Background
As advancing analytical technology leads to the detection of trace quantities of an expanding universe of substances in commercial products and the environment, there are increasing demands on many industries and regulatory authorities to address the risks from these potential exposures. But exposure alone is not equivalent to risk; the dose-response relationship is key. But how should the dose-response relationship be studied at the very low doses that are relevant to everyday exposure? Is it possible to identify “thresholds”- or levels of exposure so low that risk is negligible?
The concept of a threshold for adverse effects is fundamental in regulatory toxicology, underlying basic values such as ADIs, TDIs, RfDs, and others, but recent reports have suggested replacing these values with quantitative estimates of risk generated by extrapolation from animal studies (with a linear extrapolation model as the default). The often-unstated premise is that there is some flaw in the science underlying the threshold concept. Further, it is assumed that accurate quantitative estimates of risk can, in fact, be made in this way; the experience of the scientific/regulatory community with estimation of cancer risks using extrapolation models indicates otherwise.
ILSI Research Foundation Action
To address these issues, the ILSI Research Foundation’s Global Threshold Project convened an expert working group charged with analyzing the fundamental biological processes underlying human health effects from four broad categories of agents: chemicals, microbial pathogens, allergens, and nutrients. Out of this discussion has come the Key Events Dose-response Framework, a cross-disciplinary mode-of-action based analytical approach that systematically examines key (and necessary) biological and chemical events along the pathway between exposure/intake and the ultimate effect of concern.
Over the past several months, the working group has applied the Framework to each category of agent, demonstrated that a cascade of key events can be identified (or postulated) in each case, and characterized the factors influencing the dose-response (and possible existence of thresholds) for individual events and the overall pathway. The Framework offers a powerful tool for examining the underlying basis for dose-response relationships and applying that knowledge in safety assessment and standard-setting.
Outcomes
A series of five papers were published in the September issue of Critical Reviews in Food Science and Nutrition that describes a Key Events Dose-Response Framework for chemical, microbial pathogens, allergens, and nutrients. Based on the Mode of Action Framework, this new work provides an evidence-based approach for using our growing understanding of fundamental biology and mechanistic data to reduce reliance on default assumptions, to quantify variability, and to better characterize biological thresholds. These papers are available below.
Next Steps
The next critical step is to build additional case studies to support the Key Events Framework, thus documenting its validity as a risk assessment tool. The Key Events Framework, the broader Mode of Action paradigm together with the Threshold of Toxicological Concern, a regulatory approach designed to focus attention on exposures that are most likely to cause public health concern, offer a strong rebuttal to the precautionary approach being advocated by some. The practical outcome will be to focus regulatory attention on those agents that are likely to have true public health impact, rather than scattering scarce resources across a wide array of agents many of which present a negligible risk. The potential savings for governments and industry worldwide from such a new direction are enormous.
The ILSI Research Foundation’s Phase 2 plan for the Key Events Framework includes completing 5-7 case studies in 2010 and to highlight these at multisectoral workshops and professional society meetings around the world. Given limited staff at the Research Foundation, resources will be used to foster collaboration with experts from academia and government, as well as expert consultants, to aggressively achieve this goal.
Without these efforts, the Research Foundation believes risk managers may be forced to chase after ever diminishingly smaller quantities of contaminants for no real public health benefit. Please contact Steve Olin (solin@ilsi.org) if you are interested in supporting the Foundation’s work to deliver a scientifically compelling solution that will leverage scares resources to protect public health.
Article Series in Critical Reviews in Food Science and Nutrition
Editor's Commentary
The Key Events Dose-Response Framework: A Cross-Disciplinary Mode-of-Action Based Approach to Examining Dose-Response and Thresholds (Overview)
Application of Key Events Analysis to Chemical Carcinogens and Noncarcinogens
Application of a Key Events Dose-Response Analysis to Nutrients: A Case Study with Vitamin A (Retinol)
The Key Events Dose-Response Framework: Its Potential for Application to Foodborne Pathogenic Microorganisms
The Key Events Dose-Response Framework: A Foundation for Examining Variability in Elicitation Thresholds for Food Allergens