Academic journal article Environmental Health Perspectives

Comparison of Points of Departure for Health Risk Assessment Based on High-Throughput Screening Data

Academic journal article Environmental Health Perspectives

Comparison of Points of Departure for Health Risk Assessment Based on High-Throughput Screening Data

Article excerpt

Introduction

The establishment of health-based guidance values is a key outcome of assessing the risk of chemical agents. The determination of such values includes the derivation of a point of departure (POD) from dose-response modeling or, more traditionally, use of the no-observed-adverse-effect-level (NOAEL). Dose-response modeling approaches, specifically the benchmark dose (BMD) method, are generally regarded by many international health organizations as the method of choice for derivation of the POD [Davis et al. 2011; European Food Safety Authority (EFSA) 2009].

For nongenotoxic agents, uncertainty factors accounting for inter- and intra-species differences are applied to the POD derived from the critical effect observed in animals or humans (Dourson et al. 1996). This results in a health-based guidance value, such as a tolerable daily intake (TDI), an acceptable daily intake (ADI), a reference dose (RfD), or a reference concentration (RfC). Although the exact formulation of the TDI/ADI [World Health Organization/International Programme on Chemical Safety (WHO/ IPCS) 2004] differs to some extent from that for the RfD/RfC, these quantities are derived in essentially the same manner and can thus be interpreted similarly. The TDI/ADI/RfD is generally set for dietary exposure, whereas the RfC is generally set for occupational exposures occurring via inhalation; an extensive discussion of occupational exposure limits can be found in Deveau et al. (2015).

In the case of a genotoxic agent, the U.S. EPA risk-assessment guidelines recommend low-dose linear extrapolation when a) there are data to indicate that the dose-response curve has a linear component below the POD, or b) as a default for a tumor site where the mode of action is not established (U.S. EPA 2005). Linear extrapolation to low doses permits upper-bound estimates of risk at exposure levels of interest as well as estimation of "risk-specific doses" associated with specific (upper-bound) risk levels; the typical U.S. EPA target range for risk management is a 1/1,000,000 to 1/10,000 increased lifetime risk (U.S. EPA 2005). In contrast, both the European Food Safety Authority (EFSA) and the Joint FAO (Food and Agriculture Organization of the United Nations)/WHO Expert Committee on Food Additives (JECFA) have recommended a margin of exposure (MOE) approach rather than low-dose linear extrapolation for evaluating compounds that are both genotoxic and carcinogenic. EFSA and the JECFA considered that the MOE had the potential to help risk managers to distinguish between large, intermediate, and low health concerns, and thus to provide guidance for setting priorities for risk management actions (Barlow et al. 2006). The MOE is also cited in the U.S. EPA guidelines but is positioned as a quantity that provides an indication of the extent of extrapolation of risk estimates from the observed data to the exposure levels of interest in practice (U.S. EPA 2005).

Traditional approaches to risk assessment, including the establishment of health-based guidance values based on the results of mammalian toxicology tests, have been challenged by the U.S. National Research Council (NRC) in its report, Toxicity Testing in the 21st Century: A Vision and a Strategy (NRC 2007). This report envisions that future toxicity tests will be conducted largely in human cells or cell lines in vitro by evaluating cellular responses in a suite of toxicity pathway assays using high-throughput tests. Risk assessments would be performed based on the results of such tests, and the equivalents of today's health-based guidance values would aim, according to the NRC, at representing dose levels that avoid significant perturbations of the toxicity pathways in exposed human populations. In vitro to in vivo extrapolations would rely on pharmacokinetic models to predict human blood and tissue concentrations under specific exposure conditions (Andersen and Krewski 2009; Krewski et al. …

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