Toxicology

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Toxicology

• Industrial Hygiene
• IENG 341
• Carter J. Kerk
• Industrial Engineering Department
• SD School of Mines
• Spring 2008

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Assignment

• Read Nims, Chapter 2
• HW2
• Critical Thinking Questions
• P. 46-47
• 1-5
• Due Date?

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Definitions

• Toxicity The ability of a substance to cause
  harm or adversely affect an organism
• Toxicology The science and study of harmful
  chemical interactions on living tissue

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Occupational Toxicology

• Workplace exposure to chemicals
• You or someone you know has probably experienced
  an episode of toxicology
• Injury or death due to
• Smoke inhalation
• Confined space incident
• Ingestion or absorption of a chemical

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The Dose-Response Relationship

• A time of exposure (dose) to a chemical, drug, or
  toxic substance, will cause an effect (response)
  on the exposed organism
• If the amount or intensity of the dose increases,
  there will be a proportional increase in the
  response

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Definitions

• Dose The amount of a substance administered (or
  absorbed), usually expressed in milligrams of
  substance per kilogram of the exposed organism
  (mg/kg)
• Response The effect(s) of a substance may be
  positive or negative

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Dose Response Curve
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Acute and Chronic Terminology Exposure as well
as Response

• We previously discussed acute and chronic
  exposure
• Acute exposure short time / high concentration
• Chronic exposure long-term, low concentration
• Acute response rash, watering eyes, cough from
  brief exposure to ammonia
• Chronic response emphysema from years of
  cigarette smoking

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Possible Response Levels

• No response at low dosage levels there may be
  no response at all
• Threshold dose the lowest level of dosage at
  which a response is manifested
• NOAEL no observed adverse effect level
• NEL no effect level
• Above threshold dose response can be positive
  up to a point and then could become toxic to the
  organism
• Different people or organisms will exhibit a
  variety of responses

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Indicators of Relative Toxicity

• Toxicity ability of a substance to cause harm or
  have an adverse affect
• How much harm?
• What aspect of the population?
• Notation
• LD, lethal dose
• LC, lethal concentration
• ED, effective dose
• EC, effective concentration

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LD50 a measure of relative toxicity

• Most common toxicity notation
• Determined in the lab and based on an acute
  exposure to adult test animal
• Lethal dose that produces death in 50 of the
  exposed population
• LD50, 35 mg/kg, oral, rat
• 35 mg of dose per kg of rats body weight, when
  administered orally, produces death in 50 of
  exposed population
• Comparing the LD50 between two substances gives
  the relative toxicity between the two substances

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LD50 Relative Toxicity
Agent LD50 (mg/kg)
Ethyl Alcohol 10,000
Sodium chloride 4,000
Morphine sulfate 900
Strychnine sulfate 2
Nicotine 1
Hemicholinium-3 0.2
Dioxin (TCDD) 0.001
Botulinum toxin 0.00001
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Example of Toxicity Classification
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Effect of route of administration
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Toxicity variance between organisms (Pesticide
chlorfenvinfos)
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How can we interpret animal test?

• Animal tests can give an indication of relative
  toxicity which can be extrapolated to humans
• Problems
• Toxicity variance between organisms
• Animal doses (strength or time) may be higher
  than realistic human exposures
• On a body weight basis, humans are usually more
  susceptible to toxic effects, sometimes by a
  factor of ten
• Therefore, human interpretation requires use of a
  safety factor

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Epidemiological Studies

• Prospective epidemiological study
• Take a cohort (or group of individuals) with a
  common exposure
• Follow through time to see if they develop
  disease
• Retrospective epidemiological study
• Take a cohort with a disease and trace back
  through time to see if there is a common exposure
• These are difficult with many confounding
  factors, but are quite valuable

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Latency Period

• Long delay between exposure and disease
• Some diseases may not develop for many years
• Lung cancer may occur as much as 30 years after
  exposure to asbestos
• This makes animal studies and epidemiological
  studies even more difficult, but also very
  valuable

