Hazard identification

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Chapter 2 Hazard identification
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What is toxicology?

• Toxicology-the science of poisons
• Adverse effects of chemicals or physical agents
  on living organisms
• Organ/cell/biochemical pathway

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Basic Terms

• Toxicityintrinsic capacity of a chemical to
  induce injury (adverse effect)
• Hazardthe possible threat to you and possible
  negative health outcomes under the known exposure
  conditions.

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Definitions

• Hazard identification(????)identification from
  animal and human studies of adverse effects
  associated with exposure to an agent.
• Hazard characterisation (????) consideration of
  results of hazard ID phase in relation to dose
  used.

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Definitions

• Dose-response(????)relationship between
• magnitude of dose and incidence or severity of
• adverse effect
• Threshold(??)owest dose which causes an
• effect
• NOEL-highest dose employed at which no effect was
  observed
• LOEL-lowest dose at which there was an observed
  effect
• ThresholdltLOEL but gtNOEL

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Examples of different hazards

• Clostridium botulinum toxin-extremely toxic on
  nervous system (Acute)
• Endosulfan-acute (acute-acetylcholinesterase
  inhibition) or chronic toxicity (kidney tubules)
• Heterocyclic amines (barbecued meats)-Carcinogenic
  

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When is a hazard a risk?

• The bodies adaptive mechanisms cannot cope
• Clinical, chemical, histopathological changes
  occur
• Effect is irreversible
• For food, risk of acute exposure rare, therefore,
  pay particular attention to chronic exposure
  (hence ADI)

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Hazard Assessment (Why?)

• Understanding what are the concerns about the
  chemical
• Is it likely to cause health problems?
• eg, acute toxicity, cancer, kidney damage
• Understanding the dose-response relationship
• - is it a problem at low doses?
• - is it a problem at high doses only?

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Hazard Assessment
Epidemiological data - less precise - highly
relevant

• Animal toxicity data
• more precise
• less relevant

• OUTCOMES
• Some understanding of kinetic and metabolism
• Identify target organs
• Possible mechanism of action
• Dose-response relationship
• Evidence of a threshold/NOEL

NOEL No Observed Effect Level
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Considerations

• Highest dose should not exceed gt5 of total
  diet?nutritional imbalances
• Do not want severe/extreme toxic effects that
  compromise the duration or results of the study
  ?uncertainties
• Controls-concurrent, negative/positive,
  historical, vehicle

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Considerations

• Validity of older studies
• Species-specific effects
• Statistical versus biological significance
• Limit dosing versus three doses
• Weight of evidence-judgement, adequacy, validity
  and appropriateness of data base.

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ConsiderationsPhysiological, Pharmacological or
Toxic?

• Physiology
• Variation within limits of normal function
  (pregnancy leads to increased bodyweight)
• Pharmacology
• Altered physiology through interaction with
  receptor site, reversible (chemical increase
  activity of liver enzymes)

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Considerations Physiological, Pharmacological or
Toxic?

• Toxicology
• Reversible/irreversible Injurious and therefore
  adverse and harmful
• A chemical which causes physiological or
  pharmacological effects could produce toxic
  response with long and/or high levels of exposure

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Remember

• All substances are hazardous under certain
  conditions of exposure (we are looking at the
  oral route for food)
• Sometimes need only small amounts for it to be a
  hazard (eg less than a drop) therefore, toxicity
  is a function of amount received
• Dose is very important (to be discussed later)

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What can studies tell us?

• That the chemical can in fact be a hazard-it has
  an adverse effect at a particular dose
• Lowest dose ( threshold)
• No effect or lowest effect level
• Is there a dose-response effect?
• Allows certain key toxicological parameters
  (endpoints) to be calculated

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Toxicological endpoints

• Toxicological endpoints-as increase dose reach a
  level at which a definite adverse effect is
  observed-e.g neurotoxicity, increase liver
  weights, optic nerve degeneration etc

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Example Neotame

• New food additive - intense sweetener
• Expected to be used widely in food high
  population exposure
• Studies required (pre-market assessment)

Metabolism and kinetic studies, short and
long-term studies, reproduction and developmental
studies, studies on metabolites, genotoxicity
studies, human toleration studies

• Proposed use level in food

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Example New Insecticide

• Widespread agricultural and home use high
  population exposure
• Safety studies required (pre-market assessment)

Metabolism and kinetic studies, short and
long-term studies, reproduction and developmental
studies, studies on metabolites, genotoxicity
studies (no human studies)
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Summary

• Hazard identification-?adverse effect (?liver
  changes vs neurotoxicity)
• Range toxicology studies used to determine hazard
• Toxicological endpoints, threshold, NOEL, LOEL