Measurement of exposure

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Measurement of exposure

• Measurement of agent in surroundings
• Questionnaires
• Personal dosimeters
• Blood samples (surrogate tissue)
• Target tissue

2
Biomarkers of exposure - Internal dose

• Genuine agent
• Specific metabolites
• Specific preclinical effects that are reversible
• Protein adducts
• DNA adducts

3
Markers of internal dose - chemical agents
4
Gene - environment interactions
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An example of metabolism - Benzene
Phase I ACTIVATION
Phase II CONJUGATION
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Metabolic susceptibility genes
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Xeroderma pigmentosum
Cleaver Kraemer, The metabolic basis of
inherited disease, 1989.
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DNA repair activity - case control studies
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LD50 Klassifikation af farlighed i EU
NB LD50 afhænger af administrationsvej ? skal
være den samme som mennesket udsættes for.
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Strategi for toskikologisk testning

• In vitro test (hurtige og billige)
• Ames test
• Kromosom forandringer
• Søsterkromatid forandringer
• Mikrokerne assay
• Unscheduled DNA synthesis
• TK el. HPRT mutationsfrekvens

• Basale tests (Dyreforsøg)
• Akut tests (? LD50)
• Korttidstests
• Landtidstests (??NOEL)
• Immunologiske effekter
• Neurologiske effekter
• Adfærdsændringer
• Organ toksicitet
• Special undersøgelser
• Mutagen og carcinogen effekt
• Teratogen effekt
• Irritation og sensibilisering

• Human data
• Epidemiologiske undersøgelser
• Klinisk afprøvning

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Vurdering af toksikologiske test data
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Eksponeringsvurdering
? Vurdering af hvor meget kemikalie der er i det
omgivende miljø
? Vurdering af mængden som mennesket udsættes for.
? Beregning af den totale daglige indtagelse.
? Beregning af den relative optagelse i kroppen.
Eksponeringsvurderinger beregnes ved hjælp
af computer-programmer, f. eks Monte Carlo
simulationen
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Essentials of toxicology
TOXICOKINETICS movement of chemical around the
body
TOXICODYNAMICS action of chemical in target
organ(s)
Administrated dose of chemical
Chemical at the site of action
Toxic response of the chemical
Relates the external dose to the amount delivered
to the target organ BIOAVAILABILITY CLEARANCE HAL
F-LIFE ACCUMULATION
Relates to the delivery, or internal dose, to the
target organ response DOSE-RESPONSE INTERACTION
(TOLERANCE) ACTION MECHANISM SUSCEPTIBILITY