Developing a workshop for U.S. Environmental Protection Agency

Key Questions

Topic 1: Hypothetical mechanisms or modes of action have been proposed for some toxicants, largely based on research in animal models. Consequently, it might be difficult to identify or exclude additional mechanisms for toxic effects in humans. Should mechanistic information be used in a qualitative manner, such as in Hill's biological “plausibility” criterion? Can information from observational or clinical studies on intermediate end points related to mechanisms be helpful? How can mechanistic understanding best be reflected in dose-response model selection or parameter estimation?

Topic 2: How should evidence of toxicity from high-dose animal studies be weighed against null findings from one or more epidemiologic studies at lower exposures? What level of epidemiologic evidence would be sufficient to dismiss a toxic effect in animals as irrelevant to humans? How can dose-response relationships be combined from different types of research, for example, animal bioassay and epidemiological?

Topic 3: Should positive epidemiologic studies with weaker designs (for example, ecological studies, or studies with unmeasured known confounders) or with positive but non-significant associations contribute to the weight of evidence, or should they be considered only as hypothesis generating?