Download TOXICOLOGY I

Industrial Toxicology
BASIC PRINCIPLES
Sho’im Hidayat
INTRODUCTION
What is Toxicology ?
- Traditional : the science of poisons
- The study of adverse health effects of chemicals
or physical agents on living organism
What is Industrial toxicology ?
Industrial toxicoloy is the science of poisons
whereby is used, produced or byproduced in
industry
History :
Ancient time (1500 BC):
Have recognized the use of plants and animal poisons extracts
for hunting or warfare : hemlock, opium, arrow poisons,
certain metal
With time :
Poisons become widely used and with great sophistication
Victims : Socrates, Cleopatra, Claudius
Renaissance & Enlightenment :
Fundamental concept of toxicology began to take place
(Paracelcus, 1500 AD and Orfila, 1800 AD)
Paracelcus :
- Specific chemical actually responsible for toxicity of the plant
and animal poison
- His famous statement : dose–response relationship
All substance are poisons; there is none which is not a
poison. The right dose differentiates a poison and a remedy.
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
Basic Toxicology Terminology
There are varies in terminology :
toxicant
toxin
poison
toxic agent
toxic substance
toxic chemical
Toxic agent :
Anything can produce an adverse biological
effect (chemical : cyanide; physical : radiation;
biological: snake venom)
Not included : infected by microorganism
Biological toxin :
Chemical excreted by microorganism which is
the basis of toxicity
Ex : tetanus toxin (neurotoxin), produced by
Clostridium tetani
Toxic material :
Doesn’t 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
Xenobiotics may produce :
- beneficial effects (such as pharmaceuticals)
- toxic effect (such as lead)
Systemic toxin :
Effects is in the entire body or many organs rather
than a specific organ
Ex : potassium cyanide, it effects virtually every cell and
organ
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
Lead
blood forming tissue
CNS, kidney, hematopoietic system)
DOSE and DOSE-RESPONSE
• Dose :
The amount of a substance administered at one
time
• Parameter needed : number of dose, frequency,
total time period
Ex : - 650 mg Tylenol as single dose
- 500 mg Penicillin every 8 hours for 10 days
- 10 mg DDT per day for 90 days
Type of Doses
Exposure dose
External dose*)
the amount of a xenobiotic encountered
in the environment
Absorbed dose
Internal dose*)
Effective dose*)
the actual amount of the exposed dose
that enter the body
Administered dose the quantity administered usually orally
or by injection
Total dose
The sum all individual doses
Dose Unit : mg/kg/day
Environmental exposure unit are expressed as
the amount of a xenobiotic in a unit of the media
Examples :
• mg/liter (mg/l) for liquid
• mg/gram (mg/g) for solids
• mg/cubic meter (mg/m3) for air
Smaller unit : µg/ml; ppm; ppb; ppt
Dose Response Relationship
Correlates : exposure and spectrum of effects
In general, higher dose more severe the response
(Based on observed data from animal, human clinic or cell
study)
Knowladge of dose-response relationship :
- Establish causality
- Establisth the lowest dose where the induce effect
occur
- Determines the rate which the injury build-up
(slope)
Dose-response curve : sigmoid
• The point at which toxicity first appear 
threshold dose level
• At that point  the ability of the body to detoxify
a xenobiotic or repair toxic injury has been
exeeded.
• For most organs there is a reserve capacity so
that loss of some organ function does not cause
decreased performance
• For example, the development of cirrhosis in
the liver may not result in a clinical effect
until over 50% of the liver has been replaced by
fibrous tissue.
Threshold :
• Shape and slope  important for
predicting the toxicity of substance
• Some / every substance may has a
different type of the curve
Dose estimates of toxic effect : LD50
LD50  20 mg/kg, rat, oral, 5%
Effective doses (ED) :
Indicate the effectiveness of a substance
Toxic doses (TDs) :
Indicates doses that cause adverse toxic effects
Therapeutic Index (TI) :
compare the therapeutically effective dose to the toxic dose
NOAEL and LOAEL
No Observed Adverse Effect Level
Low Observed Adverse Effect Level
TOXIC EFFECTS
Toxicity : complex process; dose is the most
important influencing factor
Xenobiotic :
- originally toxic
- after metabolized
Toxicity :
- adverse cellular
- biochemical
- macromolecular change
Examples :
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Cell replacement, such as fibrosis
Damage to an enzym system
Disruption of protein synthesis
Production of reactive chemicals in cell
DNA damage
Indirectly :
• Modification of an essential biochemical function
• Interference with nutrition
• Alteration of physiological mechanisme
Factors influencing toxicity :
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Form and innate chemical activity
Dosage, especially dose-time relationship
Exposure route
Species
Age
Sex
Ability to be absorbed
Metabolisme
Distribution within the body
Excretion
Presence of other chemicals
Form
Examples : - methyl mercury – mercury vapour (element)
- Cr3+ - Cr6+
Innate
Examples : HCN
Nicotin
cytohrome oxidase
cholinergic receptor
hypoxia
paralysis
Dosage
Toxicant :
Ethanol
Arsenic
Acute toxicity :
CNS depressant
GIT damage
Chronic toxicity :
liver cirrhosis
skin / liver damage
Exposure Route :
- Ingested chemicals : intestine
liver
distributed
- Inhaled chemicals : blood circulation
body
whole
Liver : the most active organ for chemicals
inactivation
Frequenly : diff. target organ for diff. exp. route
Selective toxicity :
Differences in toxicity between two species
- an insectcide is lethal to insect, not to human
- antibiotics lethal for microorganisme, nontoxic to
human
