Toxicology

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					Toxicology
    Toxicology
      Study of poisons.
     There are four major disciplines:
      1. Mechanistic: elucidate the cellular and biochemical
         effects of toxins.
      2. Descriptive: uses results of animal experiments to
         predict harmful effects to humans.
      3. Forensic: concerned with medicolegal consequences
         of exposure to a toxin.
      4. Clinical: the study of interrelationships between
         toxin exposure and disease states (diagnosis &
         therapeutic intervention)
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    Exposure to Toxins
     Occurs by various routes:
      Suicide (50%)
      Accidental (30%)
      Rest are related to:
        occupational exposure
        or homicide



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    Routes of Exposure
     Toxins enter the body by several routes:
      1. Ingestion
         most often seen in a clinical setting
         to exert a systemic effect, they must be absorbed into
          circulation
         most are absorbed by passive diffusion
         If not absorbed they may produce local effects, such as
          diarrhea, bleeding, or malabsorption of nutrients
      2. Inhalation
      3. Transdermal absorption
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    Dose-response relationship
     Poison
       any substance that causes a harmful effect upon
       exposure.
     Dose is a key issue.
     There are various toxic effects from drugs
      based on dose including death.
     Dose-response implies that there will be an
      increase in the toxic response as the dose is
      increased.
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    Dose-response relationship
     Not all individuals display a toxic response at the same dose.
     Cumulative frequency histogram of the % of people
      producing a toxic response over a range of concentrations




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    Dose-response relationship
     TD50
       is the dose that would be predicted to produce a
        toxic response in 50% of the population.
     ED50
       is the dose that would be predicted to be
        effective or have a therapeutic benefit in 50% of
        the population.
     LD50
       is the dose that would predict death in 50% of
7       the population.
    Dose-response relationship
     The therapeutic index is the ratio of the TD50 to
      the ED50.
     A high therapeutic index is preferable to a low
      one:
       this corresponds to a situation in which one would
       have to take a much higher dose of a drug to reach
       the lethal threshold than the dose taken to elicit the
       therapeutic effect.
     Drugs with a large therapeutic index have few
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     toxic adverse effects
    Acute and Chronic Toxicity
     Acute toxicity:
      associated with a single, short term exposure to
      a substance, the dose is sufficient to cause
      immediate toxic effect.

     Chronic toxicity:
      associated with repeated exposure for extended
      periods, at a dose that are insufficient to cause
      immediate acute response.
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         Analysis of Toxic Agents
     •    Two-steps procedure
         – Screening test:
           •    which is a rapid , simple analysis that is qualitative
                procedure to detect specific drug or substance.
               • Sensitive but lack specificity
               • Assy: E.g. immunoassays
         – Confirmatory test:
           • test utilizing more specificity- and quantitative
           • Thin layer chromatography and gas chromatography.
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     Toxicology of Specific Agents
      Alcohol:
       Exposure to alcohol causes:
         disorientation,
         confusion
         and euphoria
       can progress to unconsciousness, paralysis and
        with high-level exposure , even death.
       common depressant of the central nervous
        system.
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     Alcohol:
       There is biotransformation of alcohols to
       toxic products
       Alcohol → Aldehyde → Acid
       Chronic consumption of alcohol over a long
       period leads to accumulation of lipids in
       hepatocytes, which may progress to
       alcoholic hepatitis and finally to liver
       cirrhosis
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     Alcohol:
     Ethanol
       The economic impact is estimated to exceed $100
        billion
       one of the top 10 causes of hospital admissions
       20% of all hospital admissions have some degree of
        alcohol-related problems
       80,000 Americans die each year, either directly or
        indirectly, as a result of alcohol
       Consumption of large quantities has been associated
        with compromised function in various organ
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       alcoholic hepatitis
     Alcohol:
      Methanol:
       Common solvent ingested accidentally
       Death can occur due to the formation of formic acid leading to
        severe acidosis
       CNS depressant
      Isopropanol:
       rubbing alcohol, metabolized by liver to acetone
       CNS depressant
      Ethylene glycol:
       common component of anti-freeze.
       Causes crystallization of calcium oxalate within the renal system
        and cause tubular damage if dosage high.
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      Determination of Alcohol
      Specimen:
        serum, plasma, whole blood
        Do not use alcohol to clean area for veinpuncture
        specimens must be capped at all times to avoid
         evaporation
      Methods:
        Gas chromatography.
        Enzymatic method

                                  ADH
         Ethanol + NAD                  Acetaldehyde + NADH

15   ADH= alcohol dehydrogenase
      Carbon Monoxide
      By product of incomplete combustion of carbon
       containing substances (gasoline engines, furnaces and wood
       or plastic fires.)
      Colorless, odorless and tasteless gas that is absorbed into
       the blood from inhaled air.
      Toxic effect is due to its affinity for heme (Hb,
       myoglobulin, etc).
      Hb affinity has the most effect due to the production of
       carboxyhemoglobulin (~ 200 X greater affinity)
      Major toxic effect of carbon monoxide are seen in organs
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       with high O2 demand (brain & heart)
     Methods for CO determination
     1. Spot test:
       • using 5 ml of 40% NaOH mixed with 5 ml of
         1/20 aqueous dilution of whole blood
        •   a pink color if CO present at 20% or greater value
     2. Quantitative method
       • Gas chromatography,
       • and spectrophotometeric methods



