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Title: Human variability in kinetics for the major metabolic pathways : application to chemical risk assessment
Author: Dorne, Jean Lou Christian Michel
ISNI:       0000 0001 3429 4965
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2001
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This thesis deals with the statistical analysis of human variability in kinetics for the major metabolic pathways (Phase I (CYP isoforms (CYP1A2, CYP2C9, CYP2C19 CYP2D6, CYP2E1, CYP3A4), hydrolysis, Alcohol dehydrogenase). Phase n (N-acetyltransferases, glucuronidation, glycine conjugation, sulphation) and renal excretion) to investigate the appropriateness of the default uncertainty factor (10°^ 3.16) currently in use for the risk assessment of thresholded toxicants and accounting for human variability in kinetics. Probe substrates were selected on the basis that oral absorption was total and that the metabolic route was the primary route of elimination of the compound (60-100% of an oral). Intravenous data were used for compounds for which absorption was variable. Human variability in kinetics was quantified for each compound from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups of the population (effect of ethnicity, age and disease) using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve (AUG)) and acute exposure (Cmax). All parameters were analysed using the assumptions that data were either normally or log normally distributed and that kinetics were linear. Three sets of pathway-related uncertainty factors were calculated using the lognormal variability in kinetics to cover 95^, 97.5^ and 99"^ centile of the general healthy adult population respectively. These pathway-related uncertainty factors were also calculated for subgroups using the magnitude of the difference in internal dose between each subgroup and healthy adults (ratio of geometric means and the subgroup specific variability). Low inter-individual variability (about 21-31%) and pathway-related uncertainty factors (1.6- 2.2, 99*^ centile) were found for all monomorphic pathways with the exception of CYP3A4 metabolism for which variability after oral dosing was 46% (2.8, 99"^ centile). Polymorphic pathways showed that the current kinetic default would not be adequate to cover healthy adult poor metabolisers for CYP2D6 and CYP2C19 metabolism and slow acetylators for N-acetylation and uncertainty factors of 26, 52 and 5.2 would cover these subgroups to the 99* centile respectively. Comparisons between subgroups and healthy adults showed that neonates would be the most susceptible subgroup for compounds handled via CYP1A2, glucuronidation, glycine conjugation and renal excretion. No reliable data were available for polymorphic pathways in neonates. Pathway-related uncertainty factors for interethnic differences were above the 3.16 kinetic default for CYP2C19 and CYP3A4 metabolism. The 3.16 would not be adequate for CYP2D6, CYP2C19, CYP3A4 metabolism, N-acetylation and renal excretion in the elderly and both polymorphic CYP isoforms in children. Since many environmental contaminants are eliminated by several pathways, a preliminary study focusing on multiple pathways for compounds partially metabolised by polymorphic enzymes (propranolol and diazepam) was undertaken to test the validity of a Monte Carlo model to predict varability in kinetics. The variability for the different pathways (CYP1A2, CYP2D6, glucuronidation for propranolol and CYP2C19, CYP3A4 for diazepam) has been combined in the Monte Carlo model and compared to variability in propranolol and diazepam kinetics from individual in vivo studies. Results showed that the Monte Carlo model could be of potential use to predict human varability in kinetics for compounds handled by multiple pathways. However, a full validation of the model including more compounds would be required. Applications of pathway-related uncertainty factors for chemical risk assessment are discussed and a knowledge-based framework to predict human variability in kinetics for thresholded toxicants is proposed to move away from default assumptions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available