Insecticides is the term coined to describe chemicals used to control pest insects and related invertebrate pest species. Insects are by far the most important species against which these chemicals are targeted. Other major groups of pest organisms include mites, ticks, and nematodes. Acaricides (for the control of mites and ticks) and nematocides (for the control of nematodes) are chemicals specifically used to control these pests, but they are still considered subgroups of the broadly defined “insecticides” group.
Not all insecticides are designed to kill pest insects, despite the use of the suffix ” -cides” which gives the connotation of biocidal agents. Insecticides have been defined to include any chemical that can be used to reduce damage caused by insects. Thus, nonlethal chemicals such as pheromones, repellents, hormone mimics, growth regulators, feeding inhibitors, anorectic agents (which cause loss of appetite), behavioral disrupters, food attractants (used in traps and as bait), and anesthetics, as well as those causing physical problems such as surfactants, sticky substances, desiccants, and barriers (such as oil film on the surface of water for mosquito larval control), are considered to be insecticides.
BRIEF HISTORY
Insecticides used prior to the 1940s were mostly inorganic compounds such as arsenicals. After World War II, DDT and other chlorinated pesticides came on the market. There is no question about the spectacular insect-controlling effects achieved on many crops, and populations of some pests that affect both public and veterinary health were greatly diminished. The shortcomings of these compounds, particularly their lack of selectivity and harmful environmental effects, were eventually realized, however, leading to the termination of their use by the late 1970s. Meanwhile, organophos-phorus and carbamate insecticides gained in popularity and have established themselves as two of the major classes of insecticides. Many of them offer at least some degree of selectivity (malathion is particularly outstanding in this regard) and are less persistent in the environment. In more recent years, functional synthetic analogues of naturally occurring toxic chemicals were developed. Pyrethroids, for example, are essentially synthetic mimics of naturally occurring pyrethrins found in the flowers of species of chrysanthemum. The synthetic neonicotinoids mimic naturally occurring nicotine from tobacco plants. Useful microbial products were also developed in the 1980s and 1990s; examples are Bacillus thuringiensis (Bt) toxins, avermectins, and spinosyns. Modern insecticides used today are generally very selective, mostly affecting only the targeted pest insect. They are potent, requiring only small quantities to achieve their effects, and they are much less persistent in the environment.
CLASSIFICATION OF INSECTICIDES
Synthetic organic insecticides may be divided into several major classes: (1) chlorinated hydrocarbons, (2) organophosphorus compounds (often referred to as organophosphates), (3) carbamates, (4) pyrethroids, (5) nicotinoids, (6) fumigants, (7) y-aminobutyric acid (GABA) receptor antagonists, (8) chitin synthesis inhibitors (benzoy-lureas), (9) mitochondrial poisons, and (10) insect hormone mimics. These classifications are based on either group-specific chemical characteristics (classes 1-6) or their action mechanisms (classes 7-10).
Other insecticides belonging to minor classes (i.e., fewer compounds per class or less frequent use) are: (11) botanically derived naturally occurring insecticides (other than pyrethroids and nicoti-noids), (12) microbially produced insecticides, (13) synergists, (14) semiochemicals such as attractants, including pheromones, (15) insect repellents or feeding deterrents, and (16) behavior-modifying agents for use on insects.
