What is toxicology?toxicology …………

• Is the study of the harmful effects of chemicals and physical agents on living organisms

• Examines adverse effects ranging from acute to long-term

• Is used to assess the probability of hazards caused by adverse effects

• Is used to predict effects on individuals, populations and ecosystems

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These adverse effects may occur in many forms, ranging from immediate death to subtle changes not realized until months or years later. 

They may occur at various levels within the body, such as an organ, a type of cell, or a specific biochemical.

Sources of toxic compoundsSynthetic organic compound1. Air, water, and food pollutants

Air-CO, oxides of nitrogen, oxides of sulfur, hydrocarbons and particulatesWater-agricultural chemicals including pesticides, herbicides, fugicides, nematocides, rodenticides, fertilizer

Halogenated hydrocarbons- chloroform, dichloroethane, tetrachloride

Clorinated aromatics-PCB, TCDDDetergents-alkyl benzene sulfonates

Food contaminants-bacterial toxin, mycotoxin, plant alkaloids, animal toxins, pesticide residues, and residues of animal food additives (DES, antibiotics)

2. Chemical additives in food

As preservatives-antibacterial, antifungal, or antioxidant

To change physical characteristics, taste, color, odor

.

3.Chemicals in work place Inorganics-metals and flurides, CO, etc. Organic compounds-aliphatic hydrocarbons (hexene)

aromatic hydrocarbons (eg. benzene, toluene)halogenated hydrocarbonsalcoholsestersorganometallicsamino compounds

4. Drugs of abuseCNS depressants-ethanol,secobarbitalCNS stimulants-cocaine, methamphatamine,

nicotine, caffeineOpioids-heroin, morphineHallucinogens-PCP, LSD,THC

5.Therapeutic drugs The danger to the individual depends on :

the nature of the toxic responsethe dose necessary to produce the toxic resp

onsethe relationship between the therapeutic do

se and the toxic doseeg, anticancer drugs are carcinogens

Diethylstilbestrol (DES)Thalidomide

Chloroquinol-SMON-subacute myelo-optic neuropathy

Methyldopa, chloropromazine, methotrexate

In general, toxic side effects are not common and may occur only in susceptible individuals or

populations.

6. Pesticides

7. Solvents

8. Polycyclic aromatic hydrocarbons (PAH) 多環芳香

Incomplete combustion of organic materials, in smoke from wood, coal, oil, tobacco, in tar and broiled foods

Carcinogens

9. Cosmetics

Allergic reactions and contact dermatitis

Bromate, cold-wave neutralizer

Thioglycolates and tioglycerol-cold-wave lotion and depilatories

Sodium hydroxide-hair straighteners

Naturally occurring toxins1. Mycotoxins2. Microbial toxins3. Plant toxins4. Animal toxins Environmental movement of toxicants

Bioaccumulation-lipid soluble toxicantsBioamplification

DDT (ppm) amplificationWater 0.000003 Floating 0.04 13000Small fish 0.5 170000Big fish 2 667000Bird 25 8330000

An interdisciplinary field…………Descriptive Toxicology: The science of toxicity testing to provide information for safetyevaluation and regulatory requirements.

Mechanistic Toxicology: Identification and understanding cellular, biochemical andmolecular basis by which chemicals exert toxic effects.

Regulatory Toxicology: Determination of risk based on descriptive and mechanisticstudies, and developing safety regulations.

Clinical Toxicology: Diagnosis and treatment of poisoning; evaluation of methods of detection and intoxication, mechanism of action in humans (human tox, pharmaceutical tox) and animals (veterinary tox). Integrates toxicology, clinical medicine, clinical biochemistry/pharmacology.

Occupational Toxicology: Combines occupational medicine and occupational hygeine.

Environmental Toxicology: Integrates toxicology with sub-disciplines such as ecology,wildlife and aquatic biology, environmental chemistry.

The scope of toxicity A. Mechanisms of Toxic Action

1. Biochemical toxicology

2. Behavioral toxicology-behavior is the final integrated expression of nervous function

3. Nutritional toxicology-the effects of diet

4. Carcinogenesis-cell growth

5. Teratogenesis-developmental process

6. Mutagenesis-genetic material

7. Organ toxicity-organ function

B. Measurement of toxicants and toxicity1. Analytic toxicology2. Toxicity testing3. Toxicologic pathology4. Structure-activity study5. Biomathematics and statistics6. Epidemiology

C. Applied Toxicology1. Clinical toxicology2. Veterinary toxicology3. Forensic toxicology4. Environmental toxicology5. Industrial toxicology

D. Chemical use classes1. Agricuture chemicals2. Clinical drugs3. Drugs of abuse4. Food additives5. Industrial chemicals6. Naturally occurring substances- phytotox

in, mycotoxin, inorganic minerals7. Combustion products

"Toxin"=refers to toxic substances that are produced naturally

"Toxicant"=substance that is produced by anthropogenic origin

 E. Regulatory Toxicology

1. Legal aspects-formulation of

laws and regulations and their

enforcement

2. Risk assessment-

the definition of risks, potential

risks and risk- benefit equations

F. Development of antidotes

 

