CAS No. 120068-37-3
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ACTIVITY: Acaracide, Insecticide (pyrazole), Wood Preservative (to control termites)

CAS NAME: 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile



2004-2006 - US EPA CHEERS study in Jacksonville, Duval County, Florida.
This 2-year study of children's exposure to selected pesticides and chemicals has ignited enormous controversy. Fipronil was one of 16 pesticides selected to be monitored in children (ages 0-3 years). See FAN's updates on this study.

See reports available from The National Technical Information Service


Brain Res Bull. 2009 Mar 30;78(6):313-22.

Is fipronil safer than chlorpyrifos? Comparative developmental neurotoxicity modeled in PC12 cells.

Lassiter TL, MacKillop EA, Ryde IT, Seidler FJ, Slotkin TA.

Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. tll18@duke.edu

Fipronil, a GABA(A) receptor antagonist, is replacing many insecticide uses formerly fulfilled by organophosphates like chlorpyrifos. Few studies have addressed the potential for fipronil to produce developmental neurotoxicity. We compared the neurotoxicity of fipronil and chlorpyrifos in undifferentiated and differentiating neuronotypic PC12 cells, evaluating indices of cell replication, cell number, differentiation, and viability for short- and long-term exposures. Fipronil inhibited DNA and protein synthesis in undifferentiated PC12 cells and evoked oxidative stress to a greater extent than did chlorpyrifos, resulting in reduced cell numbers even though cell viability was maintained. In differentiating cells, fipronil displayed an even lower threshold for disruption of development, reducing cell numbers without impairing cell growth, and promoting emergence of neurotransmitter phenotypes; superimposed on this effect, the phenotypic balance was shifted in favor of dopamine as opposed to acetylcholine. Differentiation also enhanced the susceptibility to fipronil-induced oxidative stress, although antioxidant administration failed to provide protection from cell loss. At low concentrations maintained for prolonged periods, fipronil had a biphasic effect on cell numbers, increasing them slightly at low concentrations, implying interference with apoptosis, while nevertheless reducing cell numbers at higher concentrations. Our results suggest that fipronil is inherently a more potent disruptor of neuronal cell development than is chlorpyrifos. The neurodevelopmental effects are not predicated on GABA(A) antagonist properties, since PC12 cells lack the GABA(A) receptor. If fipronil is intended to provide greater safety than chlorpyrifos, then this will have to entail advantages from factors that are yet unexamined: exposure, persistence, pharmacokinetics.


Toxicology. 2009 Jan 8;255(1-2):38-44.

Fipronil-induced disruption of thyroid function in rats is mediated by increased total and free thyroxine clearances concomitantly to increased activity of hepatic enzymes.

Leghait J, Gayrard V, Picard-Hagen N, Camp M, Perdu E, Toutain PL, Viguié C.

UMR181 Physiopathologie et Toxicologie Expérimentales, INRA, ENVT, 23 Chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France.

Fipronil is a widely used phytosanitary product and insecticide for pets. In the rat, fipronil can disrupt thyroid function by decreasing plasma concentrations of total thyroxine (T4) likely through increased T4 clearance. However, the mechanism of fipronil action on thyroid function remains unclear. The goals of the present study were to evaluate the effects of fipronil on thyroid hormone (TH) concentrations and elimination in the rat under well characterized plasma exposure to fipronil and its main metabolite fipronil sulfone. In thyroid-intact female rats, fipronil treatment (3 mg/(kg day) per os for 14 days) decreased both total and free TH plasma concentrations concomitantly to increased thyroid stimulating hormone plasma concentrations. A T4-free euthyroid-like model consisting of thyroidectomized rats treated with tri-iodothyronine (12 microg/(kg day), sc) was developed to evaluate both total and free T4 clearances. In this model, fipronil treatment induced a twofold increase in total and free T4 clearances. The same fipronil treatment increased antipyrine clearance in thyroid-intact rats suggesting an increase in the activity of cytochrome P450 enzymes. Finally, this treatment was also associated with an increase in hepatic microsomal 4-nitrophenol UDP-glucuronosyltransferase activity involved in T4 glucuronidation. Thus, fipronil-induced thyroid disruption results from an increased rate of T4 elimination likely mediated by increased hepatic enzyme activity. Plasma concentrations of fipronil sulfone were at least 20-fold higher than those of fipronil. This highlights the need to further investigate the contribution of fipronil sulfone to the fipronil-induced thyroid disruption.


Environ Health Perspect. 1998 Aug;106(8):437-45.

Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents.

Hurley PM.

Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC 20460 USA.

Of 240 pesticides screened for carcinogenicity by the U.S. Environmental Protection Agency Office of Pesticide Programs, at least 24 (10%) produce thyroid follicular cell tumors in rodents. Thirteen of the thyroid carcinogens also induce liver tumors, mainly in mice, and 9 chemicals produce tumors at other sites. Some mutagenic data are available on all 24 pesticides producing thyroid tumors. Mutagenicity does not seem to be a major determinant in thyroid carcinogenicity, except for possibly acetochlor; evidence is less convincing for ethylene thiourea and etridiazole. Studies on thyroid-pituitary functioning, including indications of thyroid cell growth and/or changes in thyroxine, triiodothyronine, or thyroid-stimulating hormone levels, are available on 19 pesticides. No such antithyroid information is available for etridiazole, N-octyl bicycloheptene dicarboximide, terbutryn, triadimefon, and trifluralin. Of the studied chemicals, only bromacil lacks antithyroid activity under study conditions. Intrathyroidal and extrathyroidal sites of action are found: amitrole, ethylene thiourea, and mancozeb are thyroid peroxidase inhibitors; and acetochlor, clofentezine, fenbuconazole, fipronil, pendimethalin, pentachloronitrobenzene, prodiamine, pyrimethanil, and thiazopyr seem to enhance the hepatic metabolism and excretion of thyroid hormone. Thus, with 12 pesticides that mode of action judgments can be made, 11 disrupt thyroid-pituitary homeostasis only; no chemical is mutagenic only; and acetochlor may have both antithyroid and some mutagenic activity. More information is needed to identify other potential antithyroid modes of thyroid carcinogenic action.

PMID: 9681970 [PubMed - indexed for MEDLINE]


Toxicol Lett. 2004 Jan 15;146(2):121-7.
Reproductive adverse effects of fipronil in Wistar rats.

Ohi M, Dalsenter PR, Andrade AJ, Nascimento AJ.

Departamento de Farmacologia, Setor de Ciencias Biologicas, Universidade Federal do Parana, 81531-980 /PR Curitiba, Brazil. pdalsenter@ufpr.br

The purpose of the present study was to investigate possible reproductive adverse effects of fipronil (Frontline TopSpot) in female Wistar rats. The pesticide was topically applied to rats (single dose) at different concentrations (70, 140 and 280 mg/kg) and hormonal analysis, estrous cycle, and pregnancy and outcome data were determined. Treatment with fipronil altered cyclicity of female rats lengthening the estrous cycle (days) after a single topic administration of 70 mg/kg (9.7+/-1.18) or 280 mg/kg (14.5+/-1.45) when compared to control (4.8+/-0.17). In the mating study fipronil reduced the pregnancy index (67%) in the highest dose group (280 mg/kg). Plasma progesterone and estradiol levels, obtained in different periods after treatment with fipronil (70 mg/kg), were significantly different 96 h after treatment, when compared to controls. In summary, the results of the present study indicate that fipronil may alter the normal functioning of the endocrine system and cause adverse reproductive effects in female rats.

PMID: 14643964 [PubMed - indexed for MEDLINE]

See Also


Bull Environ Contam Toxicol. 2003 Sep;71(3):497-503.

Effects of fipronil and chlorpyrifos on endocrine-related endpoints in female grass shrimp (Palaemonetes pugio).

Volz DC, Wirth EF, Fulton MH, Scott GI, Strozier E, Block DS, Ferry JL, Walse SS, Chandler GT.

Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA.

PMID: 14567575 [PubMed - indexed for MEDLINE]


Rev Environ Contam Toxicol. 2003;176:1-66.

Fipronil: environmental fate, ecotoxicology, and human health concerns.

Tingle CC, Rother JA, Dewhurst CF, Lauer S, King WJ.

Natural Resources Institute, University of Greenwich at Medway, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.

Fipronil is a highly effective, broad-spectrum insecticide with potential value for the control of a wide range of crop, public hygiene, amenity, and veterinary pests. It can generally be applied at low to very low dose rates to achieve effective pest control. Application rates vary between 0.6 and 200 g a.i./ha, depending on the target pest and formulation. It belongs to the phenyl pyrazole or fiprole group of chemicals and is a potent disrupter of the insect central nervous system via interference with the gamma-aminobutyric acid (GABA-) regulated chloride channel. Fipronil degrades slowly on vegetation and relatively slowly in soil and in water, with a half-life ranging between 36 hr and 7.3 mon depending on substrate and conditions. It is relatively immobile in soil and has low potential to leach into groundwater. One of its main degradation products, fipronil desulfinyl, is generally more toxic than the parent compound and is very persistent. There is evidence that fipronil and some of its degradates may bioaccumulate, particularly in fish. Further investigation on bioaccumulation is warranted, especially for the desulfinyl degradate. The suitability of fipronil for use in IPM must be evaluated on a case-by-case basis. In certain situations, fipronil may disrupt natural enemy populations, depending on the groups and species involved and the timing of application. The indications are that fipronil may be incompatible with locust IPM; hence, this possibility requires further urgent investigation. It is very highly toxic to termites and has severe and long-lasting negative impacts on termite populations. It thus presents a long-term risk to nutrient cycling and soil fertility where termites are "beneficial" key species in these ecological processes. Its toxicity to termites also increases the risk to the ecology of habitats in which termites are a dominant group, due to their importance as a food source to many higher animals. This risk has been demonstrated in Madagascar, where two endemic species of lizard and an endemic mammal decline in abundance because of their food chain link to termites. Fipronil is highly toxic to bees (LD50 = 0.004 microgram/bee), lizards [LD50 for Acanthodactylus dumerili (Lacertidae) is 30 micrograms a.i./g bw], and gallinaceous birds (LD50 = 11.3 mg/kg for Northern bobwhite quail), but shows low toxicity to waterfowl (LD50 > 2150 mg/kg for mallard duck). It is moderately toxic to laboratory mammals by oral exposure (LD50 = 97 mg/kg for rats; LD50 = 91 mg/kg for mice). Technical fipronil is in toxicity categories II and III, depending on route of administration, and is classed as a nonsensitizer. There are indications of carcinogenic action in rats at 300 ppm, but it is not carcinogenic to female mice at doses of 30 ppm. The acute toxicity of fipronil varies widely even in animals within the same taxonomic groups. Thus, toxicological findings from results on standard test animals are not necessarily applicable to animals in the wild. Testing on local species seems particularly important in determining the suitability of fipronil-based products for registration in different countries or habitats and the potential associated risk to nontarget wildlife. Risk assessment predictions have shown that some fipronil formulations present a risk to endangered bird, fish, and aquatic and marine invertebrates. Great care should thus be taken in using these formulations where they may impact any of these endangered wildlife groups. Work in Madagascar has highlighted field evidence of this risk. The dose levels at which fipronil produces thyroid cancer in rats are very high and are unlikely to occur under normal conditions of use. There is also dispute as to whether this is relevant to human health risk. However, as fipronil is a relatively new insecticide that has not been in use for long enough to evaluate the risk it may pose to human health, from data on human exposure to the product, a precautionary approach may be warranted. The use of some fipronil-based products on domestic animals is not recommended where handlers spend significant amounts of time grooming or handling treated animals. In general, it would appear unwise to use fipronil-based insecticides without accompanying environmental and human health monitoring, in situations, regions, or countries where it has not been used before, and where its use may lead to its introduction into the wider environment or bring it into contact with people. Further work is needed on the impacts of fipronil on nontarget vertebrate fauna (amphibians, reptiles, birds, and mammals) in the field before the risk to wildlife from this insecticide can be adequately validated. Further field study of the effects of fipronil on the nutrient cycling and soil water-infiltration activities of beneficial termites is required to assess the ecological impacts of the known toxicity of fipronil to these insects.