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     Caustic Agents
      Occupational or household exposure of cleaning
       agents.
      Aspiration and ingestion present the greatest
       hazard
      Ingestion produces lesions in the esophagus and
       gastrointestinal tract, which may produce
       perforations
      Corrective therapy for ingestion is usually by
       dilution
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     Cyanide
      Supertoxic substance that exist as a gas, solid or in
       solution.
      Exposure can occur through inhalation, ingestion, or
       transdermal absorption.
      Found in insecticides and rodenticides
      Toxic effect involves its ability to bind heme iron.
      Cyanide clearance is mediated by enzymatic conversion
       to thiocyanate, a nontoxic product rapidly cleared by
       renal filtration.
      Method for analysis: Ion specific electrode and
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       photometric analysis.
     Metals and Metalloids
     Arsenic:
       exist bound or as primary constituent of organic
        and inorganic compounds.
       Found naturally and can be manmade forms.
       Environmental exposure or occupational
       Absorption of arsenic depends on the form.
       Toxicity related to the binding ability to protein.
       Assay: atomic absorption spectrophotometry.

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     Metals and Metalloids
      Cadmium
       Metal found in industrial processes
        (electroplating)
       Pigment found in paints and plastics.
       Significant environmental pollutant.
       Exposure occurs through inhalation, toxicity
        related to ability to bind to protein & tends to
        accumulate in the kidney’s.
       Assay: atomic absorption spectrophotometry.
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     Metals and Metalloids
     Lead
       Common environmental contaminant
       Use to be used in household paint and gasoline.
       Exposure can occur in various route- most is through
        dietary ingestion of contaminated material.
       Toxicity related to ability to bind to macromolecular
        structures.
       Distributes into the bones and soft tissue.
       Elimination occurs through the renal system.
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      Lead
       Lead toxicity has various physical effects
        (neurological, decreased intelligence).
       Potent inhibitor of many enzymes (Vit. D, heme
        synthetic pathway) resulting in changes in bone
        and calcium metabolism and in anemia.
       Assay: chromogenic reaction
       Most common method Graphite furnace atomic
        absorption spectrometry
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     Metals and Metalloids
      Mercury
       Exposure occurs through inhalation and ingestion
        (contaminated food)
       Toxicity related to ability to bind protein
        resulting in a change of structure and function.
       Inhibits a number of enzyme activities.
       Many biological effect most noted is renal.
       Assay: AAS

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     Pesticides
      Substance that are intentionally used to kill or
       harm an undesirable life form.
      Categorized as insecticide and herbicides which are
       used to control of vector-borne disease and pest
       and to improve agricultural productivity.
      Contamination of food is the major route of
       exposure.
      Inhalation, transdermal absorption and ingestion
       through hand-to mouth contact are common
25     occupational and accidental exposure.
     Pesticides
      Actions of most are nonselective and result in toxic
       effect to various organs.
      Wide variation of pesticides that range from salts
       to heavy metals.
      Organophosphate and carbamates function by
       inhibition of acetylcholine esterase.
        Acetylcholine is a neurotransmitter and has many effects
        in the body.
      Test utilized to test for toxic pesticides- serum
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      psuedocholinesterase activity (SChE).
      Toxicology of Therapeutic Drugs
      Analyze the overdose effects of pharmaceutical
       drugs.

      Salicylates:
        Aspirin: analgesic, antipyretic, and anti-inflammatory
         drug.
        Various bodily effects:
          Because aspirin is an acid leads to metabolic acidosis.
        Assay: Gas or liquid chromatography, Immunoassay &
         Chromogenic method
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     Amphetamines
      Amphetamine and methamphetamines are therapeutic
       drugs used for narcolepsy and attention deficit disorder.
      Stimulants with high abuse potential.
      Produce an initial sense of increased mental and physical
       capacity
      Overdose results in hypertension, cardiac arrhythmia,
       convulsions and possibly death.
      Assay for amphetamine requires urine specimen,
        immunoassay is a screening test,
        confirmation by liquid or gas chromatography.
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     Anabolic Steroid
      Chemical compound that is chemically related to
       male sex hormone testosterone.
      Used to increase muscle mass and enhance
       performance.
      Various physical effects including toxic hepatitis
       with chronic use, enlarge heart, atherosclerosis.
      Assay: gas chromatography with mass
       spectrometry


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     Cocaine
      Effective local anesthetic with few side effects at
       therapeutic concentration.
      At High levels it is a potent CNS stimulator.
      Alkaloid salt that can be administered by IV and /or
       inhaled in free base form.
      Primary product of hepatic metabolism is benzoylecgonine
       in urine.
      Detected in urine 4-7 hrs after use and detected up to 3
       days after single use and 20 days in chronic use.
      Confirmation test is done by gas chromotograhy.
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     Opiates
      Capable of analgesic and anesthesia
      Derived from opium poppy, naturally occurring
       substances include opium, morphine, and codeine.
      Heroin and hydromorphone are common synthetic
       substances.
      High abuse potential.
      Acute overdose present with respiratory acidosis
       due to depression of respiratory center and cardiac
       damage.
31    Initial detection immunoassay.

				
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posted:8/11/2012
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