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TOXICOLOGY

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TOXICOLOGY & POLLUTION BIOLOGY Dr Liz Dyrynda Lectures: Monday: 13.15, Tuesday: 17.15, Friday: 14.15 (except Mon 17th & Tues 18th May) Assessment - (computer-based ... – PowerPoint PPT presentation

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Title: TOXICOLOGY


1
TOXICOLOGY POLLUTION BIOLOGY   Dr
Liz Dyrynda Lectures Monday 13.15, Tuesday
17.15, Friday 14.15 (except Mon 17th Tues 18th
May) Assessment - (computer-based test, 10 of
module mark). Details will be given later.
2
  • INTRODUCTION TO TOXICOLOGY
  • History, definitions, types of exposure, routes
    of entry and excretion in animals
  •  
  • TOXIC EFFECTS
  • Overview of toxic effects at cell and tissue
    levels
  •  
  • TOXIC COMPOUNDS 
  • Organic contaminants (e.g. pesticides, PCBs)
  • Metals
  • Food Drugs
  • Natural products
  • Radioactivity
  • Atmospheric pollutants

3
TOXICOLOGY THE SCIENCE OF POISONS, THE STUDY OF
THE HARMFUL INTERACTIONS BETWEEN CHEMICALS AND
BIOLOGICAL SYSTEMS Toxic comes from Greek
toxicon used in reference to a bow (poisonous
arrows for hunting). Toxin/poison any
substance that has a harmful effect on a living
organism
Xenobiotic a substance or chemical that is
foreign to a living organisms body, i.e. no role
in normal biochemistry. Can be of natural or
man-made origin, e.g. drugs, pesticides,
pollutants, industrial chemicals, toxins, etc.
4
Ebers papyrus (circa 1500 BC) Collection of
medical texts describing poisons
Hippocrates (circa 400 B.C.) introduced clinical
toxicology principles with concepts of
bioavailability and overdose.
Dioscorides Greek physician, developed
descriptions of common poisons, which led to a
classification system that lasted for
approximately 16 centuries.
5
Poisoning widespread in Roman politics 82 B.C.
first law against poisoning issued, the Lex
Cornelia.
6
THE MIDDLE AGES
Use of poisons common in eliminating political
contenders, spouses and competition.
Borgias
Pope Alexander VI
Cesare Borgia
Lucretia Borgia
7
THE MIDDLE AGES
Catherine de Medici experimented with poisons on
the sick, appearing a "good Samaritan". She
evaluated the toxic response, dose-effectiveness,
parts of the body affected and symptoms of the
victims.
Signora Guilia Toffana marketed cosmetics and
beauty aids containing arsenic. Thought to have
poisoned around 600 people
8
15th century occupational hazards first
documented, adverse effects associated with
exposure to heavy metals e.g. in mining and
goldsmithing. Paracelsus (1493-1541) Father of
Toxicology - described the principle that the
dose makes the poison. "All substances are
poisons there is none which is not a poison. The
right dose differentiates a poison from a
remedy. Principle underpins safe drug doseage,
and risk assessment exercises in the workplace
9
  • Main Contributions by Paracelsus
  • Established the relationship between dose and
    effect, all substances can be toxic if the right
    dose is used.
  • Described relationship between chemical structure
    and toxicity, stating that toxicity is basically
    a chemical interaction. Recognised target
    organ concept
  • Studied and described the main clinical
  • symptoms of arsenic and mercury.

10
Percival Pott described relationship between
soot and cancer in chimney sweeps. First time an
environmental agent associated cancer occurrence.
Orfila developed forensic toxicology, used
chemical analysis autopsy-related materials as
proof of poisoning in a court of law.
19th century rapid advent of organic chemistry,
many new chemical compounds synthesized which had
to be tested for toxicological properties.
Principle still practised today.
11
The 20th Century Two World Wars significant
development of chemicals used for warfare, e.g.
gas, pesticides, ammunitions and drugs. 
Late 50s development of research programmes to
evaluate safety to humans of foods, drugs and
cosmetics.
Incidents related to chemical toxicity become
more frequent e.g. Thalidomide, discovery of
TCDD in herbicide Agent Orange (19 million tons
sprayed over Vietnam during 1960s), effects of
dioxin on birds of prey.
12
TOXICOLOGY
  • Essential for detection/treatment of chemical
    effects
  • Given rise to legal framework for
    detection/control of chemicals
  • Relevant to environmental problems, safety of
    chemicals in industry
  • Important in drug development, use of food
    additives/preservatives

13
THREE MAJOR AREAS   1- Mechanistic the
molecular mechanisms by which chemicals cause
toxicity.  E.g. development of antidote for
organophosphate poisoning achieved from
understanding interaction with enzyme acetyl
cholinesterase.   2- Descriptive testing
chemical toxicity and recording signs and
symptoms.  Determines adverse effects with aim of
predicting toxic effects in humans and
wildlife.                     3- Regulatory
studying data concerning a chemical and
evaluating risk.  E.g. USA, Food and Drug
Administration (FDA) regulates food additives,
drugs and cosmetics.  
14
Human poisonings
Fatalities Approx. 70 arise from legal drugs
and medicines, both accidental and
intentional Non-fatal incidents Approx. 700 000
cases reported per year 60 of these in children
under 6 years old Painkillers, household
cleaners, cosmetics toxic plants largely
responsible (data from US Poison Control
Centers)
15
Domestic animal poisonings
Circa 42 000 per year 33 pesticides 25
veterinary drugs 12 toxic plants (data from US
Poison Control Centers)
Wildlife poisonings
16
WHAT ARE TOXINS? HOW DO THEY ENTER LEAVE THE
BODY?
  • Physical states
  • Solid
  • Liquid
  • Gas
  • Aerosols i.e. fine suspension of liquid/particles
    in gas
  • Dust, e.g. asbestos
  • Fumes/smoke

