Toxicology Letters 180 (2008) 100–109 Contents lists available at ScienceDirect Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet On the incorporation of chemical-specific information in risk assessment Harvey J. Clewell III a,∗ , Melvin E. Andersen a , Bas J. Blaauboer b a The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA b Institute for Risk Assessment Science, University of Utrecht, Utrecht, The Netherlands article info Article history: Available online 8 June 2008 Keywords: Risk assessment Mode of action Physiological modelling Biokinetics PBPK abstract This paper describes the evolution of chemical risk assessment from its early dependence on generic default approaches to the current situation in which mechanistic and biokinetic data are routinely incorporated to support a more chemical-specific approach. Two methodologies that have played an important role in this evolution are described: mode-of-action evaluation and physiologically based biokinetic (PBBK) modelling. When used together, these techniques greatly increase the opportunity for the incorporation of biokinetic and mechanistic data in risk assessment. The resulting risk assess- ment approaches are more appropriately tailored to the specific chemical and are more likely to provide an accurate assessment of the potential hazards associated with human exposures. The appro- priate application of PBBK models in risk assessment demands well-formulated statements about the chemical mode of action. It is this requirement for an explicit, mechanistic hypothesis that gives bio- logically motivated models their power, but at the same time serves as the greatest impediment to the acceptance of a chemical-specific risk assessment approach by regulators. The chief impediment to the regulatory acceptance and application of PBBK models in risk assessment is concern about uncertainties associated with their use. To some extent such concerns can be addressed by the devel- opment of generally accepted approaches for model evaluation and quantitative uncertainty analysis. In order to assure the protection of public health while limiting the economic and social consequences of over-regulation, greater dialogue between researchers and regulators is crucially needed to foster an increased use of emerging scientific information and innovative methods in chemical risk assess- ments. © 2008 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Until quite recently, approaches for quantitative chemical risk assessment relied almost exclusively on default approaches that could be applied across a wide variety of chemicals and effects. These default methods were easy to use because they required lit- tle to no information about the chemical or the manner in which it caused toxicity. However, it was recognized that a number of chemical-specific factors, such as biokinetics 1 and mechanism of toxicity, that could greatly impact the relative risks for different chemicals were ignored by the default approaches. ∗ Corresponding author. Tel.: +1 919 558 1211; fax: +1 919 558 1300. E-mail address: hclewell@thehamner.org (H.J. Clewell III). 1 The time-course of drugs in biological systems has traditionally been referred to as pharmacokinetics. On the other hand, it has become popular to use the term toxicokinetics when dealing with chemicals that are toxic. This, of course, ignores the wisdom of Paracelsus: only the dose differentiates a poison and a remedy. To avoid this false distinction, the term biokinetic will be used in this paper. To compensate for the uncertainty associated with the lack of chemical-specific information, the default approaches made heavy use of health-conservative assumptions and/or safety (uncertainty) factors to assure the protection of public health. The evolution of chemical risk assessment in recent years has been characterized by a steady movement away from these default approaches and toward approaches that attempt to tailor the risk assessment to the chemical being evaluated. This has primarily been accomplished by the incorporation of three types of chemical-specific data: (1) data on the dose–response for the effects of the chemical, (2) data on the mechanism by which the chemical causes toxicity, and (3) data on the uptake, distribution, metabolism and elimination of the chemical. This paper provides an overview of the evolution of risk assess- ment from its early reliance on generic default approaches to the current situation in which mechanistic and biokinetic data are rou- tinely incorporated to support a more chemical-specific approach. Two methodologies that have played an important role in this evolution are described: mode-of-action evaluation and physio- logically based biokinetic (PBBK) modelling. Impediments to the greater acceptance of these methodologies are then discussed, and 0378-4274/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2008.06.002