Use of threshold and mode of action in risk assessment.

Crit Rev Toxicol 41(8):637-50 (2011) PMID 21718086

Under current guidelines, exposure guidelines for toxicants are determined by following one of two different tracks depending on whether the toxicant's mode of action (MOA) is believed to involve an exposure threshold. Although not denying the existence of thresholds, this paper points out problems with how the threshold concept and MOA is used in risk assessment. Thresholds are frequently described using imprecise terms that imply some unspecified increase in risk, which robs them of any meaning (any reasonable dose response will satisfy such a definition) and tacitly implies a value judgment about how large a risk is acceptable. MOA is generally used only to inform a threshold's existence and not its value. Often MOA is used only to conclude that the adverse effect requires an upstream cellular or biochemical response for which a threshold is simply assumed. Data to inform MOA often come from animals, which complicates evaluation of the role of human variation in genetic and environmental conditions, and the possible interaction of the toxicant with processes already producing background toxicity in humans. In response to these and other problems with the current two-track approach, this paper proposes a modified point of departure/safety factor approach to setting exposure guidelines for all toxicants. MOA and the severity of the toxic effect would be addressed using safety factors calculated from guidelines established by consensus and based on scientific judgment. The method normally would not involve quantifying low-dose risk, and would not require a threshold determination, although MOA information regarding the likelihood of a threshold could be used in setting safety factors.