Combined Actions and Interactions of Chemicals in Mixtures

They found that the effect of mixture A on acetylcholinesterase activity was equal
to that of the most potent compound, diazinon. Dimethoate was not active at the
concentrations used in the experiment (1, 10 and 100 µg/ml). Dimethoate, diazinon
and azinophos-methyl all have the same mode of action (inhibition of
acetylcholinesterase). One would therefore expect to observe a simple similar
action of the compounds in the mixture, which in fact was reported. A significant
inhibition of protein synthesis after 4 hours of treatment were only seen for
azinophos-methyl at the highest concentration tested (60 µg/ml). Dimethoate and
diazinon were not active at all. The inhibition of protein synthesis of mixture A at
the highest concentrations (100+40+60 µg/ml) was nevertheless greater than that of
azinophos at 4 hours thus showing a potentiation effect.
The authors claim that mixture B of benomyl and pirimiphos-methyl was ”more
potent than benomyl” in inhibition of the protein synthesis. As pirimiphos-methyl
did not inhibit the protein synthesis mixture B also showed a potentiation. However
since the two compounds does not act by the same mode of action one would
expect a simple dissimilar action so this result is somewhat surprising.
The acetylcholinesterase activity of mixture C containing all five pesticides was
equal to that of the most potent agent in the mixture thus showing a simple similar
action. Mixture C was found to potentiate the protein synthesis at 4 hours as the
protein synthesis was higher for the mixture compared to that of the single
compounds. In the experiment made in relation to this they found that only
benomyl had a significant effect on protein synthesis at the concentrations used.
7.6.6.2 Organic solvents
Several studies indicate that exposure to mixtures of solvents may be more harmful
than exposure to single solvents (WHO, 1985, Organic solvents and the nervous
system, 1990). Among 30 publications investigating cytochrome P-450 isoenzyme
activity caused by solvent combinations, effects greater than mere addition were
reported for 11 of the 23 solvent combinations investigated. The interactions of the
solvents styrene, n-hexane, xylene, dichloromethane and toluene were described.
The authors concluded that the rule of additivity should be used with caution when
dealing with combined exposure for organic solvents in industry. Certain solvents
should not be used together (Noraberg, 1993). It is not known whether the combined
effect is the result of each chemical acting via the same or via different mechanisms.
It is generally believed that the narcotic effect induced by a mixture of solvents,
including ethanol, equals the sum of the effect of the individual solvents. If the effect
observed is greater than additive, then this is probably related to kinetic interaction. A
number of reports of ethanol-induced enhancement of solvent neurotoxicity can be
explained by kinetic factors.
However, ethanol intake six days before and during p-xylene inhalation exposure
reduced the severity of the neurotoxic effect in rats (Padilla et al., 1992).
Methylethylketone-induced potentiation of n-hexane/methyl n-butylketone
neurotoxicity, through enhanced formation of 2,5-hexanedione, appears to have been
responsible for the outbreak of an occupational neuropathy among textile workers
(Allen et al., 1975).
7.6.6.3 Metals
Toxic metals cannot be degraded but may react chemically with important sites. Most
metals affect multiple organ systems, and the targets for toxicity are specific enzymes
and/or membranes of cells and organelles, and biochemical reactions (chelation,
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