Toxicology 1

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 produce
Dose - amount of a chemical that gains access to the body
Exposure - contact providing opportunity of obtaining a poisonous dose
Hazard - likelihood that the toxicity will be expressed

TOXINS
What 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 STUDY
1. Toxicant/ Toxin/ Poison/ Hazard
any agent capable of producing a deleterious response in a biological system
2. Adverse/Toxic effects
any unwanted change from an organisms 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 TOXICOLOGY
1. 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

Toxicology 3

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



LD
50
Comparison
- half of the dose that is lethal
Chemical LD
50
(mg/kg)
Ethyl Alcohol 10,000
Sodium Chloride 4,000
Ferrous Sulfate 1,500
Morphine Sulfate 900
Strychnine Sulfate 150
Nicotine 1
Black Widow 0.55
Curare 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 RESPONSE
Acute vs. Chronic
Allergic (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 organisms genetic material
Teratogens:
cause birth defects in offspring following exposure of a pregnant female

TOXICITY INTERACTIONS
Additive : 2+2 = 4
Synergism : 2+3 = 10
Potentiation : 0+3 = 5
Antagonism : 2+(-2) = 0
Chemical antagonism
Dispositional antagonism
Functional antagonism
Pharmacological antagonism

SYNERGIST / SYNERGISM:
Synergism is increased activity (toxicity) resulting from the effect of one chemical on another.
LD
50
DDT = 250 mg/kg
LD
50
synergist = 1,000 mg/kg
LD
50
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 - Miners 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 EXPOSURE
1. 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 XENOBIOTICS
Recall: 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) Redistribution
2) Excretion (primarily water soluble compounds) - kidney and liver
3) 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
Skin - UV light, gold, nickel
Reproductive System dibromochloropropane
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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.