Toxicology and Human Health (Moeller Chapter 2)

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Toxicology and Human Health(Moeller Chapter 2)
Geography 361aEnvironment and Health

• Context
• What is toxicology?
• Toxins in the body
• Toxicity of chemicals
• Tests for toxicity
• Outcomes measured
• Establishing exposure limits

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ContextChemicals in the Environment

• Outline some of the challenges this table
  represents.
• How can we (society) address those challenges?

Author Chemicals in Existence New Chemicals/Year
Moeller (2003) 70,000 200-1000
Philp (1995) 64,000 700
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Toxicology Definition

• The study of the harmful effects of chemicals on
  the health of organisms (ultimately, humans).
• (see models of health/causality from last day)

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Environmental Toxicology Definition

• The study of the harmful effects of (combinations
  of) chemicals on the health of entire ecosystems.

• See Health Canadas Chemical Substances Portal
• (useful for assignment 1 too)

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Toxins into the Body

• lungs, gastrointestinal tract, skin
• most toxins enter how?

respiratory system
GI tract
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Toxins in the Body

• biological transformation
• transformation from one organ or tissue to
  another
• chemical conversion to new compound
• typically less absorbable (excreted)
• bioactivation
• biological transformation that forms a compound
  that is more toxic than the substance
  inhaled/ingested/absorbed

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Toxins removed from the Body

• excretion
• urination main form of excretion
• lungs
• GI tract least important
• organs liver and kidneys
• health of these systems can effect bodys ability
  to withstand toxic insults

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Toxins in the Body

• Other factors influencing response
• age young and old most vulnerable
• sex particularly reproductive impacts

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Toxins in the Body

• Environmental factors influencing response
• ambient temperature (e.g. ? temp dinitrophenol
  herbicide ? toxicity)
• humidity ? typically worse
• light diurnal pattern ? light typically worse
• social lab animals housed singly or in groups

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Toxicity of Chemicals

• What is it that is not poison? All things are
  poison and nothing is without poison. It is the
  dose only that makes a thing not a poison.
  (Paracelsus, 16thC, emphasis added)

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Toxicity of Chemicals
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Toxicity of Chemicals

• qualitative ranking of toxicity of chemicals

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Toxins in the Environment

• biomagnification
• up the food chain
• typically fat soluble toxins

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Tests for Toxicity Exercise

• Suggest ways that the toxicity of substances
  might be tested scientifically.
• What problems are involved?

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Tests for Toxicity

• laboratory highly controlled, randomization
• animals rats or mice typically
• ethical issues

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Tests for Toxicity Types of Studies

• acute toxicity
• single or multiple doses (high)
• short period of time
• short-term (subacute, subchronic)
• repeated (daily) doses
• period 10 of animal lifespan (e.g, rat 3mo)
• long-term (chronic)
• entire lifespan of animal

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Tests for Toxicity Outcomes

• change in body weight
• growth of tumours
• change in body size
• death (typically) (see LD50)
• MTD
• maximum tolerable dose
• highest dose below which cancer does not occur
• debated whether high doses exaggerate
  carcinogenicity (but see precautionary principle)

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Acute Toxicity Studies

• some animals are more susceptible, some more
  resistant

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Acute Toxicity Studies

• LD50 using cumulative curves

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Example LD50 Values

• dichlorvos, an insecticide commonly used in
  household pesticide strips
• Oral LD50 (rat) 56 mg/kg
• Dermal LD50 (rat) 75 mg/kg
• Injected to abdomen LD50 (rat) 15 mg/kg
• Inhalation LC50 (rat) 1.7 ppm (15 mg/m3) 4-hour
  
• Oral LD50 (rabbit) 10 mg/kg
• Oral LD50 (pigeon) 23.7 mg/kg
• Oral LD50 (mouse) 61 mg/kg
• Oral LD50 (dog) 100 mg/kg
• Oral LD50 (pig) 157 mg/kg

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Acute Toxicity Studies Summary

• Benefits
• death is easily measured
• autopsies info on probable target organs
• determine doses to be used in longer-term studies
• Drawbacks
• death is only one of many possible outcomes
• humans rarely exposed at such high levels

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Short and Long-Term Toxicity Studies

• typically 2 or more species (rat dog)
• animal to biotransform chemical much like human
  would in real world
• three dose ranges high(wont kill) medium
  low(no expected effects)

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Longer Term Toxicity Studies Summary

• Benefits
• biotransformation measured
• assess acceptable intake values
• NOEL no observed effect level
• Drawbacks
• biotransformation assumptions different species

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Outcomes Measured

• carcinogenesis
• staged initiation, promotion, progression
• some chemicals do one, two or all three
• Ames Test
• in vitro test of mutagenicity to bacteria
• very inexpensive
• assumes mutatagenicity similar to carcinogenicity

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Outcomes Measured

• reproductive toxicity
• both parents and offspring
• e.g. mother during or prior to gestation
• developmental toxicity (teratogenesis)
• congential effects
• e.g. growth retardation, malformations
• e.g. thalidomide

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Outcomes Measured

• Neurotoxicity
• cognitive, sensory, motor
• often wide variation between rat/dog and human
  responses of this type
• 1000 chemicals identified as neurotoxicants
  (only 10 - 7000 - tested though)

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Outcomes Measured

• Immunotoxicity
• suppression of immune function
• host vulnerable to infection (incl. cancer)
• e.g., multiple chemical sensitivity syndrome
  low dose exposure AIDS-like response
• very controversial at this point
• emerging area of research

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Outcomes Measured

• Summary
• most chemicals (only 20 of chemicals in use
  today) assessed for carcinogenesis only
• being revisited under USA SARA legislation
• Agency for Toxic Substances and Disease Registry
  (ATSDR) data base growing (slowly) as a result
• (keep in mind 99 of all toxic human exposures
  from natural environment e.g., bacteria)

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Extrapolating from Animals

• relative responsiveness
• small animals to large humans
• dose
• relatively high doses for short periods of time
  versus low doses over long periods of time
• this type creates highest uncertainty and highest
  controversy
• e.g., what is the shape of the dose-response
  below the minimum does administered in toxicity
  experiments? linear or threshold?

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Establishment of Exposure Limits

• Two Principles (order of importance)
• use human data whenever possible
• use surrogate species or surrogate chemicals if
  scientific basis for comparability with target
  population
• most frequently principle 1 not satisfied.

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Establishment of Exposure Limits

• Steps
• establish range of effects for target or
  surrogate chemical (chemicals database)
• establish dose-response relationship in target
  species or surrogate species
• establish exposure limit by adding in safety
  factor

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Establishment of Exposure Limits

• Safety Factor (or Uncertainty Factor UF) of
• 10 (account for most sensitive human)
• i.e., 10 NOEL or threshold level
• valid chronic human exposure data
• 100 (account for interspecies extrapolation)
• i.e. 100 NOEL or threshold level
• no human data
• satisfactory chronic exposure data in other
  species
• 1000 (account for interspecies extrapolation)
• i.e. 1000 NOEL or threshold level
• chronic exposure data incomplete for other species

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Dose/Response Curves

• many acute effects are threshold effects
• many chronic/cancer effects are non-threshold
  effects

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Dose/Response Curves

• most animal studies involve medium or high doses
  that must be extrapolated backwards
• if C is limit set safe according to
  extrapolation B but unsafe according to
  extrapolations D and especially, E

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Conservative Estimates

• precautionary principle
• see tutorial slides from Rachel

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Assignment 1
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Assignment 1