A unified approach to risk assessment for cancer and noncancer endpoints based on benchmark doses and uncertainty safety factors

A fundamental goal of toxicology is to determine safe levels of human expos ure to toxic substances. In the absence of information to establish dose-re sponse relationships at low exposure levels generally experienced by humans , high-dose to low-dose linear extrapolation is generally used for estimati ng carcinogenic risks and the no-observed-adverse-effect-level divided by u ncertainty (safety) factors is widely used for establishing human exposure guidelines for noncancer effects. The basis and impact of this dichotomy is examined and questioned. It is proposed that a unified approach be adopted for establishing human exposure guidelines for both cancer and noncancer e ndpoints. It is suggested that a lower confidence limit on the dose estimat ed to produce an excess incidence of adverse health effects in 10% of the i ndividuals in a human study or 10% of the animals in laboratory experiments be used as a point-of-departure. This dose would be divided by appropriate uncertainty factors to establish human exposure guidelines. For severe irr eversible adverse health effects we suggest a total default uncertainty fac tor (divisor) for animal data on the order of 10,000, which is comparable t o current guidelines. For reversible biological effects a smaller default u ncertainty factor on the order of 1000 may be employed. This is comparable to the divisor often used currently when the point-of-departure is the lowe st-observed-adverse-effect-level. It is asserted that the toxicological inf ormation generally available does not warrant numerical estimates of risk a t low levels of human exposure. Rather, we support a unified approach for a ll adverse health effects of dividing a benchmark dose by appropriate uncer tainty factors to establish guidelines for human exposures to toxic substan ces. (C) 1999 Academic Press.