More-than additive interactions

A recent study of Moser eoworkers (2005) Mo,ser et uL (2005), using a do.se-additive design with mixtures of five commonly used OP pesticides (chlorpyrifos, diazinon, dimeihoate, acephaic, and malathion), showed a more-than-additive interaction on multiple end points blood and brain cholinesterase inhibition, motor activity, and gait score (tail-pinch response did not. show a more-than-additive interaction). This study is noteworthy because (i) relatively sensitive end points were used to test the toxic interaction of the OP pesticides, such as cholinesterase inhibition or depression of motor activity (ii) more than two OP compounds were used in the mixture and (iii) comprehensive statistical analyses of the data were performed. The pharmacokinetic interaction of two of the aimpounds in the mixture, chlorpyrifos and diazinon, has been studied in rats (Timchalk et a ., 2004). The authors found that one compound did not affect the pharmacokinetics of the other unless high doses were given, concluding that a more-than-additive interaction is unlikely at environmentally relevant concentrations. 

In summary, there is some evidence that high doses of some but not all binarj combinations of OP compounds show a raorc-than-addilivc interaction. In the one study using lower dosages of multiple OP compounds (Moser et ai, 2005), a more-than-additive interaction was noted for multiple end points at low dosages. 

Chlordane interacts with other chemicals to produce additive or more-than-additive toxicity. For example, chlordane increased hepatotoxic effects of carbon tetrachloride in the rat (USEPA 1980 WHO 1984), and in combination with dimethylnitrosamine acts more than additively in producing liver neoplasms in mice (Williams and Numoto 1984). Chlordane in combination with either endrin, methoxychlor, or aldrin is additive or more-than-additive in toxicity to mice (Klaassen et al. 1986). Protein deficiency doubles the acute toxicity of chlordane to rats (WHO 1984). In contrast, chlordane exerts a protective effect against several organophosphorus and carbamate insecticides (WHO 1984), protects mouse embryos against influenza virus infection, and mouse newborns against oxazolone delayed hypersensitivity response (Barnett et al. 1985). More research seems warranted on interactions of chlordane with other agricultural chemicals. 

Situations where more than one phytotoxicant is present in the atmosphere commonly occur and the possibility of synergistic (greater than additive) or antagonistic (less than additive) interactions resulting from the pollutant combinations should be recognized. The potentiation of injury symptoms by plant... 

If V < 0.7, there is antagonism if V = 0.7 - 1.3, an additive effect occurs if V = 1.3 - 1.8, the effect is more than additive if V > 1.8, there is synergism or potentiation. For further discussion, see Brown (4) and references therein. Note that these interactive effects may occur with single acute doses or repeat dosing, and may depend on the timing of the doses relative to each other. 

Interactions between substances are expressed in terms of synergism, potentiation and antagonism, sometimes with more than additive and less than additive effects. The terms synergism and potentiation are often used to express the same type of phenomenon, a more than additive effect. Sometimes, however, the term synergism is restricted to the case where one of the compounds has no influence on the toxic effect under study at actual exposure level but strongly enhances the effect of the other in the combined exposure situation. Potentiation is then restricted to describing effects where two or more compounds each contribute to an overall toxicity that is more than additive. 

In summary, CM/OP interactions arc not necessarily less than additive, a.s is the general expectation given the well-known antagonism between CMs and nerve agents. In fact, there are quite a few indications that in some. systems there is a more-than-addilive interaction between the two. Moreover, the type of interaction likely depends on the proponioti of each pesticide in the mixture. 

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