Toxicology 101

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Toxicology 101

• Ted Schettler MD, MPH
• April 2004
• Portland, Oregon

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From Exposure to Toxicity

• Exposure applied dose, from outside
• Absorption internal dose
• Distribution target organ dose
• Biological effect
• Biochemical changes
• Symptoms
• Health effectobvious, not so obvious specific,
  non-specific
• Late disease?

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Dose and toxicity

• Amount, timing, pattern, duration
• Health effects
• depend on exposure and susceptibility of the
  individual or population.
• depend on interaction of genetics, nutrition,
  social environment, cumulative exposures.
• one chemical may have a variety of health effects
  that occur at different doses, timing, and
  patterns of exposure (dose-response)

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Dose-response

• The shape of the dose response curve is essential
  for predicting toxicity and health effects
• Dose-response curves have different shapes
• Dose-response curve varies for different health
  effects from the same chemical e.g. the dose
  response curve for death from exposure to a
  pesticide will differ from the curve for impacts
  on the developing brain
• If we focus on acute, obvious effects we will
  miss more subtle or delayed effects.

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Non-linear dose-response curve with threshold
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Acute Effects
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Route of exposure

• Ingestion
• Inhalation
• Intravenous
• Through the skin (dermal)
• Health effect often vary with the route of
  exposure (e.g. asbestos)
• Toxicity may vary with the route of exposure
  (e.g. metallic mercury)

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What happens to the chemical after exposure?

• Rapidly metabolized and excreted?
• Stored? In fat? (dioxin) In bone? (lead)
• In multiple organs? (mercury)
• Half-lifeseconds, hours, days, years?
• benzene-minutes some pesticides-hours
• methylmercury-months dioxin-years
• leadyears
• Challenge of estimating peak exposure level

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Chemicals and the Food Chain

• Persistence
• Bioconcentration
• Persistent and bioaccumulative chemicals are
  often measured others frequently ignored

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Mechanisms of toxicity

• Many different ways that a chemical can cause
  toxicity or a health effect
• Direct damage to parts of cells or organs (e.g.
  mercury)
• DNA damage or mutation (e.g. benzene)
• Interfere with gene expressionmultiple impacts
  (e.g. dioxin)
• Interfere with normal enzyme levels, affecting
  metabolism (e.g. dioxin, solvents)
• Etc.

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Diagram of Dioxin Molecule
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(No Transcript)
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Dioxinbiological effects

• Changes in enzyme and hormone levels
• Developing organism most susceptible at lowest
  doses
• Immune, reproductive, nervous, endocrine systems
• Cancers (non-specific do not carry a dioxin
  fingerprint)
• Chloracne (skin)

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Dioxin

• Effects on enzyme levels and immune system
  development begin at picogram or nanogram/kg/day
  (animal/human studies)
• Chloracnemuch larger doses required
• Route of exposureprimarily dietary fat soluble,
  bioconcentration in food chain, air and water
  levels very low
• ?importance of dust contamination in homes

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Toxicity of mercury

• Depends on chemical form metallic, inorganic,
  organic
• Organic mercury (methylmercury) is the form in
  fish bioaccumulates to high levels
• Organic mercury from fish is the most significant
  source of human exposure
• Brain and nervous system toxicity
• Cardiovascular toxicity

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Organic mercury

• Readily absorbed from intestine
• Half-life 70-80 days
• Primarily fecal excretion
• Organic Hg
• 90 of blood MeHg is bound to hemoglobin
• 50 of dose in liver 10 in head

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Organic mercury

• Readily crosses the placenta and enters the brain
  of the fetus (and adult)
• Converted to inorganic Hg in brain with long
  half-life (?months, years)
• High fetal exposures mental retardation,
  seizures, blindness
• Low fetal exposures memory, attention, language
  disturbances

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Mechanisms of Hg neurotoxicity

• Attaches to proteins and damages lipids
• Adverse impacts on enzymes, membrane function,
  neurotransmitter levels, mitochondria
• Impairs cellular division and migration in
  developing brain
• No single mechanism is explanatory

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Criteria for an Environmental Illness

• Documented exposure to agent
• Clinical picture compatible with agent
• Temporal relationship between exposure and
  health effect
• Similar problems in other exposed individuals
  (?)
• Biological plausibility

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When is proof of causation difficult to
establish?

• Chains of causation complex interactions among
  exposures, genetics, nutrition, etc. (e.g. lead)
• Non-specificity many diseases have multiple
  causes e.g. heart disease (genes, diet, blood
  pressure, smoking, arsenic, mercury, etc.)
• Long latent period between exposure and disease
• Windows of vulnerability exposure or activity is
  most hazardous when it occurs at a particular
  time

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References/resources

• http//toxnet.nlm.nih.gov/ (a cluster of
  databases)
• http//www.epa.gov/tri/ (Toxics release
  inventory)
• Woodruff TJ, et al. Public health implications
  of 1990 air toxics concentrations across the
  United States. Environ Health Perspect.
  May106(5)245-51, 1998.
• Steven Gilbert. "A Small Dose of Toxicology" -
  www.asmalldoseof.org