USE PATTERNS
Insecticides as a class of pesticides constitute about one-quarter of total pesticides (approximately a billion pounds per year) used in the United States. By far the largest volume of pesticides used is herbicides (620 million pounds), followed by insecticides (247 million pounds) and fungicides (131 million pounds) (all 1993). Approximately 75% of all pesticides used in 1993 were for the control of agricultural pests. Other uses are for pests found in the home (including gardens), industry, commerce, and public and veterinary health. The top 17 insecticides (used in 1993) were: (1) chlorpyrifos, (2) terbufos, (3) methyl parathion, (4) carbofuran, (5) carbaryl, (6) phorate, (7) cryolite, (8) aldicarb, (9) propargite, (10) acephate, (11)
malathion, (12) fenofos, (13) methomyl, (14) dimethoate, (15) azin-phos-methyl, (16) ethyl parathion, and (17) profenfos. Most of these are organophosphates (1-3, 6, 10-12, and 14-17) or carbamates (4, 5, 8, and 13), but propargite is a sulfite ascaricide and cryolite (sodium fluoroaluminate, Na3AlF6) is a naturally occurring inorganic fluoride compound. Of these, the use of methyl parathion (3) and ethyl par-athion (16) has been phased out. Among organochlorine insecticides, most of which have been eliminated, the only ones remaining are endosulfan (19th) and dicofol (22nd). The most popular pyrethroid is permethrin (25th, approximately 1,000,000 pounds) followed by cypermethrin (225,000 pounds) and fenvalerate (66,000 pounds). Pyrethroids are used in much lower quantities than organophosphates and carbamates mainly because the former compounds are much more powerful than the latter, and therefore only small amounts of pyrethroids per hectare are needed to control insect pests.
MECHANISMS OF ACTION OF INSECTICIDES
The great majority of insecticides used today are nerve poisons. This is because insects have highly developed nervous systems, and furthermore, many of their sensory receptors are exposed to the atmosphere outside the insect body. The insect nervous system relies on several key functions that have been exploited as the targets of insecticides: the sodium channel, acetylcholinesterase, the GABA receptor, and the acetylcholine receptor.
The sodium channel, which is the insecticidal target of DDT, pyrethroids, pyrethrins, and other minor classes of insecticides, lines the outer surface of the neurons and functions as the voltage-dependent sodium ion pore (i.e., the pore opens or closes depending on the change in voltage). Upon the arrival of stimuli, this pore allows the selective entry of sodium ions into the neuron for a brief moment and then abruptly shuts down the flow (this phenomenon is called “inactivation”). Thereafter, the sodium channel goes through an internal rearrangement to recover its original state. Such an action causes a brief local equalization of sodium ions between the outside and the inside of the neuron (depolarization), and this change is sensed as a local signal for excitation by the affected neuron. These insecticides delay the shutdown process and furthermore delay the recovery process, resulting in a prolongation of the period of excitation. Insects thus affected continue in a state of hyperexcitation, leading to exhaustion and, at high doses of the insecticide, death.
The next important insecticidal target is acetylcholinesterase, which is attacked by organophosphorus and carbamate insecticides. This enzyme, by inducing hydrolysis, inactivates the interneu-ron nerve transmitter acetylcholine. This excitatory transmitter is released upon the arrival of a signal from the distal end of one neuron, travels across the intercellular gap, arrives at the frontal end of the second neuron, and reacts with its specific acetylcholine receptor on the surface that sends the signal of excitation to the second neuron. It is important to stress here that such a successful signal transmission must be followed with an abrupt termination of the action of the transmitter; this allows for the second neuron to recover quickly enough and thereby stay ready for the next message, maintaining the normal function of the message-transmitting neuron. This termination action is mainly carried out by acetylcholinesterase, which eliminates acetylcholine from the vicinity of the acetylcholine receptor of the second neuron. All organophosphorus and carbamate insecticides, or their active metabolites, show potent inhibitory actions on acetylcholinesterase of insects as well as other animals. The insects affected by these chemicals show overt signs of excitation, exhaustion and, at sufficient doses, death.
The acetylcholine receptor also can be deactivated to cause the same type of hyperexcitation. Indeed, nicotinoids (which include naturally occurring nicotine analogues and their modern derivatives, sometimes called “neonicotinoids”), such as imidacloprid, are known to directly activate the acetylcholine receptor, just like acetylcholine. Nicotine’s excitatory action is well known. Neonicotinoid derivatives readily penetrate the insect’s body and nerve sheath, arriving at critical sites of neurons, and persisting there long enough to exert a powerful excitant effect.
