Botanical insecticides have long been touted as attractive alternatives to synthetic chemical insecticides for pest management because botanicals reputedly pose little threat to the environment or to human health. The body of scientific literature documenting bioactivity of plant derivatives to arthropod pests continues to expand, yet only a handful of botanicals are currently used in agriculture in the industrialized world, and there are few prospects for commercial development of new botanical products. Pyrethrum and neem are well established commercially, pesticides based on plant essential oils have recently entered the marketplace, and the use of rotenone appears to be waning. A number of plant substances have been considered for use as insect antifeedants or repellents, but apart from some natural mosquito repellents, little commercial success has ensued for plant substances that modify arthropod behavior. Several factors appear to limit the success of botanicals, most notably regulatory barriers and the availability of competing products (newer synthetics, fermentation products, microbials) that are cost-effective and relatively safe compared with their predecessors. In the context of agricultural pest management, botanical insecticides are best suited for use in organic food production in industrialized countries but can play a much greater role in the production and postharvest protection of food in developing countries.

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Botanical insecticides, deterrents, and repellents in modern agriculture and an increasingly regulated world

Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub- to low-mug/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for approximately 60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research.

Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: a review and roadmap for research.

As the largest class of natural products, terpenes have a variety of roles in mediating antagonistic and beneficial interactions among organisms. They defend many species of plants, animals and microorganisms against predators, pathogens and competitors, and they are involved in conveying messages to conspecifics and mutualists regarding the presence of food, mates and enemies. Despite the diversity of terpenes known, it is striking how phylogenetically distant organisms have come to use similar structures for common purposes. New natural roles undoubtedly remain to be discovered for this large class of compounds, given that such a small percentage of terpenes has been investigated so far.

The function of terpene natural products in the natural world.

▪ Abstract The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-π interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate ...

NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action

Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense

Insecticide research led to the first "complete" victories in combatting pests almost 50 years ago with the chlorinated hydrocarbons followed quickly by the organophosphates, methylcarbamates, and pyrethroids--all neuroactive chemicals. This Golden Age of Discovery was the source of most of our current insecticides. The challenge then became health and the environment, a Golden Age met with selective and degradable compounds. Next the focus shifted to resistance, novel biochemical targets, and new chemical approaches for pest control. The current Golden Age of Genetic Engineering has curtailed, but is unlikely to eliminate, chemical use on major crops. Insecticide research, having passed through several Golden Ages, is now in a renaissance of integrating chemicals and biologicals for sustainable pest control with human safety.

Golden age of insecticide research: past, present, or future?

https://cfpub.epa.gov/ncer_abstracts/index.cfm/fuseaction/display.files/fileID/13730

Organophosphate toxicology: safety aspects of nonacetylcholinesterase secondary targets.

A peptide (Manduca sexta allatostatin) that strongly inhibits juvenile hormone biosynthesis in vitro by the corpora allata from fifth-stadium larvae and adult females has been purified from extracts of heads of pharate adult M. sexta by a nine-step purification procedure. The primary structure of this 15-residue peptide has been determined: pGlu-Val-Arg-Phe-Arg-Gln-Cys- Tyr-Phe-Asn-Pro-Ile-Ser-Cys-Phe-OH, where pGlu is pyroglutamate). To our knowledge, this neuro-hormone has no sequence similarity with any known neuropeptide from other organisms. The synthetic free acid and amide forms showed in vitro activity indistinguishable from that of native M. sexta allatostatin. The ED50 of synthetic M. sexta allatostatin on early fifth stadium larval corpora allata in vitro was approximately 2 nM. This inhibition was reversible. In a cross-species study, M. sexta allatostatin also inhibited the corpora allata of adult female Heliothis virescens but had no effect on the activity of corpora allata of adult females of the beetle Tenebrio molitor, the grasshopper Melanoplus sanguinipes, or the cockroach Periplaneta americana.

https://www.pnas.org/content/pnas/88/21/9458.full.pdf

Identification of an allatostatin from the tobacco hornworm Manduca sexta.

Purification and characterization of two classes of neurotoxins from the funnel web spider, Agelenopsis aperta.

Neuropathy target esterase (NTE) is involved in neural development and is the target for neurodegeneration induced by selected organophosphorus pesticides and chemical warfare agents. We generated mice with disruptions in Nte, the gene encoding NTE. Nte(-/-) mice die after embryonic day 8, and Nte(+/-) mice have lower activity of Nte in the brain and higher mortality when exposed to the Nte-inhibiting compound ethyl octylphosphonofluoridate (EOPF) than do wild-type mice. Nte(+/-) and wild-type mice treated with 1 mg per kg of body weight of EOPF have elevated motor activity, showing that even minor reduction of Nte activity leads to hyperactivity. These studies show that genetic or chemical reduction of Nte activity results in a neurological phenotype of hyperactivity in mammals and indicate that EOPF toxicity occurs directly through inhibition of Nte without the requirement for Nte gain of function or aging.

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Gary B. Quistad

Papers

Golden age of insecticide research: past, present, or future?

Organophosphate toxicology: safety aspects of nonacetylcholinesterase secondary targets.

Identification of an allatostatin from the tobacco hornworm Manduca sexta.

Purification and characterization of two classes of neurotoxins from the funnel web spider, Agelenopsis aperta.

Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity.