Toxicology 101 - PowerPoint PPT Presentation

Loading...

PPT – Toxicology 101 PowerPoint presentation | free to view - id: ed272-ZDc1Z



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Toxicology 101

Description:

Ted Schettler MD, MPH. Hoosier Environmental Council. Indianapolis, ... Biomonitoring is sometimes useful for estimating the body burden. What is biomonitoring? ... – PowerPoint PPT presentation

Number of Views:159
Avg rating:3.0/5.0
Slides: 45
Provided by: tsc75
Category:
Tags: toxicology

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Toxicology 101


1
Toxicology 101
  • Ted Schettler MD, MPH
  • Hoosier Environmental Council
  • Indianapolis, IN
  • Nov., 2004

2
Outline
  • What is toxicology?
  • Hazards, exposures, risks
  • Doseresponse
  • Body burden/biomonitoring
  • Mechanisms of toxicity
  • Examples

3
Toxicology
  • The study of the adverse effects of chemical
    agents on living things
  • Individuals
  • Communities
  • Ecosystems

4
Toxicology
  • Adverse effects depend on
  • Exposure to a chemical substance
  • Susceptibility of individual or population
  • Interactions with genetic, nutritional, and
    social factors

5
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.

6
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)

7
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?

8
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)

9
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.

10
Non-linear dose-response curve with threshold
11
Acute Effects
12
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

13
Chemicals and the Food Chain
  • Persistence
  • Bioconcentration
  • Persistent and bioaccumulative chemicals are
    often measured others frequently ignored

14
Biomonitoring and body burden
  • Body burdenthe total amount of a chemical agent
    in an individual
  • Biomonitoring is sometimes useful for estimating
    the body burden

15
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

16
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

17
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

18
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

19
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

20
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.

21
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

22
(No Transcript)
23
(No Transcript)
24
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)

25
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

26
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

27
Health effects - PCBs
  • Cancer
  • Reproductive
  • Developmental
  • Nervous system
  • Immune system
  • Endocrine
  • Dermatologic (high dose)

28
PCBs Neurodevelopmental Effects
  • Infant
  • Birth weight
  • Head circumference
  • Gestational age
  • Performance on Brazelton Neonatal Behavioral
    Assessment (BNBA) - motor immaturity, poor
    lability, startle

29
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

30
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
31
(No Transcript)
32
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

33
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
34
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

35
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

36
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

37
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

38
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

39
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

40
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

41
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

42
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

43
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?

44
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
About PowerShow.com