Human variability in the renal elimination of foreign compounds and renal excretion-related uncertainty factors for risk assessment

Dorne, Jean‐Lou; Walton, K; Renwick, A.G.

doi:10.1016/j.fct.2003.09.002

Cited by 44 publications

(19 citation statements)

References 170 publications

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“…Inter‐individual differences in the elderly (healthy adults >70 years of age) were similar to those observed in healthy adults with the general trend that monomorphic pathways showed less variability than polymorphic pathways [27–33]. However, CYP3A4 activity (constituting half of the total cytochrome P450 content in the human liver [75,76]) and renal excretion in the elderly were 1.8‐ and 2‐fold lower than that in healthy adults ( n = 163 and 105, respectively) [30,32]. These results are in agreement with previous conclusions that both the liver and the renal function are reduced in old age with a more pronounced reduction in the renal function [77,78] and these alterations are closely associated with changes in liver blood flow, drug binding, distribution and excretion [79].…”

Section: The Elderlysupporting

confidence: 88%

“…This default uncertainty factor comprises the product of two 10-fold factors which allow for interspecies differences and human variability [1,17]. A number of analyses have been performed in recent years to investigate the scientific basis of the 100-fold uncertainty factor which had not been clearly defined when it was first introduced [9,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Renwick [21] suggested a subdivision of the interspecies and the human variability uncertainty factors to allow for toxicokinetic (·4) and toxicodynamic (·2.5) differences so that chemical-specific data (toxicokinetic or toxicodynamic data) could replace the defaultuncertainty factors with a data-derived factor [21], renamed recently as a chemical-specific adjustment factor (CSAF) [35].…”

Section: H I S T O R Y O F U N C E R T a I N T Y F A C T O R S U S E mentioning

confidence: 99%

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Impact of inter‐individual differences in drug metabolism and pharmacokinetics on safety evaluation

Dorne

2004

Fundamemntal Clinical Pharma

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Safety evaluation aims to assess the dose-response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is 'without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 10(0.5) (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment.

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Section: The Elderlysupporting

confidence: 88%

Section: H I S T O R Y O F U N C E R T a I N T Y F A C T O R S U S E mentioning

confidence: 99%

Impact of inter‐individual differences in drug metabolism and pharmacokinetics on safety evaluation

Dorne

2004

Fundamemntal Clinical Pharma

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“…homozygous EMs (Dorne et al, 2004b). Based on limited data (n < 15), the default factor (3.16) would not appear to adequately protect individuals carrying the *3/*3 alleles and a CYP2C9-related uncertainty factor of 6.5 would be necessary to cover 99% of this subgroup.…”

Section: Polymorphic Pathways In Healthy Adultsmentioning

confidence: 96%

Human variability in hepatic and renal elimination: implications for risk assessment

Dorne¹

2007

J of Applied Toxicology

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Hepatic metabolism and renal excretion constitute the main routes of xenobiotic elimination in humans. Improving human risk assessment for threshold contaminants requires the incorporation of quantitative data related to their elimination (toxicokinetics) and potential toxic effects (toxicodynamics). This type of data provides a scientific basis to replace the standard uncertainty factor (UF = 10) allowing for the consideration of human variability in toxicokinetics and toxicodynamics. This review focuses on recent research efforts aiming to incorporate human variability in hepatic and renal elimination (toxicokinetics) into the risk assessment process. A therapeutic drug database was developed to quantify pathway-related variability in human phase I and phase II hepatic metabolism as well as renal excretion in subgroups of the population (healthy adults, neonates and the elderly), using data on compounds cleared primarily through each route (> 60% dose). For each subgroup of the population and elimination route, pathway-related UFs were then derived to cover 95-99% of each subgroup. Overall, the default toxicokinetic UFs would not cover neonates, the elderly for most elimination routes and any subgroup of the population for compounds metabolized via polymorphic isozymes (such as CYP2C19 and CYP2D6). These pathway-related UFs allow the incorporation of in vivo metabolism and toxicokinetic data in the risk assessment process and provide a flexible intermediate option between the default UF and chemical-specific adjustment factors (CSAFs) derived from physiologically based pharmacokinetic models. Implications of human variability in hepatic metabolism and renal excretion for chemical risk assessment are discussed.

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“…() as well as Dorne and colleagues investigated a therapeutic drug database with regard to population distributions of pharmacokinetic parameters and corresponding kinetic variability factors for oral and intravenous exposures to pathway‐specific probe substrates (Dorne, ; Dorne and Renwick, ; Dorne et al ., ). Precisely, clearance pathways extensively investigated include those related to glucuronidation (Dorne et al ., ), renal function (Dorne et al ., ) or hepatic metabolism by CYP [i.e., CYP1A2 (Dorne et al ., ), CYP2C19 (Dorne et al ., ), CYP2D6 (Dorne et al ., ), and CYP3A4 (Dorne et al ., )]. Ratios of upper percentile values of relevant pharmacokinetic parameters in sensitive subpopulations relative to the central tendency in adults were reported for a variety of drugs (Table ), but these do not necessarily reflect the pathway‐related interindividual differences during lifetime exposure to environmental contaminants.…”

Section: Impact Of the Physico/biochemical Characteristics Of Xenobiomentioning

confidence: 99%

Characterization of the human kinetic adjustment factor for the health risk assessment of environmental contaminants

Valcke

Krishnan

2013

J of Applied Toxicology

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A default uncertainty factor of 3.16 (√10) is applied to account for interindividual variability in toxicokinetics when performing non-cancer risk assessments. Using relevant human data for specific chemicals, as WHO/IPCS suggests, it is possible to evaluate, and replace when appropriate, this default factor by quantifying chemical-specific adjustment factors for interindividual variability in toxicokinetics (also referred to as the human kinetic adjustment factor, HKAF). The HKAF has been determined based on the distributions of pharmacokinetic parameters (e.g., half-life, area under the curve, maximum blood concentration) in relevant populations. This article focuses on the current state of knowledge of the use of physiologically based algorithms and models in characterizing the HKAF for environmental contaminants. The recent modeling efforts on the computation of HKAF as a function of the characteristics of the population, chemical and its mode of action (dose metrics), as well as exposure scenario of relevance to the assessment are reviewed here. The results of these studies, taken together, suggest the HKAF varies as a function of the sensitive subpopulation and dose metrics of interest, exposure conditions considered (route, duration, and intensity), metabolic pathways involved and theoretical model underlying its computation. The HKAF seldom exceeded the default value of 3.16, except in very young children (i.e., <≈ 3 months) and when the parent compound is the toxic moiety. Overall, from a public health perspective, the current state of knowledge generally suggest that the default uncertainty factor is sufficient to account for human variability in non-cancer risk assessments of environmental contaminants.

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Human variability in the renal elimination of foreign compounds and renal excretion-related uncertainty factors for risk assessment

Cited by 44 publications

References 170 publications

Impact of inter‐individual differences in drug metabolism and pharmacokinetics on safety evaluation

Impact of inter‐individual differences in drug metabolism and pharmacokinetics on safety evaluation

Human variability in hepatic and renal elimination: implications for risk assessment

Characterization of the human kinetic adjustment factor for the health risk assessment of environmental contaminants

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