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Toxicity data limitations

• Although there is considerable toxicity data
  available, for most chemicals it is still limited
• Less than 10 of the thousands of chemicals have
  regulatory or recommended standards for safe
  exposure

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Routes of Exposure

• Inhalation
• Ingestion
• Absorption through the skin
• Less common
• Injection
• Absorption through eyes and ear canals

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Inhalation

• Most common route of entry into body
• Therefore our area of highest concern
• Lungs are designed for efficient gas exchange
  between the air and bloodstream
• Lungs have up to 1000 square feet of exchange
  area (about 32 feet by 32 feet)
• Normal days breathing volume 8 cu ft
• Therefore great potential for toxins to enter
  bloodstream
• ACB Respiratory System 91, 96

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Skin Absorption (2nd most important route)

• Skin surface area is about 20 square feet (4.5 ft
  by 4.5 ft)
• Compare to 1000 sq ft for lungs
• Materials can be absorbed into blood stream just
  below the skin surface or toxins can be stored in
  fat deposits
• Obviously workers can easily expose their hands
  into solvents, oils, chemicals, etc., plus these
  materials can be sprayed or rubbed on other parts
  of the body
• Many chemicals are either soluble in water or in
  oil (fat, lipid)
• The skin easily absorbs lipid-soluble materials
• Solvents
• Water-soluble materials are not easily absorbed
• Lipid layer on skin provides a barrier
• ACB Skin 161

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Ingestion (3rd most important route)

• Ingestion is not usually intentional
• Unintentional ingestion
• Failure to wash hands and face before meals
• Eating/drinking in areas where airborne hazards
  exist
• Lighting cigarettes with dirty hands
• Application of cosmetics
• Use of chewing tobacco or gum in contaminated
  areas

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Ingestion

• The digestive tract is moist and designed for
  efficient absorption
• Surface area of intestines is greatly increased
  by small projections (villi)
• Thin surfaces, highly vascularized
• Materials easily transferred to bloodstream
• ACB Digestive System 98, 104

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Injection

• Less common
• Possible hazards
• Outdoor work, construction sites, hazardous waste
  sites, plants, animals, reptiles, insects,
  abrasions, puncture wounds, cuts

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Absorption into eyes and ears

• Much less common but possible
• Moist surfaces

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Distribution of Toxins

• Once toxins are in the body, there are several
  mechanism of movement and action
• Inhalation
• Toxics may enter bloodstream
• Toxics may irritate or scar lung tissues directly
• Skin Absorption
• Toxics may enter bloodstram
• Toxics may irritate, corrode or burn skin directly

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Once absorbed into the body, toxins can move to
other tissues and organs through various ways

• Filtration
• Toxins move through membrane pores
• Diffusion
• Movement from higher concentration to lower
  concentration
• Active transport
• Movement across a membrane otherwise impermeable
  by a transport mechanism
• Chemical reaction or carrier molecule, requires
  energy
• Phagocytosis
• Toxins eat or engulf other cells or by use of
  white blood cells

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Biotransformation Excretion of Toxins

• Water soluble substances easily to eliminate
• Lipid soluble substances are difficult to
  eliminate
• Biotransformation process by which materials
  are chemically altered to make them easier to
  eliminate (as in lipid soluble substances)
• Biotransformation and excretion through the liver
• Filtration and excretion through the kidneys
• Therefore, liver and kidneys are useful in
  eliminating toxins from the body, but on the
  other hand become target organs of toxins because
  of their nature

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Liver

• Important in metabolism, energy storage, protein
  synthesis
• Receives blood from digestive tract and works to
  concentrate, transform, and excrete substance
  (both good and bad toxins)
• Thus produces bile (enriched) which is returned
  to the intestines
• ACB Digestive System 106

