Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

Bhat, Virunya S.; Meek, M.E.; Valcke, Mathieu; English, Caroline; Boobis, Alan R.; Brown, Richard J.

doi:10.1080/10408444.2017.1303818

Cited by 63 publications

(43 citation statements)

References 50 publications

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“…This large variation in CYP 3A activity may result in marked variations in the metabolic profile of PAs and thus different susceptibilities towards pyrrolizidine alkaloid intoxication (Fu et al 2004). Therefore, human inter-individual and inter-ethnic (Chinese and Caucasian) variation upon PA metabolism may be higher than the default uncertainty factor of 3.16 for interindividual human kinetic differences (IPCS 2005;Bhat et al 2017) that is used to derive health-based guidance values for the risk assessment of compounds with non-genotoxic critical effects, indicating the need for a chemical specific adjustment factor (CSAF) (Bhat et al 2017). For risk assessment of compounds that are both genotoxic and carcinogenic, the default uncertainty factor of 3.16 for inter-individual human kinetic differences is part of the cut-off value of 10,000 for evaluating the margin of exposure (MOE) (EFSA 2005(EFSA , 2012(EFSA , 2015.…”

Section: Introductionmentioning

confidence: 99%

Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine

2019

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The aim of the present study was to predict the effect of inter-individual and inter-ethnic human kinetic variation on the sensitivity towards acute liver toxicity of lasiocarpine in the Chinese and the Caucasian population, and to derive chemical specific adjustment factors (CSAFs) by integrating variation in the in vitro kinetic constants Vmax and Km, physiologically based kinetic (PBK) modelling and Monte Carlo simulation. CSAFs were derived covering the 90th and 99th percentile of the population distribution of pyrrole glutathione adduct (7-GS-DHP) formation, reflecting bioactivation. The results revealed that in the Chinese population, as compared to the Caucasian population, the predicted 7-GS-DHP formation at the geometric mean, the 90th and the 99th percentile were 2.1-, 3.3- and 4.3-fold lower respectively. The CSAFs obtained using the 99th percentile values were 8.3, 17.0 and 19.5 in the Chinese, the Caucasian population and the two populations combined, respectively, while the CSAFs were generally 3.0-fold lower at the 90th percentile. These results indicate that when considering the formation of 7-GS-DHP the Caucasian population may be more sensitive towards acute liver toxicity of lasiocarpine, and further point out that the default safety factor of 3.16 for inter-individual human kinetic differences may not be sufficiently protective. Altogether, the results obtained demonstrate that integrating PBK modelling with Monte Carlo simulations using human in vitro data is a powerful strategy to quantify inter-individual variations in kinetics, and can be used to refine the human risk assessment of pyrrolizidine alkaloids.

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Section: Introductionmentioning

confidence: 99%

Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine

2019

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“…Chemical-specific in vitro hepatic metabolic clearance data can also be used to refine the extrapolation of toxicological results from animals to humans (Lipscomb et al, 2004). For example, when extrapolating from rat to human, understanding the qualitative and quantitative differences in clearance between species provides the basis for the derivation of chemical-specific adjustment factors as an informed alternative to using the usual default factor of 4 (the kinetics contribution to the value of 10 used for interspecies variability) (Dorne and Renwick, 2005;Bhat et al 2017). Clearance data can also be incorporated into Physiologically Based Kinetic (PBK) models to perform In Vitro In Vivo Extrapolation (IVIVE) to support risk assessment using non-animal in vitro approaches (Bessems et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Gouliarmou¹,

Lostia²,

Coecke³

et al. 2018

Toxicology in Vitro

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Hepatic metabolic clearance is one of the most important factors driving the overall kinetics of chemicals including substances used in various product categories such as pesticides, biocides, pharmaceuticals, and cosmetics. A large number of in vitro systems from purified isozymes and subcellular organelles to hepatocytes in simple cultures and in complex scaffold setups are available for measuring hepatic metabolic clearance for different applications. However, there is currently no approach for systematically characterising and comparing these in vitro methods in terms of their design, applicability and performance. To address this, existing knowledge in the field of in vitro human hepatic metabolic clearance methods was gathered and analysed in order to establish a framework to systematically characterise methods based on a set of relevant components. An analogous framework would be also applicable for non-human in vitro systems. The components are associated with the biological test systems used (e.g. subcellular or cells), the in vitro method (e.g. number of cells, test item solubility), related analytical techniques, data interpretation methods (based on substrate depletion/metabolite formation), and performance assessments (precision and accuracy of clearance measurements). To facilitate the regulatory acceptance of this class of methods, it is intended that the framework provide the basis of harmonisation work within the OECD.

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“…A WHO chemical risk assessment network is in place to enhance global efforts to assess the risk to human health from exposure to chemicals by developing tools and guidance documents. A participant reported in our survey that the Chemical-specific Adjustment Factor (CSAF) working group, as part of the WHO Chemical Risk Assessment Network, released a manuscript that discusses recent challenges and experiences in gaining regulatory acceptance of chemical-specific adjustment factors and PBK models ( Bhat et al., 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications

Paini

Leonard

Kliment³

et al. 2017

Regulatory Toxicology and Pharmacology

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Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration. Despite significant advancements in good modelling practice (GMP) for model development and evaluation, there remains some reluctance among regulatory agencies to use such models during the risk assessment process. Here, the results of a survey disseminated to the modelling community are presented in order to inform the frequency of use and applications of PBK models in science and regulatory submission. Additionally, the survey was designed to identify a network of investigators involved in PBK modelling and knowledgeable of GMP so that they might be contacted in the future for peer review of PBK models, especially in regards to vetting the models to such a degree as to gain a greater acceptance for regulatory purposes.

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Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

Cited by 63 publications

References 50 publications

Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine

Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications

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