Definitions of Toxicology• The science that studies the poisonous,

or toxic, properties of substances.– (National Safety Council)

• The study of chemical and physical agents that produce adverse responses in the biological systems with which they interact.– Williams and Burson

• The study of the adverse effect of chemical agents on biological systems.– (Cassaret and Doull).

Definition of Toxicology

– The study of the adverse effects of xenobiotics on living organisms

• What is a “xenobiotic”?– Foreign compound– Chemicals that are not endogenous to

the biological system– Chemicals that have little or no value in

sustaining normal biochemistry/cell function

Modern Toxicology● Exogeneous agents● Endogenous compounds

● Oxygen radical● Reactive intermediates generated from

xenobiotics and endobiotics

Contributions of toxicologists● Mechanism of action● Exposure to chemicals as a cause of illness● Using toxic chemicals to understand physiological

phenomena● Recognition, identification and quantification of

hazards from occupational exposure and public health aspects of chemicals in the environment, food and drugs.

● Involved in discovery and development of new drugs, food additives, and pesticides

● Development of standards and regulations designed to protect human health and environment from the adverse effects of chemicals

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.

2700 B.C. - Chinese journals: plant and

fish poisons

1900-1200 B.C. - Egyptian documents that had directions for collection, preparation, and administration of more than 800 medicinal and poisonous recipes.

800 B.C. - India - Hindu medicine includes

notes on poisons and antidotes.

50-100 A.D. - Greek physicians classified over

600 plant, animal, and mineral poisons.

50- 400 A.D. - Romans used poisons

for executions and

assassinations.

The philosopher, Socrates, was

executed using hemlock for

teaching radical ideas to

youths.

Avicenna (A.D. 980-1036) Islamic

authority on poisons and antidotes.

1200 A.D. - Spanish rabbi Maimonides

writes first-aid book for poisonings,

Poisons and Their Antidotes

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.”

(Paracelsus (1493-1541):All substances are poisons; there is none

that is not a poison. The right dose differentiates a poison and a remedy.

1. experimentation is essential in examination of responses to chemicals2. One should make a distinction between the therapeutic and toxic properties3. Properties can be indistinguishable

except by dose4.Once can ascertain a degree of specificity of chemicals and their therapeutic or toxic effect

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).

describing "asthma" in bakers, miners, farmers, gilders, tinsmiths, glass-workers, tanners, millers, grain-sifters, stonecutters, ragmen, runners, riders, porters, and professors. Ramazzini outlined health hazards of the dusts, fumes, or gases that such workers inhaled. The bakers and horse riders described by Ramazzini would today probably be diagnosed as suffering from allergen-induced asthma. The lung diseases suffered by most of the other workers would now be classified as "pneumoconiosis," a group of dust-related chronic diseases.

HistoryItalian physician

Ramazzini (1713) published“De Morbis Artificum”

(Diseases of Workers)

Spanish physician Orfila (1815) established toxicology as

a distinct scientific discipline.

20th Century

Paul Ehrlich –developed staining procedures to observe cell and tissues and pioneered the understanding of how toxicants influence living organisms.

20th Century

Rachel Carson - alarmed public

about dangers of pesticides

in the environment.

Ukrainian president Viktor Yushchenko, after alleged poisoning with dioxin, and, possibly endotoxin, prior to the 2004 elections.

19

●

March 2002 Dec 2004

Viktor Yushchenko

Mechanistic Toxicology

● Identification and understanding cellular, biochemical and molecular basis by which chemicals exert toxic effects.● Saccharin and bladder cancer● Thalidomide● 6-mercaptopurine leukemia

Descriptive Toxicology:

● The science of toxicity testing to provide information for safety evaluation and regulatory requirements.

-Toxicity tests

Regulatory Toxicology

● Determination of risk based on descriptive and mechanistic studies, and developing safety regulations.

● FDA (FFDCA)● EPA (TSCA, FIFRA)● OSHA

Forensic Toxicology: the cause of death in a

postmortem investigation

Clinical Toxicology: Diagnosis and treatment of

poisoning; evaluation of methods of detection and intoxication, mechanism of action in humans and animals

Occupational Toxicology: Combines occupational medicine and occupational hygeine.

Environmental Toxicology: Integrates toxicology with sub-

disciplines such as ecology,wildlife and aquatic biology,

environmental chemistry.

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Areas of Knowledge

Food Toxicology

Involves delivering a safe and edible supply of food to the consumer

• Despite great advances made by toxicology in assuring that our food is uncontaminated, it is still important to know what products are safe to eat and in what quantities. In addition to concerns about naturally occurring substances in foods, food toxicologists also investigate the safety of other components of food that have

been added deliberately or accidentally.

Clinical ToxicologyIs concerned with diseases and illnesses associated with short term or long term exposure to toxic chemicals

• Toxicological research is critical in the development and production of

pharmaceuticals. • At the beginning of the drug discovery process,

toxicity tests help to determine which potential pharmaceuticals are likely to be safe enough for humans and thus warrant further development.

Safety of Pharmaceuticals

General Toxicology Questions

What are Harmful or Adverse Effects?Those effects which are damaging to either the survival or normal function of the

individual

What is Toxicity ?

The term “toxicity” is used to describe the nature of adverse effects produced and conditions necessary for their production.

Before toxicity can develop, a substance must come into contact with a body surface such as skin, eye or mucosa of alimentary or respiratory tract.

What is Toxic ?This term relates to poisonous or

deadly effects on the bodyWhat is Xenobiotic ?

■ Xenobiotic is the general term that is used for a foreign substance taken into the body. 

