Toxicology

1
Toxicology

• Industrial Hygiene
• IENG 341
• Carter J. Kerk
• Industrial Engineering Program
• SD Tech
• Spring 2005

2
Reading Assignment

• Nims, Chapter 2

3
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

4
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

5
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

6
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

7
Dose Response Curve
8
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

9
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

10
(No Transcript)
11
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

12
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

13
LD50 Relative Toxicity
14
Example of Toxicity Classification
15
Effect of route of administration
16
Toxicity variance between organisms (Pesticide
chlorfenvinfos)
17
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

18
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

19
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

20
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

21
Routes of Exposure

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

22
(No Transcript)
23
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

24
(No Transcript)
25
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

26
(No Transcript)
27
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

28
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

29
(No Transcript)
30
Injection

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

31
Absorption into eyes and ears

• Much less common but possible
• Moist surfaces

32
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

33
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

34
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

35
(No Transcript)
36
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

37
(No Transcript)
38
Hepatoxic Effects

• Hepatoxic liver toxins
• Necrosis cell death
• Steatosis intercellular fat accumulation, fatty
  liver
• Cirrhosis fibrosis, collagen fibers deposited
  throughout liver

39
(No Transcript)
40
Kidneys

• Receive 25 of cardiac output for filtration
• Primarily for elimination of water soluble
  molecules
• Large molecules (proteins) and lipid soluble
  materials are 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

41
(No Transcript)
42
Classes of Toxins and Toxic Responses

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

43
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

44
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)

45
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

46
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

47
(No Transcript)
48
(No Transcript)
49
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

50
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

51
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

52
(No Transcript)
53
(No Transcript)
54
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