TOXICOLOGY-The study of the adverse effects of a toxicant on living organisms.- Toxicology related closely to Pharmacology, Biochemistry, Molecular biology, Chemistry, Epidemiology, Pathology, Genetics, Public Health, Medicine, etc.

Toxicity - adverse effects that a chemical may produceDose - amount of a chemical that gains access to the bodyExposure - contact providing opportunity of obtaining a poisonous doseHazard - likelihood that the toxicity will be expressed

TOXINSWhat is toxicology? The study of the effects of poisons.

Poisonous substances are produced by plants, animals, or bacteria. Phytotoxins Zootoxins Bacteriotoxins (C.tetani)

Toxicant - the specific poisonous chemical.Xenobiotic - man-made substance and/or produced by but not normally found in the body.

Facts: 92% of all poisonings happen at home. The household products implicated in most poisonings are: cleaning solutions, fuels, medicines, and

other materials such as glue and cosmetics. Certain animals secrete a xenobiotic poison called venom, usually injected with a bite or a sting, and

others animals harbor infectious bacteria. Some household plants are poisonous to humans and animals.

3 BASIC COMPONENTS IN TOXICOLOGY STUDY1. Toxicant/ Toxin/ Poison/ Hazard

any agent capable of producing a deleterious response in a biological system2. Adverse/Toxic effects

any unwanted change from an organism’s normal state dependent upon the concentration of active compound at the target site (receptor)for a

sufficient time.3. Living organism

cellular target sites/ storage depots and enzymes

FUNDAMENTAL RULES OF TOXICOLOGY1. Exposure must first occur for the chemical to present a risk.2. The magnitude of risk is proportional to both the potency of the chemical and the extent of exposure.3. “The dose makes the poison” (amount of chemical at the target site determines toxicity).

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HISTORY Swiss physician Paracelsus (1493-1541) credited with being “the father of modern toxicology.”

“All substances are poisons: there is none which is not a poison. The right dose differentiates a poison from a remedy.”

Dose Response relationship. Mercury for the treatment of Syphilis.

The Dose Makes the Poison An apparently nontoxic chemical can be toxic at high doses. (Too much of a good thing can be bad). Highly toxic chemicals can be life saving when given in appropriate doses. (Poisons are not harmful at a

sufficiently low dose).

DOSE

THRESHOLD EFFECTS FOR DOSE

LETHAL DOSES

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WHAT IS A RESPONSE? Change from normal state

- could be on the molecular, cellular, organ, or organism level--the symptoms Graded vs. Quantal

- degrees of the same damage vs. all or none

DOSE-RESPONSE

LD50 Comparison- half of the dose that is lethal

Chemical LD50 (mg/kg)Ethyl Alcohol 10,000 Sodium Chloride 4,000Ferrous Sulfate 1,500Morphine Sulfate 900Strychnine Sulfate 150Nicotine 1 Black Widow 0.55Curare 0.50 Rattle Snake 0.24 Dioxin (TCDD) 0.001 Botulinum toxin 0.0001

TOXICITY RATING

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CLASSIFICATION OF TOXIC AGENTS– Target organ/site (e.g., liver, kidney, blood, lung, nerves) – Use (e.g., pesticide, solvent, food additive)– Effects (e.g., cancer, mutation, liver injury)– Labeling requirements (e.g., explosive, flammable, oxidizer)– Poisoning potential (e.g., very or slightly toxic)

TYPE OF TOXIC RESPONSEAcute vs. ChronicAllergic (hypersensitivity)Idiosyncratic (e.g. G6PD def.)Local vs. Systemic Reversible vs. Irreversible

Acute Toxicity Chronic Toxicity

Examples: Chronic Effects Carcinogens:

– Cause cancer Mutagens:

– Cause mutations in an organism’s genetic material Teratogens:

– cause birth defects in offspring following exposure of a pregnant female

TOXICITY INTERACTIONSAdditive : 2+2 = 4Synergism : 2+3 = 10Potentiation : 0+3 = 5 Antagonism : 2+(-2) = 0

Chemical antagonismDispositional antagonismFunctional antagonismPharmacological antagonism

SYNERGIST / SYNERGISM:Synergism is increased activity (toxicity) resulting from the effect of one chemical on another.

LD50 DDT = 250 mg/kgLD50 synergist = 1,000 mg/kgLD50 DDT + synergist = 50 mg/kg

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OCCUPATIONAL AND ENVIRONMENTAL TOXICOLOGY

Environmental toxicants (air and water pollutants) are substances harmful to the environment and to humans.