■ It is derived from the Greek term xeno which means "foreigner." 

■ Xenobiotics may produce beneficial effects (such as a pharmaceuticals) or they may be toxic (such as lead).

What is a Toxicant ?The term “toxicant” refers to toxic

substances that are produced by or are a by-product of human-made activities.

What is a Toxin?The term “toxin” refers to toxic substances that are produced naturally.

Sources of toxic compounds

Synthetic compound

1.Air, water, and food pollutants✓ Air-CO, oxides of nitrogen, oxides of

sulfur, hydrocarbons and particulates✓ Water-agricultural chemicals including pesticides, herbicides, fugicides, nematocides, rodenticides, fertilizer

Sources of toxic compoundsSynthetic compound

2.As preservatives-antibacterial, antifungal, or antioxidant To change physical characteristics, taste, color, odor3.Chemicals in work place Inorganics-metals and flurides, CO, etc. Organic compounds-aliphatic hydrocarbons (hexene) aromatic hydrocarbons (eg. benzene, toluene)

Sources of toxic compoundsSynthetic compound4. Drugs of abuse

CNS depressants-ethanol,secobarbitalCNS stimulants-cocaine, methamphatamine,

nicotine, caffeine5. Therapeutic drugs The danger to the individual depends on : 1. the nature of the toxic response 2. the dose necessary to produce the toxic response 3. the relationship between the therapeutic dose and the toxic dose

eg, anticancer drugs are carcinogensDiethylstilbestrol (DES)Thalidomide

Sources of toxic compoundsSynthetic compound

6. Pesticides

7. Solvents

8. Polycyclic aromatic hydrocarbons (PAH)

9. Cosmetics

Naturally occurring toxins

1. Mycotoxins

2. Microbial toxins

3. Plant toxins

4. Animal toxins

■ What is a Toxic Effect?■ Toxic Effects Toxicity is complex with many

influencing factors; dosage is the most important.  Xenobiotics cause many types of toxicity

by a variety of mechanisms.  • Some chemicals are themselves

toxic.  • Others must be metabolized

(chemically changed within the body) before they cause toxicity.

■ Many xenobiotics distribute in the body and often affect only specific target organs.

■ Others, however, can damage any cell or tissue that they contact. 

■ The target organs that are affected may vary depending on dosage and route of exposure. 

■ For example, the target for a chemical after acute exposure may be the nervous system, but after chronic exposure the liver.

What is Selective Toxicity ?This means that a chemical will produce injury to one kind of living matter without harming another form of life, even

though the two may exist close together

■ Toxicity can result from adverse cellular, biochemical, or macromolecular changes. 

■ Examples are:

*cell replacement, such as fibrosis.*damage to an enzyme system.*disruption of protein synthesis.*production of reactive chemicals in cells.*DNA damage.

■ Some xenobiotics may also act indirectly by:

• modification of an essential biochemical function.

• interference with nutrition.• alteration of a physiological

mechanism.

What is a Poison?

All substances are poisons;

there is none that is not a poison.

The right dose

differentiates a poison and a remedy.

Paracelsus (1493-1541)

DOSETHE KEY CONCEPT IN TOXICOLOGY

Father of Modern ToxicologyParacelsus—1564

“All things are poisonous, only the dose makes it non-poisonous”

Dose alone determines toxicityAll chemicals—synthetic or natural—have the

capacity to be toxic

Dose by definition is the amount of a substance administered at one time.

The dose is dependent upon• The environmental concentration• The properties of the toxicant• The frequency of exposure• The length of exposure• The exposure pathway

What is a dose ?

A common dose measurement is mg/kg body weight.

The commonly used time unit is one day and thus, the usual dosage unit is mg/kg/day.

Environmental exposure units (Concentration) are expressed as the amount of a xenobiotic in a unit of the media.

mg/liter (mg/l) for liquids mg/gram (mg/g) for solids mg/cubic meter (mg/m3) for air

Other commonly used concentration units for substances in media are parts per million (ppm), parts per billion (ppb) and parts per trillion (ppt).

What is a Response?The degree and spectra of responses depend upon the dose and the organism--describe exposure conditions with description of dose

• Change from normal state– could be on the molecular, cellular,

organ, or organism level--the symptoms• Local vs. Systemic • Reversible vs. Irreversible• Immediate vs. Delayed• Graded vs. Quantal

degrees of the same damage vs. all or none

DoseAll Interaction between chemicals and biological systems follow a Dose-Response

Relationship

DOSE

Determines Whether a Chemical Will Be Beneficial or Poisonous

Beneficial Dose Toxic Dose

Aspirin 300 – 1,000 mg 1,000 – 3,000 mg

Vitamin A 5000 units/day 50,000 units/day

Oxygen 20% (air) 50 – 80% (air)

DoseWoman 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

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

Dose-Response Relationship:

As the dose of a toxicant increases, so does the response.

2

3

4

0 1 DOSE

RESPONSE

0-1 NOAEL2-3 Linear Range4 Maximum Response

DOSE DETERMINES THE BIOLOGICAL RESPONSE

NOAEL=No Observed Adverse Effect Level .

Every substance is toxic at a sufficiently

high quantity

LD50• Quantal responses can be treated as gradient

when data from a population is used.

• The cumulative proportion of the population responding to a certain dose is plotted per dose--10-30 fold variation w/in a population

• If Mortality is the response, the dose that is lethal to 50% of the population LD50 can be generated from the curve

• Different toxicants can be compared--lowest dose is most potent

LD50 Comparison