DEET, Already linked to Gulf War illness, Now linked to Neural Damage in Mice

More research needed to see if compound has same effect in humans, experts say

By Amanda Gardner, HealthDay Reporter

WEDNESDAY, Aug. 5 (HealthDay News) -- New French research suggests the main ingredient used in many insect repellants may affect the central nervous system, at least in mice.

And combining this ingredient -- DEET (N,N-Diethyl-3-methylbenzamide) -- with carbamates, a type of pesticide that is often used with DEET, compounded the effects.

Although the authors, publishing online Aug. 5 in BMC Biology, warn of potential dangers to humans, they also acknowledge the need for more studies on the subject.

Meanwhile, people should probably worry more about the health risks from mosquitoes and other insects than about the potential harms of DEET, experts said.

"This work was done primarily in test tubes in order to try to understand some of the mechanisms," said Dr. Ted Schettler, science director of the Science & Environmental Health Network. "The mechanistic information is very useful but the jury is still out on what implications this has for humans."

"DEET has been used for a very long time with very few bad outcomes," added Susan Paskewitz, a professor of entomology at the University of Wisconsin, Madison. "People have killed themselves by drinking it, but you can do that with alcohol or salt. And a few have had neurological symptoms after application for long periods and high doses."

As for the combination of DEET and carbamates, Paskewitz added, "if there are the kinds of synergies suggested by the study, they aren't happening very often. I also would guess that the actual concentration in the body is much lower than they had to use in the study to see an effect in the mouse tissues."

But by better understanding the mechanisms by which DEET works, scientists may be able to come up with better repellant products, said Paul Sanberg, distinguished professor of neurosurgery and director of the University of South Florida Center for Aging and Brain Repair in Tampa.

DEET is the most common active ingredient in insect repellents and is used worldwide by about 200 million people annually. However, relatively little is known about how the compound actually works.

From this study, it now appears that not only does DEET change the behavior of insects, it also inhibits the acetylcholinesterase enzyme, which is involved in the central nervous system, in both insects and mice.

Organophosphates and carbamate insecticides employ the same mechanism of action and, when combined with DEET in these experiments, increased the toxicity of the chemicals.

"This study demonstrates the vital importance of looking at chemicals in combination," Schettler said. "This shows that when you combine chemicals, you can get unpredictable results."

The authors, from different research institutions in France, say this is the first time a molecular target for DEET has been identified.

Interestingly, the class of drugs known as cholinesterase inhibitors are used to treat Alzheimer's and can delay the decline of symptoms for up to a year.

Sanberg said the effects of DEET, like many chemicals and drugs, can simply depend on the individual using it.

An earlier study found a strong association between exposure to acetylcholinesterase inhibitors and the Gulf War illness suffered by many veterans. Organophosphates have also been linked with acute lymphoblastic leukemia, the most common form of leukemia in children.

More information

The U.S. Environmental Protection Agency has more on DEET.

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Popular Insect Repellent Deet Is Neurotoxic

(ScienceDaily - Aug. 6, 2009) — The active ingredient in many insect repellents, deet, has been found to be toxic to the central nervous system.

Researchers say that more investigations are urgently needed to confirm or dismiss any potential neurotoxicity to humans, especially when deet-based repellents are used in combination with other neurotoxic insecticides.

Vincent Corbel from the Institut de Recherche pour le Développement in Montpellier, and Bruno Lapied from the University of Angers, France, led a team of researchers who investigated the mode of action and toxicity of deet (N,N-Diethyl-3-methylbenzamide). Corbel said, "We've found that deet is not simply a behavior-modifying chemical but also inhibits the activity of a key central nervous system enzyme, acetycholinesterase, in both insects and mammals".

Discovered in 1953, deet is still the most common ingredient in insect repellent preparations. It is effective against a broad spectrum of medically important pests, including mosquitoes. Despite its widespread use, controversies remain concerning both the identification of its target sites at the molecular level and its mechanism of action in insects. In a series of experiments, Corbel and his colleagues found that deet inhibits the acetylcholinesterase enzyme – the same mode of action used by organophosphate and carbamate insecticides.

