Toxicology 101

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Toxicology 101

• Ted Schettler MD, MPH
• Hoosier Environmental Council
• Indianapolis, IN
• Nov., 2004

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Outline

• What is toxicology?
• Hazards, exposures, risks
• Doseresponse
• Body burden/biomonitoring
• Mechanisms of toxicity
• Examples

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Toxicology

• The study of the adverse effects of chemical
  agents on living things
• Individuals
• Communities
• Ecosystems

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Toxicology

• Adverse effects depend on
• Exposure to a chemical substance
• Susceptibility of individual or population
• Interactions with genetic, nutritional, and
  social factors

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Hazards, exposures, risks

• Hazarda chemical or physical agent capable of
  causing harm the potential to cause harm
• Exposuresthe applied dose of a chemical agent
• Riskthe probability of harm. Hazard plus
  exposure produces risk.

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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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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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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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Biomonitoring and body burden

• Body burdenthe total amount of a chemical agent
  in an individual
• Biomonitoring is sometimes useful for estimating
  the body burden

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What is biomonitoring?

• Measurement of a parent chemical or metabolite in
  a body fluid, organ, tissue (rarely, exhaled air
  is tested)
• Examples
• Lead in blood or bone
• Brominated flame retardants in breast milk
• DDE, a metabolite of DDT, or dioxin in adipose
  tissue
• Phthalate metabolite in urine
• Mercury in hair

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What biomonitoring reveals

• The presence of a chemical means that an exposure
  has occurred that some dose has been
  internalized
• What the measured level implies with respect to
  level of exposure depends on
• Toxicokinetics of the chemical, including
  half-life, metabolism, tissue distribution,
  excretion

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Limits of biomonitoring

• Single, one-time samples are of little value when
  half-life (T ½) is short, unless the sample is
  obtained shortly after exposure
• Tissue distribution may make monitoring
  difficult e.g., a chemical stored in a solid
  organ
• Technical aspects may be complex e.g., volatile
  compounds with short T ½ sample storage and
  analysis

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Importance of biomonitoring study design

• What tissue, fluid, organ to sample?
• Will vary with the purpose of the study and the
  chemical of interest.
• Blood and urine specimens are most convenient
• Hair samples are useful for measuring exposure to
  some heavy metals (e.g, mercury) over time.
• Technical considerations

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Utility of biomonitoring

• Documenting exposure
• Facilitating health impact studies
• Prioritizing safety assessment of chemicals of
  concern
• Identifying sources of exposure
• Truth testing risk assessments (be careful)
• Political action

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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, PCBs)
• Interfere with normal enzyme levels, affecting
  metabolism (e.g. dioxin, solvents)
• Interfere with function of hormones or other
  signaling molecules
• Etc.

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Examples

• Dioxin and PCBs
• Persistent and bioaccumulative
• Historic and ongoing releases
• Dietary exposures Great Lakes fish
• Leadongoing exposures from older paint
• Mercuryexposures from fish contamination

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Dioxinbiological effects

• Changes in levels of enzymes, hormones, and
  growth factors
• Developing organism most susceptible at lowest
  doses
• Impacts on 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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PCBs

• Some are dioxin like similar toxicity
• PCBs also interfere with thyroid hormone
  function modify gene expression triggered by
  thyroid hormone
• (Thyroid hormone essential for normal brain
  development)
• Some PCBs alter neurotransmitter levels

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Health effects - PCBs

• Cancer
• Reproductive
• Developmental
• Nervous system
• Immune system
• Endocrine
• Dermatologic (high dose)

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PCBs Neurodevelopmental Effects

• Infant
• Birth weight
• Head circumference
• Gestational age
• Performance on Brazelton Neonatal Behavioral
  Assessment (BNBA) - motor immaturity, poor
  lability, startle

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PCBs Neurodevelopmental Effects

• Early Childhood
• Memory, attention, verbal ability, information
  processing
• Psychomotor development
• Sustained activity, high level play
• Withdrawn, depressed behavior
• Hyperactivity
• Preteen
• Word and reading comprehension
• Full scale and verbal IQ
• Memory and attention

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Cellular Events in Neurodevelopment

• Each of these events is subject to disruption by
  environmental agents
• Division
• Migration
• Differentiation
• Formation of synapses
• Pruning of synapses
• Apoptosis
• Myelination

Active throughout childhood adolescence
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Lead, alcohol, nicotine

• Recognized as neurodevelopmental toxicants for
  years
• Alcohol hyperactivity, cognitive deficits
• Nicotine IQ deficit, learning and attention
  deficits
• Lead impaired IQ, learning, attention
  hyperactivity, impulsiveness, aggression
  failure to complete school, trouble with the law

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Association of Teacher Ratings With Student Lead
Burden
Lead
Class Dentine Lead (ppm) 1 lt5.1 2 5.1-8.1 3 8.2-1
1.8 4 11.9-17.1 5 17.2-27.0 6 gt27
Percent
Class Distractible Nonpersistent Dependent
Not Hyperactive Impulsive
Organized
Class Blood Lead, (micrograms/dl) 1 7-10 2 11-1
2 3 13-16 4 17-32
Percent
Class Distracted Persist Work
Disorganized Hyperactive Impulsive
Independent Organized
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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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Proof

• Scientific proof depends on the kind of study
  and the criteria that are agreed upon to
  establish proof
• What constitutes proof is a mixture of
  scientific, social, and political factors

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When is proof of causation difficult to
establish?

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

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Sources of uncertainty in toxicology

• Knowing when windows of vulnerability occur
• Extrapolating from animal data to humans for
  lead, mercury, PCBs, animal data under-estimate
  human sensitivity by 100-10,000 fold
• Exposures to mixtures of chemicals
• Variability in genetics, nutrition, and social
  circumstances

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Resolving uncertainties

• Easiest (not necessarily least expensive)
• More comprehensive safety testing designing
  better epidemiologic studies
• Quantifying exposures general population, groups
  at risk
• Improved tracking of health outcomes
• More difficult
• Exposures to chemical mixtures
• Understanding interactions of toxicants with
  genetic, nutritional, and social factors

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Policy questions and implications

• When is evidence sufficient to trigger action?
  Do we require proof of harm?
• What kinds of effects trigger concern?
• What chemical properties are of concern? e.g.,
  persistence, bioaccumulation
• How much safety testing before a chemical can be
  marketed?
• Who decides?

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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
• www.protectingourhealth.org and
  www.cheforhealth.org