Protection of the general population and susceptible subpopulations from bioactive agents that may pose health risks is a primary public health challenge. The agents of potential concern include food allergens, pathogens, environmental chemicals (i.e., chemicals introduced into the environment via industrial processes, consumer products, etc.), and high intakes of certain nutrients. For each of the many potential exposure scenarios—chemical contaminants in consumer products, pathogens in water, allergens in food, nutrients in dietary supplements, etc.—public health authorities must make judgments regarding “safe levels” (i.e., levels of exposure or intake where risk is considered negligible).
Ideally, determinations regarding safe levels are informed by a thorough knowledge of the dose-response relationship for the agent and population of concern. In practice, however, decisions must often be made without complete information, requiring the use of extrapolation and assumptions. Also, each type of bioactive agent has its own particular challenges in assessing dose-response. In the case of pathogenic microorganisms, for example, the bioactive agent may multiply after intake, substantially increasing the dose. With essential nutrients, adverse effects may potentially result from deficient intake as well as excess intake. With food allergens, both the nature and the severity of the response to a given dose vary considerably even within the susceptible subpopulation. In general, discipline-specific approaches for identifying safe levels have evolved. However, the disciplines share some fundamental challenges regarding dose-response assessment, and there is a common need to advance methodology and to harmonize approaches to the extent possible.
To address this need, the International Life Sciences Institute Research Foundation (ILSI RF) convened a working group with experts from a range of disciplines, including cancer risk assessment, microbial risk assessment, food allergies, nutrition, and dose-response modeling. Working group participants are listed in .
ILSI RF Threshold Working Group
The members of the group were asked to consider two main questions:
- How can we make better use of current data and methods to advance understanding of dose-response relationships, especially with regard to dose levels relevant to public health?
- How can we make practical use of an improved understanding of dose-response for assessing risk, developing regulatory standards, designing nutrition programs, etc.?
Initial discussions by the group considered a range of agent-endpoint combinations (e.g., chloroform and liver carcinogenicity, Listeria monocytogenes
and fetal death), focusing on what is known about the fundamental biology. The cross-disciplinary approach promoted a fresh look at long-held assumptions and traditional approaches to assessing dose-response. In these initial discussions it became clear, however, that the term “threshold” is commonly used to refer to several diverse concepts. Thus, definitions were adopted for terms used in this effort, in particular, the biological threshold and the population threshold. These are discussed in the Appendix
Despite the wide range of agents considered, the group came to develop and adopt a common analytical framework that is based on mode-of-action concepts. This paper describes this analytical approach, referred to as the “Key Events Dose-Response Framework,” and provides a summary of the general findings and conclusions from this effort.