial (心肌的)
necrosis(坏疽) in dogs and guinea(几内亚) pigs
within 5 days when administered orally at a dose
of 40 mg/kg/day when the extent of ethyoxylation
ranges between 14 to 29 ethoxy units
  n=14~29, intense myocardial (心肌的)
  necrosis(坏疽)
  n<14 or n>29, no such effects
   Polyethoxylated Nonylphenols
     used as emulsifiers/surfactants,
predominately in detergents and inks
 Although the mechanism of myocardial
  toxicity is unknown, the structure-activity
  relationship data described above are
  nonetheless useful in designing safer
  polyethoxylated nonylphenols.
 Clearly, chemists should intentionally
  design and use polyethoxylated
  nonylphenols with fewer than 14 or more
  than 29 ethoxy subunits.
Glycidyl Ethers (缩水甘油醚)
having the type of structure below


              CH2—CH—(O—CH2)nCH3



                   O



       used as synthetic reagents for
       a variety of purposes
     Glycidyl Ethers (缩水甘油醚)
    It has been shown that glycidyl ethers of the
    type represented above are mutagenic(诱导有
    机体突变的) and cause testicular(双丸状的)
    lesions(损害) in rats and rabbits following oral
    and inhalation administration when the alkyl
    substituent is an n-octyl (n = 7), n-nonyl (n=8)
    or n-decyl (n=9) .
    These toxic effects are not observed, however,
    when the alkyl substituent ranges from dodecyl
    (n=11) to tetradecyl (n=13).

    n=7~9, mutagenic, testicular lesions(引发睾丸损伤)
    n=11~13, no such toxicity
         Glycidyl Ethers (缩水甘油醚)
   As in the case of polyethoxylated nonylphenols,
    the mechanism responsible for the toxicity of
    these glycidyl ethers is not known, although the
    epoxide moiety is almost certainly the toxicophore.
   Nonetheless, these structure-activity relationship
    data are useful for the design of safer glycidyl
    ethers. Chemists should avoid designing and
    using glycidyl ethers of the type represented
    above in which the length of the alkyl moiety
    ranges from 8 to 10 carbons.
    Whenever possible, chemists should design and
    use glycidyl ethers in which the length of the alkyl
    moiety is at least 12 carbon atoms.
      l,2,4-Triazole-3-thiones
        (1,2,4-三唑-3-硫酮)
   The thiocarboxamide (-C-N) group is
    found in a variety of commercial
    substances.
   However, the thiocarboxamide group
    is often toxicophoric. Many
    thiocarboxamides are toxic to the
    thyroidgland (甲状腺) (i.e.,
    thyrotoxic(甲状腺机能亢进的)).
          l,2,4-Triazole-3-thiones
            (1,2,4-三唑-3-硫酮)
   The thyrotoxicity is manifested by an
    inhibition in the thyroid‘s ability to synthesize
    thyroid hormone(甲状腺激素), which ultimately
    leads to hypothyroidism(甲状腺机能衰退). In
    fact, some thiocarboxamides (乙二酰二胺)(e.g.,
    propylthiouracil(丙基硫尿嘧啶),
    methimazole(甲硫咪唑)) are used medically to
    treat hyperthyroidism (甲亢).
        l,2,4-Triazole-3-thiones
          (1,2,4-三唑-3-硫酮)
   The specific mechanism by which the
    thiocarboxamide moiety is thyrotoxic is
    unknown, but is believed to involve
    inhibition of thyroid peroxidase, the enzyme
    that catalyzes the incorporation of iodine
    into tyrosine (酪氨酸) residues during
    thyroid hormone synthesis.
         The structure and toxicity of substituted
                l,2,4-Triazole-3-thiones

         General        R1   R2     R3   Relative Toxicity
         Structure
                       CH3   H     H      1.0
         1       2   R2 H    CH3   H      1.2
         N N
                       H     H     CH3     212.0
     5
             4 3
R3           N       S CH3   H     CH3     7.1
                       H     H     C6H5- 5.7
             R1
                       CH3   CH3     H      4.7
                       H     H      H       3.6
Carboxylic Acids

       (C)—C—C—C—CO2H
         n     4     3
         2
     The toxicity of carboxylic acids
includes hepatotoxicities(肝中毒), Fetus
deforming(畸胎作用), etc.
     It is rather safe when C2 connects to
merely H atoms or merely substitutes. It is
also safe while the chemical bonds between C 2
and C3 or C3 and C4 are double bonds.。
       Quantitative Structure-Activity
          Relationships (QSARs)
It is often possible to quantify structure-activity
relationship data by correlating into a
regression equation(回归方程式) the biological
property with one or more physicochemical
properties of a set of analogous substances.

In quantitative structure-activity relationships (QSARs)
chemical structure is transformed into quantitative
numerical values that describe physicochemical
properties relevant to a given biological activity.
       Quantitative Structure-Activity
          Relationships (QSARs)

Quantification of structure-activity relationships for
a given series of substances depends, therefore,
on the successful identification of one or more
physicochemical properties correlating with the
biological property.

The physicochemical properties that correlate with
the biological property are most likely related to
the mechanism of biological activity, and are often
referred to as "descriptors" of biological activity.
Quantitative Structure-Activity Relationships (QSARs)
  An example of a general QSAR equation is illustrated by
  equation :

    log(1/C)=a(x)2 + b(x)+
    c(y)+dn               r
        s
1/C: biological activity:
(C is a standard concentration or dose of a substance required to elicit the
biological activity)
x & y: physicochemical descriptors of the activity;
a,b,c & d: coefficients;
n: number of substances
r : correlation coefficient
s : standard deviation of the regression.
    Quantitative Structure-Activity
       Relationships (QSARs)
   The application of QSAR:
    delineate(描绘) the change in biological
    potency that is (or would be) accompanied by a
    given change in structure more precisely.

   For example
    using a QSAR correlation for acute lethality(致命性),
    one can predict the median(中值的) lethal dose(致
    命剂量) (LD50) of an untested substance directly from
    a physical property of that substance.
         Quantitative Structure-Activity
            Relationships (QSARs)
   The application of QSAR:
   it is not necessary to synthesize a substance in
    order to measure those physicochemical
    properties
   (Because there are methods for accurately
    estimating most physicochemical properties
    directly from structure)
      Quantitative Structure-Activity
         Relationships (QSARs)
   Shortly, one can estimate those properties,
    incorporate them into the appropriate QSAR
    regression equation and predict the biological
    property of the substance even though the
    substance does not exist!

   Medicinal chemists have, for many years, used QSAR as
    a tool for drug design.
   The U.S. Environmental Protection Agency (EPA) has
    used QSAR since 1981 to predict the aquatic toxicity of
    new, untested commercial chemical substances in the
    absence of test data.
    3.2 Designing Safer Chemicals Using
          Isosteric Replacements
   Substances
   similar molecular and electronic characteristics
   have similar physical or other properties.
   Langmuir called:
    Phenomenon: isosterism(电子等排同物理性质现象), m
    Compound: isostere(电子等排物).

   According to Langmuir‘s definition, isosteres are
    substances or substituents that have the same charge,
    caused by the same number and arrangement of
    electrons and the same number of atoms.
      Designing Safer Chemicals Using
          Isosteric Replacements
   Based on molecular orbital theory, several
    variations of Langmuir's definition of isosterism
    were expressed by others.
   Burger’s definition:
   isosterism also encompasses(包含) chemical
    substances, atoms or substituents that possess
    near equal or similar molecular shape and volume,
    approximately the same distribution of electrons,
    and which exhibit similar physicochemical
    properties.
   —H and —F              —OH and NH2
   —CH3 and —SH and —Cl
   —CH2— and —NH— and
    —O—and —S—and —SiH2—
   —N= and        —CH= and —S—
   In cyclic structure
   CH=CH— and —S— and —O— and —NH—

