For Tomorrow's Infantry: SS-220, a Gunsight-friendly Insect Repellent

Since 1948, military men and women have smeared on DEET, otherwise known as N,N-diethyl-3-methylbenzamide, to repel the itchy, the deadly, and the otherwise annoying. DEET is effective but unloved--it literally melts plastic--and the US military has been working for some time to find a replacement. The newcomer is called SS-220. At the army's Aberbeen Proving Ground in Maryland, SS-220 has passed toxicity tests for short-duration exposure. Lab tests with human volunteers and mosquitoes, Anopheles stephensi (a malaria carrier) and Aedes aegypti (a yellow fever carrier) confirm that SS-220 repels as well as DEET.1 Col. Daniel Strickman of the Walter Reed Army Institute of Research, in Washington, DC, who has access to one of the few sand fly colonies in the country, says that SS-220 equals DEET in repelling the sand flies, which transmit leishmaniasis. A company now negotiating to develop SS-220 "has done its homework" says Jerome Klun, research entomologist at the Department of Agriculture's (USDA) Beltsville Agricultural Research Center in Maryland. Klun, the developer of the substance, says he believes SS-220 will be "cosmetically more pleasing" than DEET. Though from different compound classes, DEET and SS-220 have a common place of origin the USDA. SS-220 has been around since 1978, though not in its current form. A13-37220 (1-[3-cyclohexen-1-ylcarbonyl]-2-methylpiperidine) was a highly praised racemate comprising SS-220 and three other stereoisomers. Challenging DEET across the board, A13-37220 generated excitement in the early 1980s that, unfortunately, generated a little too much public attention. Its chemical structure and repellent potential became matters of public record, grounding the patent process. Research, however, continued. "Extensive field studies showed [A13-37220] was 40 to 50% better than DEET in terms of duration," says Strickman. Ultimately the repellent's building reputation brought reversal of fortune. In the mid-1990s, Klun decided to examine A13-37220's stereoisomers individually. His team faced big obstacles. Not only did they need to separate the four compounds, they needed new assays, too. Repellent assays available at that time required orders of magnitude more than the milligram quantities they could isolate. Overcoming those difficulties consumed several years of work before Klun learned his hunch was right: Among the isolates, SS-220 was a standout repellent, actually superior to its parent.2 Public attention was largely avoided, and the SS-220 patent was issued in May. Aberdeen biologist Hubert L. Snodgrass says that now that SS-220 has passed toxicity tests for exposure of short duration, it must pass safety tests for cancer and mutagenicity at a 90-day exposure. If it does so, this molecule, which Snodgrass calls "the best new repellent in 50 years," will then need a topical formulation with long-lasting protection that the troops will accept. ETCHED IN PLASTIC Dethroning DEET requires multifaceted excellence. Potency is not enough: The interloper also must repel as long as DEET; the spectrum of insect genera repulsed must be as broad; feel and smell must be superior; and safety goes without saying. Particularly challenging has been matching DEET's duration. Numerous repellents are just as potent but fade much faster, says Joel R. Coats, professor of entomology and toxicology at Iowa State University in Ames. Courtesy of Jerome Klun BUG BUGGERS: US Department of Agriculture research entomologist, Jerome Klun (right), and team chemist Ashot Khrimian with 1kg of SS-220 test solution. The official army repellent is 33% DEET mixed into a polymer cream that prolongs its duration. It's "a bit less thick than toothpaste," says Strickman. While it's understandable that soldiers would want to avoid such a cream and instead turn to medicine-cabinet remedies for relief, the risks are serious. Consider Vietnam: The army lost an estimated 2 million man-days to malaria due in part to a dislike of DEET. The plastic problem is another issue. Press a DEET-coated thumb into many kinds of plastic and its dissolving action quickly preserves a thumbprint for posterity. To prevent this sort of thing, "Army equipment is actually designed around DEET," Strickman says. Before the army approves new equipment such as a gas mask or gunsight, suppliers must show that DEET won't soften plastic parts. The product is a major reason that army eyeglass lenses are made of polycarbonate. Susceptible plastics are permitted only when they have an inconsequential use. Plastic frames for eyeglasses, grasped in DEET-covered