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• Idiosyncratic response


  Uncommon, unpredictable reaction or response to a drug or other substance, sometimes impossible to understand whether it is the result of a genetic predisposition or has some other cause such as the status of the immune system
• Factors influencing toxicity


  • Form and innate chemical activity
  • Dosage, especially dose-time relationship
  • Exposure route
  • Species
  • Life stage, such as infant, young adult, or elderly adult
  • Gender
  • Ability to be absorbed
  • Metabolism
  • Distribution within the body
  • Excretion
  • Health of the individual, including organ function and pregnancy, which involves physiological changes that could influence toxicity
  • Nutritional status
  • Presence of other chemicals
  • Circadian rhythms (the time of day a drug or other substance is administered)
• Form of a substance


  May have a profound impact on its toxicity, especially for metallic elements, also termed heavy metals
• Form of a substance

  • Mercury vapor differs greatly from methyl mercury
  • Cr3+ is relatively nontoxic whereas Cr6+ causes skin or nasal corrosion and lung cancer
• Innate chemical activity


  Some substances can quickly damage cells causing immediate cell death, others slowly interfere only with a cell's function
• Innate chemical activity


  • Hydrogen cyanide binds to the enzyme cytochrome oxidase resulting in cellular hypoxia and rapid death
  • Nicotine binds to cholinergic receptors in the central nervous system (CNS) altering nerve conduction and inducing gradual onset of paralysis
• Dosage


  The most important and critical factor in determining if a substance will be an acute or a chronic toxicant
• Virtually all chemicals can be acute toxicants if sufficiently large doses are administered
• Often the toxic mechanisms and target organs are different for acute and chronic toxicity
• Exposure route


  The way an individual comes in contact with a toxic substance, important in determining toxicity
• Exposure route


  • Ingested chemicals, when absorbed from the intestine, distribute first to the liver and may be immediately detoxified
  • Inhaled toxicants immediately enter the general blood circulation and can distribute throughout the body prior to being detoxified by the liver
• Different target organs often are affected by different routes of exposure
• Exposure routes


  • Ingestion
  • Inhalation
• Absorption


  The ability to be absorbed is essential to systemic toxicity
• Absorption


  • Ethanol is readily absorbed from the gastrointestinal tract but poorly absorbed through the skin
  • Organic mercury is readily absorbed from the gastrointestinal tract; inorganic lead sulfate is not
• Selective toxicity


  Species differences in toxicity between two species simultaneously exposed, the basis for the effectiveness of pesticides and drugs
• Selective toxicity


  • An insecticide is lethal to insects but relatively nontoxic to animals
  • Antibiotics are selectively toxic to microorganisms while virtually nontoxic to humans
• Life stage


  An individual's age or life stage may be important in determining his or her response to toxicants
• Life stage


  • Parathion is more toxic to young animals
  • Nitrosamines are more carcinogenic to newborn or young animals
• Gender


  Can play a big role in influencing toxicity, physiologic differences between men and women, including differences in pharmacokinetics and pharmacodynamics, can affect drug activity
• Gender


  • Gender plays a role in alcohol metabolism and its toxic effects due to differences in the activity levels of ADH and ALDH enzymes between men and women
  • Women have a lower level of ADH and ALDH enzymes, resulting in slower metabolism and increased toxicity
  • Male rats are 10 times more sensitive than females to liver damage from DDT
  • Female rats are twice as sensitive to parathion as are male rats
• Metabolism


  The conversion of a chemical from one form to another by a biological organism, a major factor in determining toxicity
• Types of metabolism


  • Detoxification - converting a xenobiotic to a less toxic form
  • Bioactivation - converting a xenobiotic to more reactive or toxic forms
• Metabolism


  • In the elderly, CYP450 metabolism of drugs such as phenytoin and carbamazepine may be decreased, therefore the effect of those drugs may be less pronounced
  • CYP450 metabolism can be inhibited by many drugs, risk of toxicity may be increased if a CYP450 enzyme-inhibiting drug is given with one that depends on that pathway for metabolism
• Distribution within the body

  Determines the sites where toxicity occurs, a major determinant is lipid solubility
• Distribution within the body

  • If a toxicant is lipid-soluble, it readily penetrates cell membranes
  • Many toxicants are stored in the body, common storage sites are fat tissue, liver, kidney, and bone
• Excretion


  The site and rate of excretion is another major factor affecting the toxicity of a xenobiotic
• Excretion


  • The kidney is the primary excretory organ, lipid-soluble toxicants are reabsorbed and concentrated in kidney cells, impaired kidney function causes slower elimination of toxicants and increases their toxic potential
• Health status


  The health of an individual or organism can play a major role in determining the levels and types of potential toxicity
• Nutritional status


  Diet can be a major factor in determining who does or does not develop toxicity
• Nutritional status


  • Consumption of fish that have absorbed mercury from contaminated water can result in mercury toxicity, an antagonist for mercury toxicity is the nutrient selenium
  • Some vegetables can accumulate cadmium from contaminated soil, an antagonist for cadmium toxicity is the nutrient zinc
  • Grapefruit contains a substance that inhibits the P450 drug detoxification pathway, making some drugs more toxic
• Presence of other chemicals

  May decrease toxicity (antagonism), add to toxicity (additivity), or increase toxicity (synergism or potentiation)
• Presence of other chemicals

  • Antidotes used to counteract the effects of poisons function through antagonism (atropine counteracts poisoning by organophosphate insecticides)
  • Alcohol may enhance the effect of many antihistamines and sedatives
  • A synergistic interaction between the antioxidant butylated hydroxytoluene (BHT) and a certain concentration of oxygen results in lung damage in the form of interstitial pulmonary fibrosis
• Poison


  Any substance that is harmful to the body, capable of causing illness or death of living organism when introduced or absorbed
• Types of poisoning


  • Deliberate
  • Accidental
  • Environmental
  • Industrial exposures
• Substances that may act as poisons

  • Cleaning products
  • Household products, such as nail polish remover and other personal care products
  • Pesticides
  • Metals, such as lead, Mercury, which can be found in old thermometers and batteries
  • Prescription and OTC drugs when combined or taken the wrong way
  • Contaminated food
  • Plants, such as poison ivy and poison oak
  • Venom from certain snake

  
• Symptoms of poisoning


  • Vomiting
  • Diarrhea
  • Nausea
  • Redness or sores around the mouth
  • Drooling or dry mouth
  • Dilated pupils or constricted pupils
  • Rash
  • Confusion
  • Shaking or seizures
  • Trouble breathing
  • Unconsciousness (fainting)
• Management of poisoning


  • Resuscitation and stabilization
  • Toxic diagnosis
  • Therapeutic interventions
  • Decontamination
  • Enhanced elimination of absorbed toxins
  • Antidotes
  • Supportive care
• Resuscitation and stabilization


  First priorities are ABC's (Airways, Breathing, & Circulation), vital signs including pulse and hypoglycemia must be corrected, unresponsive patients treated empirically with coma cocktail (oxygen, naloxone, dextrose 50W (D50W), and 100mg thiamine)
• Toxicological diagnosis


  Includes obtaining history, physical examination, and toxicological investigation