Species-specific uncertainty factors for compounds eliminated principally by renal excretion in humans
Species-specific uncertainty factors for compounds eliminated principally by renal excretion in humans
An uncertainty factor of 100 is used to derive health-based guidance values for human intakes of chemicals based on data from studies in animals. The 100-fold factor comprises 10-fold factors for species differences and for interindividual differences in response. Each 10-fold factor can be subdivided into toxicokinetic and toxicodynamic aspects with a 4.0-fold factor to allow for kinetic differences between test species and humans. The current work determined the extent of interspecies differences in the internal dose (toxicokinetics) of compounds which are eliminated primarily by renal excretion in humans. An analysis of the published data showed that renal excretion was also the main route of elimination in the test species for most of the identified probe substrates. Interspecies differences were apparent for both the mechanism of renal excretion (glomerular filtration, tubular secretion and/or reabsorption) and the extent of plasma protein binding, both of which may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which are eliminated unchanged by both humans and the test species, the average differences in the internal doses between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats and 13 for mice. This suggests that for renal excretion, the differences between humans and the rat and especially the mouse may exceed the 4.0-fold default factor for toxicokinetics.
species differences, toxicokinetics, uncertainty factors, renal excretion, risk assessment
261-274
Walton, K.
024c9ff2-0a40-4fda-a213-db73d9971871
Dorne, J.L.C.M.
bb24d5c7-c4fd-445a-9785-0a03d216fdc2
Renwick, A.G.
596705ab-5418-4e02-9ad7-c4309326df46
2004
Walton, K.
024c9ff2-0a40-4fda-a213-db73d9971871
Dorne, J.L.C.M.
bb24d5c7-c4fd-445a-9785-0a03d216fdc2
Renwick, A.G.
596705ab-5418-4e02-9ad7-c4309326df46
Walton, K., Dorne, J.L.C.M. and Renwick, A.G.
(2004)
Species-specific uncertainty factors for compounds eliminated principally by renal excretion in humans.
Food and Chemical Toxicology, 42 (2), .
(doi:10.1016/j.fct.2003.09.001).
Abstract
An uncertainty factor of 100 is used to derive health-based guidance values for human intakes of chemicals based on data from studies in animals. The 100-fold factor comprises 10-fold factors for species differences and for interindividual differences in response. Each 10-fold factor can be subdivided into toxicokinetic and toxicodynamic aspects with a 4.0-fold factor to allow for kinetic differences between test species and humans. The current work determined the extent of interspecies differences in the internal dose (toxicokinetics) of compounds which are eliminated primarily by renal excretion in humans. An analysis of the published data showed that renal excretion was also the main route of elimination in the test species for most of the identified probe substrates. Interspecies differences were apparent for both the mechanism of renal excretion (glomerular filtration, tubular secretion and/or reabsorption) and the extent of plasma protein binding, both of which may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which are eliminated unchanged by both humans and the test species, the average differences in the internal doses between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats and 13 for mice. This suggests that for renal excretion, the differences between humans and the rat and especially the mouse may exceed the 4.0-fold default factor for toxicokinetics.
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Published date: 2004
Keywords:
species differences, toxicokinetics, uncertainty factors, renal excretion, risk assessment
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Local EPrints ID: 27473
URI: http://eprints.soton.ac.uk/id/eprint/27473
ISSN: 0278-6915
PURE UUID: 8a9f639e-ac05-48bd-aeca-33f15d832317
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Date deposited: 26 Apr 2006
Last modified: 15 Mar 2024 07:18
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Author:
K. Walton
Author:
J.L.C.M. Dorne
Author:
A.G. Renwick
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