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BASIC PRINCIPLES
Shoim Hidayat
INTRODUCTION
What is Toxicology ?
- Traditional : the science of poisons
- The study of adverse health effects of chemicals
or physical agents on living organism
With time :
Poisons become widely used and with great sophistication
Victims : Socrates, Cleopatra, Claudius
Orfila :
- Often referred as founder of toxicology
- Prepared a systematic correlation between chemical and
biological properties of poisons
- Demonstrates effect of poison in specific organ by autopsy
Industrial Revolution :
Industrial toxicology becomes more
impotant
Recently :
About 100 thousands chemicals used in
human activity both organics and anorganics
both in industry and occupation as well as in
household setting
Effects of long-term exposure and chronic /
incurable disease doe to chemicals more
attractive to study
The 20th century is marked by an advanced level
of understanding of toxicology:
toxicant
toxin
poison
toxic agent
toxic substance
toxic chemical
Racun
Bahan kimia yang dalam jumlah sedikit
jika masuk ke dalam tubuh menyebabkan
gangguan kesehatan atau kematian
Biological toxin :
Chemical excreted by microorganism which is
the basis of toxicity
Ex : tetanus toxin (neurotoxin), produced by
Clostridium tetani
Toxic material :
Doesnt consist of an exact chemical
Ex : asbestos (fiber and other chemical)
Organic toxin :
Substance originally derived from living organism
(named organic)
Contain carbon, large molecule
Inorganic toxin :
Specific chemical not derived from living organism
(mineral)
Generally small molecule, consist of few atoms
Xenobiotic :
Foreign substance taken in to the body
xeno = foreign
Organ toxin :
Effects only in specific cell or organ (target organ or
target tissue), not producing damage to the body as a
whole
Ex : Benzene blood forming tissue
Lead CNS, kidney, hematopoietic system)
Industrial Toxicology is an applied science
needs basic knowledge of :
chemistry
physics
anatomy and physiology
biochemistry
pathology
pharmacology
EFEK Lebih toksik
Penyimpanan Efek
Ekskresi
S
O M = molecule
C = Cell
T T
S
T = Tissue
o S
C O = Organ
x
i M S
c
a
g F
e
n F
t F
F
Toxicological Paradigm
Toxicokinetics Toxicodynamics
What We do to the Chemical What the Chemical Does to Us
Examples :
mg/liter (mg/l) for liquid
mg/gram (mg/g) for solids
mg/cubic meter (mg/m3) for air
Xenobiotic :
- originally toxic
- after metabolized
Toxicity :
- adverse cellular
- biochemical
- macromolecular change
Examples :
Age :
- parathion is more toxic to young animals
- nitrosamines are more carcinogenis to newborne
or young animals
Sex :
- male rats 10 x more sensitive to liver damage from
DDT
- female rats 2x more sensitive to parathion
Ability to be absorbed :
- ethanol is readily absorbed from GIT but poorly
absorbed through the skin
- organic mercury is readily absorbed from GIT, but
inorganic mercury is not
Metabolism = biotransformation
Is a major factor in determining toxicity
- detoxification (bioinactivation) : process by which a
xenobiotic is converted to a less toxic form water
soluble
- bioactivation : process by which a xnobiotic may be
converted to more reactive or toxic form.
Distribution :
Determine the sites where toxicity occur.
Depend on how the lipid-solubility
Excretion :
Another major factor affecting the toxicity
Excretory organ : kidney, GIT, lung. Sometime
also : sweat, tears, milk
1. ABSORPTION
2. DISTRIBUTION - STORAGE
3. BIOTRANSFORMATION
4. EXCRETION
Toxicokinetics determines the severity of
toxicity, through :
- duration & concentration of substance at portal
of entry
- rate & amount that can be absorbed
- distribution in the body & concentration at
specific sites
- efficiency of biotransformation & nature of
metabolites.
- ability of substance pass through cell membra-
ne & reactivity to specific cell component
- the rate and sites of excretion
1. ABSORPTION :
Process whereby toxicants gain entrance
into the body
Varies with specific chemicals and the route
of exposure
Factors influencing the absorption :
- route of exposure
- concentration of the substance at the site of
contact
- biochemical and physical properties of the
substance
Primary route of exposure/absorption :
Diagram how chemicals pass through membrane
How chemicals pass through membrane
1. Passive transfer : simple diffusion
- Difference concentration on opposite sides
- Ability of substance to move through small
pores in membrane
It is depend on : lipid solubility, molecule size
and degree of ionozation
2. Facilitated transfer :
- facilitated diffusion
- active transport
- endocytosis (phagocytosis & pinocytosis)
Large molecules and particles can not enter
cell via passive or active mechanism
by endocytosis
- phagocytosis (cell eating)
- pinopcytosis (cell drinking)
Route of entry :
1. Respiratory tract
The most chemicals in industry absorbed /
inhaled via respiratory tract :
- aerosol : dust, fume, mist
- gas / vapour
Region :
- nasopharyngeal
- tracheobronchial
- pulmonary
Toxic effect on respiratory tract, caused by:
- gas / vapour:
- irritant
- aphyxiant
- Dust
- nonspecific
- specific (fibrogenic, carcinogenic)
Irritant gas / vapour :
- NH3, Cl2, HCl, formaldehyde, phosgen, etc.
- Inflammatory effect
- Sites of effect depend on the water solubility of
the substance
Dust
- Deposition at epithel
- Inflammatory effect (nonspecific)
- Specific effect
Asphyxiant gases :
1. Simple asphyxiant
due to decreasing of partial pressure of oxygen in
atmosphere
2. Chemical asphyxiant
- Monoxide gas (CO) more reactive to haemoglobine
competitive inhibitor
- Cyanides gas blocking to cytochrome enzyme
2. Gastrointestinal Tract
3 factors affect absorption :
- type of cell at the specific site
- period of time that the substance
remain at the site
- pH of stomach or intestinal
3. Skin
Consist of 3 main layer :
- epidermis
- dermis
- subcutaneus tissue
Examples : oxygenation
dehydrogenation
electron transfer
Illustration of oxidation :
Reduction :
Chemical reaction in which the substance gain
electrons
Most likely to occur with xenobiotic in which
oxygen content is low
Reduction can occur across nitrogen-nitrogen
double bond (azo reduction) or on nitro group
(NO2)
Amina compound oxidized forming toxic
metabolites
Carbon tetrachloride free radicals
Reduction :
Hydrolysis :
Phase 2 reaction : conjugation
Phase 1 new intermediate metabolite
that contains a reactive chemical group :
- hydroxyl (-OH)
- amino (-NH2)
- carboxyl (-COOH)
CONJUGATION
The Biotransformation of Benzene
Modifier of Biotransformation :
- age
- genetic variability
- enzym inhibition and enzym induction
- dose level
EXCRETION
Major route :
- gastrointestinal tract, sweat and saliva
- mother milk, tears and semen
- urinary excretion, feces excretion, and
exhaled air (main route of excretion)
Urinary excretion :
- primary route of excretion
- Nephron : functional unit (about one million per
kidney) :
- glomerulus
- proximal tubule
- distal tubule
Fecal excretion :
- excretion in bile, then enters the intestin
- direct excretion into the lumen of GIT
- enterohepatic circulation will prolong the
life of xenobiotic in the body
Exhaled air :
Main route excretion of volatile liquid
Other route of excretion :
Milk : DDT, polybrominated biphenyl, lead
Saliva
Sweat : cadmium, copper, iron, lead, zinc
Tears, hair, skin