Toxicologists have long understood that the behavior of one chemical in the body is affected by other chemicals. The underlying idea is that the body’s own chemicals (often referred to as endogenous chemicals) can and do affect the kinetics, toxicokinetics and toxicodynamics of chemicals that are foreign to the body (that is, xenobiotics. Or, in other words, the chemical mixture (of both endogenous and xenobiotic chemicals) can interact with each other. Pharmacologists (pharmacology is study of drugs and is a sister field to toxicology) have been aware of the potential for multiple chemical interactions in the form of drug interactions since at least the mid-1960’s, when one of the earliest conferences on drug interactions took place. One outcome of this awareness is the warning labels on pharmaceuticals. These labels often list other drugs or foods, or such practices as exposure to the sun, that should be avoided to protect against adverse drug interactions.
Potential for interactions of chemical mixtures was noted even earlier when C.I. Bliss defined three main categories of interaction or ‘joint action’ of chemicals:
- Independent joint action, which refers to chemicals that act independently; and that have different modes of action (i.e. they cause their effects by different mechanisms), such that the presence of one chemical will not have an impact upon the action of another chemical. As a result the toxicity of the combination can be predicted from knowledge of the independent chemicals;
- Similar joint action, which refers to chemicals that cause similar effects often through similar mechanisms of action. In this case the presence of one chemical may impact the action of another chemical. For example, if two chemicals, A and B act by combining with the same receptor in the body, the impact of B will depend on how much of chemical A is present (such that its effect might be heightened if A is present, in contrast to the presence of chemical B by itself). In this case, as with Independent joint action, toxicity can be predicted with knowledge of independent chemicals; and
- Synergistic action or synergy, where “the effectiveness of the mixture cannot be assessed from that of the individual ingredients but depends upon a knowledge of their combined toxicity when used in different proportions. One component synergizes or antagonizes the other. Today we use synergy to refer only to mixtures that result in enhanced toxicity and antagonism that results in reduced toxicity.
These terms describing interactions that may occur in chemical mixtures were set forth by Bliss in 1939. Yet it is the rare study that addresses exposure to either simple mixtures, which consist of a few well-defined chemicals (as might occur in a contaminated groundwater situation or a drug combination); or complex mixtures, which consist of many undetermined chemical components (such as in diesel exhaust, cigarette smoke, or—in some cases—hazardous waste sites).
A cursory review of toxicological journals by Dr. Raymond Yang in 1992 revealed that nearly 95 percent of the papers published related studies of single chemicals or at best, pre-exposure to one chemical followed by exposure to another chemical. His review suggests that some "95 percent of the resources in toxicology is devoted to single-chemical studies” .
To date, the field of toxicology has done little to further advance Bliss’s early work on chemical interactions. Of the 5 percent of toxicological studies that do address mixtures, the great majority focus on binary mixtures (or two chemicals at a time); employ relatively high chemical concentrations; and observe relatively crude endpoints, or focus on such complex chemical mixtures as diesel fuel mixtures or contaminated water samples where the chemical composition was unknown. In general these studies add little to our understanding of chemical mixtures as they exist in the environment. There are two relatively recent studies that have addressed environmentally-relevant mixtures (i.e. low dose mixtures of several constituents). Interestingly, the results from those studies have led their authors to opposing conclusions. While one group suggests that “as a rule” such mixtures should present no health concern, the other group more cautiously suggests that even low level exposure to chemicals over long periods of time may cause subtle, more difficult to detect, effects.
- Bliss, C.I. 1939. The Toxicity of Poisons Applied Jointly. Annals of Applied Biology. 26:585-615.
- Yang, R. 1994. Introduction to the Toxicology of Chemical Mixtures. In Toxicology of Chemical Mixtures. Yang (ed.). Academic Press, Inc. 1-10 pp.
- Hertzberg, R., Teuschler, L. 2002. Evaluating Quantitative Formulas for Dose-Response Assessment of Chemical Mixtures. Environmental Health Perspectives 110 (6): 695-970.