Publication Types: Review; Review, Academic

PMID: 12442503 [PubMed - indexed for MEDLINE]

From Dart Special at Toxnet: http://toxnet.nlm.nih.gov/

Neurotoxicology 2000 Feb-Apr;21(1-2):251

Retrospective analysis of EPA's developmental neurotoxicity testing battery.

Makris S

US Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic Substances, Washington, DC.

On December 8, 1998, a study entitled "A Retrospective Analysis of Twelve Developmental Neurotoxicity Studies Submitted to the USEPA Office of Prevention, Pesticides, and Toxic Substances (OPPTS)", co-authored by Susan Makris, William Sette, Kathleen Raffaele, and Jennifer Seed, was presented to the FIFRA Scientific Advisory Panel. In this paper, the methods and results (maternal and offspring) of all developmental neurotoxicity studies received in OPPTS and reviewed by EPA scientists as of November, 1998 were summarized. This data set included studies on 9 pesticides (aldicarb, carbaryl, carbofuran, chlorpyrifos, DEET, emamectin, fipronil, molinate, and "chemical X" which was not identified by name since it had not yet been registered) and 3 solvents (1,1,1-trichloroethane, triethylene glycol monomethyl ether, and isopropanol). For each chemical, the data on prenatal developmental toxicity, reproductive toxicity, and acute and subchronic adult neurotoxicity were summarized for comparison to the developmental neurotoxicity study findings. Additionally, the studies, NOELs and endpoints selected for acute and chronic dietary risk assessment for these chemicals were presented. The offspring NOELs from the developmental neurotoxicity studies were compared with those of the other studies within each chemical database, as well as with those studies that were selected for risk assessment. The conclusions of this analysis are considered preliminary, given the limited number of studies available, the lack of breadth of chemical classes evaluated, and other confounding factors that may have influenced study design and interpretation of results. The analysis revealed that positive findings in the offspring were noted across studies for all types of observations recorded: developmental landmarks, behavioral/functional observations, sensory function, motor activity, learning and memory, brain weight, and/or neuropathology. In addition, there was a high degree of coincident findings in the functional and structural assessments; for five of the six pesticides for which morphometric analysis was conducted, alterations were identified in both behavior and brain morphology. The detection of coincident findings in the developmental neurotoxicity studies was considered to be likely due to a variety of biological and methodological factors, including the focus of these studies on developmental profiles derived from assessments at multiple time points. This supports the need to assess a variety of functional and developmental neurobehavioral and neuropathological endpoints to screen for effects on nervous system development. It was concluded that the evaluation of effects on neurological development, through conduct of the OPPTS developmental neurotoxicity study, can be a sensitive indicator of toxicity to offspring. This was, in part, demonstrated by the fact that for two of the nine pesticides evaluated, the NOEL for developmental neurotoxicity was lower than or equal to that for any adult or offspring endpoint from the prenatal developmental, reproduction, or neurotoxicity studies. Additionally, since this study examines endpoints which are not evaluated in any other guideline toxicology study, it is a valuable tool in the characterization of hazard to infants and children. The paper proposed ways in which developmental neurotoxicity data should be considered in the process of selecting endpoints for risk assessment of pesticides in EPA. In the course of this review, various general issues were raised pertaining to the developmental neurotoxicity study methodology and interpretation of results, and have provided a preliminary focus for discussions that are expected to culminate in future guideline revision. The topics include: the route of administration, the duration of treatment, the use of combined protocols, biochemical measures of exposure or effect (e.g., cholinesterase inhibition), pharmacokinetic data, and age-related susceptibility.

From Toxline at Toxnet: http://toxnet.nlm.nih.gov/

Year of Publication: 2002



Zip Code: 94720-3112




Source: Crisp Data Base National Institutes of Health

The long-term objective is to define the fundamental basis for the selective toxicity of insecticides acting at the gamma-aminobutyric acid (GABA) receptor of mammals and insects. This is the target of major neurotoxic insecticides acting as both blockers and activators of the GABA-gated chloride channel. More than 5,000,000,000 pounds of these channel blockers have been used for pest control in the past 50 years and they range in chlorine content from 52-73%. The major channel blockers used at present, representing 6% of the insecticide market, are endosulfan and lindane and this market share will increase with expanded use of the newly-commercialized polyhalogenated fipronil. The activators such as avermectin and moxidectin are also used in ever increasing quantities as insecticides and anthelmintics. More specifically, the goal is to provide toxicological profiles and maps for the insecticide blocker site and the insecticide activator site by designing and using high-affinity radioligands (the insecticide itself or a closely-related model compound) and photoaffinity probes to study binding site interactions and localization in the brain and chloride channel. Emphasis will be placed on the discovery of differences between the GABA receptors of mammals and insects that confer preferential sensitivity to insecticides and safety to mammals. The proposal is to prepare suitable radioligands and photoaffinity probes and use them to localize the binding sites as to brain region, receptor subunit and specific derivatized amino acid(s) in the chloride channel of mammals (bovine) and insects (Drosophila); the chemistry to achieve this end comes largely from discoveries in this laboratory. The research also involves rat cerebellar granule cells in primary culture to study radioligand binding and chloride flux in intact cells, localization of radioligand binding in mouse brain slices following in vitro and in vivo exposure to unlabeled toxicants, and receptors derived from Sf9 cells transfected with cDNs of human GABAa receptor subunits.

From Toxline at Toxnet: http://toxnet.nlm.nih.gov/



Year of Publication: 2002

Zip Code: 60611-3008

Mode of Action of Insecticides: Electrophysiological



Source: Crisp Data Base National Institutes of Health

The long-term goal of the proposed study is to elucidate the mechanism by which neuroactive insecticides exert their toxic actions. The specific aims of the proposed renewal application are to elucidate the physiological mechanisms that underlie the selective toxicity of several selected newer insecticides between mammals and insects. Most insecticides are much more toxic to insects than to mammals, and the mechanism of selective toxicity lies in many cases in differential actions on the target neuroreceptors/ion channels. Although recent developments and applications of molecular biology and genetics techniques have identified the molecular structures such as amino acid compositions of target receptors/channels that are deemed responsible for differential actions, almost nothing is known about how the differential actions are brought about as a result of the difference in molecular structures. Our working hypothesis is that the differential actions of insecticides on the target receptor/channels of mammals and insects could be caused by some difference in the kinetics of receptors/channels. For example, insecticide modification of the channel may be dependent upon the channel open or closed state, the kinetics of insecticide binding and unbinding, the temperature coefficient, etc. In order to elucidate the physiological mechanisms of selective toxicity, patch clamp data on the kinetics of receptors/channels and those of insecticide modification will be compared between rat and cockroach neurons for fipronil modulation of GABA receptors, imidacloprid modulation of neuronal nicotinic acetylcholine receptors (nnAChRs), spinosad modulation of nnAChRs and GABA receptors, and indoxacarb modulation of sodium channels, nnAChRs and GABA receptors. The results thus obtained are expected to answer the question of how selective toxicity between mammals and insects can be explained in terms of the differential actions on the target receptors/channels. This information will significantly contribute to the development of newer therapeutic means of insecticide intoxication of humans and of more effective and safer insecticides.

March 3, 2004. Federal Register. Docket No. ORD-2003-0011.

Longitudinal Study of Young Children's Exposures in their Homes to Selected Pesticides, Phthalates, Brominated Flame Retardants, and Perfluorinated Chemicals (A Children's Environmental Exposure Research Study--CHEERS).

Abstract: The U.S. EPA's Office of Research and Development's National Exposure Research Laboratory proposes to conduct a two-year longitudinal field measurement study of young children's (aged 0 to 3 years) potential exposures to current-use pesticides and selected phthalates, polybrominated diphenyl ethers, and perfluorinated compounds that may be found in residential environments. The study will be conducted in Duval County, Jacksonville, Florida over a two-year period from 2004 to 2006. Sixty young children will be recruited into this study in two cohorts: (1) infants recruited into the study soon after birth, and, (2) children recruited into the study at approximately 12 months of age.

Part A: Supporting Statement - EPA ICR Number: 2126.01 - 61 pages
From Table 2:
• Of 16 pesticides included in this study, 4 are fluorinated:
Bifenthrin, Fipronil, lamda-Cyhalothrin, and Cyfluthrin I, II, III, IV, total
• Perfluorinated chemicals:
Perfluorooctanoic acid (PFOA) and Perfluorooctane sulfonate (PFOS)
From Table 3: List of chemicals to be analyzed in biological media:
• one is fluorinated: 4-fluoro-3-phenoxybenzoic acid
• Perfluorooctanoic acid/Perfluorooctane sulfonate

Full free report at http://www.fluoridealert.org/pesticides/fipronil.ca.epa.2001.pdf

December 2001


Pete Connelly

Environmental Monitoring Branch, Department of Pesticide Regulation, California Environmental Protection Agency

This document reviews the environmental fate and environmental effects of fipronil (5-
pyrazole). Fipronil (C12H4Cl2F6N4OS), a phenylpyrazole insecticide, was discovered by Rhone-Poulenc Agro in 1987, introduced in 1993, and registered as a pesticide in the U.S in 1996 ...


Invert Neurosci. 2005 Sep 20;:1-15 [Epub ahead of print]
Ion channels: molecular targets of neuroactive insecticides.

Raymond-Delpech V, Matsuda K, Sattelle BM, Rauh JJ, Sattelle DB.

MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK, david.sattelle@anat.ox.ac.uk.

Many of the insecticides in current use act on molecular targets in the insect nervous system. Recently, our understanding of these targets has improved as a result of the complete sequencing of an insect genome, i.e., Drosophila melanogaster. Here we examine the recent work, drawing on genetics, genomics and physiology, which has provided evidence that specific receptors and ion channels are targeted by distinct chemical classes of insect control agents. The examples discussed include, sodium channels (pyrethroids, p,p'-dichlorodiphenyl-trichloroethane (DDT), dihydropyrazoles and oxadiazines); nicotinic acetylcholine receptors (cartap, spinosad, imidacloprid and related nitromethylenes/nitroguanidines); gamma-aminobutyric acid (GABA) receptors (cyclodienes, gamma-BHC and fipronil) and L: -glutamate receptors (avermectins). Finally, we have examined the molecular basis of resistance to these molecules, which in some cases involves mutations in the molecular target, and we also consider the future impact of molecular genetic technologies in our understanding of the actions of neuroactive insecticides.

PMID: 16172884 [PubMed - as supplied by publisher]


Cell Biol Toxicol. 2009 May 15.

Morphological alterations induced by boric acid and fipronil in the midgut of worker honeybee (Apis mellifera L.) larvae : Morphological alterations in the midgut of A. mellifera

da Silva Cruz A, da Silva-Zacarin EC, Bueno OC, Malaspina O.

Biology Department, CEIS-Social Insects Studies Center, UNESP, Av. 24-A, 1515, CEP: 13506-900, Rio Claro, SP, Brazil.

Morphological alterations, by means of histological and ultrastructural analysis, have been used to determine the effects of boric acid and fipronil on midgut tissues of honeybee worker, Apis mellifera L. larvae. In order to observe possible morphological alterations in the midgut, two groups of bioassays were performed. In the first one, the larvae were chronically treated with different concentrations of boric acid added to the food (1.0, 2.5 and 7.5 mg/g). In the second group, the larvae were fed with diets containing different concentrations of fipronil (0.1 and 1 mug/g) and compared with control groups without these chemical compounds. In the first bioassay, the larvae were collected on day 3 and in the second bioassay on day 4, when the mortality rate obtained in the toxicological bioassay was not very high. The larval midguts were removed and processed for morphological analyses using a light and transmission electron microscopy. We observed cytoplasmic vacuolizations, with the absence of autophagic vacuoles, and chromatinic compacting in most of the cells in the groups treated with pesticides. The morphological alterations were far greater in the larvae treated with boric acid than in the larvae treated with fipronil. Our data suggest that the midgut cell death observed was in response to boric acid and fipronil action. This study significantly improves the understanding of the toxicological effect of these insecticides from the ecotoxicological perspective.