The GABA receptor, in contrast, acts as the receiver for the inhibitory transmitter, GABA. That is, unlike acetylcholine, it is not an excitatory transmitter. The signal generated by this GABA-GABA receptor interaction is converted to the opening of chloride channels, which upon the arrival of the signal permit Cl~ ions to come into the signal-receiving cells (either neurons or muscle cells), to make them nonresponsive to excitation stimuli. Those insecticides—chlorinated hydrocarbon insecticides, cyclodienes (such as y-HCH, dieldrin, endosulfan, and toxaphene), and more modern insecticides (such as fipronil)—render the chloride channel inoperative so that chloride ions cannot come into the cells. Cells thus affected fail to receive the inhibitory signal of GABA and therefore cannot counterbalance any excitatory forces. One group of insecticides, avermectin analogues, keep the chloride channel stuck in the open position, an action opposite from that of the excitation-inducing insecticides. These compounds induce long-lasting inhibition of excitation in insects. Insects thus affected by avermectin analogues show diminished activities, nonresponse to stimuli, and slow death through paralysis.
Certainly there are other mechanisms by which normal functions of insects may be affected. The main ones are as follows:
1. Mitochondrial poisons, such as rotenone, which causes respiratory failure.
2. I nhibitors of cuticle formation, via the action of dimilin, including the rest of the diflubenzyron derivatives, which cause difficulty in molting and maintaining protective shields.
3. Insect hormone mimics such as juvenile hormone analogues that keep affected insects as immature forms (this method is effective against insects that cause damage only as adults, e.g., mosquitoes). Another group is ecdysone analogues, which affect insect development, including molting.
4. Bt toxins, which mainly affect the potassium channel in insect digestive systems.
5. Formamidine analogues, such as chlordimeform, which mimics octopamine, a naturally occurring transmitter/hormone, by acting on its receptor. Octopamine is used by insects and mites to control their behavior (among many of its actions), and therefore chlo-rdimeform analogues are known to modify many behavioral patterns of insects and mites, and thereby protect crops from those pests.
INSECTICIDE RESISTANCE
In 1958, A.W. A. Brown’s landmark publication, Insecticide Resistance in Arthropods, established the principle that insects as well as other related invertebrates are capable of developing resistance to insecticides through natural selection. The probability of the development of resistance largely depends on (1) the frequency of the resistance-conferring gene in the given population, (2) the level of selection pressure, (3) the degree to which resistant gene density is diluted by susceptible genes through influx of individuals from untreated areas, and (4) the stability of the resistance gene in the given population. In some cases, once established, resistance genes may persist in the same locality for many years. A good example may be the pyrethroid resistance of the moth Helicoverpa armigera in Australia.
How insects develop resistance to insecticides is a topic that has fascinated many entomologists. Basically, there are two major ways through which insect pests acquire resistance: increased detoxification capabilities and alteration of the insecticide target sites (target sensitivity). The first type of resistance occurs more frequently than the second type, as well as all others. Detoxification of toxic insec-ticidal chemicals is carried out by specialized enzymes designed to handle all chemicals toxic to insects, not just insecticides. Insects, particularly those feeding on plants that produce naturally large amounts of toxic chemicals, have well-developed detoxification enzymes. There are three major types of detoxification enzymes: (1) broad-spectrum oxidases such as mixed function oxidases catalyzed by cytochrome P450, (2) hydrolases that break up esters, ethers, and epoxides, and (3) conjugation systems such as glutathione S-transferase, which are mediated to cover up the reactive part of the toxic chemical and further facilitate its removal. Every type of detoxification enzyme has been documented to play a role in the development of some form of resistance against various classes of insecticides.
In determining which type of detoxification enzymes will become the key player in the development of resistance, the most important factor for consideration is the chemical properties of the insecticide. For instance, carbamates and pyrethrins are readily detoxified by mixed function oxidases; therefore, if resistance is reported against these insecticides, one must first look for increased activities of mixed function oxidases in the resistant insects. If higher activity levels are found, the resistance spectrum (i.e., cross-resistance of carbamate-resistant insects to other types of insecticide) is usually wide because mixed function oxidases are capable of detoxifying chemicals of many different types. In contrast, organophos-phorus and pyrethroid insecticides are mainly degraded by hydrolases. Thus, the involvement of an increased hydrolytic enzyme activity may be suspected when insects develop resistance against these chemicals.
