CC 2 LEC - TOXICOLOGY PART 1

Maimonides (1135-1204)

He included a treatise on the treatment of poisonings from insects, snakes and mad dogs

Maimonides

He was the 1st one to introduce the concept of "bioavailability"

Paracelsus

formulated many revolutionary views that remain integral to the structure of toxicology, pharmacology and therapeutics today.

Orfila

Founder of Toxicology

Orfila

proponent who introduced the legal proof of poisoning

Magendie

Mechanisms of action of emetine and strychnine

Bernard

Physiological actions of poisons specifically curare and carbon monoxide gas

Toxicologist

persons trained to examine the nature of those effects.

1. dose

2. duration and route of exposure

3. shape and structure

4. individual human factors

The toxicity depends on a variety of factors (4):

Environmental toxicology

Includes the evaluation of environmental chemical pollutants and its effect on human health

Occupational toxicology

Is concerned with health effects from exposure to chemicals in the workplace

Regulatory toxicology

Uses combined data from the mechanistic and descriptive in which they use the data to establish standards which will define the level of exposure

Food toxicology

Is involved in delivering a safe and edible supply of food to the consumer.

Clinical toxicology

Focuses on the relationships between Xenobiotics and disease states

Descriptive toxicology

Is concerned with gathering toxicological information from animal experimentation

Forensic toxicology

Is used to help establish cause and effect relationships between exposure to a drug or chemical and the toxic or lethal effects that result from that exposure.

Analytical toxicology

Identifies the toxicant through analysis of body fluids, stomach content, excrement, or skin.

Mechanistic toxicology

Makes observations on how toxic substances cause their effects

Toxic

relates to poisonous or deadly effects on the body by inhalation (breathing), ingestion (eating), or absorption, or by direct contact with a chemical

Toxicant

any chemical that can injure or kill humans, animals, or plants; a poison

Xenobiotics

-Exogenous agents

-This term is more often used to describe environmental exposure to different chemicals and drugs

Poison

-Exogenous agents

-substances which are coming directly from an animal, plant, mineral, or gas

Toxin

-Endogenous agents

-usually is used when talking about toxic substances produced naturally

Adverse effects

those that are damaging to either the survival or normal function of the individual.

Tolerance

state of decreased responsiveness to a toxic effect of a chemical resulting from a prior exposure to that chemical or structurally related chemical

Kidney

Liver

2 major organs considered to be mostly the target organ

Lung

Neurons

Myocardium

Bone marrow, intestinal mucosa

4 other target organs

liver

high blood flow

liver

first pass

liver

exposed to high oxidative reactions

liver

where xenobiotic biotransformation occurs

xenobiotic transformation

occurs in chemical caused by the capability of hepatocytes

cytochrome p450 isoenzyme

xenobiotic transformation is thru the action of ______

kidney

Organ: high blood flow, concentrates chemicals

lungs

high blood flow, site of exposure

molecularly

chemical can interact with the different biomolecules in the body

proteins

lipids

DNA

3 biomolecules in the body

dose

amount of chemical entering the body

mg/kg

dose is usually given as:

1. environmental concentration

2. properties of toxicant

3. frequency of exposure

4. length of exposure

5. exposure pathway

the dose is dependent upon (5):

1. dose

2. organism

the degree and spectra of responses depend upon the ___ and ___

local response

1 particular area

1. local

2. systemic

2 types of response (location wise)

graded

1. increasing response

2. increasing dose

quantal

1. all or nothing

2. specific response at a progressively increasing dose

1. revesible

2. irreversible

Effects can be: (2)

increase dose

increase response

(graph) explain dose-response relationship as:

paracelsus

indicated that all compounds are toxic

mg/kg

TD50 is normally expressed as:

TD50

chemical which produces toxic response in 50% of a population test

TD50

can be used when doing toxicological study

LD50

median lethal dose

mg/kg

LD50 is normally expressed as:

LD50

chemical which produces death in 50%

LC50

median lethal concentration

mg/L

LC50 is normally expressed as:

LC50

chemical in an environment (air or water) produces death in 50%

ED50

the effective dose

ng/ml

ED50 is normally expressed as

ED50

predicted to be effective or hve a therapeutic benefit in 50%

1. ingestion

2. inhalation

3. dermal/topical

4. injection

4 types of routes and site of exposure

intravenous > inhale > intraperitoneal > intramuscular > ingest > topical

typical effectiveness of route of exposure

1. acute

2. chronic

3. subchronic

3 duration of exposure

acute/immediate exposure

-single or short term

-less than a day

-acute toxicity

chronic exposure

-repeated exposure

-greater than half of its life-expectancy

-chronic toxicity

subchronic exposure

-repeated applications

-less than half the life expectancy

-subchronic toxicity

acute exposure

<24 hr, usually 1 exposure

1. subacute

2. subchronic

3. chronic

repeated doses

subacute

1 month exposure, repeated doses

subchronic

1-3 monhs exposure, repeated doses

chronic

>3 months exposure, repeated

absorption, distribution, metabolism, excretion

4 actions

biotransformation enzyme

wherein the body have the capability to convert compounds to make it less hazardous

antioxidants

prevents further damage to the cell

saliva

tears

fecal

urine

4 elimination mechanisms

absorption

ability of a chemical to enter the blood

inhalation

readilty absorb gases into the blood stream via the alvevoli

ingestion

absorption through GI tract

dermal

absorption through epidermis then dermis

distribution

proccess in which a chemical agent translocate throughout the body

blood

most potent carrier of toxic compound

partition coefficient

property of a particular chemical substance to distribute itself between two different immiscible phases

fat

very lipophilic compounds (DDT) will store in ___

starvation

rapid mobilization of fat thru ____ can rapidly increase blood concentration

gluconeogenesis

process of inducing lipolysis

fluoride

lead

strontium

3 chemicals analogous to calcium

plasma proteins

compounds which will be requiring carrier protein

free

available for adverse effects or excretion

active compound at target site

adverse effect dependes on the concentration of ________ over time

chemical and enzymatic reaction

modification of toxic compounds occurs thru ____ and ____

metabolism

process by which the administered chmical are modified by the organism by enzymatic reactions

primary objective

make chemicals agent more water soluble and easier to excrete

decrease lipid solubility

decrease amount at target =

increase excretion rate

decrease toxicity =

bioactivation

result in the formation of reactive metabolites

urinary excretion

primary excretion route

urinary excretion

water soluble products are filtered out by the kidney

exhalation

excretion of volatile compounds thru:

biliary/fecal excretion

extracted by the liver and excreted into the bile:

milk, sweat, saliva excretion

excretion of exposed to toxic compounds that is passed thru ____, _____, ______