Synergism, Antagonism, Additive Effects

In the preparation of commercial pesticide formulations, the biochemical and toxic properties undergo phenomenal modifications. These reactions (and the effects thereof) are called synergism, antagonism, and additive effects. In pest control management, different OPs are mixed to achieve quick knock-down effects, and absence of residues effects, for the better killing of crop pests (Table 5-2). 

OPs are chemicals used in agriculture as acaricides, herbicides, and insecticides (Appendix 5-A-l). Because of their toxicity, several of these chemicals are being phased out from use parathion (ethyl) is an example. Many have been now classified by the United States Environmental Protection Agency (USEPA) as a restricted use pesticide (RUP) or a general use pesticide (GUP). Pesticide chemistry has taken a turn for the synthesis, manufacture, and use of still safer compounds. A list of OPs considered for banning has been identified by the USEPA (Table 5-3). The following pages will briefly discuss the uses and toxicity of different OPs. 

TABLE 5-2 Synergistic Effects of Organophosphorus Insecticides in Rats 

Nature of Effect Combination of Insecticides Percent Mortality 

TABLE 5-3 Organophosphorus Pesticides Cancelled or Proposed for Cancellation  

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If the organism undergoes simultaneous action of two antimicrobial drugs, it can result in an additive effect, synergism, or antagonism. 

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. 

Differentiate among synergism, potentiation, and antagonism. What is an additive effect ... 

E. Kandare, G. Chigwada, D. Wang, C.A. Wilkie, and J.M. Hossenlopp, Probing synergism, antagonism, and additive effects in poly(vinyl ester)(PVE) composites with fire retardants, Polym. Degrad. Stabil., 2006,91 1209-1218. 

Thus, synergisms and antagonisms are defined in quantitative terms, in relation to a specific additivity expectation. The additive effects of a combination of chemicals that can be calculated by using CA or IA serve as a point of reference for identifying a synergism or antagonism. 

In summary, deviations from expected additive effects are well documented and can be assessed in terms of synergism or antagonism. In some cases, the mechanisms underlying such deviations are well understood. A typical case of interaction occurs when 1 substance induces toxifying (or detoxifying) steps effective for another mixture component, which in turn alters profoundly the efficacy of the second chemical. 

Based on these considerations, the following 2 minimal quality criteria for low-dose mixture experiments suggest themselves for assessments of studies published in the literature 1) The effects of individual mixture components should have been determined under conditions similar to those of the mixture. 2) NOAELs (or NOELs and NOECs when a neutral effect concept is adopted) should have been estimated for each mixture component, and the absence of observable effects demonstrated directly. In addition to these 2 minimal requirements, it would be desirable to calculate quantitative additivity expectations. This would allow evaluations of combination effects in terms of synergism, antagonism, or additivity. 

Additive effect Synergism Indifferent effect Antagonism... 

On the right side of equation (3.13), the first two terms represent the additive effect and the third is the interaction term. Additivity, synergism, or antagonism are represented by a = 0, a > 0, and a < 0, respectively. 

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. 

Fig. 7, Effects of a 1 1 mixture of copper-mercury (— —) on developmental stages of the rainbow trout. The mixture was less toxic than copper (—) at low exposure levels but equally toxic as mercury (—) when the concentration was increased to 0.05 mg/liter. When LCjo values for individual metals were compared, mercury was approximately 25 times more toxic than copper. The curve for calculated additive effects (solid line) served as a basis for assessing antagonism and synergism. [Reprinted with permission from Copper in the Environment (J. O. Nriagu, ed.). Copyright , John Wiley and Sons, Inc., New York.]...

When two or more stabilizers are combined, it is often observed that their total effect is stronger than the additive superposition of individual effects, a phenomenon also called synergism. The inverse effect - antagonism - is not desired and occurs much less frequently. 

All cases of retardation by mixtures of inhibitors can be reduced in their effect on the oxidation process to the following three ones additive ejfect when the retardation effect of a mixture is equal to the sum of retardation effects of each component, antagonism when inhibitors impede each other, and synergism when the effect of a mixture is greater than the sum of retardation effects of the components. 

Although testing of the whole mixture as such seems to be the proper way to approach the risk assessment of exposure to that mixture, it will not provide data on combined actions and/or interactions between the individual components of the mixture. Even if the effect of the mixture is compared with the effects of each individual component at comparable concentrations, this will not allow a description of potential synergism, potentiation, or antagonism, and it is even doubtful that deviations from additivity can be concluded. This can only be achieved if dose-response curves are obtained for each of the single compounds. 

Drugs are considered to act additively when the activity of drugs in combination are equal to the sum of their independent activity. The overall effect of two antimicrobial drugs can be less (antagonism) or more (synergism) than the sum effect. 

The determination of a permissible exposure to a toxic substance requires evaluation of qualitative and quantitative factors including the identification and health significance of the adverse effect the sensitive members of and the size of the exposed population, biological absorption, distribution, metabolism, and excretion and the possible additivity, synergism, or antagonism with coexposed substances. 

It is possible that the combined effect of a mixture of chemicals is different from the effect expected to occur on the basis of the assumption that neither mixture component influences another s action (the additivity or noninteraction assumption). Such deviations from expected additivity are usually assessed in terms of synergisms or antagonisms. If the mixture effect is larger than expected, there is said to be synergism if the mixture effect is smaller than expected, there is antagonism. 

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