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Euromodule Food Safety and Risk Assessment Willem Gerritsen, Hogeschool van Amsterdam

Unit 3: Key stages in the proces of risk assessment Hazard characterisation Chemical risks Non-cancer and cancer. Euromodule Food Safety and Risk Assessment Willem Gerritsen, Hogeschool van Amsterdam Version 1, July 2004. Contents. Threshold and non-threshold 3 - 6

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Euromodule Food Safety and Risk Assessment Willem Gerritsen, Hogeschool van Amsterdam

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  1. Unit 3: Key stages in the proces of risk assessmentHazard characterisation Chemical risks Non-cancer and cancer Euromodule Food Safety and Risk Assessment Willem Gerritsen, Hogeschool van Amsterdam Version 1, July 2004

  2. Contents • Threshold and non-threshold 3 - 6 • ADI, RfD, uncertainty factors 7 - 10 • Benchmark dose 11 - 13 • Non-threshold, extrapolation 14 - 20 • ALARA 21

  3. http://www.pesticides.gov.uk/uploadedfiles/Web_Assets/PRC/Renwick%20Risk%20Presentation.pdfhttp://www.pesticides.gov.uk/uploadedfiles/Web_Assets/PRC/Renwick%20Risk%20Presentation.pdf

  4. Threshold dose • Dose below which no adverse effects are observable in a population of exposed individuals • Threshold dose approximated by a NOAEL (No Observed Adverse Effect Level)

  5. Non-threshold effects • Thresholds are assumed not to exist for genotoxic carcinogens http://www.iupac.org/publications/cd/essential_toxicology/IUPACTOX4.pdf

  6. Safe dose for threshold effect NOAEL approach • Identify the adverse effect that occurs at the lowest dose • Determine the NOAEL or LOAEL for that endpoint • Divide NOAEL/LOAEL by uncertainty factors

  7. ADI, RfD • ADI (acceptable daily intake): estimated (maximum) amount of an agent, expressed on a body mass basis, to which a subject may be exposed over his lifetime without appreciable health risk (also TDI, tolerable daily intake) • RfD (reference dose): an estimate of the daily exposure that is likely to be without appreciable health effect even if continued exposure occurs over a lifetime (OECD, 2002)

  8. ADI from NOAEL • ADI (or RfD) derived from NOAEL by the use of uncertainty factors UFs (or safety factors SFs) http://www.pesticides.gov.uk/uploadedfiles/Web_Assets/PRC/Renwick%20Risk%20Presentation.pdf

  9. Uncertainty factors • Default values: UFinterspecies = 10 , UFhuman variability = 10 http://www.pesticides.gov.uk/uploadedfiles/Web_Assets/PRC/Renwick%20Risk%20Presentation.pdf

  10. Additional uncertainty factors • Sometimes applied: UFLOAEL-NOAEL = 3 or 10 UFsubchronic-chronic = 3 or 10 UF database insufficiences = up to 10 • MF, modifying factor for professional judgement: up to 10 • RfD = NOAEL (or LOAEL) / UF1 UF2 UF3 MF

  11. Benchmark Dose approach • NOAEL approach uses only single points, shape of dose-response is ignored • Bench mark dose (BMD) is calculated from the curve fitted to the dose-reponse data, so all information is used • BMD can only be used when available data are suitable for modelling • Not replacement for NOAEL, but additional tool

  12. Benchmark Dose in 4 steps 1. 2. 3. 4. http://europe.ilsi.org/file/ilsiadi.pdf

  13. Benchmark Dose, the 4 steps • A mathematical model is applied to the experimental data to produce a dose-response curve of best fit. • By statistical calculation an upper 95% confidence limit of the curve is determined • The Benchmark Response is defined as 10% (or 5%, or 1%). • The Benchmark Dose corresponds to the bench mark response on the upper confidence limit curve.

  14. Non-threshold? Absence of a detectable effect at low doses is either because the dose is below a threshold or because the response is below the level that can be detected by the test sytem. http://europa.eu.int/comm/food/risk/session2_5_en.pdf

  15. Threshold or non-threshold • Presence of a threshold cannot be proven from experimental data. • Conclusions about existence of a threshold are based on biological plausibility and expert judgement. • Genotoxic effects (DNA dammage leading to cancer) are thought to be possible at any level of exposure, so no threshold.

  16. Low-dose extrapolation • Dose-response curve is use to extrapolate to doses lower than then the experimental region.

  17. Calculated risk or safe dose Extrapolation may be used to calculate: • the risk associated with a known intake. • intake associated with a de minimis risk, e.g. an increased life time risk of developing cancer of 1 in 106 (‘virtually safe dose’, VSD).

  18. Linear low-dose extrapolation • Assumption: linear relationship between dose and biological response

  19. Linear extrapolation from LED10 LED10: low confidence limit of dose with response of 10%

  20. From LED10 to VSD • If LED10 = 57 mg/kg/day (response 10% or 0,1) • then VSD (virtual safe dose, response 1 in 106 or 10-6) = 57 x 10-6 / 0,1 = 5,7 x 10-4 mg/kg/day

  21. ALARA-approach • For genotoxic carcinogens (non-threshold effects) also the ALARA-approach may be followed: exposure to be reduced to as low as reasonably achievable (ALARA) or as low as reasonably practical (ALARP)

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