The Importance of Experimental Design

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The Importance of Experimental Design

• All experiments should have a control population.

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The Importance of Experimental Design

• Proper control uses a placebo instead of no
  treatment.

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Experimental Design

• Experimental design to avoid biases and
  confounders
• Biases due to
• experimenter
• subject
• population
• Confounders
• a second, unknown factor that has not been
  controlled.
• confounders may mediate effects of dependent
  variables. Example drug mixtures.

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Experimental Design Double Blind Experiments

• Members of the study group do not know if they
  are receiving the drug or the placebo.
• Scientist observing the study group do not know
  which ones have drug and which ones have placebo.
• All FDA testing must be double blind
• Early example is the early testing in the 1960s
  of Vineberg procedure for heart disease.

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Toxicity Assessment

• Gather toxic information qualitative
  quantitative
• Identify exposures periods
• Determine toxic values for non-carcinogenic
  effects
• Determine toxic values for carcinogenic effects
• Determine toxic values for endocrine disrupting
  effects

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Dose
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Steroid Hormone Molecules Enter the Cell
Hormone - Receptor Complexes Activate
Transcription
Receptors
Cytoplasm
RNA
DNA
HRE
DNA
HRE
Nucleus
Hormone Response Element
Hormone Response Element
Classical Model for Steroid Hormone
Action Figure 3
ATSDR
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Human development is disrupted at vulnerable
stages by fetal and infant exposure to endocrine
disruptors.
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Human Health Effects of Dioxin

• Cancer
• Known human carcinogen
• Neonatal Abnormalities
• Change in sex ratio
• Altered level of thyroid hormone
• Skin Disorders
• Porphyria cutanea tarda
• Chloracne
• Neurologic Disorders
• Peripheral (animal)
• Central (PCB?)

• Immune System
• Change in immune system parameters / modulation
• Endocrine System Effects
• Low levels of testosterone
• Increase glucose intolerance or diabetes
• Decreased estrogen estrogen-receptor levels
  after fetal exposure

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Other determinants of toxicity

• Timing of exposure (a dose taken all at once
  usually more dangerous than the same dose divided
  over a longer period of time)
• Route of exposure how you are exposed
  (inhalation, ingestion, skin) often determines
  the type of health effect

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Acceptable Risk

• For no threshold chemicals (e.g. carcinogens,
  we set the probability of effect that we are
  willing to accept (usually 1/100,000 or
  1/1,000,000)

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Ecotoxicology

• Remember the system as a whole can be important.

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Other ways to be toxic

• There is the same old ways hurt, kill, or mutant
  and individual (whether it is a cell, organ or
  being).
• Others
• Immune system dysfunction.
• Endocrine disruption.
• Alter reproductive capability, maleness,
  femaleness, etc...
• Alteration of systems patterns.
• Pattern change can impact the system drastically.
• Lose of diversity.

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Lets step back, and revisit the definition of
ecosystem.

• A set of species living together in one place in
  a definable environment. classic
• A system through which energy flows in various
  forms with the participation of biota to a
  variable degree. thermodynamic
• The ecosystem is a stationary entity of abiotic
  and biotic compartments, in which energy,
  material, and information reside and flow in
  various forms. - new

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Key concepts - Ecotoxicology

• Biomagnification
• Another human exposure concern
• Population effects
• Community effects
• Ecosystem effects
• How do we define natural?

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Loss of maleness
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Declining Sex Ratios Reduced Ratio of Male to
Female Births in Several Industrial Countries
Davis DL et al. JAMA 279(13) 1018-1023. (1998)
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Declining Sperm Density A Meta-Analysis
1938-1996
Mean sperm density by year and geographic region.
Swan, SH et al., Environ Health Persp 108(10)
961-966 (2000)
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Diversity

• Genetic diversity is very important to the health
  of the system.
• Since a toxin typically acts at a very specific
  molecular site (i.e., a key only fits into a
  specific lock), any slight alteration in your (or
  some other species) molecular makeup may allow
  you to be immune to the toxin.
• Examples
• More diverse field of grass is more drought
  resistant.
• Corn crop failure in early 1990s.
• Tons more.

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Risk Characterization

• Calculation of risks
• What toxin(s) are present
• Exposures how long, how much,
  frequency, route(s)
• Toxicity in vivo

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Risk Assessment
Exposure Assessment
Data Collection Hazard Identification
Risk Characterization
Toxicity Assessment
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Public Health Interventions

• Surveillance
• Evaluation
• Prevention
• - Risk Communication
• - Health Education
• - Infrastructure
• Impact Assessment

ATSDR
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• Slides Developed From
• Association of Occupational Environmental
  Clinics
• The Agency for Toxic Substances Disease
  Registry
• Collegues at University of Illinois
• Postings on the Internet