VSC/BMB497A 8

Xenobiotic

O

O

O

O O

OMe

Target OrganismCommunity/Population

Ecosystem

Absorption

Target Tissue

Target Cell

Exposure

Distribution

Metabolism

Classical

Toxicology

Xenobiotic

O

O

O

O O

OMe

MembraneTransport

OrganismToxicity

TissueToxicity

Reg

ulat

ory

Tox

icol

ogy

Excretion

Epidemiology/Environmental Toxicology

TargetMolecule

Cellular andMolecular Events

CellularToxicity

Mol

ecul

aran

d C

ellu

lar

Tox

icol

ogy

Genetic SusceptibilityBiomarkers

Risk assessment

Mechanismsand treatmentof toxicity

Risk characterization

Biology

Response

Metabolism

Toxic Effects1. Immediate effect and delayed effect

CO, cyanide2. Local effect and systemic effect

target organ3. Reversible and irreversible effect4. Anaphylactic reaction (allergic reaction)5. Idiosyncratic reaction 特異體質反應

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

However, other parameters are needed to characterize the exposure to xenobiotics. The most important are the number of doses, frequency, and total time period of the treatment.For example:

650 mg Tylenol as a single dose

500 mg Penicillin every 8 hours for 10 days 10 mg DDT per day for 90 days

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

Fractionating a total dose usually decreases the probability that the total dose will cause toxicity. The reason for this is that the body often can repair the effect of each subtoxic dose if sufficient time passes before receiving the next dose. In such a case, the total dose, harmful if received all at once, is non-toxic when administered over a period of time. For example, 30 mg of strychnine swallowed at one time could be fatal to an adult whereas 3 mg of strychnine swallowed each day for ten days would not be fatal.

vinyl chloride,

high dose-hepatotoxicant

long latent period at lower doses-carcinogen

very low dose-no effect

aspirin

chronic use-deleterious effects on the gastric mucosa

fatal dose 0.2-0.5 g/kg

metals

dietary essentials eg. Iron, copper, magnesium, cobalt, manganese, and zinc

toxic at higher dose

1493-1541-Paracelsus determined that specific chemicals were actually responsible for the toxicity of a plant or animal poison.  He also documented that the body's response to those chemicals depended on the dose received.  His studies revealed that small doses of a substance might be harmless or beneficial whereas larger doses could be toxic.  This is now known as the dose-response relationship, a major concept of toxicology.  Paracelsus is often quoted for his statement:  "All substances are poisons; there is none which is not a poison.  The right dose differentiates a poison and a remedy."

Dose Response The dose-response relationship is a fundamental and essential concept in toxicology.  It correlates exposures and the spectrum of induced effects.  Generally, the higher the dose, the more severe the response.  The dose-response relationship is based on observed data from experimental animal, human clinical, or cell studies.

Knowledge of the dose-response relationship:

establishes causality that the chemical has in fact induced the observed effects establishes the lowest dose where an induced effect occurs - the threshold effect determines the rate at which injury builds up - the slope for the dose response.

Dose Response

Individual, or graded, dose-response relationship

results from an alteration of a specific biochemical process

Quantal dose-response relationship

in a population-”all or none”

determination of the LD50LD (lethal dose)50-the dose required to kill 50% of a population of an organism under stated conditions

Normal equivalent deviations(NEDs)NED for 50% response is 0NED for 84.1% response is 1Probit (probability unit)=NED+5

Compounds may also be toxic under some circumstances, but not other, or, perhaps, toxic in combination with another compound but nontoxic alone.

The measurement of toxicity is also complex. Toxicity may be acute or chronic, and may vary from one organ to another as well as with the age, sex, diet, physiological condition, or health status of the organism. Even the LD50 values vary markedly from one laboratory to another.

LC50

ED50

TD50

Descriptive animal toxicity tests

Two main principle

1. The effects produced by a compound

in laboratory animals, when properly

qualified, are applicable to humans.

2. 2. The exposure of experimental

animals to toxic agents in high dose

is necessary and valid method of

discovering possible hazards in

human.

Descriptive animal toxicity tests

Acute Single dose with effects occurring for a short period of time (usually up to 96 hr)

Acute lethality (die in a 14-day period)

LD50 (Median Lethal Concentration)

Skin & eye irritation

sensitization

Subacute Multiple doses administered for up to 14 days

Subchronic Continuous dosing for up to 90 days

NOAEL-no observed adverse effect level

Chronic Continuous dosing for up to 6 months to 2 years

carcinogenic potential

• Acute effects do not predict chronic effects

• Doses causing chronic effects may not cause acute or sub-acute effects

• Chronic effects of a chemical exposure may manifest themselves as a common disease and go unnoticed

Course Objectives

Understand…….

• mechanisms by which chemicals cause cell injury and cell death

• the mode of action of specific organic and inorganic chemicals

• how to interpret results of in vitro tests for the evaluation of in vivo toxicity

• How multiple chemical exposures and other stressors can alter toxicity

• What factors influence individual susceptibility

• the importance of dose in determining adverse effects

of chemicals

• what factors influence the target organ dose of a chemical

• mechanisms by which chemicals affect specific organ system functions

Homework:

1. Compare graded dose response vs. quantal dose response.

2. Define the following terms

toxin

toxicant

LD50

ecotoxicology

bioactivation

detoxification

3.What are the goals of acute, subacute, subchronic, chronic toxicity?