Environmental toxicants are both natural and man made. Public perception that man-made ones are more serious than natural ones - Reality: both are serious. 5,000,000 yearly deaths worldwide due to bacterial toxicants (Salmonella, E. coli)

1. PARACELSUS - Miner’s Disease (1533) came from inhaling metal vapors, foundation for the field of chemotherapy.

2. HILL (1761) linked tobacco (snuff) to cancer.3. POTT (1775) linked scrotal cancer and soot (benzo(a)pyrene) in chimney sweeps.

EXPOSURE CONCEPTS

Different toxic responses may arise from different:1. Routes of exposure.2. Frequencies of exposure.3. Duration of exposure (acute vs. chronic).

ROUTES OF ENVIRONMENTAL EXPOSURE1. Ingestion (water and food)2. Absorption (through skin)3. Injection (bite, puncture, or cut)4. Inhalation (air)

DURATION & FREQUENCY OF EXPOSURE Duration and frequency are also important components of exposure and contribute to dose. Acute exposure - less than 24 hours; usually entails a single exposure Repeated exposures are classified as:

– Subacute - repeated for up to 30 days– Subchronic - repeated for 30-90 days– Chronic -repeated for over 90 days

BIOACCUMULATION Why human have to concern with other species toxicology and/or environmental health?

INDIVIDUAL RESPONSES CAN BE DIFFERENT The variety of responses among organisms that get the same dose of chemical is due to individual

susceptibility. Dose and individual susceptibility play roles in all situations involving chemicals, including those making

medicine and caffeine.

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INTRODUCTION TO XENOBIOTICSRecall: Foreign chemicals are synthesized within the body are termed xenobiotics (Gr.Xenos meaning “strange”)

• Xenobiotics may be naturally occurring chemicals produced by plants, microorganisms, or animals (including humans).

• Xenobiotics may also be synthetic chemicals produced by humans. • Poisons are xenobiotics, but not all xenobiotics are poisonous.

HOW DOES THE BODY PREVENT THE ACTIONS OF XENOBIOTICS ?1) Redistribution2) Excretion – (primarily water soluble compounds) - kidney and liver3) Metabolism – the major mechanism for terminating xenobiotic activity, and is frequently the single most important determinant of the duration and intensity of toxic responses to a xenobiotic. - LIVER, kidney, lung, GI, and others

Note: 1) and 2) are highly dependent upon 3)

XENOBIOTICS AT WORK

HOW XENOBIOTICS CAUSE TOXICITY?Some xenobiotics cause toxicity by disrupting normal cell functions:

– Bind and damage proteins (structural, enzymes)– Bind and damage DNA (mutations)– Bind and damage lipids– React in the cell with oxygen to form “free radicals” which damage lipid, protein, and DNA

TYPES OF TOXIC EFFECTS Death - arsenic, cyanide Organ Damage - ozone, lead Mutagenesis - UV light Carcinogenesis - benzene, asbestos Teratogenesis - thalidomide

TARGET ORGAN TOXICITY Central Nervous System – lead Immune System - isocyanates Liver - ethanol, acetaminophen

Respiratory Tract - tobacco smoke, asbestos, ozone

Eye - UV light (sunlight) Kidney - metals

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Skin - UV light, gold, nickel Reproductive System – dibromochloropropane WHAT DO TOXICOLOGISTS DO?Most toxicologists work to develop a mechanistic understanding of how chemicals affect living systems:

– Develop safer chemical products– Develop safer drugs– Determine risks for chemical exposures– Develop treatments for chemical exposures– Teach ( e.g. other toxicologists, graduate students, and youth)

1. Mechanistic toxicologists study how a chemical causes toxic effects by investigating its absorption, distribution, and excretion. They often work in academic settings or private industries and develop antidotes.

2. Descriptive toxicologists evaluate the toxicity of drugs, foods, and other products. They often perform experiments in a pharmaceutical or academic setting.

3. Clinical toxicologists usually are physicians or veterinarians interested in the prevention, diagnosis, and treatment of poisoning cases. They have specialized training in emergency medicine and poison management.

4. Forensic toxicologists study the application of toxicology to the law. They uses chemical analysis to determine the cause and circumstances of death in a postmortem investigation.

5. Environmental toxicologists study the effects of pollutants on organisms, populations, ecosystems, and the biosphere.

6. Regulatory toxicologists use scientific data to decide how to protect humans and animals from excessive risk. Government bureaus such as the FDA and EPA employ this type of toxicologist.

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