Environ Toxicol Chem. 2009 Apr 8:1.

Enantioselectivity in Fipronil Aquatic Toxicity and Degradation.

Nillos MG, Lin K, Gan J, Bondarenko S, Schlenk D.

Fipronil and its transformation products are being increasingly detected in aquatic ecosystems due to widespread use. Fipronil is a chiral compound and enantioselectivity may greatly impact its environmental fate and effects. In the present study, fipronil enantiomers were isolated and used to investigate the possibility of enantioselectivity in their acute toxicity to Japanese medaka (Oryzias latipes), and cytotoxicity to primary hepatocytes from rainbow trout (Oncorhynchus mykiss). Enantioselectivity was further evaluated in fipronil degradation in sediments under aerobic and anaerobic conditions, and in field-contaminated runoff water from urban watersheds. The 96-h median lethal concentration (LC50) to Japanese medaka were 94.2 (95% CI: 82.9-107.1), 98.3 (95% CI: 85.6-113.0) and 95.4 (95% CI: 74.7-121.9) mug/L, for the racemic, R-(-)- and S-(+)- fipronil, respectively, suggesting absence of enantioselectivity. The 24-h median effect concentration (EC50) of racemic fipronil to primary rainbow trout hepatocyte was 26.7 (95% CI: 25.6-27.9) mug/ml. In contrast, exposure of the cells to the S-(+)- and R-(-)- enantiomers resulted in respective 19.7 and 7.8% reductions in cell viability at the highest treatment concentrations (100 mug/ml), potentially indicating a greater than additive interaction between enantiomers. Under aerobic or slightly reduced conditions, biodegradation of fipronil in sediments was found to be essentially non-stereoselective with enantiomer fraction (EF) similar to racemic (EF = 0.5) after 168 days of incubation. However, EF decreased to as low as < 0.1 following short incubations under anaerobic conditions, suggesting preferential degradation of S-(+)-fipronil in strongly reduced sediments. A survey of urban runoff samples consistently showed near racemic EF, indicating fipronil degradation that was not enantioselective. Results suggest that site-specific characteristics are critical in accurately predicting fipronil fate and toxicity in the environment.


J Pharmacol Exp Ther. 2005 Jul;314(1):363-73. Epub 2005 Feb 8.
Sulfone metabolite of fipronil blocks gamma-aminobutyric acid- and glutamate-activated chloride channels in mammalian and insect neurons.

Zhao X, Yeh JZ, Salgado VL, Narahashi T.

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.

Fipronil sulfone, a major metabolite of fipronil in both insects and mammals, binds strongly to GABA receptors and is thought to play a significant role in poisoning by fipronil. To better understand the mechanism of selective insecticidal action of fipronil, we examined the effects of its sulfone metabolite on GABA- and glutamate-activated chloride channels (GluCls) in cockroach thoracic ganglion neurons and on GABA(A) receptors in rat dorsal root ganglion neurons using the whole-cell patch-clamp technique. Fipronil sulfone blocked both desensitizing and nondesensitizing GluCls in the cockroach. Activation was required for block and unblock of desensitizing GluCls. In contrast, activation was not prerequisite for block and unblock of nondesensitizing channels. After repetitive activation of the receptors, the IC50 of fipronil sulfone to block the desensitizing GluCls was reduced from 350 to 25 nM and that for blocking nondesensitizing GluCls was reduced from 31.2 to 8.8 nM. This use-dependent block may be explained by its slow unbinding rate. In cockroach and rat neurons, fipronil sulfone blocked GABA receptors in both activated and resting states, with IC50 values ranging from 20 to 70 nM. In conclusion, although fipronil sulfone is a potent inhibitor of cockroach GABA receptors, desensitizing and nondesensitizing GluCls, and rat GABA(A) receptors, its selective toxicity in insects over mammals appears to be associated with its potent blocking action on both desensitizing and nondesensitizing GluCls, which are lacking in mammals.

PMID: 15701711 [PubMed - indexed for MEDLINE]


J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2005 Sep;191(9):823-36. Epub 2005 Sep 13.
Acetylcholine, GABA and glutamate induce ionic currents in cultured antennal lobe neurons of the honeybee, Apis mellifera.

Barbara GS, Zube C, Rybak J, Gauthier M, Grunewald B.

Institut fur Biologie, AG Neurobiologie, Freie Universitat Berlin, Konigin-Luise-Str. 28-30, 14195, Berlin, Germany, gruenewa@zedat.fu-berlin.de.

The honeybee, Apis mellifera, is a valuable model system for the study of olfactory coding and its learning and memory capabilities. In order to understand the synaptic organisation of olfactory information processing, the transmitter receptors of the antennal lobe need to be characterized. Using whole-cell patch-clamp recordings, we analysed the ligand-gated ionic currents of antennal lobe neurons in primary cell culture. Pressure applications of acetylcholine (ACh), gamma-amino butyric acid (GABA) or glutamate induced rapidly activating ionic currents. The ACh-induced current flows through a cation-selective ionotropic receptor with a nicotinic profile. The ACh-induced current is partially blocked by alpha-bungarotoxin. Epibatidine and imidacloprid are partial agonists. Our data indicate the existence of an ionotropic GABA receptor which is permeable to chloride ions and sensitive to picrotoxin (PTX) and the insecticide fipronil. We also identified the existence of a chloride current activated by pressure applications of glutamate. The glutamate-induced current is sensitive to PTX. Thus, within the honeybee antennal lobe, an excitatory cholinergic transmitter system and two inhibitory networks that use GABA or glutamate as their neurotransmitter were identified.

PMID: 16044331 [PubMed - in process]


Pharmacol Biochem Behav. 2005 Aug 12; [Epub ahead of print]
Effects of sublethal doses of fipronil on the behavior of the honeybee (Apis mellifera).

El Hassani AK, Dacher M, Gauthier M, Armengaud C.

Centre de Recherches sur la Cognition Animale, Universite Paul Sabatier Toulouse III-CNRS UMR 5169, 118 Route de Narbonne, 31062 Toulouse Cedex 04, France.

Fipronil is a phenylpyrazole insecticide introduced for pest control, but it can also affect non-target insects such as honeybees. In insects, fipronil is known to block GABA receptors and to inhibit ionotropic glutamate-gated chloride channels, but the behavioral effects of low doses are not yet fully understood. We have studied the effect of sublethal doses of fipronil on the behavior of the honeybee (Apis mellifera) under controlled laboratory conditions. The drug was either administered orally or applied topically on the thorax. A significant reduction of sucrose sensitivity was observed for the dose of 1 ng/bee 1 h after a thoracic application. No significant effect on sucrose sensitivity was obtained with acute oral treatment. A lower dose of fipronil (0.5 ng/bee applied topically) impaired the olfactory learning of the honeybees. By contrast, locomotor activity was not affected. Our results suggest a particular vulnerability of the olfactory memory processes and sucrose perception to sublethal doses of fipronil in the honeybee.

PMID: 16102801 [PubMed - as supplied by publisher]


Arch Environ Contam Toxicol. 2005 Feb;48(2):242-50. Epub 2005 Feb 15.
Comparative sublethal toxicity of nine pesticides on olfactory learning performances of the honeybee Apis mellifera.

Decourtye A, Devillers J, Genecque E, Le Menach K, Budzinski H, Cluzeau S, Pham-Delegue MH.

Association de Coordination Technique Agricole, Maison des Agriculteurs, La Tour de Salvagny, France. axel.decourtye@acta.asso.fr

Using a conditioned proboscis extension response (PER) assay, honeybees (Apis mellifera L.) can be trained to associate an odor stimulus with a sucrose reward. Previous studies have shown that observations of conditioned PER were of interest for assessing the behavioral effects of pesticides on the honeybee. In the present study, the effects of sublethal concentrations of nine pesticides on learning performances of worker bees subjected to the PER assay were estimated and compared. Pesticides were tested at three concentrations. The highest concentration of each pesticide corresponded to the median lethal dose value (48-h oral LD50), received per bee and per day, divided by 20. Reduced learning performances were observed for bees surviving treatment with fipronil, deltamethrin, endosulfan, and prochloraz. A lack of behavioral effects after treatment with lambda-cyalothrin, cypermethrin, tau-fluvalinate, triazamate, and dimethoate was recorded. No-observed-effect concentrations (NOECs) for the conditioned PER were derived for the studied pesticides. Our study shows that the PER assay can be used for estimating sublethal effects of pesticides on bees. Furthermore, comparisons of sensitivity as well as the estimation of NOECs, useful for regulatory purposes, are possible.

PMID: 15750780 [PubMed - indexed for MEDLINE]



Bull Environ Contam Toxicol. 2005 May;74(5):872-9.

Acute toxicity of imidacloprid and fipronil to a nontarget aquatic insect, Simulium vittatum Zetterstedt cytospecies IS-7.

Overmyer JP, Mason BN, Armbrust KL.

University of Georgia, Department of Entomology, 413 Biological Sciences Building, Athens, GA 30602, USA.

No abstract available

PMID: 16097320 [PubMed - indexed for MEDLINE]



Environ Toxicol Chem. 2005 Sep;24(9):2350-5.

Acute enantioselective toxicity of fipronil and its desulfinyl photoproduct to Ceriodaphnia dubia.

Konwick BJ, Fisk AT, Garrison AW, Avants JK, Black MC.

Department of Environmental Health Science, University of Georgia, Athens, Georgia 30602, USA.

Fipronil is a phenylpyrazole insecticide increasingly used in applications such as rice culture, turf grass management, and residential pest control, with a high probability to contaminate aquatic environments. As a chiral pesticide, fipronil is released to the environment as a racemic mixture (equal amounts of optical isomers called enantiomers). Enantiomers can have different toxicological and biological activity; however, information on these differences, which is necessary for accurate risk assessment of chiral pesticides, is limited. Here we examine the acute toxicity of fipronil enantiomers, the racemate, and its photoproduct (desulfinyl fipronil) to Ceriodaphnia dubia. The 48-h median lethal concentration (LC50) values based on measured concentrations of each compound indicate the (+) enantiomer (LC50 = 10.3 +/- 1.1 microg/L, mean +/- standard error [SE]) was significantly more toxic to C. dubia than either the (-) enantiomer (LC50 = 31.9 +/- 2.2 microg/L) or racemate (LC50 = 17.7 +/- 1.3 microg/L). To account for any potential loss of fipronil through photolysis, tests were performed under light (fluorescent) and dark exposure conditions, and no significant differences in toxicity were observed. Desulfinyl fipronil, the major photodegradation product, which is not chiral, was detected at < 1% of each parent compound in test solutions after 48 h. Separate toxicity tests with desulfinyl fipronil found a > 20-fold higher LC50 (355 +/- 9.3 microg/L) compared to the fipronil racemate, suggesting lower adverse effects to C. dubia as a result of fipronil photolysis. The present results suggest selection of the (-) enantiomer in fipronil production for lower impacts to C. dubia; however, the consistency and relevancy of fipronil's enantiomer-specific activity at both acute and chronic levels of concern to additional target and nontarget species needs further consideration.

PMID: 16193765 [PubMed - in process]

Toxicology - Article in Press, Corrected Proof
Received 7 April 2005;  revised 27 May 2005;  accepted 31 May 2005.  Available online 11 July 2005.

Transient alterations in neuronal and behavioral activity following bensultap and fipronil treatment in rats

Viktor Szegedi, György Bárdos, László Détári, Attila Tóth, Ilona Banczerowski-Pelyhe and Ildikó Világi,

Eötvös Loránd University, Department of Physiology and Neurobiology, 1117 Budapest, Hungary

In the present multilevel study, neuromodulatory effect of two insecticides, bensultap and fipronil were investigated in rats. Although the new generation of insecticides shows greater affinity to invertebrate as compared to mammalian receptors, toxic effect of these compounds in vertebrates cannot be excluded. The aim of the study was to follow the course of neuronal changes in rats for 1 week after a high-dose insecticide exposure. Alterations in synaptic excitability, in sleep–wake pattern and in behavior were analyzed using conventional in vitro brain slice method, long-lasting EEG recordings, and open-field tests. The two chemicals examined in this study induced only weak and transient effects. Bensultap, acting on nicotinic acetylcholine receptors, caused a transient decrease in neuronal excitability. Sleep and behavioral changes demonstrated a similar time course. Fipronil, on the other hand, increased excitability and its effect lasted slightly longer. All effects were greatest on the first day following ‘poisoning’, and measured variables usually returned to normal within a week. These results suggest that the studied compounds do have some effects on the mammalian nervous system, but this effect is usually mild and temporary.

Ecotoxicology and Environmental Safety ; Volume 62, Issue 1 , September 2005, Pages 11-16

Toxicity and hazard assessment of fipronil to Daphnia pulex

John D. Stark (a) , and Roger I. Vargas (b)

(a) Department of Entomology, Washington State University, Puyallup Research and Extension Center, Pioneer Way East 7612, Puyallup, WA 98371, USA
(b) USDA-ARS, P.O. Box 4459, Hilo, HI 96720, USA

Received 20 September 2004;  revised 24 February 2005;  accepted 25 February 2005.  Available online 11 April 2005.

Hazard assessments based on two measures of toxicity were conducted for the water flea, Daphnia pulex (Leydig) exposed to the insecticide, fipronil. The measures of toxicity obtained were 48 h acute lethal concentration estimates, and a direct measure of population growth rate, the 10-day instantaneous rate of increase (ri). Additionally, life tables were developed after exposure to several concentrations to tease out the apparent sublethal effects of this insecticide to D. pulex. The acute LC50 was estimated to be 0.0156 (0.0088–0.083) mg/L. In the 10-day population growth rate study, extinction of D. pulex populations occurred after exposure to 0.08 mg/L of fipronil, which was equivalent to the 48 h acute LC75. The NOEC and LOEC for population size after a 10-day exposure to fipronil were 0.03 and 0.05 mg/L, respectively. An expected environmental concentration (EEC) in freshwater lakes/ponds based on an application rate of 250 mg ai/ha (recommended rate for use in Tephritid fruit fly control programs) was estimated to be 0.00017 mg/L. Hazard assessments were developed by dividing the EEC by the LC50 and NOEC for population size. The assessments based on the LC50 and NOEC for population size were 0.011 and 0.0057, respectively, indicating that fipronil does not pose a hazard to D. pulex when applied at the rates recommended for control of Tephritid fruit flies. Life tables were developed after exposure to two insecticide concentrations and a control. Exposure to 0.015 mg/L, the approximate 48 h acute LC50, resulted in only a slight decrease in the net reproductive rate (Ro), birth rate (b), and intrinsic rate of increase (rm) and an increase in generation time (T), death rate (d), and doubling time (DT) compared to the control. Exposure to 0.03 mg/L, the approximate 48 h acute LC60, and NOEC in the 10-day study, resulted in a 57% decline in the net reproductive rate, a 1.45-fold decrease in birth rate, a 1.5-fold decrease in the intrinsic rate of increase, a 6-day increase in generation time, a 4-fold increase in death rate, and a 1.5-fold increase in doubling time. The stable age distribution (after 60 days) of D. pulex changed after exposure to fipronil. Increasing concentrations of fipronil resulted in a decrease in the percentage of individuals in the first, second, third, and fourth juvenile stages, an increase in the adult stage, and no change in the adolescent stage. These results indicate that certain concentrations of fipronil approaching the LC50 can negatively affect population parameters of D. pulex, but that EECs, at least for fruit fly control, should be lower than the concentration necessary to cause damage.

4. Discussion
Results of our study indicate that formulated fipronil is toxic to D. pulex causing both lethal and sublethal effects. Chaton et al. (2002) found that D. pulex was insensitive to fipronil and was not affected even at concentrations close to the water solubility of fipronil. However, Chaton et al. (2002) evaluated unformulated technical grade fipronil, while in our study, we evaluated formulated fipronil (Regent 4SC). The water solubility of fipronil is approximately 2.4 mg/L and according to Aventis, the formulation will not increase the solubility of the active ingredient. The 4SC formulation is a suspension concentrate; particles of fipronil are finely ground and suspended in water using a proprietary system of suspension agents. The formulation, therefore, has no effect on the water solubility of the active ingredient. However, smaller particle sizes in the formulated product may result in more active ingredients being ingested by Daphnia compared to the unformulated product. Furthermore, the formulation itself might be toxic. Because the formulated product is used for pest control, it has the potential to enter aquatic ecosystems and as such should be evaluated for toxicity to aquatic organisms.

Fipronil (Icon 6.2 FSTM) is also used as a seed treatment for rice to control rice water weevil. Schlenk et al. (2001) found that fipronil was very toxic to two crayfish species (Procambarus clarkii and P. zonangulus) with LC50 estimates of 14 and 19 µg/L, respectively. Their LC50 estimates are similar to the estimate developed for D. pulex (16 µg/L) in our study. Furthermore, Schlenk et al. (2001) conducted an in situ study in culturing ponds and found high levels of mortality in crayfish. A hazard quotient revealed that fipronil in water from Icon-treated rice seed plantings poses a significant risk to crayfish survival.

In contrast to the study by Schlenk et al. (2001), the study by Lahr (1998) indicated that fipronil was one of the least ecologically damaging insecticides to aquatic ecosystems in the Sahel.

Chandler et al. (2004) studied the effects of fipronil on the estuarine copepod, Amphiascus tenuiremis. Fipronil was highly toxic to A. tenuiremis with a 96-h acute LC50 of 6.8 µg/L. Additionally, exposure to fipronil delayed female and male development and nearly eliminated reproduction after exposure to 0.42µg/L.

Furthermore, our comparison of the EEC for rates of fipronil labeled for fruit fly control to toxicity endpoints indicated that fipronil should not pose a hazard to wild D. pulex populations. An interesting result in our study is that the NOEC in the 10-day population growth study was estimated to be 0.03 mg/L. However, exposure to this same concentration in the life table study resulted in a 1.5 decline in the intrinsic rate of increase. This can be explained by the fact that in the 10-day population study, D. pulex was only exposed for 10 days while in the life table study D. pulex was exposed over a lifetime. Walthall and Stark (1997) indicated that 10-day studies for aphids yielded population growth rates that were similar to those produced by life tables. However, in their study, exposures in both the 10-day and the life table experiments were similar in that aphids were exposed to plants that were sprayed once at the onset of the study. Demography and other population growth rate measures of toxicity are being used more frequently to evaluate toxicity (Stark and Wennergren, 1995; van Straalen and Kammenga, 1998; Forbes and Calow, 1999; Kammenga and Laskowski, 2000; Stark and Vargas, 2003; Herbert et al., 2004). Because demography takes into account all effects (lethal and sublethal) that a toxicant might have on a population and these studies are usually conducted throughout the life span of an organism, a complete measure of effect can be obtained (Stark and Banks, 2000 and Stark and Banks, 2003). A comparison of demographic and other endpoints of toxic effect has indicated that demographic toxicological endpoints and other measures of population effect such as the instantaneous rate of increase are superior to other endpoints of effect (Forbes and Calow, 1999; Herbert et al., 2004). Therefore, demographic and other population approaches for the evaluation of toxic effects should be more widely adopted.

Chandler, 2004 G.T. Chandler, T.L. Cary, D.C. Volz, S.S. Walse, J.L. Ferry and S.L. Klosterhaus, Fipronil effects on estuarine copepod (Amphiascus tenuiremis) development, fertility, and reproduction: a rapid life-cycle assay in 96-well microplate format, Environ. Toxicol. Chem. 23 (2004), pp. 117–124.

Chaton et al., 2002 P.F. Chaton, P. Ravanel, M. Tissut and J.C. Meyran, Toxicity and bioaccumulation of fipronil in the nontarget arthropodan fauna associated with subalpine mosquito breeding sites, Ecotoxicol. Environ. Saf. 52 (2002), pp. 8–12.

Forbes and Calow, 1999 V.E. Forbes and P. Calow, Is the per capita rate of increase a good measure of population-level effects in ecotoxicology?, Environ. Toxicol. Chem. 18 (1999), pp. 1544–1556.

Herbert et al., 2004 I.N. Herbert, C. Svendsen, P.K. Hankard and D.J. Spurgeon, Comparison of instantaneous rate of population increase and critical-effect estimates in Folsomia candida exposed to four toxicants, Ecotoxicol. Environ. Saf. 57 (2004), pp. 175–183.

Kammenga and Laskowski, 2000 J. Kammenga and R. Laskowski, Demography in Ecotoxicology, Wiley, West Sussex, England (2000).

Lahr, 1998 J. Lahr, An ecological assessment of the hazard of eight insecticides used in desert locust control, to invertebrates in temporary ponds in the Sahel, Aquat. Ecol. 32 (1998), pp. 153–162.

Schlenk et al., 2001 D. Schlenk, D.B. Huggett, J. Allgood, E. Bennett, J. Rimoldi, A.B. Beeler, D. Block, A.W. Holder, R. Hovinga and P. Bedient, Toxicity of fipronil and its degradation products to Procambarus sp.: field and laboratory studies., Arch. Environ. Contam. Toxicol. 41 (2001), pp. 325–332.

Stark and Banks, 2000 J.D. Stark and J.E. Banks, The toxicologists and ecologists point of view—unification through a demographic approach. In: J. Kammenga and R. Laskowski, Editors, Demography in Ecotoxicology, Wiley, West Sussex, England (2000), pp. 9–20.

Stark and Banks, 2001 J.D. Stark and J.E. Banks, Selective pesticides: are they less hazardous to the environment?, BioScience 51 (2001), pp. 980–982.

Stark and Vargas, 2003 J.D. Stark and R.I. Vargas, Demographic changes in Daphnia pulex (Leydig) after exposure to the insecticides, spinosad and diazinon, Ecotoxicol. Environ. Saf. 56 (2003), pp. 334–338.

Stark and Wennergren, 1995 J.D. Stark and U. Wennergren, Can population effects of pesticides be predicted from demographic toxicological studies?, J. Econ. Entomol. 88 (1995), pp. 1089–1096.

Van Straalen and Kammenga, 1998 N.M. Van Straalen and J.E. Kammenga, Assessment of ecotoxicity at the population level using demographic parameters. In: G. Shüürmann and B. Markert, Editors, Ecotoxicology, Ecological Fundamentals, Chemical Exposure, and Biological Effects, Wiley, New York (1998), pp. 622–644.

Walthall and Stark, 1997 W.K. Walthall and J.D. Stark, Comparison of two population-level ecotoxicological endpoints: the intrinsic (rm) and instantaneous (ri) rates of increase, Environ. Toxicol. Chem. 16 (1997), pp. 1068–1073.


Arch Environ Contam Toxicol. 2005 Feb;48(2):242-50. Epub 2005 Feb 15.
Comparative sublethal toxicity of nine pesticides on olfactory learning performances of the honeybee Apis mellifera.

Decourtye A, Devillers J, Genecque E, Le Menach K, Budzinski H, Cluzeau S, Pham-Delegue MH.

Association de Coordination Technique Agricole, Maison des Agriculteurs, La Tour de Salvagny, France. axel.decourtye@acta.asso.fr

Using a conditioned proboscis extension response (PER) assay, honeybees (Apis mellifera L.) can be trained to associate an odor stimulus with a sucrose reward. Previous studies have shown that observations of conditioned PER were of interest for assessing the behavioral effects of pesticides on the honeybee. In the present study, the effects of sublethal concentrations of nine pesticides on learning performances of worker bees subjected to the PER assay were estimated and compared. Pesticides were tested at three concentrations. The highest concentration of each pesticide corresponded to the median lethal dose value (48-h oral LD50), received per bee and per day, divided by 20. Reduced learning performances were observed for bees surviving treatment with fipronil, deltamethrin, endosulfan, and prochloraz. A lack of behavioral effects after treatment with lambda-cyalothrin, cypermethrin, tau-fluvalinate, triazamate, and dimethoate was recorded. No-observed-effect concentrations (NOECs) for the conditioned PER were derived for the studied pesticides. Our study shows that the PER assay can be used for estimating sublethal effects of pesticides on bees. Furthermore, comparisons of sensitivity as well as the estimation of NOECs, useful for regulatory purposes, are possible.

PMID: 15750780 [PubMed - indexed for MEDLINE]


Huan Jing Ke Xue. 2005 Jan;26(1):185-9.

[Joint acute toxicity of fipronil and bata-cypermethrin to protozoa community]

[Article in Chinese]

Liu GG, Xu HJ, Wang LX, Zheng LQ.

Henan Key Laboratory for Environmental Pollution control, College of Chemistry and Environmental Science, Henan Normal University, Xinxiang 453002, China. guoguangliu@263.net

Compared with the toxicity test on single organism, the effects of toxic pollutants on organisms at community level are more reliable. The acute single and joint toxic effects of Fipronil and Bata-cypermethrin on freshwater protozoa community are studied in this paper. The results show that the 48h-LC50 of Fipronil and Bata-cypermethrin to the microbial community was 35.83mg x L(- 1), 1.92mg x L(-1), the joint toxicity of Bata-cypermethrin and Fipronil was antagonism in 48h with toxicity 1: 1 to freshwater protozoa community, and Additive Index was -0.08. The structure of protozoa community would change in a low concentration of Bata-cypermethrin and Fipronil mixture; the species and population of Algivores(A) and Predators Raptors (P) would reduce but Bactivoresdetrivores(B) would become predominant relatively.

PMID: 15859435 [PubMed - in process]


J Toxicol Clin Toxicol. 2004;42(7):955-63.

Acute human self-poisoning with the N-phenylpyrazole insecticide fipronil--a GABAA-gated chloride channel blocker.

Mohamed F, Senarathna L, Percy A, Abeyewardene M, Eaglesham G, Cheng R, Azher S, Hittarage A, Dissanayake W, Sheriff MH, Davies W, Buckley NA, Eddleston M.

South Asian Clinical Toxicology Research Collaboration, Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka.

OBJECTIVE: Fipronil, a broad spectrum N-phenylpyrazole insecticide that inhibits GABAA-gated chloride channels, has been in use since the mid-1990s. A high affinity for insect compared to mammalian GABA receptors results in lower animal toxicity than other insecticides blocking this channel. To date, only two accidental cases of fipronil poisoning in humans have been published.
CASE SERIES: We report seven patients with fipronil self-poisoning seen prospectively in Sri Lanka together with pharmacokinetics for four patients. Non-sustained generalized tonic-clonic seizures were seen in two patients (peak measured plasma fipronil concentrations 1600 and 3744 microg/L); both were managed with diazepam without complications. A patient with a peak measured plasma concentration of 1040 microg/L was asymptomatic throughout his stay. Plasma concentration was still high at discharge 3-4 days post-ingestion when the patients were well. Retrospective review of >1000 pesticide poisoning deaths since 1995 found only one death from fipronil-based products. In contrast to the good outcome of the above cases, this patient required intubation and ventilation and had continuous fits despite therapy with barbiturates and benzodiazepines.
CONCLUSIONS: Our experience with prospectively observed patients suggests that fipronil poisoning is characterized by vomiting, agitation, and seizures, and normally has a favorable outcome. Management should concentrate on supportive care and early treatment of seizures. However, further experience is needed to determine whether increased susceptibility to fipronil or larger doses can produce status epilepticus.

Publication Types:
• Case Reports

PMID: 15641641 [PubMed - indexed for MEDLINE]


Neurotoxicology. 2004 Dec;25(6):967-80.
Kinetic and pharmacological characterization of desensitizing and non-desensitizing glutamate-gated chloride channels in cockroach neurons.

Zhao X, Salgado VL, Yeh JZ, Narahashi T.

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.

Glutamate-gated chloride channels (GluCls) are found only in invertebrate nerve and muscle, where they mediate inhibitory synaptic transmission, and are important target sites of insecticides. Two GluCl subtypes have previously been distinguished in isolated cockroach CNS neurons based on differential pharmacology. The present study characterizes the kinetics and pharmacological properties of desensitizing and non-desensitizing GluCls. Both types of GluCls were sensitive to glutamate and ibotenic acid. The non-desensitizing GluCl subtype was elicited by glutamate with an EC(50) of 115.8 microM and a Hill coefficient of 2.6 and was also sensitive to the agonist ibotenic acid with an EC(50) of 42 microM and a Hill coefficient of 1.7. The desensitizing and non-desensitizing currents were carried by chloride ions, and occurred either separately or in combination in individual neurons. The GluCls were also found to coexist with and function independently of the GABA-activated chloride channels. The desensitizing and non-desensitizing GluCls exhibited different sensitivities to the ligand-gated channel blocker picrotoxinin. The desensitizing GluCls were blocked only 8% by 30 microM picrotoxinin, whereas the non-desensitizing GluCls were potently blocked by picrotoxinin with an IC(50) of 4.1 microM. The insecticides fipronil and dieldrin at 1 microM inhibited the desensitizing currents by 56 and 13%, respectively, and the non-desensitizing currents by 98 and 43%, respectively. It is concluded that the two types of GluCls found in cockroach neurons exhibit significantly different electrophysiological and pharmacological characteristics.

PMID: 15474615 [PubMed - in process]


Arch Environ Contam Toxicol. 2004 Oct;47(3):387-95.
A method to quantify and analyze the foraging activity of honey bees: relevance to the sublethal effects induced by systemic insecticides.

Colin ME, Bonmatin JM, Moineau I, Gaimon C, Brun S, Vermandere JP.

Universite de Montpellier II, Laboratoire de Pathologie Comparee des Invertebres, CC 101, Batiment 24, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France. colinme@ensam.inra.fr

The assessment of agropharmaceuticals' side effects requires more realistic simulations of field conditions than those deduced from the dose-lethality relation obtained under laboratory conditions. Because the presence of sublethal doses or concentrations may also alter the behavior of foraging insects, we attempted to devise a quantifiable and accurate protocol for evidencing various alterations in free-flying bees. Such a protocol was illustrated by testing new classes of systemic insecticides. The protocol focused on video recording to quantify the foraging activity of small colonies of honey bees confined in insect-proof tunnels. The basis of the protocol was not the colony itself but the change in each colony on a specific day and between days. First, the paradigms of attendance at a safe feeding source were established by observing 8 control colonies at different times of the season during 5 days after the necessary forager training was accomplished. Second, on three different colonies we considered the paradigms on the control day before contamination and during 4 days after the feeding source was contaminated. During the same period, one more colony was exclusively fed with safe food to serve as control. Two plant-systemic insecticides were tested at contamination levels 70 times lower than the 50% of the lethal concentration. Imidacloprid, at 6 microg/kg, clearly induced a decrease in the proportion of active bees. Fipronil, at 2 microg/kg, induced an additional decrease in attendance at the feeder. Such levels are still higher than the corresponding lowest observable effect concentration (LOEC). Our protocol, which provided intermediate conditions between field and laboratory conditions, allowed the quantification, with an enhanced level of sensitivity, of sublethal effects on foraging bees. Copyright 2004 Springer Science + Business Media, Inc.

PMID: 15386133 [PubMed - indexed for MEDLINE]

Environmental Pollution Volume 131, Issue 3 , October 2004, Pages 365-371

The effects of the contemporary-use insecticide (fipronil) in an estuarine mesocosm

E. F. Wirth (a), P. L. Pennington (b), J. C. Lawton (c), M. E. DeLorenzo (b), D. Bearden (a), B. Shaddrix (a), S. Sivertsen (a) and M. H. Fulton (a)

(a) Center for Coastal Environmental Health and Biomolecular Research, NOAA, 219 Fort Johnson Road, Charleston, SC 29412, USA
(b) Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
(c) Office of Response and Restoration, National Oceanic and Atmospheric Administration, 77 West Jackson SR_6J, Chicago, IL 60604, USA

"Capsule": Fipronil exposure at environmentally relevant concentrations had a significant toxic effect on grass shrimp in mesocosms.  Available online 4 June 2004.

Abstract: To examine the effects of environmentally realistic fipronil concentrations on estuarine ecosystems, replicated mesocosms containing intact marsh plots and seawater were exposed to three treatments of fipronil (150, 355, and 5000 ng/L) and a Control. Juvenile fish (Cyprinidon variegatus), juvenile clams (Mercenaria mercenaria), oysters (Crassostrea virginica), and grass shrimp (Palaemonetes pugio) were added prior to fipronil in an effort to quantify survival, growth, and the persistence of toxicity during the planned 28-day exposure. Results indicated that there were no fipronil-associated effects on the clams, oysters, or fish. Shrimp were sensitive to the highest two concentrations (40% survival at 355 ng/L and 0% survival at 5000 ng/L). Additionally, the highest fipronil treatment (5000 ng/L) was toxic to shrimp for 6 weeks post dose. These results suggest that fipronil may impact shrimp populations at low concentrations and further use in coastal areas should be carefully assessed.


J Toxicol Clin Toxicol. 2004;42(2):189-90.

Accidental dermal and inhalation exposure with fipronil--a case report.

Chodorowski Z, Anand JS.

Department of Internal Medicine and Toxicology, Medical University of Gdansk, Gdansk ul., Lanowa, Poland.

BACKGROUND: Fipronil which has initiated the new generation of insecticides and possesses greater affinity at GABA receptors in insects than humans is supposed to be safer than the old generation of insecticides. Dermal and inhalation exposure to fipronil has not been reported in the literature.
CASE REPORT: A 50-year-old male was admitted to the Clinic after 5h of spraying his field with the solution of fipronil. The patient was fully conscious with the BP and HR within normal range. There were no seizures, other neurological deficits, signs of conjunctivitis or skin irritation. Physical examinations and biochemical results were normal. The patient complained of a headache, nausea, vertigo and weakness. All symptoms resolved spontaneously after about 5h. During hospitalization and the follow up after three weeks he was asymptomatic.
CONCLUSIONS: Further investigations should be carried on to evaluate the risk of fipronil in humans. The benzodiazepines are drugs of choice during seizures, B1 agonists and steroids may be useful during severe inhalation exposure.

Publication Types:
* Case Reports

PMID: 15214624 [PubMed - indexed for MEDLINE]


Environ Pollut. 2004 Oct;131(3):365-71.
The effects of the contemporary-use insecticide (fipronil) in an estuarine mesocosm.

Wirth EF, Pennington PL, Lawton JC, DeLorenzo ME, Bearden D, Shaddrix B, Sivertsen S, Fulton MH.

Center for Coastal Environmental Health and Biomolecular Research, NOAA, 219 Fort Johnson Road, Charleston, SC 29412, USA.

To examine the effects of environmentally realistic fipronil concentrations on estuarine ecosystems, replicated mesocosms containing intact marsh plots and seawater were exposed to three treatments of fipronil (150, 355, and 5000ng/L) and a Control. Juvenile fish (Cyprinidon variegatus), juvenile clams (Mercenaria mercenaria), oysters (Crassostrea virginica), and grass shrimp (Palaemonetes pugio) were added prior to fipronil in an effort to quantify survival, growth, and the persistence of toxicity during the planned 28-day exposure. Results indicated that there were no fipronil-associated effects on the clams, oysters, or fish. Shrimp were sensitive to the highest two concentrations (40% survival at 355ng/L and 0% survival at 5000ng/L). Additionally, the highest fipronil treatment (5000ng/L) was toxic to shrimp for 6 weeks post dose. These results suggest that fipronil may impact shrimp populations at low concentrations and further use in coastal areas should be carefully assessed.

PMID: 15261399 [PubMed - in process]


Environ Sci Technol. 2004 Jul 15;38(14):3908-15.

Role of dissolved organic matter, nitrate, and bicarbonate in the photolysis of aqueous fipronil.

Walse SS, Morgan SL, Kong L, Ferry JL.

Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, USA.

A multivariate kinetic model of aqueous fipronil photodegradation was developed as a function of dissolved organic matter (DOM), bicarbonate, and nitrate at concentrations that bracketthose commonly observed in natural waters (ca. 0-10 mg/L). Several pathways were available for fipronil photodegradation in this system, including direct photolysis and indirect photooxidation by species produced during the illumination of natural waters (e.g., 3NOM*, 1O2*, *OH, *CO3(1-), *OOR, *OOH, e(aq)-, O2(*-)). Product studies indicated that fipronil was quantitatively converted to fipronil desulfinyl, a product that is associated with direct photolysis alone. DOM was the only variable that affected fipronil degradation; it decreased the rate of fipronil photodegradation primarily through competitive light absorption (i.e., attenuation) and the quenching of fipronil*. The addition of sodium chloride (30 percent per thousand) resulted in a more rapid rate (approximately 20%) of fipronil loss in comparison to equivalent experiments performed without sodium chloride, implying that fipronil may be more photolabile in marine environments.

PMID: 15298200 [PubMed - in process]


Pest Manag Sci. 2004 May;60(5):487-92.

Fipronil modulation of GABAA receptor single-channel currents.

Ikeda T, Nagata K, Kono Y, Yeh JZ, Narahashi T.

Institute of Agriculture and Forestry, University of Tsukuba, Tsukuba 305-8572, Japan.

Fipronil is the first phenylpyrazole insecticide introduced for pest control. Although fipronil is known to inhibit GABA receptors, the detailed mechanism of action remains to be seen. In order to elucidate the mechanism of fipronil interaction with the mammalian GABAA system, single-channel patch clamp experiments were performed using rat dorsal root ganglion neurons. The amplitude of main conductance state (27pS) current was not significantly altered by co-application of 10 microM fipronil and 10 microM GABA. The histograms of open time distribution were fitted to a sum of three exponential functions. After application of 10 microM fipronil, the proportion of the fastest component increased slightly and that of the slowest component decreased slightly. Thus, the mean open time was decreased from 11.4 ms to 7.8 ms by fipronil. The histograms of closed time distribution were fitted to a sum of four exponential functions. Fipronil 10 microM prolonged the slowest time constant resulting in a prolongation of the mean closed time from 29.7 ms to 52.8 ms. Thus, the frequency of channel openings was reduced. Thus, the fipronil suppression of GABA-induced whole-cell currents is caused in part by decreases in the channel open time and the frequency of channel openings.

PMID: 15154517 [PubMed - in process]


Chem Biol Interact. 2004 Apr 15;147(3):319-29.
In vitro metabolism of fipronil by human and rat cytochrome P450 and its interactions with testosterone and diazepam.

Tang J, Amin Usmani K, Hodgson E, Rose RL.

Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695, USA.

Fipronil (5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile) is a highly active, broad spectrum insecticide from the phenyl pyrazole family, which targets the gamma-amino butyric acid (GABA) receptor. Although fipronil is presently widely used as an insecticide and acaricide, little information is available with respect to its metabolic fate and disposition in mammals. This study was designed to investigate the in vitro human metabolism of fipronil and to examine possible metabolic interactions that fipronil may have with other substrates. Fipronil was incubated with human liver microsomes (HLM) and several recombinant cytochrome P450 (CYP) isoforms obtained from BD Biosciences. HPLC was used for metabolite identification and quantification. Fipronil sulfone was the predominant metabolite via CYP oxidation. The K(m) and V(max) values for human liver microsomes are 27.2 microM and 0.11 nmol/mg proteinmin, respectively; for rat liver microsomes (RLM) the K(m) and V(max) are 19.9 microM and 0.39 nmol/mg proteinmin, respectively. CYP3A4 is the major isoform responsible for fipronil oxidation in humans while CYP2C19 is considerably less active. Other human CYP isoforms have minimal or no activity toward fipronil. Co-expression of cytochrome b(5) (b(5)) is essential for CYP3A4 to manifest high activity toward fipronil. Ketoconazole, a specific inhibitor of CYP3A4, inhibits 78% of the HLM activity toward fipronil at a concentration of 2 microM. Oxidative activity toward fipronil in 19 single-donor HLMs correlated well with their ability to oxidize testosterone. The interactions of fipronil and other CYP3A4 substrates, such as testosterone and diazepam, were also investigated. Fipronil metabolism was activated by testosterone in HLM but not in CYP3A4 Supersomes. Testosterone 6beta-hydroxylation in HLM was inhibited by fipronil. Fipronil inhibited diazepam demethylation but had little effect on diazepam hydroxylation. The results suggest that fipronil has the potential to interact with a wide range of xenobiotics or endogenous chemicals that are CYP3A4 substrates and that fipronil may be a useful substrate for the characterization of CYP3A4 in HLM.

PMID: 15135087 [PubMed - indexed for MEDLINE


Environ Toxicol Chem. 2004 Feb;23(2):298-305.

An enzyme-linked immunosorbent assay for lipovitellin quantification in copepods: a screening tool for endocrine toxicity.

Volz DC, Chandler GT.

Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina 29208, USA.

Vitellogenin (VTG) has been widely used as a biomarker of estrogenic exposure in fish, leading to the development of standardized assays for VTG quantification. However, standardized quantitative assays for invertebrate, particularly crustacean, lipovitellin (also known as vitellin [VTN]) are lacking. In this study, a fluorescence-based VTN enzyme-linked immunosorbent assay (ELISA) was developed to quantify microquantities of VTN in the estuarine, sediment-dwelling copepod Amphiascus tenuiremis. This ELISA utilizes a VTN-specific polyclonal antibody developed against amphipod (Leptocheirus plumulosus) embryo VTN and exhibits specificity toward female copepod proteins. In routine assays, the working range of the ELISA was 31.25 to 1,000 ng/ml (75-25% specific binding/maximum antibody binding [B/B0]) with a 50% B/B0 intra- and interassay variation of 3.9% (n = 9) and 12.5% (n = 26), respectively. This ELISA is capable of detecting VTN as low as 2 ng/ml, and can accurately detect VTN in as few as four copepods. The ELISA significantly discriminated positive (gravid female) and negative (male) samples, and was suitable for screening endocrine toxicity in copepods. Stage-I juvenile copepods were individually reared to adults in aqueous microvolumes of the phenylpyrazole insecticide, fipronil, and whole-body homogenate extracts were assayed for VTN levels. Fipronil-exposed virgin adult females, but not males, exhibited significantly higher levels of VTN relative to control males and females. This crustacean VTN ELISA is likely useful for evaluating endocrine activity of environmental toxicants in copepods and other crustacean species.

PMID: 14982375 [PubMed - indexed for MEDLINE]


Environ Sci Technol. 2004 Jan 15;38(2):522-8.

Phenylpyrazole insecticide fipronil induces male infertility in the estuarine meiobenthic crustacean Amphiascus tenuiremis.

Cary TL, Chandler GT, Volz DC, Walse SS, Ferry JL.

Department of Environmental Health Sciences, Norman J. Arnold School of Public Health, University of South Carolina, Columbia, South Carolina 29208, USA.

Copepods are the most abundant arthropods on earth and are often the most important secondary producers in estuarine/marine food webs. The new GABA (gamma-aminobutyric acid)-disrupting insecticide fipronil (FP) induces unique sex-specific reproductive dysfunction in male meiobenthic copepods, leading to trans-generational population depression at environmentally realistic concentrations (0.63 microg/L). Using a newly developed 96-well microplate lifecycle bioassay, more than 700 individual Stage-I juveniles were reared to adulthood in as short as 12 days in only 200 microL of control (CTL) or 0.63 microg-FP/L seawater solution. Individual virgin male: female pairs were then cross-mated for all possible combinations within and across rearing treatments and allowed to mate for an additional 12 days in CTL or 0.63 microg-FP/L solution. FP at 0.63 microg/L caused no significant lethality to any mating combinations but evoked 73% or 89% inhibition of reproduction when FP-reared males were mated with either a control- or FP-reared female in FP solution, respectively. In contrast, when CTL-reared males were mated with FP-reared females in FP solution, there was no difference in reproductive success compared to FP-free controls. When FP-reared males were mated with either female group in FP-free solution, these mating pairs displayed a 3-day delay in time to brood sac extrusion but ultimately did reproduce. As fipronil (1) has a high K(ow), (2) is persistent in sediments where meiobenthic copepods live, and (3) has been detected in estuarine waters >0.7 microg/L, it may pose high risk to copepod production in estuarine systems.

PMID: 14750729 [PubMed - indexed for MEDLINE]


J Environ Monit. 2004 Jan;6(1):58-64. Epub 2003 Nov 26.

The fate of fipronil in modular estuarine mesocosms.

Walse SS, Pennington PL, Scott GI, Ferry JL.

Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA.

The degradation and corresponding product manifold for the pesticide fipronil was determined in three replicate estuarine mesocosms. Aqueous fipronil concentrations rapidly decreased over the 672 h timescale of the experiment (95% removal). Loss was apparently first-order in fipronil, although there appeared to be a change in the removal mechanism after 96 h that corresponded to a dramatic slowdown in its disappearance. The reduction product of fipronil, fipronil sulfide, was not detected in the water column; however, it formed rapidly in sediments and was identified as the major product of fipronil degradation in the system (20% yield at 672 h, with respect to initial fipronil concentration). Fipronil sulfone is thought to form primarily via biological oxidation; and, although it was generated rapidly in the water column (10% yield), only trace amounts were detected in the sediment (1% yield). The direct photolysis product of fipronil, fipronil desulfinyl, was present in all samples; it formed rapidly in the water column (4% yield) and partitioned into the sediment phase (7% yield) over the course of the experiment. The mass balance on fipronil and associated products was 42% at 672 h.

PMID: 14737471 [PubMed - indexed for MEDLINE]


J Econ Entomol. 2004 Apr;97(2):601-5.

Impacts of residual insecticide barriers on perimeter-invading ants, with particular reference to the odorous house ant, Tapinoma sessile.

Scharf ME, Ratliff CR, Bennett GW.

Center for Urban and Industrial Pest Management, Department of Entomology, Purdue University, West Lafayette, IN 47907-2089, USA. scharfm@purdue.edu

Three liquid insecticide formulations were evaluated as barrier treatments against perimeter-invading ants at a multifamily housing complex in West Lafayette, IN. Several ant species were present at the study site, including (in order of abundance) pavement ant, Tetramorium caespitum (L.); honey ant, Prenolepis imparis (Say); odorous house ant, Tapinoma sessile (Say); thief ant, Solenopsis molesta (Say); acrobat ant, Crematogaster ashmeadi (Mayr); crazy ant, Paratrechina longicornis (Latrielle), field ants, Formica spp.; and carpenter ant Camponotus pennsylvanicus (DeGeer). Studies began in May 2001 and concluded 8 wk later in July. Individual replicate treatments were placed 0.61 in (2 feet) up and 0.92 m (3 feet) out from the ends of 46.1 by 10.1-m (151 by 33-foot) apartment buildings. Ant sampling was performed with 10 placements of moist cat food for 1 h within treatment zones, followed by capture and removal of recruited ants for later counting. All treatments led to substantial reductions in ant numbers relative to untreated controls. The most effective treatment was fipronil, where 2% of before-treatment ant numbers were present at 8 wk after treatment. Both imidacloprid and cyfluthrin barrier treatments had efficacy comparative with fipronil, but to 4 and 2 wk, respectively. Odorous house ants were not sampled before treatment. Comparisons of ant species composition between treatments and controls revealed an increase in odorous house ant frequencies at 1-8 wk after treatment in treated locations only. These results demonstrate efficacy for both nonrepellent and repellent liquid insecticides as perimeter treatments for pest ants. In addition, our findings with odorous house ant highlight an apparent invasive-like characteristic of this species that may contribute to its dramatic increase in structural infestation rates in many areas of the United States.

PMID: 15154488 [PubMed - indexed for MEDLINE]


Pest Manag Sci. 2003 Dec;59(12):1273-5.

Insecticidal activity of the enantiomers of fipronil.

Teicher HB, Kofoed-Hansen B, Jacobsen N.

Cheminova A/S, PO Box 9, DK-7620 Lemvig, Denmark. hbt@cheminova.dk

The two enantiomers of the insecticide fipronil were made by preparative HPLC. The insecticidal activities of the racemic mixture and the two enantiomers against selected agricultural or household pests (cotton stainer, Dysdercus cingulatus F; grain weevil, Sitophilus granarius L and house fly, Musca domestica L) were determined. There was no significant difference in acute or residual activity between the racemic mixture and the enantiomers of fipronil, indicating that there is no preferred chiral form of the compound in these key species of important insects. This observation clearly suggests that there is no major scope for marketing the insecticide in a one-enantiomer form.

PMID: 14667049 [PubMed - indexed for MEDLINE]


Environ Toxicol Chem. 2004 Jan;23(1):117-24.

Fipronil effects on estuarine copepod (Amphiascus tenuiremis) development, fertility, and reproduction: a rapid life-cycle assay in 96-well microplate format.

Chandler GT, Cary TL, Volz DC, Walse SS, Ferry JL, Klosterhaus SL.

Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina 29208, USA. chandlgt@gwm.sc.edu

Fipronil is a novel gamma-aminobutyric acid receptor-specific phenylpyrazole insecticide commonly used near estuarine environments for rice production, turf-grass management, and residential insect control. In this study, we evaluated the acute, developmental, and reproductive toxicity of fipronil to the estuarine harpacticoid copepod Amphiascus tenuiremis. Fipronil was highly toxic to A. tenuiremis (adult 96-h median lethal concentration [LC50] = 6.8 microg/L) and was more toxic to male copepods (96-h LC50 = 3.5 microg/L) than to nongravid female copepods (96-h LC50 = 13.0 microg/L). By using a newly developed 96-well microplate-based life-cycle toxicity test, we successfully reared single individuals of A. tenuiremis to adulthood in 200-microl microwells and concurrently assessed developmental and reproductive effects (after paired virginal matings) of environmentally relevant aqueous fipronil concentrations (0.16, 0.22, and 0.42 microg/L measured). Throughout the entire life cycle, copepod survival in all treatments was >90%. However, fipronil at 0.22 microg/L and higher significantly delayed male and female development from stage 1 copepodite to adult by approximately 2 d. More importantly, fipronil significantly halted female egg extrusion by 71% in the 0.22-microg/L fipronil treatment, and nearly eliminated reproduction (94% failure) in the 0.42-microg/L fipronil treatment. A three-generation Leslie matrix-based population growth model of fipronil reproductive and life-cycle impacts predicted a 62% decline in population size of A. tenuiremis relative to controls at only 0.16 microg/L.

Publication Types:
* Historical Article

PMID: 14768875 [PubMed - indexed for MEDLINE]


J Agric Food Chem. 2003 Nov 19;51(24):7055-61.
Phenylpyrazole insecticide photochemistry, metabolism, and GABAergic action: ethiprole compared with fipronil.

Caboni P, Sammelson RE, Casida JE.

Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.

Ethiprole• differs from fipronil, the major phenylpyrazole insecticide, only in an ethylsulfinyl substituent replacing the trifluoromethylsulfinyl moiety. This study compares their photochemistry, metabolism, action at the gamma-aminobutyric acid (GABA) receptor, and insecticidal potency. On exposure to sunlight as a thin film, ethiprole undergoes oxidation (major), reduction, and desethylsulfinylation but not desulfinylation whereas the major photoreaction for fipronil is desulfinylation. Metabolic sulfone formation is more rapid with ethiprole than fipronil in human expressed CYP3A4 in vitro and mouse brain and liver in vivo. High biological activity is observed for the sulfide, sulfoxide, sulfone, and desulfinyl derivatives in both the ethiprole and the fipronil series in GABA receptor assays (human recombinant beta3 homomer and house fly head membranes) with [(3)H]EBOB and in topical toxicity to house flies with and without the P450-inhibiting synergist piperonyl butoxide. On an overall basis, the ethiprole series is very similar in potency to the fipronil series.

PMID: 14611171 [PubMed - indexed for MEDLINE]

Ethiprole is an organofluroine insecticide.


Environ Toxicol Chem. 2003 Jul;22(7):1437-47.

Toxicity and pathogenicity of Metarhizium anisopliae var. acridum (Deuteromycotina, Hyphomycetes) and fipronil to the fringe-toed lizard Acanthodactylus dumerili (Squamata: Lacertidae).

Peveling R, Demba SA.

Institut fur Natur-, Landschafts- und Umweltschutz (NLU)-Biogeographie, Universitat Basel, St. Johanns-Vorstadt 10, 4056 Basel, Switzerland. ralf.peveling@unibas.ch

Reptiles in arid and semiarid zones are frequently exposed to insecticides sprayed to control locusts and grasshoppers. We evaluated the toxicity and pathogenicity of new biological and chemical control agents to the fringe-toed lizard Acanthodactylus dumerili in Mauritania, West Africa ... The second agent tested was fipronil (Adonis), a phenylpyrazole insecticide. A single dose of 30 microg fipronil/g body weight was administered via contaminated prey or stomach instillation. The percentage of dead or moribund lizards at four weeks posttreatment was 62.5% in animals fed contaminated prey and 42.0% in gavaged animals. In both tests, survivors showed significantly reduced feeding activity, food consumption, body weight, and organ-to-body-weight ratios (liver and/or fat body). The high toxicity of fipronil to lizards was not previously known, suggesting that follow-up studies (e.g., subacute dietary tests) are needed to provide adequate data for risk assessment.

PMID: 12836967 [PubMed - indexed for MEDLINE]


J Toxicol Clin Toxicol. 2003;41(3):245-8.

A case of accidental ingestion of ant bait containing fipronil.

Fung HT, Chan KK, Ching WM, Kam CW.

Accident and Emergency Department, Tuen Mun Hospital, Hong Kong. jhtfung@netvigator.com

A 77-year-old woman accidentally ingested a commercial ant bait containing fipronil without development of obvious toxicity, supporting the safety of this new insecticide as demonstrated in animal studies. However, concentrated agricultural products may be more toxic, and the potential for seizures should not be overlooked. The pharmacological action, mechanism of selective insect toxicity, and clinical effects of fipronil are discussed.

Publication Types:
* Case Reports

PMID: 12807306 [PubMed - indexed for MEDLINE]


Biomed Environ Sci. 2003 Mar;16(1):17-28.

Genetically engineered corn rootworm resistance: potential for reduction of human health effects from pesticides.

Oehme FW, Pickrell JA.

Comparative Toxicology Laboratories, M213 Mosier Hall, 1800 Denison Ave, Kansas State University, Manhattan, KS 66506-5705, USA. oehme@vet.ksu.edu

OBJECTIVE AND METHODS: Insecticide use, grower preferences regarding genetically engineered (GE) corn resistant to corn rootworm (CRW), and the health effects of using various CRW insecticides (organophosphates, pyrethroids, fipronil and carbamates) are reviewed for current and future farm practices.
RESULTS: Pest damage to corn has been reduced only one-third by insecticide applications. Health costs from insecticide use appear significant, but costs attributable to CRW control are not quantifiable from available data. Methods reducing health-related costs of insecticide-based CRW control should be evaluated. As a first step, organophosphate insecticide use has been reduced as they have high acute toxicity and risk of long-term neurological consequences. A second step is to use agents which more specifically target the CRW.
CONCLUSION: Whereas current insecticides may be poisonous to many species of insects, birds, mammals and humans, a protein derived from Bacillus thurigiensis and produced in plants via genetic modification can target the specific insect of CRW (Coleoptra), sparing other insect and non-insect species from injury.

PMID: 12747004 [PubMed - in process]


Arch Environ Contam Toxicol. 2003 Apr;44(3):377-82.

Horizontal and trophic transfer of diflubenzuron and fipronil among grasshoppers (Melanoplus sanguinipes) and between grasshoppers and darkling beetles (Tenebrionidae).

Smith DI, Lockwood JA.

Entomology Section, Department of Renewable Resources, University of Wyoming, Laramie, WY 82071-3354, USA. dsmith@uwyo.edu

The possibility of horizontal transmission of diflubenzuron and fipronil was assessed in rangeland grasshoppers. Laboratory studies of Melanoplus sanguinipes demonstrated that fipronil was horizontally transferred at lethal levels (p < 0.05) via cannibalism through four passages when the initial dose applied to a food source was 250 times the label rate for rangeland grasshopper and locust control (label rate is 4 g AI/ha). Mortality was 100% on the first three passages through cannibalism. At 25 and 1 times the label rate, fipronil was lethal (p < 0.05) only on the first cannibalistic passage. Diflubenzuron generated significant (p < 0.05) mortality via horizontal transmission through two passages when the initial dose applied to a food source was 2,000 times the label rate for rangeland grasshopper control (label rate is 8.71 g AI/ha). There was 100% mortality in the first passage via cannibalism. At 250 and 25 times the label rate, diflubenzuron was lethal only on the first cannibalistic passage. Field applications of these two acridicides followed by collection of cadavers (Amphitornus coloradus and Ageneotettix deorum) that were fed to M. sanguinipes in the laboratory revealed that fipronil (25 times the label rate) generated significant (p < 0.05) mortality through two passages and diflubenzuron (label rate) caused no mortality via necrophagy. Tenebrionid beetles fed grasshopper cadavers collected from the field application of fipronil yielded 45% mortality, compared with 25% mortality in the controls. These findings suggest that horizontal and trophic transfer probably play a nominal ecotoxicological role in rangeland grasshopper control programs with diflubenzuron, but the transfer of fipronil to grasshoppers, scavengers, and natural enemies via necrophagy may increase both the efficacy of control programs and their environmental affects.

PMID: 12712298 [PubMed - indexed for MEDLINE]


Bull Environ Contam Toxicol. 2003 Apr;70(4):746-52.

No Abstract available

Impact of fipronil on crustacean aquatic organisms in a paddy field-fishpond ecosystem.

Shan Z, Wang L, Cai D, Gong R, Zhu Z, Yu F.

Department of Environmental Science, Nanjing University, Nanjing 210093, People's Republic of China.

PMID: 12677386 [PubMed - indexed for MEDLINE]


Bull Environ Contam Toxicol. 2003 Mar;70(3):533-40.

Toxicity of the Insecticides Fipronil and Endosulfan to Selected Life Stages of the Grass Shrimp ( Palaemonetes pugio).

Key PB, Chung KW, Opatkiewicz AD, Wirth EF, Fulton MH.

National Ocean Service, Center for Coastal Environmental Health and Biomolecular Research, 219 Fort Johnson Road, Charleston, SC 29412, USA.

PMID: 12592529 [PubMed - in process]


J Agric Food Chem. 2003 Feb 26;51(5):1347-52.

Fipronil metabolism and dissipation in a simplified aquatic ecosystem.

Aajoud A, Ravanel P, Tissut M.

Laboratoire Ecosystemes et Changements Environnementeaux, Universite Joseph Fourier, B.P. 53, 38041 Grenoble Cedex 09, France.

Several phenylpyrazole derivatives are selective inhibitors of chloride channel activities in insects. In this chemical family, fipronil is a powerful insecticide now widely used for several purposes. The dissipation of this molecule in a simplified aquatic ecosystem has been studied for 3 months, using (14)C-labeled fipronil. The main features of the complex process leading to fipronil transformation in this system were the following. The fipronil aqueous solution was submitted to two chemical transformations: the photodependent desulfuration of the side chain bound to the 4-position of the heterocyclic ring and the chemical hydrolysis of the nitrile function bound to the 3-position. Fipronil, rapidly transferred from the water solution to the organic matter, was protected from the previously mentioned chemical transformations but evolved to give two main metabolites, which were either reduced or oxidized in the side chain on the 4-position. These derivatives were powerful insecticides as shown by LC(50) measurements on Aedes aegypti larvae (LC(50) for CF(3)-S-R and CF(3)-SO(2)-R = 8.8 nM). During the course of this experiment, nitrile hydrolysis took place slowly, originating either from the chemical hydrolysis in the aqueous solution or from enzymatic hydrolysis inside the microbial biomass. The fipronil-amide (3-NH(2)-CO-R') derivative, although much more polar than fipronil itself, was mostly bound to the organic matter. Other more polar derivatives were also detected but in very small amounts. No (14)CO emission was observed during the experiment.

PMID: 12590480 [PubMed - indexed for MEDLINE]


Bull Soc Pathol Exot. 2002 Nov;95(4):299-303.

[An experimental tool essential for the evaluation of insecticides: the testing huts]

[Article in French]

Darriet F, N'Guessan R, Hougard JM, Traore-Lamizana M, Carnevale P.

Laboratoire de lutte contre les insectes nuisibles, 911 Avenue Agropolis, BP 64501, 34394 Montpellier, France. darriet@mpl.ird.fr

The following study analyses the potentialities of the experimental huts built in M'be Valley (Cote d'Ivoire) where the evaluations of the insecticide products have been carried out for many years in line with the WHOPES protocol on the methodology of stage 2 assays. Starting a testing station first requires a good knowledge of the sensitivity of Anopheles gambiae to the main insecticide families. Then thanks to the experimental huts the efficacy of the various means of treatment can be compared with the one in untreated huts; this study focuses on house spraying using 100 mg a.i./m2 and bednets impregnated with lambda-cyhalothrin at a dose of 15 mg a.i./m2. The fipronil used in house spraying doesn't show any repellent effect, however it does have an irritating effect that increases the natural exophily of An. gambiae females entering the testing huts. The blood-feeding rate recorded in the treated huts was reduced to 24% and to 38% mortality rate consisting mainly of a 24 hours delayed mortality. The bednets treated with lambda-cyhalothrin have greatly reduced the contact between man and vector since the entry rate of An. gambiae females was cut down by 68% compared to the control. The exophily of this anopheles was twofold greater with the impregnated bednets and the blood-feeding rate reduced to 47%. Finally the global mortality rate, two thirds of immediate mortality, one third of delayed mortality, reached 35%. The experimental huts in the M'be Valley therefore provide essential information regarding the selection of the most efficacious insecticides against An. gambiae. This experimental method must be extended to other sites in order to finalize ever more selective and appropriate means of control against nuisance and disease-vector mosquitoes.

PMID: 12596384 [PubMed - indexed for MEDLINE]


Mini Rev Med Chem. 2002 Aug;2(4):419-32.

Nerve membrane ion channels as the target site of insecticides.

Narahashi T.

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, IL 60611, USA. tna597@nwu.edu

Most insecticides are potent neurotoxicants that act on various neuroreceptors and ion channels. However, the major target receptors are limited to sodium channels, GABA receptors, and nicotinic acetylcholine receptors. DDT and pyrethroids act similarly on sodium channels to keep them open leading to hyperexcitation. Indoxacarb inhibits sodium channels and certain subtypes of nicotinic receptors. Dieldrin, lindane and fipronil block GABA receptors. Imidacloprid modulates nicotinic receptors in a complex manner. Spinosad's major target site appears to be nicotinic receptors.

Publication Types: Review; Review, Tutorial

PMID: 12370061 [PubMed - indexed for MEDLINE]


Vet Hum Toxicol. 2002 Oct;44(5):301-3.

Human exposure to fipronil from dogs treated with frontline.

Jennings KA, Canerdy TD, Keller RJ, Atieh BH, Doss RB, Gupta RC.

Department of Agriculture, Murray State University, KY 42071-1906, USA.

This investigation determined fipronil residues on gloves worn while petting dogs after Frontline application. Frontline contains 9.8% fipronil, which controls fleas and ticks on dogs for at least 30 d. Frontline (1.34 ml) was applied topically on adult household dogs and gloves worn for 5 min during pettingwere collected 24 hr and 1, 2, 3, 4 and 5 w post-Frontline application for fipronil residue determinations using GC/MS. The highest concentration of fipronil (589.3 +/- 205.7ppm) was detected 24 h after Frontline application and was undetectable in the gloves collected at 5w. Repeated exposure to such contamination can pose human health risks.

PMID: 12361121 [PubMed - indexed for MEDLINE]


Environ Toxicol Chem. 2001 May;20(5):972-7.

Abiotic processes influencing fipronil and desthiofipronil dissipation in California, USA, rice fields.

Ngim KK, Crosby DG.

Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, California 95616, USA.

Fipronil insecticide dissipated in California rice fields, producing half-lives of 10.5 to 125 h in water and 44.5 to 533 h in soil, depending on the formulation applied and the resulting differences in water solubility. The major degradation products were desthiofipronil in water and fipronil-sulfide in soil, while the sulfone and amide were less abundant. Fipronil was photolyzed rapidly to desthiofipronil in deionized water in the laboratory (t1/2 = 7.97-9.42 h) and even faster in the presence of H2O2 (t1/2 = 0.874-4.51 h). Fipronil was also hydrolyzed to amide in base (t1/2 = 542 h at pH 9) and volatilized slowly from water (H = 6.60 x 10(-6) m3.atm/mol), properties not explaining its rapid field water dissipation. Desthiofipronil was more stable than fipronil to direct photolysis (t1/2 = 120-149 h), was indirectly photolyzed in the presence of H2O2 (t1/2 = 0.853-3.76 h), and was nonvolatile from water. The desthiofipronil observed in field water was formed photochemically from fipronil, accumulated due to slower photolysis and lack of volatility from water, but eventually dissipated.

PMID: 11337886 [PubMed - indexed for MEDLINE]


J Agric Food Chem. 2000 Oct;48(10):4661-5.

Elucidation of fipronil photodegradation pathways.

Ngim KK, Mabury SA, Crosby DG.

Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, California 95616, USA.

The phenylpyrazole insecticide fipronil (I) photolyzes to its desthio product (II) in aqueous solution. However, the necessity of an intervening oxidation to a sulfone intermediate (III) has not been resolved, and the photodegradation products of II have not been identified. Using GC-MS, HPLC-UV/vis, electrospray MS, (19)F NMR, and GC-TSD, our objective was to characterize the photodegradation pathways of I, which would clarify the role of III, identify products of II, and explain unbalanced mass accounts in previous studies. Findings showed that II is formed directly and photochemically from I, confirmed by the greater stability of III (t(1/2) 112 h), and that successive oxidations of I to III and then a sulfonate (IV) comprise a second pathway. Compound II underwent photodechlorination, substitution of chlorine by trifluoromethyl, and pyrazole ring cleavage. This work is significant to understanding the photochemistry of novel phenylpyrazole pesticides in the environment.

PMID: 11052715 [PubMed - indexed for MEDLINE]


Aust Vet J. 1999 Mar;77(3):202.

Product warning: FRONTLINE.

Webster M.

Publication Types: Letter

PMID: 10197255 [PubMed - indexed for MEDLINE]


Chem Res Toxicol. 1998 Dec;11(12):1529-35.

Mechanisms for selective toxicity of fipronil insecticide and its sulfone metabolite and desulfinyl photoproduct.

Hainzl D, Cole LM, Casida JE.

Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.

Fipronil, an N-phenylpyrazole with a trifluoromethylsulfinyl substituent, initiated the second generation of insecticides acting at the gamma-aminobutyric acid (GABA) receptor to block the chloride channel. The first generation includes the polychlorocycloalkanes alpha-endosulfan and lindane. In this study, we examine the mechanisms for selective toxicity of the sulfoxide fipronil and its sulfone metabolite and desulfinyl photoproduct relative to their target site interactions in vitro and ex vivo and the importance in fipronil action of biooxidation to the sulfone. Differences in GABA receptor sensitivity, assayed by displacement of 4'-ethynyl-4-n-[2, 3-3H2]propylbicycloorthobenzoate ([3H]EBOB) from the noncompetitive blocker site, appear to be a major factor in fipronil being much more toxic to the insects (housefly and fruit fly) than to the vertebrates (humans, dogs, mice, chickens, quail, and salmon) examined; in insects, the IC50s range from 3 to 12 nM for fipronil and its sulfone and desulfinyl derivatives, while in vertebrates, the IC50 average values are 1103, 175, and 129 nM for fipronil, fipronil sulfone, and desulfinyl fipronil, respectively. The insect relative to the vertebrate specificity decreases in the following order: fipronil > lindane > desulfinyl fipronil > fipronil sulfone > alpha-endosulfan. Ex vivo inhibition of [3H]EBOB binding in mouse brain is similar for fipronil and its sulfone and desulfinyl derivatives at the LD50 dose, but surprisingly, at higher doses fipronil can be lethal without detectably blocking the [3H]EBOB site. The P450 inhibitor piperonyl butoxide, acting in houseflies, increases the metabolic stability and effectiveness of fipronil and the sulfone but not those of the desulfinyl compound, and in mice it completely blocks the sulfoxide to sulfone conversion without altering the poisoning. Thus, the selective toxicity of fipronil and fipronil-derived residues is due in part to the higher potency of the parent compound at the insect versus the mammalian GABA receptor but is also dependent on the relative rates of conversion to the more persistent and less selective sulfone metabolite and desulfinyl photoproduct.

PMID: 9860498 [PubMed - indexed for MEDLINE]

Full free article available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=8917493

Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12764-7.

Fipronil insecticide: novel photochemical desulfinylation with retention of neurotoxicity.

Hainzl D, Casida JE.

Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720-3112, USA.

Fipronil is an outstanding new insecticide for crop protection with good selectivity between insects and mammals. The insecticidal action involves blocking the lambda-aminobutyric acid-gated chloride channel with much greater sensitivity of this target in insects than in mammals. Fipronil contains a trifluoromethylsulfinyl moiety that is unique among the agrochemicals and therefore presumably important in its outstanding performance. We find that this substituent unexpectedly undergoes a novel and facile photoextrusion reaction on plants upon exposure to sunlight, yielding the corresponding trifluoromethylpyrazole, i.e., the desulfinyl derivative. The persistence of this photoproduct and its high neuroactivity, resulting from blocking the lambda-aminobutyric acid-gated chloride channel, suggest that it may be a significant contributor to the effectiveness of fipronil. In addition, desulfinylfipronil is not a metabolite in mammals, so the safety evaluations must take into account not only the parent compound but also this completely new environmental product.

PMID: 8917493 [PubMed - indexed for MEDLINE]


Annu Rev Entomol. 1996;41:163-90.

Ion channels as targets for insecticides.

Bloomquist JR.

Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0319, USA.

Ion channels are the primary target sites for several classes of natural and synthetic insecticidal compounds. The voltage-sensitive sodium channel is the major target site for DDT and pyrethroids, the veratrum alkaloids, and N-alkylamides. Recently, neurotoxic proteins from arthropod venoms, some of which specifically attack insect sodium channels, have been engineered into baculoviruses to act as biopesticides. The synthetic pyrazolines also primarily affect the sodium channel, although some members of this group target neuronal calcium channels as well. The ryanoids have also found use as insecticides, and these materials induce muscle contracture by irreversible activation of the calcium-release channel of the sarcoplasmic reticulum. The arylheterocycles (e.g. endosulfan and fipronil) are potent convulsants and insecticides that block the GABA-gated chloride channel. In contrast, the avermectins activate both ligand- and voltage-gated chloride channels, which leads to paralysis. At field-use rates, a neurotoxic effect of the ecdysteroid agonist RH-5849 is observed that involves blockage of both muscle and neuronal potassium channels. The future use of ion channels as targets for chemical and genetically engineered insecticides is also discussed.

Publication Types: Review; Review, Academic

PMID: 8546445 [PubMed - indexed for MEDLINE]

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