A good example of this is malathion resistance. Malathion molecules contain two extra carboxylic acid ethyl ester parts. Malathion-resistant insects always show increased carboxylesterase activity. Esterases of these types are not broad-spectrum enzymes, and therefore malathion resistance is usually specific (i.e., usually the insects resistant to malathion are not resistant to other insecticides). Insecticides with labile halogens, epoxides, methoxy unsatu-ration, and some aliphatic unsaturation may be degraded through these glutathione-mediated detoxification systems, and hence their elevated presence could be suspected to cause resistance. This scheme is, however, merely a rough guess about the possible mechanism of development of metabolic resistance. Indeed, unexpected and unique resistance mechanisms have been reported to occur in some combinations of insecticides and insects (e.g., DDT resistance in Drosophila ) . The recommended method of identification of the metabolic cause is to co-treat insects with the insecticide and specific inhibitors for each type of metabolic detoxification system, such as piperonyl butoxide for mixed function oxidase and DEF for esterases.
In studies of mechanisms for target insensitivity resistance, mutations occurring in the sodium channel, the GABA receptor, and acetylcholinesterase have been found in insects resistant to DDT/ pyrethroids, cyclodiene insecticides, and organophosphorus and car-bamate insecticides, respectively. Those resistances are characterized by their specificity (low degrees of cross-resistance) and the general stability of resistance among insect populations in given localities.
REGULATIONS OF INSECTICIDE USES
Insecticides, like all other types of pesticide, are highly regulated by governments in all countries. In the United States, the main law governing the use of insecticides is the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), which mandates registration with the U.S. Environmental Protection Agency of all insecticides used in the country. The initial data requirements for successful registration (so-called Tier 1) depend on the extensiveness of the projected use, the levels of acute toxicity of the agent contemplated, its effectiveness as an insect control agent (called “efficacy”), the intended modes of usage, and the availability of background knowledge, among other requirements. Occasionally, experimental use permits are given after this Tier 1 examination/process (e.g., for insect pheromones, which are already known to be almost nontoxic and are to be used only for a specific pest in small areas). Usually, however, registrants are required to go through a much more extensive and rigorous process of registration, data procurement, and evaluation. For example, extensive tests are required for acute, chronic (such as carcinogenicity tests), genetic, pathogenic, reproductive, hormonal, and immune toxicities along with the environmental behavior of chemicals and limited wildlife toxici-ties. Such registration processes, which must be completed before a new chemical pesticide can be sold in the United States, typically require 7-10 years and roughly $100 million.
Despite the thoroughness of the registration processes, occasionally problems come to the attention of the scientific community or the regulatory agencies. Sometimes, for example, old pesticides are not registered despite the availability of extensive records of their actual use. This is partly the result of the relative ease of the registration process in the past and partly from the absence of the main registrant, who is not economically motivated to reregister the compound because the patents for those chemicals (and thereby the exclusive marketing right) have expired. The second type of problem is due to the failure of the regulatory agency/scientific community to address the special vulnerability of certain groups of human populations or ecosystems. Examples include the lack of toxicological data on infants and embryos, women, and the aged, and science’s incomplete understanding of the hormonal effects of pesticides on humans and wildlife. The third type of problem is caused mostly by unforeseen scientific or technological developments, or unfortunate circumstances that are difficult to predict. The question of the safety of genetically modified crops and the assessment of strategies to study the recently discovered skin-hypersensitizing action of some pesticides serve as examples.
A recent trend is to look at this issue from the consumer’s side. A good example is the enactment of the Food Quality Protection Act (FQPA), which addresses the presence of pesticide residues and other toxic chemicals in food and drinking water. A key part of this regulation is the consideration of children’s health. Here, an extra safety factor of 10 X is demanded to accommodate the postulated extra vulnerability of embryos, infants, and developing children. This requirement is enforced unless registrants can provide actual safety data to demonstrate that the susceptibility of these groups to the hazardous effects of the compound is equal to or less than that of adults.
I n the end, the toxicological methods of evaluation, including overall risk assessment approaches, address the majority of health concerns. Future improvements are needed, however, to deal with unresolved environmental and human health risks.
