Toxicology Concepts 2008 Society of Toxicology Risk The

Toxicology Concepts © 2008 Society of Toxicology

Risk The likelihood of injury or disease resulting from exposure to a potential hazard Evaluation of risk embodies all the basic concepts of toxicology © 2008 Society of Toxicology

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……. © 2008 Society of Toxicology AND Spinach.

Exposure Sources of exposure to chemicals • Environmental, including home and school • Occupational • Therapeutic • Dietary • Accidental • Deliberate © 2008 Society of Toxicology

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 © 2008 Society of Toxicology =

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 © 2008 Society of Toxicology

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) © 2008 Society of Toxicology

Dose THE KEY CONCEPT in Toxicology Father of Modern Toxicology Paracelsus— 1564 “All things are poisonous, only the dose makes it nonpoisonous. ” Dose alone determines toxicity All chemicals—synthetic or natural—have the capacity to be toxic © 2008 Society of Toxicology

Dose All Interactions between chemicals and biological systems follow a Dose-Response Relationship © 2008 Society of Toxicology

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 © 2008 Society of Toxicology

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. © 2008 Society of Toxicology

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 © 2008 Society of Toxicology

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) © 2008 Society of Toxicology

Dose-Response Curves “The Dose Makes the Poison” Maximum Response 1. 0 Maximum Response Rate 0. 5 Threshold EC 50 0 0 Approx. Linear Range 20 40 60 80 100 EC 50 0 0. 1 1. 0 10 Concentration Arithmetic Scale Logarithmic Scale © 2008 Society of Toxicology 100

Dose-Response Relationship Effective Dose 100 80 60 ED 50 40 20 1 2 3 5 7 10 Animals Killed (%) Animals Sleeping (%) “The Dose Makes the Poison” 100 Lethal Dose 80 60 LD 50 40 20 10 20 30 Phenobarbital (mg/kg) Log Scale © 2008 Society of Toxicology 50 100

Population Dose-Response Number of Individuals Many Resistant Individuals Minimal Effect Majority of Individuals Average Effect Sensitive Individuals Maximal Effect Few Mild © 2008 Society of Toxicology Response to SAME dose Extreme

Adverse response 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 Threshold Dose © 2008 Society of Toxicology

Organs Respond to Chemicals in Various Ways Blood Organs Desired Effects Nutritive Therapeutic Undesired Effects Toxic © 2008 Society of Toxicology

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 © 2008 Society of Toxicology

Some Chemicals are Partially Converted to Products that are More Toxic than the Parent Substance Liver and other Organs Activation More Toxic Metabolic Product © 2008 Society of Toxicology

Toxicological Paradigm Exposure Toxicokinetics Toxicodynamics What We do to the Chemical What the Chemical Does to Us Internal Dose Absorption Distribution Metabolism Excretion Storage © 2008 Society of Toxicology Biologically Effective Dose Early Biological Effect Altered Structure & Function Susceptibility and Modifying Factors (Genetics and Nutritional Status) Disease

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 Biotransformation occurs in the Liver, kidney, lung, gastrointestinal track, and other organs © 2008 Society of Toxicology Liver The LIVER is the primary site of metabolism

Pharmacogenetics of Metabolism Fast Metabolizers 20 Harmful Side Effects (# of individuals) Response Frequency 25 15 Slow Metabolizers 10 (elevated plasma levels) 5 0 0 2 4 6 8 Drug Concentration ( g/m. L) Plasma levels 6 hrs after oral dose © 2008 Society of Toxicology 10 12

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 “normal” responses Id e wi ntif ch th y p em dif eo se ic fer ple ns al/ en iti dru t vi ty g More Sensitive © 2008 Society of Toxicology Less Sensitive

Tools of Modern Molecular Toxicology: Genomics and Proteomics NH 2 R -COOH K -COOH