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Hepatoxic Effects

• Hepatoxic liver toxins
• Necrosis cell death
• Steatosis intercellular fat accumulation, fatty
  liver
• Cholestasis interference with the production of
  bile and biliary excretion
• Immune cell infiltrate presence of abnormally
  high numbers of immune cells
• Neoplasia cancer
• Cirrhosis fibrosis, collagen fibers deposited
  throughout liver
• Causes chronic alcoholism, hepatitis
• Collagen
• interferes with normal function and the internal
  architecture
• a protein-based connective tissue that is not
  normally present in the liver
• Normally found as a component of tendons,
  ligaments, and bones

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Kidneys

• Receive 25 of cardiac output for filtration
• Primarily for elimination of water soluble
  molecules
• Large molecules (proteins) and lipid soluble
  materials are reabsorbed through the tubules of
  the nephron
• Nephron functional unit of the kidney (see next
  slide
• Materials pass by filtration, diffusion, active
  transport
• ACB Urinary System 108, 110-112

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Classes of Toxins and Toxic Responses

• Irritants and Sensitizers
• Systemic Toxins
• Neurotoxins
• Reproductive Toxins
• Carcinogens

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Irritants

• Localized, some physical damage
• To skin, eyes, respiratory system
• Corrosion most severe response
• Ulceration, tissue damage, usually permanent
• E.g., chemical burns from acids and bases
• Acute irritations
• Redness, inflammation, usually reversible

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Sensitizers

• Substances that stimulate a response from the
  immune system, usually the second exposure
• Triggering exposure can be extremely low dose
• Immune system recognize and reject foreign
  objects in the body, including infectious disease
  and hazardous materials
• Allergic reaction releases antibodies to attack
• Reaction ranges from skin rash to anaphylactic
  shock (life threatening)

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Systemic Toxins

• Toxins that affect target organs
• Vinyl chloride liver (cancer)
• Cadmium kidney
• Benzene blood marrow (leukemia)
• Toxicity mechanism is often related to the normal
  function of the target organ

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Neurotoxins

• Compounds that negatively affect the nervous
  system
• Response can be mild to severe
• Effects can impact thinking ability, motor
  control, regulation of breathing and heartbeat
• Central Nervous System CNS (brain, spinal cord)
• Coordination, emotion, speech, memory
• Peripheral Nervous System PNS (all but brain,
  spinal cord)
• Sensory info (touch, heat/cold, proprioception,
  pain)
• Motor impulses (movement)
• Autonomic Nervous System ANS
• heart rate, breathing, organ control, reflexes
• Neurotoxins can produce neuropathy a toxic
  effect characterized by progressive decline and
  death of nerves

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Reproductive Toxins

• Substances that affect the reproductive process
• May affect males, females, or both
• Lead
• Males decreased numbers of sperm or defective
  sperm
• Pregnant Females can cause deformities in
  developing fetus, especially fetus developing
  nervous system
• Teratogens (Greek monster) toxins that cause
  abnormal development or birth defects

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Thalidomide (a teratogen)

• Originally prescribed as a sedative and
  specifically advertised for safe use by pregnant
  women
• Thousands of babies were born between 1959 and
  1962 with severe deformities (no legs, arms,
  deformed ears, etc.)
• Popular use in Europe and Canada
• Use in US was delayed for FDA studies which later
  proved its danger

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DES (Diethyl stilbestrol)

• Another teratogen
• Synthetic hormone (estrogen)
• Approved in 1941 for use in women as an aid in
  the prevention of miscarriage
• Finally discontinued in 1972
• Linked to development of cancer and other
  abnormalities of their children

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Carcinogens

• Toxins that cause cancer
• Occupational carcinogens consist of a variety of
  chemical and physical agents including
• organic and inorganic solvents
• heavy metals
• solid materials (asbestos fibers)
• natural substances hormones, nitrosamine
• Materials that suppress the immune system

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Assignment

• Read Nims, Chapter 2
• HW2
• Critical Thinking Questions
• P. 46-47
• 1-5
• Due Date?