Pyrethroids Are a Moderately Large and Very Useful Class of Insecticides Based on Naturally

Pyrethroids

Background

Pyrethroids are a moderately large and very useful class of insecticides based on naturally insecticidal compounds found in chrysanthemum species. Ground up flowers of Pyrethrum cineraraefolium and C coccineum, and occasionally of other chrysanthemum species, have been used for at least a century as insecticidal preparations. Their usefulness was severely limited by the rapid degradation of the insecticidally active components, both by sunlight and by biotransformation. Insects metabolize natural pyrethrum so quickly that recovery after knockdown is not unusual. In the 1950s, efforts began to synthesize analogs to the natural pyrethrins that would be more persistent, both in the environment, and in organisms, without losing the potency or the range of insecticidal activity of the natural products. These efforts have been spectacularly successful: synthetic pyrethroids are among the most commonly used insecticides, and various congeners have proven invaluable in agriculture, in medical entomology, and in household use.

Natural pyrethrum is a mixture of plant products, consisting of esters of chrysanthemic acid or pyrethric acid with pyrethrolone, cinerolone and/or jasmololone. The basic skeleton and its variants are shown in Figure 1. Composition of the major insecticidal constituents of pyrethrum is shown in Table 1.

Figure 1: Basic structure of natural pyrethrum. R and Rí indicate substituents listed in lower half of figure. Which substituents are present in specific natural pyrethroids is shown in Table 1.

TABLE 1: Structures of components of natural pyrethrum. A, B, C, D, and E refer to moieties shown in figure 1.

Note that several of the carbon atoms in the pyrethrum skeleton have 4 different substituents, allowing for the formation of steroisomers or enantiomers. These stereoisomers have different binding capacity to pyrethrum receptors. For example, the 1R and 1S cis isomers shown in Figure 2 bind competitively to one site on the sodium channel. The 1R and 1S trans isomers, however, bind noncompetitively to a different site on the sodium channel. The 1S isomer does not alter channel function; however, it does prevent binding by the 1R isomer. (Thus, a pyrethrum mix consisting entirely of 1S isomers would not cause toxicity, but would actually protect against later exposure to 1R.) Only the 1R isomer is toxic in intact mammals. It is possible to use such stereospecific differences in toxicity to produce pure isomers with remarkably selective toxicity. Deltamethrin is one such pyrethroid. However, note that the relative absence of mammalian toxicity is primarily due to the rapid metabolism of pyrethroids to their inactive alcohol and acid components.

Figure 3: Stereoisomeric configurations of pyrethrum

Contact with the receptor ñ sodium channels in nerve and muscle cells ñ occurs at the isobutenyl moiety of the acid, the dimethylcyclopropane ring, and the unsaturated side chain of the keto-alcohol (Figure 4). In synthetic pyrethroids, the cyano[C-triple-bond-N] moiety appears to confer maximum complementarity between the pyrethroid and the receptor.

Toxicology

Mechanistically, pyrethroids without the cyano group cause the nerve channels to close very slowly, producing a prolonged after-potential. In contrast, pyrethroids containing the cyano group cause a delayed closure of sodium channels, suppressing spontaneous generation of the after-potential.

Figure 4: Interaction of Pyrethrum with its receptors occurs at 3 points of the structure.

Toxicity

Pyrethroids, like OPs and carbamates, are neurotoxins when administered systemically. And, like all other insecticides, they affect nerve cell function. They do not kill cells. Unlike OPs and carbamates, pyrethroids as a class exhibit several different kinds of toxicity, to some extent depending on route of administration. Topical application produces a very different syndrome from ingestion. Moreover, systemic toxicity falls into roughly 2 types ñ which are rather mundanely named Type I and Type II forms of toxicity.

Type I toxicity is due primarily to action of the pyrethroid on the central nervous system, notably the brain stem. (The cerebrum and cerebellum do not appear to be involved.) Symptoms in milder cases include a progressive development of fine whole body tremor and an exaggerated startle response, which are associated with a large increase in metabolic rate. In more severe cases, there is uncoordinated twitching of dorsal muscles, hyperexcitability and hyperthermia. Death results from hyperthermia and/or metabolic exhaustion.

Type II toxicity is somewhat more complex, since it involves pyrethroid effects on all levels of the brain, rather than mostly on the brain stem. Salivation may be profuse. A rolling gait is seen due to increased extensor tone in the hind limbs; incoordination progresses to a coarse tremor; sensory stimuli produce writhing spasms, tonic seizures, apnea, and death.

Topical application of natural or synthetic pyrethroids also produces contact dermatitis, which is not uncommon after household use of natural or synthetic pyrethroids. Pure synthetic pyrethroids can also produce an irritant effect. that is not associated with inflammation, lasts up to 24 hours, and may include numbness or parasthesias. It is characterized as annoying but not disabling and does not appear to cause long-lasting damage. It is most commonly seen in occupational exposure.

Not often noted in the literature is the potential for allergic reactions to chrysanthemums and to pyrethroids. These allergic responses include asthma, which can be a life-threatening disease. Pneumonia is also a possible allergic response to pyrethroid exposure. It is advisable for people who use pyrethroids (whether occasionally or frequently) to be aware of their reactions to these otherwise benign insecticides. It is also advisable for people who recommend pesticides to lay people to be aware that pyrethroids, while ordinarily considered the least dangerous insecticides for household use, may be quite hazardous for a subset of the population.

There are no specific antidotes for pyrethroid poisoning. Therapy consists of mitigating the symptoms: bringing down fever, preventing seizures, etc. Atropine will decrease the amount of saliva produced, but is not particularly effective against other symptoms.

Ecotoxicology

Pyrethroids are extremely toxic to fish and should not be used in locations or under conditions that result in their presence in water. Since natural pyrethrum and the early pyrethroids are so short-lived, this was not a significant problem in pyrethroid use. The more recent pyrethroids, on the other hand, are sufficiently persistent to allow them to reach streams or lake after terrestrial use. It is perhaps fortunate that these newer pyrethroids are also applied at very low levels ñ as little as 1/20th of the lb/A application rates for OP and carbamate insecticides. The low level of application means less risk of water contamination.

With the exception of toxicity to fish, the pyrethroids are considered ecologically benign, since they are not overly persistent and not very toxic to mammals.

Table 2: Selected pyrethroids. (gen) refers to the generation, with later generations being more persistent in the environment. Generation 4 contain a cyano (CN) group.