What gaps are there in our knowledge of pyrethroids?

Testing pharmacology

There is a lot which is unknown about pyrethroids; they have quite bizarre pharmacology, probably thanks to their imperturbable affinity for anything lipid. This has made a lot of traditional experiments tricky to perform, as the pyrethroid tends to become associated with cell membranes and lipid micelles, rather than obeying water-soluble kinetics [Trainer et al, 1997].

While the unique and remarkable characteristics of pyrethroids will probably fascinate us indefinitely, one must be pragmatic. Gaps in our knowledge concerning the effects of these compounds on health are the most pressing, and hence also the best funded.

Multiple exposure to pyrethroids

Humans are exposed to a diverse range of pyrethroids in various combinations. Often, pyrethroids are sold and/or used as mixtures containing a combination of two or more compounds [Farm Chemicals Handbook 1997]. Even when pyrethroids aren't intentionally mixed, it is possible to be exposed through contact with, for instance, an agricultural spray at work and then a fly-spray at home. However it is unknown how doses of multiple, different pyrethroids will manifest compared with individual doses. This problem isn't easy to tackle, as there are scores of synthetic pyrethroids available, making a cross-comparison of the toxicity of each a massive, unviable task.

Some published work has generated interest into the interactions of pyrethroids, particularly between the two subfamilies - Types I and II. This work demonstrated that in both single TTX-insensitive sodium channels and in rat dorsal root ganglion cells, pyrethroids acted competitively, rather than additively as one might expect [Song et al., 1996; Motomura et al,. 2001]. The experiments which this site focuses on was done to see whether competition between Type I and Type II pyrethroids, as described in vitro, is a common effect and of importance in whole organisms.

Other gray areas - the class divide

All pyrethroids are known to act upon voltage-sensitive sodium channels, and their acute toxic effects originate from prolonging the kinetics of channel opening and closing. Acute poisoning manifests with common hyperexcitable symptoms, however there are two distinct classes of poisoning syndrome seen in mammals and insects. The two poisoning syndromes are tightly correlated with structural features of the pyrethroid molecule, with Type II pyrethroids usually containing an α-cyano moiety. There are also some pyrethroids which fit into neither category, producing mixed Type I and Type II effects.

Sodium, chloride, or what?

It seems plausible that the differences in effects between Type I and II pyrethroids may be due to the degree of influence they have on sodium channel kinetics. However there is a continuous spectrum of of effect across different pyrethroid structures [Burr & Ray, 2004]. This spectrum is also seen in the rat hippocampal paired-pulse inhibition paradigm. How then to reconcile the clear bimodal symptoms seen in whole animal intoxication? It is likely that variation in the molecular targets for each compound underlies the variation seen in macroscale symptoms. Sodium channel variants selectively expressed in certain tissues could be affected to varying degrees.

Other ion channels, such as the maxi chloride channel are known to be blocked by Type II pyrethroids. Antagonising the pyrethroid effect with chloride channel opening drugs like Ivermectin relieves the salivation component of poisoning, while pentobarbitone relieves motor components [Forshaw et al, 1999]. Phenobarbitone, which does not affect chloride channels, had no protective effects. This suggests that the voltage sensitive chloride channels may be another important target for central and peripheral symptoms of pyrethroid poisoning.