Health risk of low-dose pesticides mixtures: A review of the 1985-1998 literature on combination toxicology and health risk assessment

A literature review covering the last 14 yr has been performed in the field of combination toxicology and human risk assessment from exposure to chemi cal mixtures, with special emphasis on mixtures of pesticides at low doses, that is, at levels likely to occur in human diet and environment. Despite a large body of knowledge in the field of risk assessment methodologies for exposure to chemical and pesticide mixtures, there is no single methodolog ical approach in "combination toxicology" and health risk assessment of che mical mixtures, and therefore professional judgment is still required Gener ally, the dose or response additivity approach that may be applied to evalu ate potential risk for chemical mixtures in human toxicology overestimates the risk of a combination of chemicals. The recent endocrine disrupter issu e demonstrated the difficulty of reproducibility of data when testing envir onmental toxicants at very low levels, and the need for more basic work in this; field The use of integrated methodological approaches may provide mor e reliable predictive data in the risk assessment of chemical mixtures in f uture. Yet data have demonstrated that exposure to a combination of compoun ds does not cause effects stronger than the ones of their most active compo nent, provided components are present at low concentration levels, like acc eptable daily intake (ADI) or reference dose (RfD) levels, well below their respective no-observed-adverse-effect levels (NOAELs), Although it has bee n demonstrated that a combination of compounds with the same target organ a nd the same or very similar mechanisms of action may cause additive or syne rgistic effects, the chance of such effects will most likely diminish with decreasing exposure levels to such combinations. Synergism and antagonism m ay both occur at the same time at different organs or targets in the same o rganism. However, and despite some exceptions, it has been demonstrated tha t interaction between components is not a common event at low levels of hum an exposure such as those that may occur through pesticides residues in foo d or drinking water. The introduction of a special safety factor as a stand ard for mixtures in addition to those normally used for deriving ADIs, RfDs , or minimal risk levels is not supported by data. it can be concluded from our review that, as a general rule, exposure to mixtures of pesticides at low doses of the individual constituents does not represent a potential sou rce of concern to human health.