                   O
              O                         H       H         H    H
                                        N       N         N    N
          C        S       NH                       and
                                            C                 C
              OH
                   O                        O                 N CN

          O                 O       O
      C                C        C
          O                HN   H2C
Examples
Benzene is isosteric with thiophene and pyridine because
the CH=CH- group is isosteric with -N= and -S- atoms



                           S                  N

Although these substances are structurally different,
some of their chemical properties are nonetheless
similar.
All of them are aromatic, all are liquid, and all are
about equal in molecular size and volume. In fact,
both 12 and 41 boil at about 81 °C.
It is also possible that biological properties may be
bestowed(给予), exacerbated(恶化) or attenuated
when isosteric modifications are made.
                     2   site of epixidation
         H       1



                           •7-Methyl-benzo[a]anthracene
                           • (7-甲基苯并蒽),
                           • is a known carcinogen.
       CH3
                     2   Epoxide formation is blocked
             F   1




                           7-methyl-l-fluorobenzo[a]anthracene
                           (7-甲基-1-氟苯并蒽)
       CH3
                           is not .
Acetic acid , on the other hand, is essentially
nontoxic but its fluoro-isostere, fluoroacetic acid ,
is highly toxic (human oral LD50 is estimated to be
2-5 mg/kg
        CH3COOH            FCH2COOH
         non toxic          oral LD50 2-5 mg/kg
In the body acetic acid reacts with coenzyme A(辅酶
A)(CoA) to form acetyl-CoA(乙酰辅酶A), which is an
important precursor of the citric acid cycle(柠檬酸循环)(a
biochemical cascade essential for energy production).
•Fluoroacetic acid is so sterically similar to acetic acid that
it also reacts with CoA, and forms fluoroacetyl-CoA.
Fluoroacetyl-CoA enters the citric acid cycle and forms
fluorocitrate, which is a potent inhibitor of aconitase(鸟头
酸酶), a critical enzyme of the citric acid cycle
FCH2COOH
                       Example 3
  During the development of anti-ulcer(抗溃疡)
  medications, for example, it was found that metiamide
  (麦角胺) greatly reduced acid secretion(分泌) in the
  gastrointestinal tract.
           H3C    H2C   S   CH2CH2 NH HN

                                     O
            NH     N



  Its potential as a useful anti-ulcer medication was
lessened by the toxic effects caused by the thiourea
(硫脲) moiety.
 Isosteric replacement of the thiourea moiety with
the cyanoquanidine(氰基胍)moiety gave
cimetidine,, a potent H2-receptor antagonist that
lacks the toxicity of metiamide.
         H3C     H2C   S   CH2CH2 NH HN

                                    N CN
           NH     N



Cimetidine is one of the most widely used anti-
ulcer medications in the world because of its
effectiveness in treating ulcers and relative safety.
It is noteworthy that in this example this
   isosteric modification selectively reduced
   toxicity without affecting pharmacological
   activity.

This is a main reason why isosteric
 substitution is a common practice among
 medicinal chemists for the design of drug
 products.
    Metallized azo dyes(金属偶氮染料)

   Metallized azo dyes: Historically, chromium was
    a metal of choice in many metallized azo dyes
    because it imparts the desired color and
    fastness.

   Hexavalent chromium (Cr VI) was often used in
    making such dyes. Hexavalent chromium is a
    known human carcinogen, however, and its
    commercial use is strictly regulated and highly
    discouraged by environmental authorities.
    Metallized azo dyes(金属偶氮染料)

   An alternative metal to chromium in premetallized
    azo dyes would have to have the same color and
    fastness properties as chromium but without the
    toxicity.
   It has been found that iron (Fe), which is
    essentially nontoxic, often imparts the same
    desirable qualities as chromium when used in azo
    dyes. This is exemplified in comparing azo dyes.
    Dyestuff 50 has the same color and fastness as 49,
    but does not contain chromium. Other examples of
    dyestuffs that use iron rather than chromium are
    available
Designing Metallized azo dyes
(金属偶氮染料的设计)

