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

Abstract

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).

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

“…For human variability, kinetic parameters and PBPK/ PD modeling for a range of toxicological or therapeutic responses to pharmaceutical agents (Renwick 1991(Renwick , 1993Renwick & Lazarus 1998) were the basis of the kinetic and dynamic splits. The subfactors have been adopted by various national and international organizations, such as WHO/IPCS (2005), the European Food Safety Authority (EFSA 2006), and Health Canada (Meek et al 1999(Meek et al , 2002. US EPA also adopted a subfactor approach for quantitative valuation of TK and TD during derivation of inhalation RfC (US EPA 1994) and oral RfD (US EPA 2011).…”

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

“…Since the ADI for steviol glycosides is based on a chronic dietary study, as opposed to an acute effect, the use of AUC as a surrogate of exposure in relation to toxicity may be preferable to Cmax (Renwick and Lazarus, 1998;Meek et al, 2002). The AUC from time 0 to infinity (AUC0-∞) for steviol could not be calculated for all datasets within the 40 mg/kg rat study because concentrations of steviol were below the limit of detection after 24 h. In the human study concentrations of steviol were below the limit of detection by 72 h (the last sampling point) in all but one subject (Table 5).…”

Legionnaires' disease: evaluation of a quantitative microbial risk assessment model

“…These exposure assessments on the same workers and factories then led to differing epidemiologic analyses and subsequently differing risk assessments (Paustenbach et al Quantitative chemical risk assessments often utilize uncertainty factors, such as a factor of up to 10 for sensitivity differences in interspecies extrapolation and another factor of up to 10 for residual scientific uncertainty (Lewis et al 1990;Dourson et al 1996;Renwick & Lazarus 1998;Meek et al 2002). These factors seemingly indicate that the overall validity may be no closer than within a factor of 10 to 100 of the actual risk.…”