used formulation synergist (EPA 2005). Because formulation synergists are specifically used to increase the potency of pesticide active ingredients, they are most likely to produce the greatest enhancement of pesticide toxicity.

Toxicity evaluations that used the amphipod Hyalella azteca revealed that coexposure to PBO caused up to about a sevenfold increase in the toxicity of permethrin (Amweg et al. 2006). The synergistic potency of PBO increased as exposure concentration increased with a threshold concentration of 2.3 ìg/L in water. The threshold concentration for synergy to occur stands in contrast to PBO surface-water concentrations, which are typically less than 80 ng/L even after direct application to surface water for mosquito abatement (Orlando et al. 2003, 2004; LeBlanc et al. 2004; Amweg et al. 2006). Given that H. azteca is considered sensitive to pyrethroids (Werner et al. 2010), that PBO is considered the most potent of formulation synergists, and that PBO concentrations in surface water after application tend to be below concentrations necessary to elicit synergism, there is a low probability that synergists associated with pesticide formulations enhance the toxicity of pesticide active ingredients. The greatest probability of synergistic effects might be when synergist-containing pesticide formulations are applied directly to aquatic systems or when there is direct contact between the formulation and a species.

Synergistic Interactions among Active Ingredients

As discussed in Chapter 3, pesticide active ingredients have the potential to coexist in tank mixtures or as environmental mixtures. In some cases, the toxicity of pesticide active-ingredient combinations has been shown to be greater than additive. The synergy has been exploited in recommended tank formulations to treat pests. With respect to nontarget species, the synergy has been recognized as a potential source of enhanced ecological threat. The following are examples of known synergistic interactions between pesticide active ingredients.

Organophosphates and Carbamates. Organophosphates and carbamates share a mechanism of action: inhibition of the enzyme acetylcholinesterase. Accordingly, the joint toxicity of organophosphates and carbamates should conform to a concentration-addition model. Indeed, the in vitro inhibition of acetylcholinesterase activity in salmon brains by combinations of organophosphates and carbamates showed that to be the case (Scholz et al. 2006). However, in vivo exposure of salmon to binary combinations of organophosphates, carbamates, or a combination of organophosphate and carbamate resulted in greater inhibition of brain acetylcholinesterase activity than would be predicted by concentration addition (Laetz et al. 2009). Serine esterases are important in the metabolic detoxification of organophosphates and carbamates (Cashman et al. 1996). Studies have shown that those esterases can be selectively inhibited by binding of one substrate, which results in increased toxicity of another because of its reduced detoxification (Murphy et al. 1959; Clement 1984).

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