Research Article: Neurotoxicity and Mode of Action of N, N-Diethyl-Meta-Toluamide (DEET)

Date Published: August 7, 2014

Publisher: Public Library of Science

Author(s): Daniel R. Swale, Baonan Sun, Fan Tong, Jeffrey R. Bloomquist, Dmitri Boudko.


Recent studies suggest that N, N-diethyl-meta-toluamide (DEET) is an acetylcholinesterase inhibitor and that this action may result in neurotoxicity and pose a risk to humans from its use as an insect repellent. We investigated the mode of action of DEET neurotoxicity in order to define the specific neuronal targets related to its acute toxicity in insects and mammals. Although toxic to mosquitoes (LD50 ca. 1.5 µg/mg), DEET was a poor acetylcholinesterase inhibitor (<10% inhibition), even at a concentration of 10 mM. IC50 values for DEET against Drosophila melanogaster, Musca domestica, and human acetylcholinesterases were 6–12 mM. Neurophysiological recordings showed that DEET had excitatory effects on the housefly larval central nervous system (EC50: 120 µM), but was over 300-fold less potent than propoxur, a standard anticholinesterase insecticide. Phentolamine, an octopamine receptor antagonist, completely blocked the central neuroexcitation by DEET and octopamine, but was essentially ineffective against hyperexcitation by propoxur and 4-aminopyridine, a potassium channel blocker. DEET was found to illuminate the firefly light organ, a tissue utilizing octopamine as the principal neurotransmitter. Additionally, DEET was shown to increase internal free calcium via the octopamine receptors of Sf21 cells, an effect blocked by phentolamine. DEET also blocked Na+ and K+ channels in patch clamped rat cortical neurons, with IC50 values in the micromolar range. These findings suggest DEET is likely targeting octopaminergic synapses to induce neuroexcitation and toxicity in insects, while acetylcholinesterase in both insects and mammals has low (mM) sensitivity to DEET. The ion channel blocking action of DEET in neurons may contribute to the numbness experienced after inadvertent application to the lips or mouth of humans.

Partial Text

The insect repellent N, N-diethyl-meta-toluamide (DEET) is used more often than any other mosquito repellent, with over 200 million users, worldwide [1]. Because there is deliberate and widespread human exposure to DEET from its use as an insect repellent, questions have arisen regarding its toxicological profile and risk to humans. A recent study [2] suggested the toxic action of DEET may be due to an anticholinesterase effect, with implications for human safety. Large oral doses (blood concentration of 1 mmol/liter) of DEET lead to nausea, vomiting, bradycardia, and seizures [3], [4], as well as cardiotoxicity [5] in exposed humans. Contact exposure to DEET also has the potential for dermal effects, as it can lead to numbness and redness of the affected area [6]. The numbing sensation appears similar to that observed with local anesthetics, such as lidocaine, suggesting DEET might be acting on neuronal ion channels to yield an anesthetic-like effect.

DEET is of relatively low acute toxicity to insects and mammals. It is unlikely that DEET exerts its toxicity through anticholinesterase action because of its low potency for enzyme inhibition and the complete block of its neuroexcitation in housefly CNS by phentolamine, which does not occur with propoxur or 4-AP. DEET toxicity to houseflies, and likely mosquitoes, is mediated by central octopaminergic pathways via activation of octopamine receptors. The poisoning signs caused by DEET reflect an excitatory octopaminergic effect in combination with peripheral neurosuppressive actions. The low potency of DEET for inhibiting human acetylcholinesterase makes it unlikely to cause toxicity by this mechanism. Numbness of mammalian mucous membranes is explained through anesthetic-like effects of DEET on nerve conduction.