Chemical-specific Adjustment Factors Research Articles

The Sixth Annual Meeting on Chemical-Specific Adjustment Factors in Health Risk Assessment

The Sixth Annual Meeting on Chemical-Specific Adjustment Factors in Health Risk Assessment

A National and International Debate on Same Default or Chemical-Specific Adjustment Factors for Precursor and Toxicological Endpoints

A National and International Debate on Same Default or Chemical-Specific Adjustment Factors for Precursor and Toxicological Endpoints

47 Risk characterization

The acceptable daily intake (ADI) of commercially available steviol glycosides is currently 0–4 mg/kg body weight (bw)/day, based on application of a 100-fold uncertainty factor to a no-observed-adverse-effect-level value from a chronic rat study. Within the 100-fold uncertainty factor is a 10-fold uncertainty factor to account for inter-species differences in toxicokinetics (4-fold) and toxicodynamics (2.5-fold). Single dose pharmacokinetics of stevioside were studied in rats (40 and 1000 mg/kg bw) and in male human subjects (40 mg/kg bw) to generate a chemical-specific, inter-species toxicokinetic adjustment factor. Tmax values for steviol were at ∼8 and ∼20 h after administration in rats and humans, respectively. Peak concentrations of steviol were similar in rats and humans, while steviol glucuronide concentrations were significantly higher in humans. Glucuronidation in rats was not saturated over the dose range 40–1000 mg/kg bw. The AUC0-last for steviol was approximately 2.8-fold greater in humans compared to rats. Chemical-specific adjustment factors for extrapolating toxicokinetics from rat to human of 1 and 2.8 were established based on Cmax and AUC0-last data respectively. Because these factors are lower than the default value of 4.0, a higher ADI for steviol glycosides of between 6 and 16 mg/kg bw/d is justified.

An approach for the quantitative consideration of genetic polymorphism data in chemical risk assessment: examples with warfarin and parathion.

In recent years, a great deal of research has been conducted to identify genetic polymorphisms. One focus has been to characterize variability in metabolic enzyme systems that could impact internal doses of pharmaceuticals or environmental pollutants. Methods are needed for using this metabolic information to estimate the resulting variability in tissue doses associated with chemical exposure. We demonstrate here the use of physiologically based pharmacokinetic (PBPK) modeling in combination with Monte Carlo analysis to incorporate information on polymorphisms into the analysis of toxicokinetic variability. Warfarin and parathion were used as case studies to demonstrate this approach. Our results suggest that polymorphisms in the PON1 gene, that give rise to allelic variants of paraoxonase, which is involved in the metabolism of paraoxon (a metabolite of parathion), make only a minor contribution to the overall variability in paraoxon tissue dose, while polymorphisms in the CYP2C9 gene, which gives rise to allelic variants of the major metabolic enzyme for warfarin, account for a significant portion of the overall variability in (S)-warfarin tissue dose. These analyses were used to estimate chemical-specific adjustment factors (CSAFs) for the human variability in toxicokinetics for both parathion and warfarin. Implications of alternatives in the calculation of CSAFs are explored. Key decision points for applying the PBPK-Monte Carlo approach to evaluate toxicokinetic variability for other chemicals are also discussed.

Guidance for Derivation of Chemical-Specific Adjustment Factors (CSAF)—Development and Implementation

This manuscript addresses the content of and considerations in the implementation of guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for inter-species differences and human variability in dose response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector.The guidance for adequacy of data for replacement of defaults for interspecies differences and human variability commonly adopted in the derivation of Tolerable or Acceptable Intakes is presented principally through illustrative reference to case examples. The relevant guidance is addressed in the context of several generic categories, including determination of the active chemical species, choice of the appropriate kinetic parameter or endpoint (dynamic component) and nature of experimental data, the latter, which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples

Guidelines for application of chemical-specific adjustment factors in dose/concentration–response assessment

This manuscript addresses guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for interspecies differences and human variability in dose–response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector. The guidance for adequacy of data for replacement of common defaults for interspecies differences and human variability is presented in the context of several generic categories including: determination of the active chemical species, choice of the appropriate metric (kinetic components) or endpoint (dynamic components) and nature of experimental data, the latter which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples. The principal objective of this guidance developed primarily as a resource for risk assessors, is to foster better understanding of the components of and criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics. It is anticipated that this guidance will also encourage the development of appropriate data and facilitate their incorporation in a consistent fashion in dose–response assessment for regulatory purposes (IPCS, 2001).

The use of surrogate endpoints to assess potential toxicity in humans

Data on toxic effects in humans may come from epidemiology studies, accidental poisonings, surveillance schemes or following intentional exposures. In many cases, a surrogate endpoint related to the adverse effect is investigated. Effects produced following intentional exposures are usually restricted to readily reversible, mild surrogate endpoints of the adverse effect of concern. Not all initial interactions within the target organ are related to the toxic effect, and many measurements are biomarkers of exposure not response. Biomarkers of response represent surrogate endpoints of response only if they are critical to the mode of action. The use of biomarkers and the possible problems with using surrogate endpoints are illustrated with data on aniline, cadmium, carbon monoxide, erythrosine, paracetamol (acetaminophen) and styrene. In vivo surrogate endpoints are normally used in risk assessment directly, whereas in vitro surrogate endpoints can be incorporated by the development of a biologically based dose–response model, or used to replace a default uncertainty factor by a chemical-specific adjustment factor.