                         SO2NH2         M=Cr, toxic
                                        M=Fe, non-toxic
            N   N
                 M
        O
                         O        Na+
                M
    O                O
            N   N


    SO2NH2
                     Example 4
   MTI-800 is a potent insecticide that is also
    highly toxic to fish (its LC50 is 3 mg/liter), which
    limits its commercial usefulness.
                                         F



                                         O

           O

                       MTI800
                  Fish LC50=3mg/l   l
Isosteric  substitution of the quaternary carbon
with silicon resulted in a new substance that has
moderately less insecticidal potency (0.2-0.6) but
is considerably less toxic to fish (no fish mortality
occurs at concentrations of 50 mg/liter)
                                          F
                      Si

                                          O

             O


                  No motanity to
                  fish at 50mg/l
2.5 Designing Safer Chemicals Using
Retrometabolic Design (i.e., "Soft"
Chemical Design)
What is the “soft ”?
Soft drugs are defined as biologically
 active, therapeutically useful drugs
 deliberately designed to be metabolized
 quickly to non-toxic substances after
 they accomplish their therapeutic
 purpose.
     Designing Safer Chemicals Using
    Retrometabolic Design (i.e., "Soft"
    .




            Chemical Design)
 A soft drug is usually an analog of a
  pharmacologically active substance
  whose clinical utility is limited by
  toxicity or adverse effects.
 The soft drug retains the
  pharmacologic property but lacks the
  toxicity because of its rapid
  detoxication.
   The ideal soft drug:
   desired pharmacologic property
   converted into non-toxic readily excretable
    (in a single, non-oxidative, metabolic step)

   Using a pharmacologically active but toxic drug substance
    as a guide, the design of a soft drug begins with deducing
    non-toxic metabolites that can be retrometabolically
    combined (hence the term "retrometabolic design") to form
    a single structure: the soft drug.
   This relatively new approach to drug design has led to the
    development of a number of non-toxic, highly useful drug
    substances
Cetylpyridinium chloride盐酸十六烷基吡啶
An effective antiseptic(防腐剂) but is regarded as
being quite acutely toxic to mammals because it
has a rat oral median lethal dose (LD50) of 108
mg/kg

  CH3(CH2)12-CH2-CH2-CH2     N         Cl


             LD50 = 108 mg/kg

         Using this compound as a guide
Cetylpyridinium chloride盐酸十六烷基吡啶
   the design of the new compound captured the
    important structural elements that are necessary
    for antiseptic activity (i.e., the pyridinium and C-
    16 alkyl moieties),

   and structural modifications (the pyridinium
    methyl ester) that enable rapid breakdown of the
    substance to comparatively less toxic substances
    in mammals
      Cetylpyridinium chloride盐酸十六烷基吡啶
   Pyridine, formaldehyde and tetradecanoic acid were
    chosen as the "metabolites" because they are relatively
    non-toxic and can be retrometabolically combined into a
    single easily-hydrolyzable substance (new) that is a soft
    analog of the old one.
   The side chains of old one and new one are essentially 16
    carbons in length, and these substances share the same
    physicochemical and antiseptic properties.
   They differ greatly, however, in their mammalian toxicity:
    of the new one is 40 times less toxic than old one (the rat
    oral LD50 of 54 is greater than 4000 mg/kg).
   Substance NEW is less toxic than OLD because the
    pyridinium methyl ester moiety undergoes facile hydrolytic
    cleavage in the blood to pyridine, formaldehyde, and
    tetradecanoic acid.
The new soft compound

              O
CH3(CH2)12-C-O-CH2 N                   Cl

             LD50>4000mg/kg

    CH2 N
                         O
                         C O
CH3(CH2)12-                   Changed to