These insecticides are often used in combination with deet, and the researchers also found that deet interacts with carbamate insecticides to increase their toxicity. Corbel concludes, "These findings question the safety of deet, particularly in combination with other chemicals, and they highlight the importance of a multidisciplinary approach to the development of safer insect repellents for use in public health".

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Journal reference:

1. Vincent Corbel, Maria Stankiewicz, Cedric Pennetier, Didier Fournier, Jure Stojan, Emmanuelle Girard, Mitko Dimitrov, Jordi Molgo, Jean Marc Hougard and Bruno Lapied. Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet. BMC Biology, (in press) [link]

Adapted from materials provided by BioMed Central, via EurekAlert!, a service of AAAS.

Israeli Conference Focuses on Central Nervous System Damage by Chemicals

Coping with a toxic world

July 4, 2009
Written by JUDY SIEGEL-ITZKOVICH, The Jerusalem Post

There are some 80,000 man-made chemicals in the industrial environment, but only a handful of them - lead, mercury manganese, acrylamide, organophosphates, heavy metals and organic solvents - have been fully tested for potential health risks.

Prof. Donald Fox (left) of Houston and Prof. Yoram Finkelstein of Jerusalem.
Photo: Judy Siegel-Itzkovich

The realization that chemicals can damage the central nervous system is not very old, so there are not many specialists with extensive knowledge of both neurology and toxicology. Eighty of these interdisciplinary experts from 16 countries, including the US, Israel, Nigeria, Japan, Estonia, Poland, Spain, Italy, the UK, India and France met last month at the Kibbutz Ma'aleh Hahamisha Guest House outside Jerusalem to discuss the latest discoveries in the field. Few of the foreign participants had ever been here.

The five-day biennial meeting of the International Neurotoxicology Association (INA) focused on Gene-Environment Interactions in Neurotoxicology and was co-chaired by Prof. Yoram Finkelstein, director of the unit of neurology & toxicology at Jerusalem's Shaare Zedek Medical Center, and by Dr. William Boyes, INA's president. The chairman of the scientific advisory committee was Prof. Donald Fox, an expert in vision science, biology, biochemistry and pharmacology at the University of Houston in Texas.

The INA, with 300 paying members - including fewer than 10 Israelis - aims to promote science and communications among countries and foster the education of medical students. It was the 12th biennial conference, and the first outside the US or Europe.

The aim of the conference was to promote greater awareness of chemicals' adverse effects on the nervous system, update experts on the latest research and provide information to regulators. Over 70 papers were delivered on subjects ranging from how children's exposure to agricultural pesticides may be responsible for the increase in attention deficit to how chronic exposure to organic solvents can lead to schizophrenia and depression. They looked at interactions between genetic inheritance and exposure to toxins, policies to reduce exposure, and how to prevent damage to health.

FINKELSTEIN has worked a great deal on the effects of chemicals on the retina and brain, especially in animals during gestation and shortly after birth. Neurotoxicology, he said in an interview, "is a combination of two very different fields, so there aren't many who specialize in it. As far as I know, I am the only physician in Israel who deals with it."

He studied neurology at Haifa's Technion-Israel Institute of Technology's Rappaport Medical School, and went on to the Weizmann Instite of Science in Rehovot to study neurochemistry. Moving to the Rambam Medical Center, he worked at its National Poison Control Center, where experts receive calls from doctors and the general public - especially parents - who fear that someone was poisoned. Finkelstein later moved to Jerusalem and joined Shaare Zedek, where he has been for two decades.

Fox, who was born in Cleveland, went to California for his postdoctoral work, and then to Texas to conduct research. Unlike other foreigners at the conference, he has visited Israel four times.

Although pulverized asbestos in the air and other pollutants can cause disease in the lungs and other organs, Fox specializes in substances from chemical and pharmaceutical industries, and chronic damage rather than acute injury. "Half of all long-term, low-level toxicity is related to the body's neurological system, because it is much more complex and has more cell types, with every part of the system susceptible, but at even lower concentrations."