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
Presence of other chemicals
Antagonism, additivity, potentiation, synergism
SYSTEMIC EFFECTS
Toxic effects occur at multiple sites,
including :
- acute toxicity
- subchronic toxicity
- chronic toxicity
- carcinogenicity
- developmental toxicity
- genetic toxicity (somatic cells)
• Acute toxicity
– occurs almost immediatly (h / d) after exposure
– Usually single dose at large dose
– Examples : Methyl isocyanat accident in Bophal India
• Subchronic toxicity
– Results from repeated exposure for several weeks or
months
• Chronic toxicity
– Represents cumulative damage to specific organ
system and takes many months or years to become a
recognizible clinical disease
– Ex : cirrhosis in alcoholics, chronis bronchitis in longterm cigarrete smokers, pulmonary fibrosis in coal
miners
• Carcinogenicity
– Complex multistages of abnormal cell growth
and differentiation
– Need : initiator, promoter
– Mutation  results initial neoplastic
transformation of cellular gene
• Developmental toxicity
– An adverse effect on developing embryo or
fetus
– Involving : embryolethality, embryotoxicity,
terratogenicity
• Genetic toxicity
– Results from damage to DNA and altered
genetic expression  mutagenesis
– 3 types of genetic change : gene mutation,
chromosome abberation, aneploidy /
polyploidy
Organ specific toxicity
Type of organ specific toxic effect are :
- blood / cardiovasculer toxicity
- dermal / occular toxicity
- genetic (germ cell) toxicity
- hepatotoxicity
- immunotoxicity
- nephrotoxicity
- reproductive toxicity
- respiratory toxicity
• Blood & cardiovascular toxicity
– Toxicity on circulating blood, bone marrow,
heart
– Ex : - hypoxia do to monoxide
- decrease leucocyte do to chloramphenocol
- leukemia do to benzene
• Dermal and eye toxicity
– Results from direct contact or internal
distribution to the skin
– Ex : dermal irritation, dermal corrosion,
hypersensitivity, skin cancer
• Hepatotoxicity
– Toxicity to the liver, bile dict and gall bladder
• Immunotoxicity
– Toxicity of the immune system
– Forms : hypersensitivity (allergic & autoimmunity),
immunodeficiency, uncontrolled proliferation
(leukemia & lymphoma),
– Ex : contact dermatitis, systemic lupus erytematosus
(SLE)
• Nephrotoxicity
– Succeptibility factor of kidney : high volume blood flow
& filtrates amount of toxin
– Forms : decrease excrete body waste, inability to
maintain body fluid, decrease to synthesis hormon
erythropoietin
• Neurotoxicity
– Damage cell of CNS & PNS
– Types :
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Neuropathy (neuron injury)
Axonopathy (axon injury)
Demyelination (loss of axon insulation)
Interference with neurotransmitter
• Reproductive toxicity
– Male and female
– Effects :
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Impotency / decrease of libido
Infertility
Interupted pregnancy
Infant death / childhood mortality
Childhood cancer, etc
• Respiratory toxicity
– Upper and lower respiratory tract
– Forms :
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Pulmonary irritation
Asthma bronchitis
Reactive airways disease
Emphysema
Allergic alveolitis
Fibrotic lung disease
Pnumoconiosis
Lung cancer
INTERACTION
Type of interaction :
The interactions described can be
categorized by their chemical or biological
mechanisms as follows:
– chemical reactions between chemicals
– modifications in absorption, metabolism, or
excretion
– reactions at binding sites and receptors
– physiological changes
Additivity :
Tranquilizer + alcohol
Two Organophosphate
Organochlorine + halogenated solvent
Synergism :
Cigaret smoke + asbestor / radon
Ethanol + carbontetrachloride
Potentiation :
Carbontetrachloride (hepatotoxic) + isopropanol
Antagonysme :
TOXIKOKINETCS
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 membrane & 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
- Intact & dry skin is good barrier
- Lipid soluble substance more absorbable
DISTRIBUTION
Process whereby an absorbed chemical move away
from the site of absorption to other areas of the body
How do chemicals move through the body ?
- pass through cell lining of the absorbing organ
to the interstitial fluid
- leave the interstitial fluid and then :
- entering local tissue cell
- entering blood capillaries and blood
circulation system
- entering the lymphatic system
If chemicals is in the blood stream, may
be :
- excreted
- stored
- biotransformed into difference chemical
(metabolites)
- its metabolite may be excreted or stored
- the chemicals or its metabolites may
interact with cellular component
Does distribution vary with the route of
exposure ?
- Yes it does
- GIT
liver (here biotransformed)
target organ
- skin or inhaled
circulation
target
organ
Structural barrier to distribution
- Blood brain barrier
- Placenta
- Testes
Organ or tissue differ in amount of chemicals that
they receive due to 2 factors :
- volume of blood
- presence of special barrier
Storage sites :
- adipose tissue : lipid soluble toxicant
- bone : Sr, Pb
- liver : many substances
- kidney
- nail, hair
BIOTRANSFORMATION
Process whereby a substance is changed from
one chemical to another by a chemical reaction
in the body
Results called as metabolites
Metabolites : less toxic (bioinactivation /
detoxification) or more toxic (bioactivation)
Chemical Reaction :
- By enzymatic reaction
- Enzyme as a catalyst
- Generally as a complex reaction
- Phase 1 : degradation of chemicals
(parent) through oxidation,
hydrolysis and reduction, acetylation
- Phase 2 : conjugation
Oxidation :
A chemical reaction in which a substance
loses electrons.
Aerobic (need oxygen) or anaerobic (without
oxygen)
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
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