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Toxicology Concepts

Toxicology Concepts. Risk. The likelihood of injury or disease resulting from exposure to a potential hazard Evaluation of risk embodies all the basic concepts of toxicology. The science of Toxicology helps people make informed decisions and balance RISKS vs. BENEFITS.

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Toxicology Concepts

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  1. Toxicology Concepts

  2. Risk The likelihood of injury or disease resulting from exposure to a potential hazard Evaluation of risk embodies all the basic concepts of toxicology

  3. The science of Toxicology helps people make informed decisions and balance RISKS vs. BENEFITS The study found the highest levels of pesticide residues in peaches, apples, pears……. AND Spinach.

  4. Exposure Sources of exposure to chemicals • Environmental, including home and school • Occupational • Therapeutic • Dietary • Accidental • Deliberate

  5. Exposure • In order for a chemical to produce a biological effect, it must first reach a target individual (exposure pathway). • Then the chemical must reach a target site within the body (toxicokinetics). • Toxicity is a function of the effective dose (how much) of a foreign chemical (xenobiotic) at its target site, integrated over time (how long). • Individual factors such as body weight will influence the dose at the target site X =

  6. Exposure Route of Exposure • The route (site) of exposure is an important determinant of the ultimate dose—different routes may result in different rates of absorption. • Dermal (skin) • Inhalation (lung) • Oral ingestion (Gastrointestinal) • Injection • The route of exposure may be important if there are tissue-specific toxic responses. • Toxic effects may be local or systemic

  7. Exposure Time of Exposure • How long an organism is exposed to a chemical is important Duration and frequency contribute to dose. Both may alter toxic effects. • Acute Exposure = usually entails a single exposure • Chronic Exposures = multiple exposures over time (frequency)

  8. Dose THE KEY CONCEPT in Toxicology Father of Modern ToxicologyParacelsus—1564 “All things are poisonous, only the dose makes it non-poisonous.” Dose alone determines toxicity All chemicals—synthetic or natural—have the capacity to be toxic

  9. Dose All Interactions between chemicals and biological systems follow a Dose-Response Relationship

  10. Dose Woman Dies after Water-drinking Contest: Water Intoxication eyed in ‘Hold Your Wee for a Wii’ contest Death SACRAMENTO, California—A woman who competed in a radio station’s contest to see how much water she could drink without going to the bathroom died of water intoxication, the coroner’s office said Saturday. Updated: 10:24 p.m. ET Jan 13, 2007

  11. Dose-Response Relationship • A key concept in Toxicology is the quantitative relationship between the concentration of a xenobiotic in the body and the magnitude of the biological effect it produces. • The magnitude of the effect of a xenobiotic is usually a function of the amount of xenobiotic to which a person is exposed (i.e., “The Dose Makes the Poison”). • In any given population, there will be a range of sensitivities to a xenobiotic. It is extremely useful to know what is the average sensitivity of a population to a xenobiotic, and what the average dose required to elicit a toxic response will be.

  12. Dose • The magnitude of the toxic response is proportional to the concentration (how much) of the chemical at the target site. • The concentration of a chemical at the target site is proportional to the dose. • Four important processes control the amount of a chemical that reaches the target site. • Absorption • Tissue distribution • Metabolism • Excretion

  13. Dose Determines Whether a Chemical Will Be Beneficial or Poisonous Beneficial Dose Toxic Dose Aspirin 300 – 1,000 mg 1,000 – 30,000 mg Vitamin A 5000 units/day 50,000 units/day Oxygen 20% (Air) 50 – 80% (Air)

  14. Dose-Response Curves “The Dose Makes the Poison” Maximum Response Maximum Response 1.0 1.0 Rate Approx. Linear Range 0.5 0.5 Threshold EC50 EC50 0 0 0 20 40 60 80 100 0.1 1.0 10 100 Concentration Concentration Arithmetic Scale Logarithmic Scale

  15. Effective Dose Lethal Dose 100 100 80 80 60 AnimalsKilled (%) Animals Sleeping (%) 60 LD50 ED50 40 40 20 20 1 2 3 5 7 10 10 20 30 50 100 Phenobarbital(mg/kg) Log Scale Dose-Response Relationship“The Dose Makes the Poison”

  16. Many Sensitive Individuals Maximal Effect Majority of Individuals Average Effect Resistant Individuals Minimal Effect Number of Individuals Few Response to SAME dose Mild Extreme Population Dose-Response

  17. Some chemicals have both therapeutic and toxic effects: Vitamin A Too low: Blindness, dry skin, increased infections Too high: Anorexia, anemia, nose bleeds, muscle and joint pain Adverse response Threshold Dose

  18. Organs Respond to Chemicals in Various Ways Blood Desired Effects Nutritive Therapeutic Organs Undesired Effects Toxic

  19. Some Chemicals Are Transformed by the Body (Metabolized) to Aid Excretion Liver and other Organs Detoxication Less Toxic Metabolic Product Kidney Liver Lung Urine Feces / Bile Expired Air

  20. Some Chemicals are Partially Converted to Products that are More Toxic than the Parent Substance Liver and other Organs Activation More Toxic Metabolic Product

  21. Toxicological Paradigm Toxicodynamics Toxicokinetics What We do to the Chemical What the Chemical Does to Us Early Biological Effect Biologically Effective Dose Altered Structure & Function Internal Dose Exposure Disease Susceptibility and Modifying Factors (Genetics and Nutritional Status) Absorption Distribution Metabolism Excretion Storage

  22. Biotransformation Metabolism • major mechanism for terminating the biological activity of chemicals • frequently the single most important determinant of the duration and intensity of the pharmacological response to a chemical Liver The LIVER is the primary site of metabolism Biotransformation occurs in the Liver, kidney, lung, gastrointestinal track, and other organs

  23. 2 5 2 0 1 5 Response Frequency 1 0 5 0 0 2 4 6 8 1 0 1 2 Pharmacogenetics of Metabolism Fast Metabolizers Harmful Side Effects (# of individuals) Slow Metabolizers (elevated plasma levels) Drug Concentration (g/mL) Plasma levels 6 hrs after oral dose

  24. Typical Population The emerging field of “Pharmacogenomics” or “Toxicogenomics” offers the potential to identify and protect subsets of people predisposed to toxicity from chemicals or drugs Identify people with different chemical/drug sensitivity Less Sensitive Identify People with “normal” responses More Sensitive

  25. R -COOH NH2 K -COOH NH2 K -COOH NH2 Tools of Modern Molecular Toxicology:Genomics and Proteomics

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