Fox said 900,000 inner-city children in Washington, DC were affected by lead. The use of lead paints in the US was prohibited in 1959, so lead poisoning of US slum children from paints on furniture and peeling walls is much less common now, but low-level lead poisoning from lead water pipes, industrial air pollution and other sources "is most insidious. About 80% of learning disabilities result from levels of lead the US government say are safe."

The element, which has a sweet taste and thus is happily chewed by children, doesn't decay. "It remains in the dust, in the air, in the water - especially in poor areas. It accumulates in the bones. And children who were exposed to lead have grown up and are having children now, and they too can be affected," Fox explained.

Fox also noted that for many years, there were toys painted with or containing lead. "It doesn't kill children, but it can cause irreversible sensory, motor and cognitive deficits. Acute toxicity of a variety of chemicals can cause death, but we are mostly interested in the effects of long-term low levels."

The trigger for damage can appear in the fetus if the mother is exposed to toxic chemicals, but the effect can also appear decades later, said Finkelstein.

Harmful heavy metals are mostly found in factories, he said, but can also be found in nature. Volcanoes such as Krakatoa in Indonesia spread toxic heavy metals by air currents. Yet man-made chemicals that can damage health go back to the beginning of human history. "In the time of the pharoahs, lead was used for making ceramics, and was also put into makeup," said Finkelstein.

Toxic chemicals can cause symptoms that usually occur in chronic disease, such as parkinsonian tremors. Fox notes that there were very few cases of Parkinson's before 1817, when it was named - largely because people died at much younger ages from pre-antibiotic infections. But exposure to manganese or chemical solvents can create Parkinson-like symptoms. The condition called "Gulf War syndrome" suffered by US soldiers in Iraq was due to chemical exposure there, he continued.

The expert from Texas said he would not bar the use of very toxic chemicals but regulate them to prevent exposure to at-risk populations such as pregnant women, young children, the elderly and people with chronic disease or weak immune systems.

"Individuals with such disorders have to be supervised and treated differently when exposed to pollutants."

Fox, who lives two kilometers from downtown Houston, said he was well aware of pollution's toll in most city centers. "Although gasoline is cleaner today, cars still produce sulphur dioxides, nitric oxides and other dangerous particles. When water hits them, it becomes a source of acid rain. The US authorities allow 50 parts per million of arsenic in the water, but legislators are working to bring it down."

POLLUTION in China and India, with their huge populations, increased industrialization and growth in gas-powered vehicles, is growing daily, Fox continued. "India's city of Bangalore alone has 20 million people, with 3,000 new cars registered daily and no pollution controls. Environments are usually not protected during the initial stages of capitalism, so developing countries do not require catalytic converters."

Both Finkelstein and Fox use animals for research, and the animals are "brainier" species like cats or dogs. Instead, neurotoxicologists often use flies, worms, rats and zebrafish - which are commonly found in aquariums and have black and white stripes. "The brain and eyes of this little fish and man's surprisingly have a very similar biology," said Fox. "We have a lot of data on zebrafish."

Finkelstein continued that neurotoxicologists do their best to test without animal models. "We have a very good relationship with anti-vivisectionist organizations, as we are on their side. Cosmetics are quite safe in Israel, and are no longer tested for toxins because risky substances in the industry are gone."

The effects of chemicals on people are not uniform, Fox continued. "African Americans metabolize certain drugs differently than Caucasians. Diet also influences interaction with chemicals. Low-level lead exposure produces delayed-onset obesity only in male animals, so reaching conclusions about the effects of chemicals is very complicated."

In Israel, pesticides were a serious problem. The Health Ministry used to issue bulletins regularly when bug killers were used in excessive doses for strawberries. But today, pesticide use has declined somewhat due to natural enemies of bugs, as well as increasing public demand for low levels of pesticides and more organic products. Knesset members are also more aware of the dangers, said Finkelstein.

In the US, concluded Fox, "there are federal laws that set priorities for the testing of chemicals. Everybody wants to be protected, but politics and big money often interfere with the legislative process."

Fox concluded that the INA is "pleased to have its conference in Israel for the first time. We want to collaborate with our Israeli counterparts to develop the field. We hope that more legislation to protect the public from chemicals will be passed and that individuals and institutions will become more aware of the long-term effects of low-level exposure."