The Principles of Toxicology

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					Principles of Toxicology
     Dose-response Relationships
        Risk and Its Assessment
     Spectrum of Undesired Effects
        Descriptive Toxicity Tests
      Incidence of Acute Poisoning
 Prevention & Treatment of Poisoning
Major Sources of Information on Poisons
   Dose-response Relationships
 Dose-response relationships is important in toxicology
 There are 2 type of dose-response relationships i.e. graded
  dose-response relationship in an individual and quantal
  dose-response relationship in a population
 In the Graded dose-response: the magnitude of response
  increases as the dose is increased in an individual
 In the Quantal dose-response: the % of population affected
  of the dose is greater when the dose is increased
 The Quantal dose-response phenomenon is extremely
  important in toxicology and used for determining median
  lethal dose LD50
 LD50 is determined experimentally in animals
 Two figures might be displayed
 Acute LD50 values for a variety of
        chemical agents
Agent                 Species        LD50 mg/kg b.w.

Ethanol               Mouse        10,000
Sodium chloride       Mouse          4,000
Ferrous sulphate      Rat            1,500
Morphine sulphate     Rat              900
Phenobarbital Sod     Rat              150
DDT                   Rat              100
Picrotoxin            Rat                 5
Strychnine sulphate   Rat                 2
Nicotin               Rat                 1
D-Tubocurarine        Rat              0.5
Hemicholinium-3       Rat              0.2
Tetrodoxin            Rat              0.1
Dioxin (TCDD)         Guinea-pig       0.001
Botulinum toxin       Rat              0.00001
       Risks and Its Assessment
 LD50 of various chemicals divers markedly
 It is not possible to categorize a chemical either safe or
  toxic
 The real concern is the risk associated of the use of
  chemicals
 In determining the risk of a chemical we have to consider
  the dose/concentration and the harmful effect in the
  environment although it was used in the quantity and in the
  manner proposed
 Depending on the use and its disposition a toxic compound
  ultimately may be less harmful than a relatively non toxic
  one
     Risks and Its Assessment
 The risk from exposure of chemical that produced
  cancer in laboratory animals
 Most of them is not known whether they also
  produced cancer in humans
 Food additive, many people would be exposed
  while no significant beneficial effect
 Drugs: carcinogenic drugs (in animals) for mild
  ailment versus those for serious disease
 Environmental carcinogen: life time exposure →
  no more than 1 incidence in 1 million
      Risks and Its Assessment
 Acute versus chronic exposure: might be different
 Chemical forms of drugs that produced toxicity:
  “parent” drug may produced therapeutic as well as
  toxic effect. The metabolite(s) may do so as well.
  Toxic form may be produced by enzymes, light, or
  reactive oxygen species
 It is important to understand the metabolism,
  activation and decomposition of potential toxic
  compounds
       Risks and Its Assessment
 Toxic metabolites:
  Organophosphate insecticides: parathion → paraoxon
  Acetaminophen → quinone imine
  Both become more toxic when ingested after consumption
  of P450 increasing compounds such as ethanol or
  phenobarbital
 Photoallergic and phototoxic reactions: Sulfonamides
  would be more allergic in the presence of light
  Phototoxic: no immunological aspects, they chemically
  induced photosensitivity or enhance the usual effect of
  light: tetracyclines, sulfonamides, chlorpromazine, nalidixic
  acid
 Oxygen reactive species: paraquat, one-electron reduction
  Spectrum of Undesired Effects
 Desired and undesired effects
 Undesired effects may be deleterious or not
  deleterious
 Side effect usually not deleterious: dry
  mouse effect of tricyclic antidepressants
 Some side effects may be adverse or toxic:
  aplastic anemia of chlaramfenicol
          Type of Toxic Reaction
 Pharmacological toxicity: excessive depression of the CNS
  by barbiturates
 Pathological toxicity: liver injury induced by acetaminophen
 Genotoxical toxicity: neoplasm produced by nitrogen
  mustard
 The effects are likely to be reversible if the concentration of
  the chemicals do not exceed the critical level
 Pharmacological effect will be disappear when the
  chemicals are reduced by metabolism or excretion
 Pathological and genotoxic effect may be repaired
         Type of Toxic Reactions
 Local versus systemic toxicity:
  Local toxicity occurs in the site of first time contact of the
  living organism with the toxicant
  Systemic toxicity needs absorption and distribution of the
  chemical
 Those effects are not mutually exclusive: tetraethyl lead
  injures the skin at the site of contact and deleteriously
  affects the CNS when it is absorbed and distributed
 Most systemic toxicants predominantly affect one or few
  organs
 The target organ is not necessarily the site of the
  accumulation
      Types of Toxic Reactions
 The CNS involved in systemic toxicity most
  frequently
 Next in the order of frequency of the involvement
  are the circulatory system, the blood and
  haemotopoietics system, visceral organs such as
  liver, kidney and lung, and the skin
 Muscle and bone are least affected
 Local toxicity mainly occurs in the portal of entry
  (skin, GI tract, respiratory tract)
      Type of Toxic Reactions
 Reversible and irreversible toxic effect:
  depends on the capacity of tissue to
  regenerate or to recover
 Injuries to tissue such as liver usually
  reversible
 Injuries to CNS usually irreversible
       Type of Toxic Reactions
 Delayed toxicity: most toxic effects occur at a
  predictable (usually short) period after
  administration
 However, aplastic anemia caused by
  chloramphenicol may appear weeks after the drug
  has been discontinued
 Carcinogenic effect of chemical has a long latency
  of period
 Need a reliable predictive short-term toxicity test
  as well as long-term systematic surveillance for
  marketed drugs
               Chemical Carcinogens
 Chemical Carcinogenesis
*a multi-step process

