• What is the expected variability in dose response among members of the human population?

• How should data from subchronic exposure studies be used to estimate chronic effects?

• How should problems of differences in route of exposure within and between species be dealt with?

• How should the threshold dose be estimated for the human population?

• If a threshold in the dose-response relationship seems unlikely, how should a low-dose risk be modeled?

• What model should be chosen to represent the distribution of exposures in the population of interest, when data relating to exposures are limited?

• When interspecies extrapolations are required, what should be assumed about relative rates of absorption from the gastrointestinal tract of animals and of humans?

• For which percentiles on the distribution of population exposures should risks be characterized?

Depending on the nutrient under review, at least partial, empirically based answers to some of these questions may be available, but in no case is scientific information likely to be sufficient to provide a highly certain answer; in many cases there will be no relevant data for the nutrient in question.

It should be recognized that, for several of these questions, certain inferences have been widespread for long periods of time, and thus, it may seem unnecessary to raise these uncertainties anew. When several sets of animal toxicology data are available, for example, and data are insufficient to identify the set (i.e., species, strain, adverse effects endpoint) that “best” predicts human response, it has become traditional to select that set in which toxic responses occur at lowest dose (“most sensitive”). In the absence of definitive empirical data applicable to a specific case, it is generally assumed that there will not be more than a 10-fold variation in response among members of the human population. In the absence of absorption data, it is generally assumed that humans will absorb the chemical at the same rate as the animal species used to model human risk. In the absence of complete understanding of biological mechanisms, it is generally assumed that, except possibly for certain carcinogens, a threshold dose must be exceeded before toxicity is expressed. These types of long-standing assumptions, which are necessary to complete a risk assessment, are recognized by risk assessors as attempts to deal with uncertainties in knowledge (NRC, 1994).