Future of toxicology--low-dose toxicology and risk--benefit analysis.

Toxicology historically has been directed at studying the mechanisms of adverse effects of isolated compounds on living organisms at high levels of exposure, forming the basis for risk and safety assessment. One way to refocus and mobilize new research funds would be to better match the priorities in regulatory issues and direct the research within the field of toxicology more to low-dose toxicology and risk--benefit analysis. Low-dose toxicology can only be developed when taking into account mechanistic insight and will require risk-benefit analysis and a definition of interactions between compounds at realistic doses of exposure, especially in the case of dietary constituents. This is because the biological effects at low levels of exposure not only may be adverse but also can be beneficial depending on the target organ, the actual end point studied, the receptors activated, and/or the gene expression, protein, and metabolite patterns affected. Toxicologists have the tools and knowledge to study mechanisms of biological effects of chemicals on living organisms, and they should redirect their focus from looking only at adverse effects at high levels of exposure to characterizing the complex biological effects, both adverse and beneficial, at low levels of exposure. This may even result in the notion that beneficial effects can be the result of reaction pathways that are generally considered adverse and vice versa. Low-dose toxicology not only will provide a significant research challenge for the years ahead but also should contribute to better methods for low-dose risk assessment for complex mixtures of chemical compounds. This refocusing from high- to low-dose effects turns the field from a science focusing on adverse effects into a science studying the biological effects of chemical compounds on living organisms, taking into account the realization that the ultimate biological effect of a chemical may vary with its dose, the end point or target organ considered, and/or the combined exposure with other chemicals. By defining the effects of chemicals on living organisms at physiologically relevant exposure levels, toxicologists may contribute not only to better risk and safety assessment but also to preventive medicine, generating knowledge on possible adverse and also beneficial effects of chemicals. In addition, it will result in an approach for food safety assessment more in line with that for drug safety assessment taking the risk-benefit balance into consideration.