*two types of chemical carcinogens: genotoxic and non-genotoxic

*genotoxic carcinogens interact with DNA, parent compounds usually is unreactive
   (proximate/pro carcinogen), will be converted by metabolizing enzymes into ultimate
   carcinogen, then interact with DNA

*Non-genotoxic carcinogens also referred to promoters

*Non-genotoxic carcinogens do not produced tumors alone, but do potentiate the effect of
   genotoxic carcinogens

*Promotion: the facilitation of the growth of dormant/latent tumor cells

*The time from the initiation to the development of tumor cells probably depends on the
   present of such promoters

* In many human tumors the latent period is about 15 to 45 years
            Chemical carcinogens
 Carcinogenicity test
• Ames-test: mutagenicity test, most carcinogens are mutagens
        Employed microorganism certain type of Salmonella typhimurium
        Can be completed in a few days
        Can detect genotoxic carcinogen but do not detect non-genotoxic
   one
*Animal test: (rats and mice)
        1. Direct skin-painting
        2. Initiation-promotion models
        3. New-born mice
             Allergic eactions
 Chemical allergy, drug allergy, hypersensitivity
 An adverse reaction results from previous
  sensitization
 Low-m.w. chemical acts as hapten, interacts with
  endogenous protein form an antigenic complex
 Such antigen induced the synthesis of antibody,
  usually after a latent period, 1-2 weeks
 Subsequent exposure to the chemical results in
  antigen-antibody interaction that provoke allergy
                  Allergic reactions
 Four types of allergic reactions, based on the mechanism of
  immunological involvement
 Type I, anaphylactic reactions
Mediated by IgE, the Fc portion of the antibody can bind to receptors on
  mast cells and basophile. If the Fab portion then bind to antigen,
  various mediators (histamine, prostaglandins, leukotrienes are
  released and cause vasodilatation, edema and inflammatory response
The main target of this type of reaction are GI tract (food allergies), skin
  (urticaria & atopic dermatitis), respiratory system (rhinitis and asthma)
  and vasculatory (anaphylactic shock). This response tends to occur
  immediately after antigen exposure, and called immediate
  hypersensitivity reaction
 Type II
              Allergic reactions
 Type II, cytolytic reaction
Mediated by both IgG and IgM antibodies, usually atributated
  to their ability to activate the complement systems
The major target are the cells in the circulatory system.
The example of this response are, pennicilline-induced
  hemolytic anemia, methyldopa-induced hemolytic anemia,
  quinidine-induced thrombocytopenic purpura and
  sulfonamide-induced granulocytopenia
These autoimmune reactions usually subside within several
  months after removal of the offending agents
 Type III
                    Allergic reactions
 Type III: Arthus reaction are mediated predominantly by IgG antibodies
The mechanism involves the generation of Antigen-antibody complexes that
   subsequently fix complement.
The complexes are deposited in the vascular endothelium where the destructive
   inflammatory reactions occurs called serum sickness
This response is induced by antibodies directed against tissue antigen.
The clinical symptoms include urticarial skin eruption, athralgia and arthritis,
   lymphadenopathy, and fever. The reactions last faor 6-12 days and subside
   after the offending drugs are eliminated
Several drugs such as sulfonamides, penicillins, certain anticonvulsants and
   iodides may induce serum sickness. Stevens-Johnson syndrome, such as that
   caused by sulfonamides is a more severe form of immune vasculitis.
Manifestatons of this reactions include erythema multiforme, arthritis, nephritis,
   myocarditis and CNS abnormalities

