1,720,982 research outputs found
Towards next generation risk assessment of chemicals: Development and application of physiologically based kinetic models in farm animals
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219236.pdf (Publisher’s version ) (Open Access)Radboud University, 02 juni 2020Promotores : Ragas, A.M.J., Hendriks, A.J. Co-promotor : Dorne, J.L.C.M.126 p
Species-specific uncertainty factors for compounds eliminated principally by renal excretion in humans
No full textAn 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
Polymorphic CYP2C19 and N-acetylation: human variability in kinetics and pathway-related uncertainty factors
No full textCYP2C19-mediated oxidation and N-acetylation constitute major phase I and phase II polymorphic pathways of xenobiotic metabolism in humans. Analysis of human variability in kinetics for these pathways has been carried out for compounds metabolised extensively (>60%) by these routes. Data for minor substrates for CYP2C19 metabolism (10–60%) have also been analysed. Published pharmacokinetic studies (after oral and intravenous dosing) in CYP2C19 non-phenotyped healthy adults (NPs), and phenotyped extensive (EMs), slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration–time curve) and primarily to acute exposure (peak concentration). Similar analyses were performed for the N-acetylation pathway using data for fast acetylators (FA) and slow acetylators (SA). Interindividual variability in the kinetics of CYP2C19 substrates after oral dosage was greater in EMs than in NPs (60 vs 43% for clearances and 54 vs 45% for Cmax). Lower variability was found for N-acetylation for both phenotypes (32 and 22% for FA and SA, respectively). The internal dose of CYP2C19 substrates in PM subjects would be 31-fold higher than in EMs, while for N-acetylated substrates there was a three-fold difference between SA and FA subjects. Pathway-related uncertainty factors were above the default safety factor of 3.16 for most subgroups and values of 52 and 5.2 would be necessary to cover to the 99th centile of the poor metaboliser phenotype for CYP2C19 and N-acetylation, respectively. An exponential relationship (R²=0.86) was found between the extent of CYP2C19 metabolism and the difference in internal dose between EMs and PMs. The kinetic default factor (3.16) would cover PMs for substrates for which CYP2C19 was responsible for up to 20–30% of the metabolism in EMs
Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment
No full textCYP3A4 constitutes the major liver cytochrome P450 isoenzyme and is responsible for the oxidation of more than 50% of all known drugs. Human variability in kinetics for this pathway has been quantified using a database of 15 compounds metabolised extensively (>60%) by this CYP isoform in order to develop CYP3A4-related uncertainty factors for the risk assessment of environmental contaminants handled via this route. Data were analysed from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration–time curve (AUC)] and acute exposure (Cmax). Interindividual variability in kinetics was greater for the oral route (46%, 12 compounds) than for the intravenous route (32%, 14 compounds). The physiological and molecular basis for the difference between these two routes of exposure is discussed. In relation to the uncertainty factors used for risk assessment, the default kinetic factor of 3.16 would be adequate for adults, whereas a CYP3A4-related factor of 12 would be required to cover up to 99% of neonates, which have lower CYP3A4 activity
Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation)
No full textHuman variability in the kinetics of a number of phase I (CYP2A6, CYP2C9, CYP2E1, alcohol dehydrogenase and hydrolysis) and phase II enzymes (glycine and sulphate conjugation) was analysed using probe substrates metabolised extensively (>60%) by these routes. Published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and available data on subgroups of the population (effects of ethnicity, age and disease) were abstracted using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration time-curve (AUC)] and acute exposure (Cmax). Interindividual differences in kinetics for all these pathways were low in healthy adults ranging from 21 to 34%. Pathway-related uncertainty factors to cover the 95th, 97.5th and 99th centiles of healthy adults were derived for each metabolic route and were all below the 3.16 kinetic default uncertainty factor in healthy adults, with the possible exception of CYP2C9*3/*3 poor metabolisers (based on a very limited number of subjects). Previous analyses of other pathways have shown that neonates represent the most susceptible subgroup and this was true also for glycine conjugation for which an uncertainty factor of 29 would be required to cover 99% of this subgroup. Neonatal data were not available for any other pathway analysed.Abbreviations: CYP Cytochrome P450, AUC Area under the plasma-concentration-time-curve, Cmax Maximum plasma concentratio
Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?
No full textHuman variability in the kinetics of CYP2D6 substrates has been quantified using a database of compounds metabolised extensively (>60%) by this polymorphic enzyme. Published pharmacokinetic studies (after oral and intravenous dosing) in non-phenotyped healthy adults, and phenotyped extensive (EMs), intermediate or slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve) and primarily to acute exposure (peak concentration). Similar analyses were performed with the available data for subgroups of the population (age, ethnicity and disease). Interindividual differences in kinetics for markers of oral exposure were large for non-phenotyped individuals and for EMs (coefficients of variation were 67–71% for clearances and 54–63% for Cmax), whereas the intravenous data indicated a lower variability (34–38%). Comparisons between EMs, SEMs and PMs revealed an increase in oral internal dose for SEMs and PMs (ratio compared to EMs=3 and 9–12, respectively) associated with lower variability than that for non-phenotyped individuals (coefficients of variation were 32–38% and 30% for SEMs and PMs, respectively). In relation to the uncertainty factors used for risk assessment, most subgroups would not be covered by the kinetic default of 3.16. CYP2D6-related factors necessary to cover 95–99% of each subpopulation ranged from 2.7 to 4.1 in non-phenotyped healthy adults and EMs to 15–18 in PMs and 22–45 in children. An exponential relationship (R2=0.8) was found between the extent of CYP2D6 metabolism and the uncertainty factors. The extent of CYP2D6 involvement in the metabolism of a substrate is critical in the estimation of the CYP2D6-related factor. The 3.16 kinetic default factor would cover PMs for substrates for which CYP2D6 was responsible for up to 25% of the metabolism in EMs. <br/
The refinement of uncertainty/safety factors in risk assessment by the incorporation of data on toxicokinetic variability in humans
No full textThe derivation of safe levels of exposure in humans for compounds that are assumed to cause threshold toxicity has relied on the application of a 100-fold uncertainty factor to a measure for the threshold, such as the no observed adverse effect level (NOAEL) or the benchmark dose (BMD). This 100-fold safety factor consists of the product of two 10-fold factors allowing for human variability and interspecies differences. The International Programme on Chemical Safety has suggested the subdivision of these 10-fold factors to allow for variability in toxicokinetics and toxicodynamics. This subdivision allows the replacement of the default uncertainty factors with a chemical-specific adjustment factor (CSAF) when suitable data are available. This short review describes potential options to refine safety factors used in risk assessment, with particular emphasis on pathway-related uncertainty factors associated with variability in kinetics. These pathway-related factors were derived from a database that quantified interspecies differences and human variability in phase I metabolism, phase II metabolism, and renal excretion. This approach allows metabolism and pharmacokinetic data in healthy adults and subgroups of the population to be incorporated in the risk-assessment process and constitutes an intermediate approach between simple default factors and chemical-specific adjustment factors
Trends in human risk assessment of pharmaceuticals
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36639.pdf (Publisher’s version ) (Open Access
Report on the harmonisation of analytical frameworks for meta-analysis of human and ecological toxicity data
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