Response addition is a form of noninteractive joint action in which the response to a mixture is estimated on the basis of the responses (rather than the concentrations) that would be expected from the components of the mixture. Response addition does not assume that the components of a mixture act by the same or even a similar mechanism and does not assume anything about the slopes of the concentration-response curves. The slopes of the concentration-response curves for chemicals that have different mechanisms of action might or might not differ significantly. The only requirement is that the chemicals produce the same effect. In most practical applications of response addition, the end point is mortality; however, response addition can be applied to any quantal response. Response addition can take various forms, depending on assumptions about the correlation of tolerances in the population.
A review of the literature on pesticide-mixture toxicity revealed that the response-addition model provided somewhat more accurate predictions of toxicity than the concentration-addition model when the pesticide active ingredients had different mechanisms of action (Belden et al. 2007b). Response addition also has been shown to provide more accurate estimates of toxicity of mixtures that consist of dissimilarly acting pesticide and nonpesticide chemicals (Walter et al. 2002; Backhaus et al. 2004).
Arguably, the greatest concern in evaluating hazards and risks to listed species posed by chemical mixtures that contain pesticides is whether constituents of the mixtures act to enhance the toxicity of the pesticide active ingredient. Indeed, pesticide synergists are often included in pesticide formulations (Jones 1998) and can enhance the toxicity of an active ingredient to nontarget organisms by a factor of 100 (Sahay and Agarwal 1997). The activity of some pesticide active ingredients also is substantially enhanced when they are administered in combination with other pesticides. Finally, chemicals to which coexposure occurs might increase the toxicity of a pesticide active ingredient by increasing its bioavailability or potency in the environment of the exposed organism.
Pesticide Formulation Synergists
Pesticide formulation synergists typically function by inhibiting cytochrome P450-mediated inactivation of the active ingredient (Hodgson and Levi 2001). They can enhance the effects of some pyrethroids, organophosphates, carbamates, and rotenone. Formulation synergists include bucarpolate, dietholate, iprobenfos, jiajizengxiaolin, MGK 264, octachlorodipropyl ether, piperonyl butoxide (PBO), piperonyl cyclonene, piprotal, propyl isome, sesamex, sesamolin, sulfoxide, and zengxiaoan. PBO is among the most potent and widely