Type IV
            Allergic reactions
 Type IV, delayed hypersensitisity, mediated by the
  sensitized T-lymphocytes and macrophages.
When sensitized cells came in contact with antigen,
  then inflammatory reactions are generated by the
  production of lymphokines and subsequent influx
  of neutrophils and macrophages.
An example of type IV reaction is the contact
  dermatitis caused by poison of ivy
Idiosyncratic Reactions
 Interactions between Chemicals
 Pharmacokinetic interactions
 Pharmacodynamic interactions
Receptor: atropine for organophosphate
  intoxication
Non-receptor: aspirin and heparin may cause
  bleeding
       Interactions of Chem…….
 Pharmacological & Toxicological terminology of Chemical
  Interactions
Additive: Effect AB = Effect A + Effect B, the most common
  interactions
Synergistic: Effect AB > Effect A + Effect B, ethanol and CCl4
  both are hepatotoxins, the effect much more deleterious
  when ingested together
Potentiation: A toxic + B non-toxic > Effect A alone:
  isopropanol is not toxic to the liver but can greatly increase
  the hepatotoxicity of CCl4
Antagonism: Functional/physiological, chemical, dispositional
  antagonism and antagonism at the receptor
           Interactions of…….
 Functional/physiological antagonism:
Infusion of dopamine to restore the blood pressure in
  intoxication with marked low blood pressure
 Chemical antagonism (inactivation): the use of
  dimercaprol in intoxication of heavy metals
 Dispositional antagonism: antagonism in the
  pharmacokinetic processes, i.e. absorption,
  metabolism, distribution, and excretion
 Antagonism at the receptor: the use of naloxone in
  the treatment of respiratory depression by opioids
Descriptive Toxicity Tests in Animals
 Two (2) main principles underlie the descriptive
  toxicity-test performed in animals:
1.Effects of chemicals produced in animals, when
  properly qualified, apply to human
2.Exposure of experimental animals to toxic agents
  in high doses is a necessary and valid method to
  discover possible hazards to human beings who
  are exposed to much lower doses
Descriptive Toxicity Tests in Animals
 Chemicals are tested for toxicity by estimation of
  the LD50 in 2 animal species by two routes of
  administration
  One of them is the expected route of exposure in
  human beings
 The number of animals that die in 14-day period
  after a single dose is recorded
 The animals also are examined for signs of
  intoxication, lethargy, behavioral modification, and
  morbidity.
Descriptive Toxicity Tests in Animals
 Next, the chemical is tested for toxicity by
  repeated exposure, usually for 90 days.
 In two animal species by the route of
  intended use or exposure with at least three
  doses.
 A number of parameters are monitored
  during this period; and at the end of the
  study organs and tissues are examined by a
  pathologist.
Descriptive Toxicity Tests in Animals
 Long-term or chronic studies are carried out in
  animals at the same time when clinical trial are
  performed.
 For drugs the length of exposure depends on
  somewhat the intended clinical use.
 For drugs that are used for short periods, such as
  antimicrobial agent, exposure of animals for 6
  months is considered sufficient.
 For drugs that are used for long periods, the
  exposure of animals may be as long as 2 years.
Descriptive Toxicity Tests in Animals
 In addition to chronic studies, a carcinogenicity or
  teratogenicity test are required.
 Carcinogens usually are also tested for mutagenic
  activity using the Ames-test (the reverse-mutation
  test)
 Mutant of S. typhimurium, phosphoribosyl ATP
  sythetase, lack of, histidine synthesis
 Usually need activating enzymes to be added
 Detect genotoxic agent but do not detect non-
  genotoxic one
Incidence of Acute Poisoning
Antidotes
 Drugs used to     Overdose of   Counter with
  counteract drug
  overdose:         Atropine      Physostigmine

                    Opioid        Naloxone

                    Benzodiazepin Flumazenil
                    es
                    Digitalis     Antibody (Fab)

