An analysis of the need for an additional toxicokinetic uncertainity factor for neonates
An analysis of the need for an additional toxicokinetic uncertainity factor for neonates
The current risk assessment process for chemicals in food involves the use of a default safety factor to account for inter and intraspecies variability when converting data from an animal study into a safe value for human exposure. The proposal that an additional factor should by applied for determining acceptable exposures applicable to infants and children under the Food Quality Protection Act (1996), in the USA, implies that the early stages of human development may not be adequately protected by the current default factors.
The objective of this study was to determine the interspecies and age-related differences in the toxicokinetics of particular compounds for rats and humans, in order to evaluate the necessity of an additional safety factor as proposed in the USA.
Toxicokinetic profiles were determined in young (10-day old) and adult rats for 5 probe substrates representing major elimination pathways in humans. Animals received a single dose of caffeine or theophylline (to represent CYP1A2), midazolam (to represent CYP3A4), chloramphenicol (to represent glucuronidation), or amoxycillin (to represent renal clearance). Plasma was analysed using validated high performance liquid chromatography (HPLC) methods, and pharmacokinetic parameters calculated using WinNonlin, v1.5. Clearance (ml/min/kg) values in rats were compared to age-equivalent published data in human neonates, infants, children and adults. The interspecies comparison of clearance for infants, children and adults indicated that the magnitude of difference was similar to, or was less than the current default factor. However, clearance was more efficient in young rats compared to human neonates and the default factor. However, clearance was more efficient in young rats compared to human neonates and the default safety factor was exceeded slightly. These data indicate that a small additional safety factor is warranted for neonates; however, the additional safety factor of 10 proposed under the Food Quality Protection Act (1996), in the USA would be excessive for this age group and an extra factor would be unwarranted based on kinetic data for other age groups.
University of Southampton
2004
Corea, Namali V
(2004)
An analysis of the need for an additional toxicokinetic uncertainity factor for neonates.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
The current risk assessment process for chemicals in food involves the use of a default safety factor to account for inter and intraspecies variability when converting data from an animal study into a safe value for human exposure. The proposal that an additional factor should by applied for determining acceptable exposures applicable to infants and children under the Food Quality Protection Act (1996), in the USA, implies that the early stages of human development may not be adequately protected by the current default factors.
The objective of this study was to determine the interspecies and age-related differences in the toxicokinetics of particular compounds for rats and humans, in order to evaluate the necessity of an additional safety factor as proposed in the USA.
Toxicokinetic profiles were determined in young (10-day old) and adult rats for 5 probe substrates representing major elimination pathways in humans. Animals received a single dose of caffeine or theophylline (to represent CYP1A2), midazolam (to represent CYP3A4), chloramphenicol (to represent glucuronidation), or amoxycillin (to represent renal clearance). Plasma was analysed using validated high performance liquid chromatography (HPLC) methods, and pharmacokinetic parameters calculated using WinNonlin, v1.5. Clearance (ml/min/kg) values in rats were compared to age-equivalent published data in human neonates, infants, children and adults. The interspecies comparison of clearance for infants, children and adults indicated that the magnitude of difference was similar to, or was less than the current default factor. However, clearance was more efficient in young rats compared to human neonates and the default factor. However, clearance was more efficient in young rats compared to human neonates and the default safety factor was exceeded slightly. These data indicate that a small additional safety factor is warranted for neonates; however, the additional safety factor of 10 proposed under the Food Quality Protection Act (1996), in the USA would be excessive for this age group and an extra factor would be unwarranted based on kinetic data for other age groups.
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Published date: 2004
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Local EPrints ID: 465496
URI: http://eprints.soton.ac.uk/id/eprint/465496
PURE UUID: ea8a8516-de6d-414d-8fe7-9e2f953be5fd
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Date deposited: 05 Jul 2022 01:26
Last modified: 05 Jul 2022 01:26
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Author:
Namali V Corea
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