Background
Fipronil (5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)pyrazole-3-carbonitrile) (Figure 1), a compound that belongs to the phenylpyrazole family, is a broad-spectrum insecticide that is commonly used to eliminate fire ants, beetles, rootworms, ticks, termites, fleas (both larval and adult stages), grasshoppers, cockroaches, and many other kinds of insects. Fipronil has been known to cause central nervous system toxicity to insects. Due to its effectiveness, fipronil has been widely used in many commercial products that help eliminate common insects and pests. The safety concerns with fipronil involve the potential off-target effects of products which should be frequently observed to monitor long-term side effects and resistance development.
Source
Fipronil can be found in many commercialized pest control products such as:
- Ant/roach bait gel (e.g MAXFORCE FC Ant Killer Bait Gel)
- Granular pesticide (e.g. Taurus G Fipronil Granules)
- Termiticide/insecticide control products (e.g. Termidor)
- Spot-on or spray solution for dogs and cats (e.g. Frontline Plus Flea & Tick Large Breed Dog Treatment)
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Biotransformation
Fipronil can be metabolized by P450 enzymes. In general, there are three different pathways of fipronil metabolism. Fipronil can be reduced to fipronil sulfide, oxidized to fipronil sulfone, or hydrolyzed to fipronil amide (Figure 2). Animal studies have shown that fipronil sulfone is the major metabolite that can be detected in multiple organs such as brain, liver, and adipose tissues. Fipronil in the brain can be locally converted to the sulfone metabolite within 2-4 hours.
Toxicokinetics
Fipronil itself can induce oxidative stress via the molecular pathways that lead to antioxidant alteration, DNA and mitochondrial toxicities, and eventually apoptosis (Figure 3).
Regarding the metabolites of fipronil, fipronil sulfone is the major metabolite in the human and rat liver. Studies have shown that fipronil and its metabolites may be able to cross the blood-brain barrier. Fipronil-desulfinyl can reach a 10-fold higher potency in mammals, which raises a concern for neural toxicity in humans who have been exposed to fipronil. In addition, fipronil can also be metabolized to form hydroxylamine metabolites via another pathway that can generate reactive intermediates.
Fipronil is absorbed very slowly through the skin. It can remain on stratum corneum, viable epidermis, and pilo-sebaceous units with a longer half-life. If fipronil is administered orally, it can have slow absorption but a large volume of distribution. A study with orally administered fipronil showed that fipronil and its metabolites are mostly excreted in feces (45-75%) and in urine (5-25%).
Carcinogenicity
In animals, a two-year study in rats testing the highest dose showed evidence of benign and malignant follicular cell tumors. Rats fed with fipronil-desulfinyl only showed signs of toxicity without any evidence of carcinogenicity.
In humans, fipronil is classified as “Group C- possible human carcinogen” by the U.S EPA. Mutagenicity studies have not shown any evidence of mutations in human lymphocytes. Carcinogenic effects of fipronil have not been demonstrated in any studies in humans.
Mechanism of Action
Fipronil binds and blocks GABAA -gated chloride channels in the central nervous system. This causes the accumulation of GABA in the synaptic junctions and the inhibition of nerve transmission, resulting in neuronal hyperexcitability state, paralysis, and eventually death (Figure 4). Fipronil has a higher affinity for insect GABA receptors, which helps enhance the selectivity for insects and decrease the toxicity risks for mammals.
Organ(s)
Fipronil has been detected in:
- Liver
- Kidney
- Muscle
- Adrenal glands
- Fat (highest concentrations and longest half-life)
- Milk of lactating animals
Biomarker
Fipronil metabolites detected in organs mentioned above can be used as biomarkers to detect fipronil exposure.
Signs and Symptoms
Humans:
Oral ingestion – symptoms are often reversible and resolved spontaneously
- Sweating
- Nausea
- Vomiting
- Headache
- Abdominal pain
- Dizziness
- Agitation
- Weakness
- Toni-clonic seizure
Skin/eye exposure – mild symptoms
- Skin irritation, dermatitis
- Eye irritation
Inhalation – low toxicity if inhaled
Treatment and Prevention
Treatment of fipronil poisoning:
- Symptoms of inadvertent oral ingestion of fipronil are often reversible and resolved spontaneously
- Resuscitation and supportive care to improve the outcome
- Insufficient data to support activated charcoal use
- Gastric emptying procedures such as gastric lavage and forced emesis for liquid poisons are not encouraged due to low efficacy
- Ipecac is contraindicated due to seizure risks
- In case of seizures, follow the standard of care
Prevention:
- Always read and follow the instruction on the labels
- Wash clothes and body parts that have been exposed to fipronil
References
- National Pesticide Information Center (NPIC). Fipronil general fact sheet. Accessed from: http://npic.orst.edu/factsheets/fipronil.html#whatis.
- Wang X, Martínez MA, Wu Q, Ares I, Martinez-Larranaga MR, Anadón A, Yuan Z. Fipronil insecticide toxicology: oxidative stress and metabolism. Critical reviews in toxicology. 2016 Nov 25;46(10):876-99.
- Robea MA, Nicoara M, Plavan G, Strugaru SA, Ciobica A. Fipronil: mechanisms of action on various organisms and future relevance for animal models studies. Survey in Fisheries Sciences. 2018 Aug 10;5(1):20-31.
- Islam R, Lynch JW. Mechanism of action of the insecticides, lindane and fipronil, on glycine receptor chloride channels. British journal of pharmacology. 2012 Apr;165(8):2707-20.
- Mohamed F, Senarathna L, Percy A, Abeyewardene M, Eaglesham G, Cheng R, Azher S, Hittarage A, Dissanayake W, Sheriff MR, Davies W. Acute human self‐poisoning with the n‐phenylpyrazole insecticide fipronil—a gabaa‐gated chloride channel blocker. Journal of Toxicology: Clinical Toxicology. 2004 Jan 1;42(7):955-63.