BASIC PRINCIPLES

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Industrial Toxicology

• BASIC PRINCIPLES
• Shoim Hidayat

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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

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• 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)

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• Paracelcus
• Specific chemical actually responsible for
  toxicity of the plant and animal poison
• His famous statement doseresponse 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

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Basic Toxicology Terminology

• There are varies in terminology
• toxicant
• toxin
• poison
• toxic agent
• toxic substance
• toxic chemical

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• 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

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• 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

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• Xenobiotic
• Foreign substance taken in to the body
• xeno foreign
• Xenobiotics may produce
• - beneficial effects (such as pharmaceuticals)
• - toxic effect (such as lead)

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• 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 blood forming tissue
• Lead CNS, kidney,
  hematopoietic system)

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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

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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
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• Dose Unit mg/kg/day

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• 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

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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)

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• Dose-response curve sigmoid

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• 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.

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Threshold
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• Shape and slope ? important for predicting the
  toxicity of substance
• Some / every substance may has a different type
  of the curve

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Dose estimates of toxic effect LD50

• LD50 ? 20 mg/kg, rat, oral, 5

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Effective doses (ED) Indicate the
effectiveness of a substance
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Toxic doses (TDs) Indicates doses that
cause adverse toxic effects
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Therapeutic Index (TI) compare the
therapeutically effective dose to the toxic dose
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NOAEL and LOAELNo Observed Adverse Effect
LevelLow Observed Adverse Effect Level
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TOXIC EFFECTS

• Toxicity complex process dose is the most
• important influencing factor
• Xenobiotic
• - originally toxic
• - after metabolized
• Toxicity
• - adverse cellular
• - biochemical
• - macromolecular change

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Examples

• Cell replacement, such as fibrosis
• Damage to an enzym system
• Disruption of protein synthesis
• Production of reactive chemicals in cell
• DNA damage

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• Indirectly
• Modification of an essential biochemical function
• Interference with nutrition
• Alteration of physiological mechanisme

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Factors influencing toxicity

• 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

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• Form
• Examples - methyl mercury mercury vapour
  (element)
• - Cr3 - Cr6
• Innate
• Examples HCN cytohrome oxidase
  hypoxia
• Nicotin cholinergic receptor
  paralysis
• Dosage
• Toxicant Acute toxicity
  Chronic toxicity
• Ethanol CNS depressant
  liver cirrhosis
• Arsenic GIT damage
  skin / liver damage

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• Exposure Route
• Ingested chemicals intestine liver
  distributed
• Inhaled chemicals blood circulation
  whole body
• Liver the most active organ for chemicals
• inactivation
• Frequenly diff. target organ for diff. exp.
  route

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• 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

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• 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

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• 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

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• 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

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• SYSTEMIC EFFECTS
• Toxic effects occur at multiple sites, including
  
• - acute toxicity
• - subchronic toxicity
• - chronic toxicity
• - carcinogenicity
• - developmental toxicity
• - genetic toxicity (somatic cells)

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• 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 long-term cigarrete smokers, pulmonary
  fibrosis in coal miners

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• 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

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• Genetic toxicity
• Results from damage to DNA and altered genetic
  expression ? mutagenesis
• 3 types of genetic change gene mutation,
  chromosome abberation, aneploidy / polyploidy

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• 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

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• 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

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• Hepatotoxicity
• Toxicity to the liver, bile dict and gall bladder

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• 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

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• Neurotoxicity
• Damage cell of CNS PNS
• Types
• Neuropathy (neuron injury)
• Axonopathy (axon injury)
• Demyelination (loss of axon insulation)
• Interference with neurotransmitter
• Reproductive toxicity
• Male and female
• Effects
• Impotency / decrease of libido
• Infertility
• Interupted pregnancy
• Infant death / childhood mortality
• Childhood cancer, etc

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• Respiratory toxicity
• Upper and lower respiratory tract
• Forms
• Pulmonary irritation
• Asthma bronchitis
• Reactive airways disease
• Emphysema
• Allergic alveolitis
• Fibrotic lung disease
• Pnumoconiosis
• Lung cancer

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INTERACTION

• Type of interaction

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• 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

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• Additivity
• Tranquilizer alcohol
• Two Organophosphate
• Organochlorine halogenated solvent
• Synergism
• Cigaret smoke asbestor / radon
• Ethanol carbontetrachloride
• Potentiation
• Carbontetrachloride (hepatotoxic) isopropanol
  

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• Antagonysme

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TOXIKOKINETCS

• 1. ABSORPTION
• 2. DISTRIBUTION - STORAGE
• 3. BIOTRANSFORMATION
• 4. EXCRETION

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• 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

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• 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

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• Primary route of exposure/absorption

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• Diagram how chemicals pass through membrane

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• 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)

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• Large molecules and particles can not enter cell
  via passive or active mechanism by
  endocytosis
• - phagocytosis (cell eating)
• - pinopcytosis (cell drinking)

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• 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

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• Toxic effect on respiratory tract, caused by
• - gas / vapour
• - irritant
• - aphyxiant
• - Dust
• - nonspecific
• - specific (fibrogenic, carcinogenic)

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• 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

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• 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

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• 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

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• 3. Skin
• Consist of 3 main layer
• - epidermis
• - dermis
• - subcutaneus tissue
• - Intact dry skin is good barrier
• - Lipid soluble substance more absorbable

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• 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

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• 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

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• Does distribution vary with the route of
• exposure ?
• - Yes it does
• - GIT liver (here biotransformed)
  
• target organ
• - skin or inhaled circulation
  target
• organ

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• 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

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• Storage sites
• - adipose tissue lipid soluble toxicant
• - bone Sr, Pb
• - liver many substances
• - kidney
• - nail, hair

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• 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)

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• 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

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• Oxidation
• A chemical reaction in which a substance loses
  electrons.
• Aerobic (need oxygen) or anaerobic (without
  oxygen)
• Examples oxygenation
• dehydrogenation
• electron transfer

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• Illustration of oxidation

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• 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

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• Reduction
• Hydrolysis

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• Phase 2 reaction conjugation
• Phase 1 new intermediate metabolite
  that contains a reactive chemical group
• - hydroxyl (-OH)
• - amino (-NH2)
• - carboxyl (-COOH)
• CONJUGATION

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• Modifier of Biotransformation
• - age
• - genetic variability
• - enzym inhibition and enzym induction
• - dose level

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EXCRETION

• Major route
• - gastrointestinal tract, sweat and saliva
• - mother milk, tears and semen
• - urinary excretion, feces excretion, and
• exhaled air (main route of excretion)

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• Urinary excretion
• - primary route of excretion
• - Nephron functional unit (about one million
  per
• kidney)
• - glomerulus
• - proximal tubule
• - distal tubule

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• 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

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• Other route of excretion
• Milk DDT, polybrominated biphenyl, lead
• Saliva
• Sweat cadmium, copper, iron, lead, zinc
• Tears, hair, skin