17
  • Patterns of Exposure
  • Chronic low concentration, long time period
  • Acute high concentration, short time period
  • Types of exposure
  • Intentional alcohol, smoking, medicine
  • Occupational asbestos, mercury
  • Environmental- oil spill, pesticides
  • Accidental usually acute

18
HOW DOES A CHEMICAL EXERT A TOXIC EFFECT?
Must come into contact with a biological
system First contact may occur at
several sites in the body Whichever
site is involved absorption across cell
membrane essential
19
MAIN SITES OF UPTAKE (ABSORPTION)
  1. Skin

2. Lungs
Other routes Milk, Placenta
3. Gastrointestinal tract
20
Cuticle
Insect tracheae
Gills
Body wall
Carapace
Spiracle
21
SITES OF UPTAKE (ABSORPTION)
  1. Skin

22
SKIN
  1. Constantly exposed to foreign compounds
  2. Large surface area
  3. Most at risk through lipid soluble compounds
  4. Particularly easy for chemicals to cross skin in
    aquatic animals e.g. fish, amphibians

23
SITES OF UPTAKE (ABSORPTION)
2. Lungs
24
LUNGS
  1. Exposure through lungs greater risk for humans
    than skin
  2. Large surface area, excellent blood supply
  3. Concentration gradient always present

25
SITES OF UPTAKE (ABSORPTION)
2. Gastrointestinal tract
26
GASTROINTESTINAL TRACT
  1. Numerous chemicals taken in with food
  2. Internal environment varies greatly through tract
  3. Particularly important route of uptake for
    animals at top of food chain

27
CELL MEMBRANE
28
Lipids arranged in bilayer, interspersed with
proteins Exact composition of membranes
varies ALL membranes selectively permeable
  • Characteristics affecting transport of chemicals
    across membranes
  • Size
  • Lipid solubility
  • Similarity to endogenous molecules
  • Polarity/charge

29
  • Types of passage across membranes
  • Filtration
  • Passive diffusion
  • Facilitated diffusion
  • Active transport
  • Phagocytosis/pinocytosis
  • 1. Filtration
  • Small molecules pass through membrane pores
  • Movement down a concentration gradient
  • E.g. ethanol

30
2. PASSIVE DIFFUSION
  • Probably most common
  • Must have concentration gradient
  • Chemical must be lipid soluble
  • Chemical should be non-ionized

31
3. FACILITATED DIFFUSION
  • Needs specific membrane carrier
  • Concentration gradient necessary
  • Does not require energy
  • Can apply to chemicals structurally similar to
    endogenous ones

32
4. ACTIVE TRANSPORT
33
5. Phagocytosis (solid particles) Pinocytosis
(droplets)
34
WHAT HAPPENS TO A CHEMICAL ONCE IT GETS INSIDE
THE BODY?
  1. Chemicals entering via skin pass into peripheral
    circulation of the blood
  2. Chemicals in the gut cross the epithelium into
    the blood and are transported to the liver
  3. Chemicals entering via respiratory surfaces pass
    into pulmonary circulation, transported to heart,
    from which they reach all tissues organs

35
TRANSPORTED CHEMICALS
  1. Can be stored in fat, especially lipophilic
    compounds
  2. Can bind to proteins and macromolecules
  3. Can bind to nucleic acids, causing mutational
    damage leading to cancers
  4. Compounds undergo metabolism before excretion
    from the body

36
Routes of excretion
  1. Kidney
  2. Bile
  3. Lung
  4. Body fluid, e.g. milk, sweat, tears

37
1. Kidney
  1. Small, water-soluble molecules pass out in urine
  2. Large molecules (e.g. proteins) cannot pass via
    glomerulus
  3. Lipid-soluble molecules reabsorbed from tubule
  4. Receives 25 cardiac output, exposed to large
    proportion of molecules

38
Liver
  1. Important route of elimination, particularly for
    large molecules
  2. Chemicals excreted into bile and eliminated via
    faeces
  3. Chemicals therefore have second exposure to gut,
    can sometimes be metabolized by microflora

39
Lung
  1. Important route of excretion for volatile
    chemicals/metabolites
  2. Excretion occurs by passive diffusion from blood
    into alveoli
  3. Excretion aided by concentration gradient

40
CHEMICAL INTERACTIONS   1.   Additive Sum of the
effects each chemical would have if acting
independently (11 2)   2.   Synergistic Effect
of chemical combinations greater than the sum of
the effects they would produce if acting
independently (11 4)   3.   Potentiation One
chemical acting independently is harmless, but it
amplifies the effect of another (0 1 5)   4.  
Antagonistic Effects of a combination of
chemicals are less than the sum of their effects
when acting independently (11 0)
41
  • TYPES OF TOXIC RESPONSE
  •  Direct toxic action on cells/tissues
  • Necrosis Apoptosis

2. Biochemical damage
42
  • TYPES OF TOXIC RESPONSE
  •  
  • Physiological damage
  • Teratogenicity
  •  

43
  • TYPES OF TOXIC RESPONSE
  •  
  • Mutagenicity
  • Carcinogenicity Immunotoxicity

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