fingers, are a sticky mess, says Strickman. The great outdoors aren't always so great: Insects abound. They include: mosquitoes, body lice, ticks, chiggers, fleas, biting midges, kissing bugs, and flies galore--filth flies, black flies, bot flies, sand flies, deer flies, horse flies, tsetses, and tumbas. Battle gear must include a first-line defense against arthropod-borne infections, most often malaria, dengue, yellow fever, and leishmaniasis, but also viral encephalitis, three forms of typhus, spotted fever, Lyme disease, plague, visceral filariasis, onchocerciasis, myiasis, and tularemia. LEVELS OF REPULSION Strickman makes several broad observations regarding DEET. Population selection for DEET resistance is unknown, but variable response to DEET within a species does occur. Repellency also differs between species; for example, another malaria carrier, Anopheles albimanus, is about 10 times less susceptible to DEET than Aedes aegypti. Precisely the same species difference exists with SS-220, suggesting to Strickman a common mode of action. A mosquito, he explains, detects multiple signals as it homes in. Body heat is one; another is carbon dioxide expelled from the lungs. Closer to the skin, it is believed mosquitoes detect lactic acid secretions. A long-standing hypothesis states that repellents block lactic acid receptors on antennae, so "somehow they tell the mosquito it is not on a host, and it doesn't bite," says Strickman. This mechanism contrasts with that of naphthalene in mothballs, which is an irritant to moths. Lactic acid-receptor blockade seems unlikely to explain DEET's repellent mechanism, however, says Coats. Cockroaches, which do not bite, are also repelled by DEET. Rui-de Xue and colleagues at the Center for Medical, Agricultural, and Veterinary Entomology in Gainesville, Fla., learned that weak solutions (0.1%) of DEET and A13-37220 devastate first-instar mosquito larvae, killing more than 95%.3 What's more, lingering repellent deters mosquitoes from laying eggs for several months. GULF WAR ILLNESS As SS-220 safety studies proceed, the unique environment of the battlefield has led to reexamining the safety of DEET. Following the first US-Iraqi war, various maladies and symptom combinations appeared that together were eventually termed Gulf War Illness. Probes for its cause included investigations of chemical exposures, and in the case of DEET, produced a surprise. At North Carolina State University in Raleigh, pharmacologists led by Jim E. Riviere studied how oral pyridostigmine bromide and topical permethrin affected DEET penetration into the skin of pigs.4 Permethrin, an insecticide sprayed on military uniforms, kills ticks. Pyridostigmine bromide is used prophylactically to enhance survival after exposure to Soman nerve gas. Topical permethrin alone does not affect DEET absorption, but combinations of oral nerve agent and pyridostigmine bromide exposure do, thus increasing DEET absorption fivefold. Pyridostigmine bromide similarly enhanced permethrin absorption. For topical-agent pharmacologists, it's headline news that an oral drug has such an effect, according to Riviere. "People doing dermal exposure studies tend to ignore that there's a body attached to the skin," he quips. Riviere did not study whether increased absorption is harmful, nor can he connect DEET with Gulf War Illness. But his work suggests that repellent risk assessments for soldiers might not be the same as for civilians. Even if DEET's long-standing place is usurped by SS-220, DEET probably will not disappear entirely from a soldier's backpack: Plans are afoot to incorporate DEET into camouflage facepaint. Tom Hollon (thollon@starpower.net) is a freelance science writer in Rockville, Md. References 1. J.A. Klun et al., "Synthesis and repellent efficacy of a new chiral piperidine analog: Comparison with DEET and Bayrepel activity in human-volunteer laboratory assays against Aedes aegypti and Anopheles stephensi," J Med Entomol, 40:293-9, May 2003. 2. J.A. Klun et al., "Stereochemical effects in an insect repellent," J Med Entomol, 38:809-12, 2001. 3. R.D. Xue et al., "Laboratory and field evaluation of insect repellents as larvicides against the mosquitoes Aedes albopictus and Anopheles albimanus," Med Vet Entomol, 15:374-80, 2001. 4. J.E. Riviere et al., "Percutaneous absorption of topical N,N-diethyl-m-toluamide (DEET): Effects of exposure variables and coadministered toxicants," J Toxicol Environ Health, 66:133-51, Jan. 24, 2003. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

For Tomorrow's Infantry: SS-220, a Gunsight-friendly Insect Repellent

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