      Kept              -CH2-CH2-
         "soft" commercial substance

   The concept of soft drug or retrometabolic
    design can be extended to commercial
    chemical design.
   A "soft" commercial substance could be defined
    as a substance deliberately designed such that
    it contains the structural features necessary to
    fulfill its commercial purpose but, if absorbed
    into exposed individuals, it will break down
    quickly and non-oxidatively to non-toxic, readily
    excretable substances.
    2.6 Identification of Equally Useful, Less Toxic
        Chemical Substitutes of Another Class
   Another approach to designing safer chemicals is
    the identification of an equally useful less toxic
    substance that belongs to another chemical class.
   the focus of this approach is on commercial use
    (not on molecular modification), and depends upon
    the successful identification of a less toxic
    substance of a different chemical class that can
    fulfill this use.
   This approach may be particularly attractive in
    situations in which molecular modification cannot
    eliminate or reduce the toxicity of a substance
    without having a negative affect on commercial
    usefulness.
 Example 1:Acetoacetates as Substitutes for
Isocyanates in Sealants and Adhesives(用乙酰
    乙酸酯代替异氰酸酯用作密封剂和粘结剂)
 Isocyanates are widely used in industrial sealants
密封剂and adhesives粘结剂. In these applications
the sealant or adhesive effect results from reaction
of an isocyanate with a nucleophile (such as an
alcohol or amine) to yield a cross-linked adduct.
Isocyanates are particularly useful in sealants and
adhesives because of their fast cure, ability to
adhere to most substrates, and relative low price.
 Example 1:Acetoacetates as Substitutes for
    Isocyanates in Sealants and Adhesives
A major disadvantage of isocyanates,
 however, is their toxicity. Isocyanates
 cause cancer(癌症), mutations(变种),
 pulmonary sensitization(肺敏感), and
 asthma (气喘) and, as such, pose serious
 health risks to manufacturing personnel.
 They also require special handling and
 storage, and have limited package
 stability and weatherability.
 Example 1:Acetoacetates as Substitutes for
    Isocyanates in Sealants and Adhesives
The Tremco Corporation (Beachwood,
 Ohio)
 Alternative sealant-adhesive:

 This alternative sealant-adhesive system
 utilizes acetoacetate as a functional
 equivalent of isocyanate.
Example 1:Acetoacetates as Substitutes for
   Isocyanates in Sealants and Adhesives
Example 2: Isothiazolones as
Substitutes for Organotin Antifoulants
(用异噻唑酮代替有机锡防污剂 )
   The growth of marine organisms on submerged
    structures such as the hulls(船外壳) of ships can
    cause increased hydrodynamic drag, which is
    commonly referred to as fouling (污垢).
   Although seemingly harmless, fouling leads to
    increased fuel consumption, decreased ship
    speed, increased vessel servicing and cleaning
    costs, and increased dry dock time. It is estimated
    that the U.S. government spends over a billion
    dollars each year as a result of fouling of its
    military vessels
   Antifouling agents are often applied to hulls of
    ships to prevent fouling.
    Organotin(有机锡) substances are effective
    antifouling agents, but they are highly toxic to
    mussels, clams, and other non-fouling aquatic
    species.
   In addition, because many organotin substances
    are regarded as hazardous wastes, their removal
    from ships during cleaning operations must be
    performed carefully and is costly.
   Because of their ecotoxicity, the use of organotin
    antifoulants has been banned throughout the world.
      Example 2: Isothiazolones as Substitutes for
                Organotin Antifoulants
   The Rohm and Haas Company
    (Spring House, PA) has
    devoted much effort to finding          Cl       O
    antifouling agents that are not
    toxic to non-fouling aquatic
                                       Cl            N   (CH2)7 CH3
    species. They have found that
                                                 S
    isothiazolones (异噻唑龙) are
    effective marine antifoulants.
    4,5-Dichloro-2-/i-octyl-4-
    isothiazolin-3-one (4,5- 二 氯 -2-
    正 辛 基 -4- 异 噻 唑 -3- 酮 ) is a
    particularly useful antifoulant.
Example 2: Isothiazolones as Substitutes for
          Organotin Antifoulants
In addition to being an excellent biocide, it
presents little risk to non-fouling aquatic
organisms: it decomposes quickly in marine
environments and the decomposition products
bind strongly to sediment and are not available
to aquatic species.
This substance has recently been approved as
an antifoulant by the Office of Pesticides of the
U.S. Environmental Protection Agency.
Example 3: Sulfonated Diaminobenzanilides as
     Substitutes for Benzidines in Dyes
       用磺化二氨基N苯甲酰苯胺代替染料中的联苯胺


   Benzidine(联苯胺)and many of its congeners
    were at one time widely used in the synthesis of
    dyestuffs. Their unique color and fastness
    properties made them particularly useful for this
    purpose. When it became apparent that
    benzidine and a number of its congeners(同类
    物质) are highly carcinogenic their use as
    synthetic intermediates in dyestuffs dropped
    drastically
Sulfonated Diaminobenzanilides as Substitutes
            for Benzidines in Dyes
   Many researchers have attempted to find non-
    carcinogenic alternatives to benzidines that
    have the same desired properties as
    benzidines.


   Sulfonated diaminobenzanilides (磺化二氨基N
    苯甲酰苯胺代替联苯) where recently reported
    to be useful substitutes for benzidine in the
    synthesis of direct dyes.
Sulfonated Diaminobenzanilides as Substitutes
            for Benzidines in Dyes
   Although it is not yet known whether these substances
    are carcinogenic, the sulfonic acid moiety may make
    them non-carcinogenic because the carcinogenicity of
    other aromatic amines is often eliminated by the
    inclusion of this moiety.

                          O
         H2 N             C            O
                              N        S OH
                              H        O
                                     NH2
     3.7: Elimination of the Need for Associated Toxic
                         Substances
   Although a chemical substance may not be toxic,
    its storage, transportation or use may require an
    associated substance that is toxic (e.g., a solvent
    such as carbon tetrachloride).
    In such instances it is the associated substance
    that represents the toxic component. In this
    approach one needs to somehow eliminate the
    need for the associated toxic substance.
    Elimination of the Need for Associated Toxic
                     Substances
   In some cases this could be accomplished by simply
    identifying an alternative, less toxic associated
    substance that will serve the same purpose as the toxic
    substance (e.g., switching from a toxic solvent to a less
    toxic, equally useful solvent).
   In other cases, more elaborate formulation changes
    may be necessary.
   In cases where switching to a less toxic associated
    substance or reformulation is not possible, the original
    substance may have to be structurally modified to a
    new substance for which a less toxic associated
    substance can be used or reformulation is possible.
   These structural modifications should not, of course,
    impart toxicity.
         Exercises
 1、简答
  人类避免有害化学品毒性的途径
  生物放大(聚集)
  化学品产生毒性的三要素
  毒性载体(Toxicophore)
   和产毒结构(Toxicogenic)
  构效关系, 化学性质描述符
  Langmuir 电子等排同性质原理
  软化学设计
        Exercises
 2、 设计安全有效化学品的外部效应原则
  的主要内容有那些?
 3、设计安全有效化学品的内部效应原则的
  主要内容有那些?
 4、 肠胃、肺和皮肤吸收的特点有哪些?
  如何通过改变分子性质避免其被吸收?
 5、 消除化学品毒性的Phase-I 反应和
  Phase-II反应的化学本质是什么?
       Exercises
 6、 典型亲电性物质的结构特征有哪些?
  其引发的中毒化学反应主要有哪些?人体
  内细胞的哪些结构容易与亲电性物质发生
  中毒化学反应?
 7、 常见电子等排物有哪些?

 8、举例说明用无毒无害的物质取代有毒有
  害物质的重要性和可能性
         Exercises
9、某化合物的结构如下,指出其可
能引发的中毒反应

                  Cl



                       O
    NC




            NCO

								
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