Synergism increasing toxicity

Dispositional interactions are those in which one chemical affects the disposition of the other, usually metabolism. Thus, one chemical may increase or inhibit the metabolism of another to change its toxicity. For example, 2,3-methylenedioxynaphthalene inhibits cytochrome P-450 and so markedly increases the toxicity of the insecticide carbaryl to flies (potentiation) (see chap. 5). Another example, which results in synergy, is the increased toxicity of the organophosphorus insecticide malathion (see chap. 5) when in combination with another organophosphorus insecticide, EPN. EPN blocks the detoxication of malathion. Many chemicals are either enzyme inhibitors or inducers and so can increase or decrease the toxicity of other chemicals either by synergism or potentiation (see chap. 5). 

In some cases, increased toxicity of insecticides can be attributed to materials that enhance cuticular penetration of the insecticides without involving inhibition of metabolic detoxification. For example, Sun and Johnson (1972) found that carbaryl was more toxic to houseflies when topically applied in kerosene than in acetone. These authors classified this type of synergism as quasi-synergism. 

PCB 156, a mixed inducer of microsomal enzymes, significantly increases the incidences of cleft palates by 2,3,7,8-TCDD in rodents (Bimbaum et al. 1985). Interactions among polychlorinated congeners may range from antagonism to additivity to synergism (Safe 1990), and the toxicity of individual PCBs can be raised by interaction with other PCBs (Table 24.5). 

A number of studies of the toxicity of zinc oxide/hexachloroethane smoke have been conducted (Brown et al. 1990 Karlsson et al. 1986 Marrs et al. 1983). These studies demonstrate that smoke exposure results in pulmonary inflammation and irritation. When male Porton Wistar rats were exposed to hexachloroethane/zinc oxide smoke for 60 minutes, the lungs showed pulmonary edema, alveolitis, and areas of macrophage infiltration 3 days later. At 14 days, there was interstitial fibrosis and macrophage infiltration. At 28 days, increased fibrosis and macrophage infiltration were noted. However, these same symptoms occurred when the animals inhaled zinc chloride there was no apparent synergism between the zinc chloride and residual hexachloroethane (Brown et al. 1990 Richard et al. 1989). This is consistent with the fact that smoke contains little hexachloroethane and the observation that acute exposure to 260 ppm hexachloroethane had no effects on the lungs of rats (Weeks et al. 1979). 

We were able to test the analog synergism in another setting where the analogs could be produced in sufficient quantity by synthesis. The wild pepper, Piper tuberculatum, was the most active of 16 pepper plants from Costa Rica assessed in our study (Bernard et al., 1995). Four insecticidal piperamides from P tuberculatum were produced by synthesis (Scott et al., 2002) and the lethal concentrations of the compounds were assessed alone and in binary, tertiary and quaternary mixtures. Although binary mixtures were no more toxic than individual compounds, toxicity increased with three and four compounds in the mixture, while keeping the total... 

Functional interactions are those in which both of the two chemicals affect a bodily system perhaps by different mechanisms, and either increase or decrease the combined effect. For example, both atropine and pralidoxime decrease the toxic effects of organophosphate compounds by different means, a combination of the two antidotes leads to a large increase in effectiveness synergism). 

In their acute toxic effects on the skin and liver PCBs resemble the chlorinated naphthalenes. Acute yellow atrophy is produced in the liver and enhanced in the presence of CHClj (synergism). Toxicity increases with increase in chlorine content of the PCB, and with oxide formation. Skin lesions (chloracne) consist of small pimples and dark pigmentation of exposed areas. Later comedones and pustules develop. With systemic intoxication, progressive symptoms are nausea, vomiting, weight loss, jaundice, edema, abdominal pain, and, where liver damage is severe, it is followed by coma and death (Sax, 3d ed., p. 551). 

Mercier el al. (330) administered i.v. infusions of sodium salicylate to dogs and determined the lethal dose to be 1 g/kg. Simultaneous administration of papaverine resulted in a slight increase in the toxicity. Lettr6 et al. (331) studied the synergism of mitotic poisons and found that papaverine intensified the mitotic effect of colchicine on the growth of fibroblasts in vitro. The spasmolytic effect of khelline was augmented by small doses of papaverine (332). Therapeutic doses of khelline did not produce a hypotensive effect upon dogs, but in combination with barbiturates and papaverine a hypotensive effect was observed. 

In the molecule SBD, the reduction in toxicity effected by replacement of the syn-chlorine of dieldrin to give SD appears to be offset by an increase (compare BD) effected by further replacement of the vinylic chlorines, so that SBD is similar to dieldrin in toxicity In contrast, AD and ABD, which retain the syn chlorine, are poor toxicants In this series there was no appreciable synergism with the MFO inhibitor sesamex, indicating that when increased LD50s were seen, these were not the result of enhanced MFO attack consequent upon the progressive replacement of chlorine ... 

Interactions may occur when, for example, 1 mixture component interferes with the uptake or the metabolism of a second one, such that increased (or decreased) amounts of an active toxicant are present compared to the situation when the second chemical acts on its own (see Chapter 2). In the first situation, synergisms are likely to occur, while the latter case may lead to antagonisms. 

One compound may be toxic when used alone, and another may not. If a combination of the two is more toxic than the insecticidal compound alone, synergism is said to occur, and the nontoxic compound is the synergist. Several important synergists that can increase the toxicity of insecticides contain the active moiety methylendioxyphenyl (MDP) ... 

The co-administration of more than one NSAID does not produce synergism of the analgesic effect but significantly increases the risk of gastrointestinal toxicity and liver and kidney damage so should be avoided. 

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