Problem formulation in the environmental risk assessment for genetically modified plants.

Problem formulation is the first step in environmental risk assessment (ERA) where policy goals, scope, assessment endpoints, and methodology are distilled to an explicitly stated problem and approach for analysis. The consistency and utility of ERAs for genetically modified (GM) plants can be improved through rigorous problem formulation (PF), producing an analysis plan that describes relevant exposure scenarios and the potential consequences of these scenarios. A properly executed PF assures the relevance of ERA outcomes for decision-making. Adopting a harmonized approach to problem formulation should bring about greater uniformity in the ERA process for GM plants among regulatory regimes globally. This paper is the product of an international expert group convened by the International Life Sciences Institute (ILSI) Research Foundation.

The Key Events Dose-Response Framework: a cross-disciplinary mode-of-action based approach to examining dose-response and thresholds.

The ILSI Research Foundation convened a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categories of bioactive agents-food allergens, nutrients, pathogenic microorganisms, and environmental chemicals. This effort generated a common analytical framework-the Key Events Dose-Response Framework (KEDRF)-for systematically examining key events that occur between the initial dose of a bioactive agent and the effect of concern. Individual key events are considered with regard to factors that influence the dose-response relationship and factors that underlie variability in that relationship. This approach illuminates the connection between the processes occurring at the level of fundamental biology and the outcomes observed at the individual and population levels. Thus, it promotes an evidence-based approach for using mechanistic data to reduce reliance on default assumptions, to quantify variability, and to better characterize biological thresholds. This paper provides an overview of the KEDRF and introduces a series of four companion papers that illustrate initial application of the approach to a range of bioactive agents.

Application of key events analysis to chemical carcinogens and noncarcinogens.

The existence of thresholds for toxicants is a matter of debate in chemical risk assessment and regulation. Current risk assessment methods are based on the assumption that, in the absence of sufficient data, carcinogenesis does not have a threshold, while noncarcinogenic endpoints are assumed to be thresholded. Advances in our fundamental understanding of the events that underlie toxicity are providing opportunities to address these assumptions about thresholds. A key events dose-response analytic framework was used to evaluate three aspects of toxicity. The first section illustrates how a fundamental understanding of the mode of action for the hepatic toxicity and the hepatocarcinogenicity of chloroform in rodents can replace the assumption of low-dose linearity. The second section describes how advances in our understanding of the molecular aspects of carcinogenesis allow us to consider the critical steps in genotoxic carcinogenesis in a key events framework. The third section deals with the case of endocrine disrupters, where the most significant question regarding thresholds is the possible additivity to an endogenous background of hormonal activity. Each of the examples suggests that current assumptions about thresholds can be refined. Understanding inter-individual variability in the events involved in toxicological effects may enable a true population threshold(s) to be identified.

Refining the threshold of toxicological concern (TTC) for risk prioritization of trace chemicals in food.

Due to ever-improving analytical capabilities, very low levels of unexpected chemicals can now be detected in foods. Although these may be toxicologically insignificant, such incidents often garner significant attention. The threshold of toxicological concern (TTC) methodology provides a scientifically defensible, transparent approach for putting low-level exposures in the context of potential risk, as a tool to facilitate prioritization of responses, including potential mitigation. The TTC method supports the establishment of tiered, health-protective exposure limits for chemicals lacking a full toxicity database, based on evaluation of the known toxicity of chemicals which share similar structural characteristics. The approach supports the view that prudent actions towards public health protection are based on evaluation of safety as opposed to detection chemistry. This paper builds on the existing TTC literature and recommends refinements that address two key areas. The first describes the inclusion of genotoxicity data as a way to refine the TTC limit for chemicals that have structural alerts for genotoxicity. The second area addresses duration of exposure. Whereas the existing TTC exposure limits assume a lifetime of exposure, human exposure to unintended chemicals in food is often only for a limited time. Recommendations are made to refine the approach for less-than-lifetime exposures.

Scientific peer review to inform regulatory decision making: leadership responsibilities and cautions.

The article offers insights on the peer-review process as it relates to scientific and technical reports used to inform regulatory decisions. Used effectively, peer review is a powerful tool for advising organizational leaders whether the scientific foundations of their decisions can be expected to withstand scrutiny as rule-making products move through interagency reviews, public comment and stakeholder processes, congressional oversight, and judicial review. The emphasis is "heads up" rather than "how to." That is, without delving into myriad technical and administrative details, the discussion highlights nine fundamental "leadership responsibilities" that determine the nature and course of peer review.

Kinetic and mechanistic data needs for a human phsiologically based pharmacokinetic (PBPK) model for acrylamide: pharmacokinetic model for acrylamide.

A pharmacokinetic (PBPK) model has been developed for acrylamide (AMD) and its oxidative metabolite, glycidamide (GLY), in the rat based on available information. Despite gaps and limitations to the database, model parameters have been estimated to provide a relatively consistent description of the kinetics of acrylamide and glycidamide using a single set of values (with minor adjustments in some cases). Future kinetic and mechanistic studies will need to focus on the collection of key data for refining certain model parameters and for model validation, as well as for conducting studies that elucidate the mechanism of action. Development of a validated human AMD/GLY PBPK model capable of predicting target tissue doses at relevant dietary AMD exposures, in combination with expanding data on modes of action, should allow for a substantive improvement in the risk assessment of acrylamide in food.

Workshop to develop a framework for assessing risks to children from exposure to environmental agents.

Characterization of children's health risks from environmental exposures requires special consideration of life-stage-specific periods of unique susceptibility in relation to childhood activities, behaviors, and intakes. At a workshop in Stowe, Vermont, in mid-summer 2001, 54 experts developed a systematic conceptual framework for assessing the impact of these factors on children's risks. This meeting report provides a brief overview of the workshop.