                    Acetaminophen N-acetyl
                                  cysteine
Chelating agents
 Antidotes for heavy metal poisoning
 To form organo-metal complex
 Chelate, Greek origin: chele = claw
 Having high affinity: “attract” metal ons in the
  organism
 The chelates are non-toxic, excreted
  predominantly via the kidney, maintained a tight
  organometal bond, even in the concentrated
  (usually acidic) milieu of tubular urine >>> promote
  the elimination
Chelating agents
 Na2CaEDTA, antidote for Pb poisoning
 Can not penetrate cell membrane
 Must be given parentally
 Because of high affinity, Pb can displace Ca2+
  from its bond
 Excreted renally
 Unwanted effect: nephrotoxicity
 Na3Ca-Pentetate (diethylenetriamino pentaacetic
  acid = DTPA), another derivative
Chelating agents
 Dimercaprol (British Anti-Lewisite = BAL)
*Developed during W.W. II for organic arsenicals
  intoxication
*Able to chelate various metal ion
*Administered intramuscularly in oily liquid vehicle
 Dimercaptopropane sulfonic acid
*Na salt suitable for oral administration
 Unwanted effects: shivering, fever and skin
  reactions
Chelating agents
 Deferoxamine
 From Streptomyces pilosus
 Very high iron-binding capacity, but does not
  withdraw iron from Hb and cytochromes
 Poorly absorbed enterally, must be given
  parenterally
 Increased iron excretion
 Unwanted effect: allergic reaction
 Blood-letting is the most effective treatment of iron
  intoxication, but unsuitable for treating condition of
  iron over-load associated with anemia
Chelating agents
 D-penicillamine
 For copper intoxication (in Wilson’s disease
 Lead ion
 Can be given orally
 Additional uses: for cystinuria and rheumatoid arthritis
 The development of cystine stone in the urinary tract is
  prevented because the drug can form a disulfide bond with
  cysteine >>> soluble
 R.a. : can be used as basal regimen >> polymerization of
  collagens into fibrils is prevented due to the interaction with
  aldehyde
 Unwanted effects: coetaneous damage, nephrotoxicity,
  bone marrow depression, taste disturbances
Cyanide poisoning
 Cyanide ions (CN- ) enter the organism in the form
  of HCN
 HCN produced from cyanide salts which
  hydrolised by the acidic juice in the stomach, or
  enzymatic hydrolysis from bitter almonds
 LD of HCN ~ 50 mg
 CN- binds with high affinity to Fe3+ >>> arrest
  utilization of O2 via mitochondrial cytochrome
  oxidases of the respiratory chain >>> internal
  asphyxiation (histotoxic hypoxia) ensues, while
  erythrocytes remain charged with O2.
Cyanide poisoning and the antidotes
 In small amounts, CN- can be converted ti thiocyanate
  (SCN-) by hepatic rhodanase or sulfur transferase
 Thiosulfate can be given i.v. to promote formation of
  thiocyanate >>> eliminated in urine. However, this reaction
  is slow in onset.
 A more effective emergency treatment is the i.v.
  administration of 4-dimethylaminophenol (a metHb-forming
  agent) >>> rapidly generate trivalent Fe from divalent Fe in
  hemoglobin.
 Competition between metHb and Cytochrome oxidases for
  CN- favors the formation of cyanmetHb.
 Hydroxocobalamin is a very effective antidote. Its central
  Co atom binds CN- with high affinity >>> cyanocobalamin
Methaemoglobinemia
 Brown-colored metHB (Fe3+ but not Fe2+) is
  incapable of carrying O2.
 Under normal conditions, metHb is produced
  continously, but reduced again with the help of
  glucose-6-phosphate dehydrogenase.
 Substances that promote formation of metHb may
  cause a lethal deficiency of O2.
 Tolonium chloride (Toluidin Blue) a redox dye that
  can be given i.v. to reduce metHB
     Poisoning with insecticides of the
            organophosphate
    Phosphorylation of acetylcholinesterase cause irreversible inhibition
     of acetylcholine breakdown and hence flooding the nerve synaps with
     the transmitter.
    >>> exaggerated parasympathomimetic activity, blockade ganglionic
     and neuromuscular transmission, and respiratory paralysis
    Therapeutics measures include:
1.   Administration of high dose of atropine to block muscarinic receptors
2.   Reactivation of acetylcholinesterase by obidoxime (also pralidoxime),
     which succesively binds to the enzyme, captures the phosphate
     residue by a nucleophyllic attack, and then dissociates from the
     active center to release the enzyme.
    Obidoxime is an antidote used to treat poisoning with
     organophosphate insecticides.
  Ferri Ferrocyanide (Berlin Blue)
 Berlin Blue is used to treat poisoning with thallium salt (e.g.
  in rat poison)
 The initial symptoms are gastrointestinal disturbances,
  followed by nerve and brain damage, as well as hair loss.
 Thallium ions present in the body are secreted into the gut
  but undergo reabsorption.
 The insoluble, nonabsorbable colloidal Berlin Blue binds
  thallium ions.
 Given orally to prevent absorption of ingested thallium or to
  promote clearance from the body by intercepting secreted
  thallium into the intestines
Prevention and Treatment of
         Poisoning

				
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Description: The principles of toxicology