An investigation into the adequacy of the default kinetic uncertainty (safety) factors used in the risk assessment of food additives
An investigation into the adequacy of the default kinetic uncertainty (safety) factors used in the risk assessment of food additives
Four food additives were chosen as test chemicals, butylated hydroxytoluene (BHT), curcumin, propyl gallate (PG) and thiabendazole (TBZ). Separate studies were conducted in which human volunteers received the food additive at the acceptable daily intake (ADI) or 10 x ADI, and studies in which the animal was dosed at the no-observed adverse effect level (NOAEL) or 0.1 x NOAEL. Plasma samples from these subjects were analysed for the additive and used to construct concentration-time curves; where appropriate a mathematical model was used to extrapolate parameters to infinity.
The results of the studies show that the default factor of 3.16-fold for human variability is adequate for greater than 92% of the population for all test chemicals based on all PK parameters derived from the ADI studies. The inter-species default of 4.0-fold was adequate for all 4 test chemicals (comparing ADI and NOAEL data after correction for dose) based on oral clearance, and for PG and TBZ only based on Cmax. Interestingly, there was evidence of saturation kinetics in both humans and animals with TBZ. Oral clearance was ~9-fold and ~13-fold lower dose for humans and animals respectively.
In conclusion these results support the current regulatory framework and the usual default uncertainty factor. However the data suggest that the dose used in the generation of pharmacokinetic data for deriving chemical-specific adjustment factors, for substitution in the framework, will need to be carefully considered. The dose-response will need to be carefully characterised of the species of interest, and the doses administered should reflect the likely human exposure, so that the correct adjustment factor and therefore a more accurate ADI can be derived.
University of Southampton
Tullberg, Sara C
e9fe4552-0db5-4e21-8814-1b48a9963cf1
2004
Tullberg, Sara C
e9fe4552-0db5-4e21-8814-1b48a9963cf1
Tullberg, Sara C
(2004)
An investigation into the adequacy of the default kinetic uncertainty (safety) factors used in the risk assessment of food additives.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Four food additives were chosen as test chemicals, butylated hydroxytoluene (BHT), curcumin, propyl gallate (PG) and thiabendazole (TBZ). Separate studies were conducted in which human volunteers received the food additive at the acceptable daily intake (ADI) or 10 x ADI, and studies in which the animal was dosed at the no-observed adverse effect level (NOAEL) or 0.1 x NOAEL. Plasma samples from these subjects were analysed for the additive and used to construct concentration-time curves; where appropriate a mathematical model was used to extrapolate parameters to infinity.
The results of the studies show that the default factor of 3.16-fold for human variability is adequate for greater than 92% of the population for all test chemicals based on all PK parameters derived from the ADI studies. The inter-species default of 4.0-fold was adequate for all 4 test chemicals (comparing ADI and NOAEL data after correction for dose) based on oral clearance, and for PG and TBZ only based on Cmax. Interestingly, there was evidence of saturation kinetics in both humans and animals with TBZ. Oral clearance was ~9-fold and ~13-fold lower dose for humans and animals respectively.
In conclusion these results support the current regulatory framework and the usual default uncertainty factor. However the data suggest that the dose used in the generation of pharmacokinetic data for deriving chemical-specific adjustment factors, for substitution in the framework, will need to be carefully considered. The dose-response will need to be carefully characterised of the species of interest, and the doses administered should reflect the likely human exposure, so that the correct adjustment factor and therefore a more accurate ADI can be derived.
Text
968301.pdf
- Version of Record
More information
Published date: 2004
Identifiers
Local EPrints ID: 465530
URI: http://eprints.soton.ac.uk/id/eprint/465530
PURE UUID: 6e23471a-25d8-4a90-8ccb-b088bc5b2392
Catalogue record
Date deposited: 05 Jul 2022 01:38
Last modified: 16 Mar 2024 20:14
Export record
Contributors
Author:
Sara C Tullberg
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics