Page 568 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Fipronil Chapter | 42 535

VetBooks.ir CYP1A1 induction. Fipronil has the potential to interact roid disrupting properties in rats (Leghait et al., 2009;
Different studies have shown that fipronil reveals thy-
with a wide range of xenobiotics or endogenous chemi-
cals that are CYP3A4 substrates. In the case of possible
Roques et al., 2012), but not in sheep (Leghait et al.,
metabolic interactions based on the induction or inhibi- 2010). The differences between rat and sheep for thyroid
tion of xenobiotic metabolizing enzymes, concentra- disruption might be related to the difference in exposure
tions of fipronil at the active site(s) become crucial to the toxicant, the actual exposure to the sulfone metabo-
(Wang et al., 2016). lite of fipronil being lower in sheep than in rats.
Mechanistic investigations conducted with fipronil in rats
suggest that it does not interfere with the incorporation of
MECHANISM OF ACTION iodine into thyroxine (T4), but it does interfere with the
biliary clearance of this hormone. This may trigger an
In mammalian systems, the mechanism of fipronil is quite increase in the concentration of thyroid-stimulating
different from other classes of insecticides, and it is better hormone by interference with the feedback mechanism
understood in insects than in mammals. Fipronil sulfone and decreased T4 concentrations. Roques et al. (2012)
is a major metabolite of fipronil in mammals and insects. stated that the potential of fipronil sulfone to act as a thy-
In invertebrates (insects), fipronil or its metabolite non- roid disruptor is more critical because it persists much
competitively inhibits γ-aminobutyric acid (GABA A )- longer in the organism than fipronil itself.
induced ion influx by targeting the GABA A -regulated
chloride channels (Cole et al., 1993; Narahashi et al., TOXICITY
2007, 2010; Wang et al., 2016). Consequently, fipronil
binding blocks the inhibitory action of GABA A , leading Fipronil produces toxicity in insects and mammals by the
to neural hyperexcitation, and at sufficient concentrations, same mechanism; however, due to selective action, toxic-
paralysis and death (Bobe et al., 1998; Wang et al., 2016). ity is much more severe in insects than in mammals.
Fipronil exhibits .500-fold selective toxicity to insects Fipronil and other phenylpyrazole compounds exert neu-
over mammals, primarily because of affinity differences rotoxicity by blocking transmission of signals by inhibi-
in receptor binding between insect and mammalian recep- tory neurotransmitter GABA A . These compounds bind
tors (Cole et al., 1993; Grant et al., 1998; Hainzl et al., within the chloride channels and consequently inhibit the
1998; Kamijima and Casida, 2000; Ratra et al., 2001; flux of chloride ions into the nerve cell, resulting in
Zhao et al., 2005; Narahashi et al., 2007, 2010). In hyperexcitation.
essence, fipronil binds more tightly to GABA A receptors There are numerous reports regarding the effects of
(β3 subunit) in insects than in mammals. It is important to fipronil in small animals, birds and fish (http://www.cdpr.
note this, since the fipronil sulfone metabolite forms ca.gov/docs/empm/pubs/fatememo/fipronil.pdf).
rapidly. Both in vivo and in vitro studies suggest that the
majority of toxicological effects are more likely due to Laboratory Animals
fipronil sulfone than fipronil itself (Zhao et al., 2005;
Romero et al., 2016; Wang et al., 2016). Recent reports Adequate acute toxicity data are available for laboratory
indicate that fipronil and its metabolite(s) can cause toxic- animals. Fipronil is moderately hazardous to rats
ity in liver, kidney and other vital organs by dysregulating (LD 50 5 97 mg/kg body wt) and mice (LD 50 5 95 mg/kg
mitochondrial bioenergetics (by inhibiting mitochondrial body wt). In rats, signs of toxicity and death were delayed
respiratory chain) and calcium homeostasis, oxidative for up to 4 days after a single dose or repeated oral doses
and nitrosative stress, as well as damage to DNA and of 75 mg/kg body wt/day for up to 5 days. Fipronil has
proteins (Badgujar et al., 2015; de Medeiros et al., 2015; moderate inhalation toxicity with an acute LC 50 of
Khan et al., 2015; Tavares et al., 2015; Wang et al., 0.682 mg/L in rats (EPA, 1996).
2016). Cell death can occur due to apoptosis or autophagy It is nontoxic to slightly toxic via the dermal route,
(Zhang et al., 2015; Wang et al., 2016). with a reported dermal LD 50 of greater than 2000 mg/kg
The toxicity of fipronil desulfinyl is qualitatively simi- in rats (EPA, 1996). In rabbits, fipronil was found
lar to that of fipronil, but the dose effect curve for neuro- to be moderately hazardous after dermal application
toxic effects appears to be steeper for fipronil desulfinyl. (LD 50 5 354 mg/kg body wt; WHO, 1998 99). In gen-
Also, fipronil desulfinyl appears to have a much greater eral, dermal absorption of fipronil is less than 1% after
tendency than fipronil to bind to sites in the chloride ion 24 h and therefore dermal toxicity is considered very low.
channel of the rat brain GABA A receptor. This finding In a dermal toxicity study, fipronil was applied (0.5% in
appears to be consistent with the greater toxicity of fipro- carboxymethylcellulose) to the intact skin of rabbits for
nil desulfinyl, relative to fipronil, in the central nervous 6 h/day, 5 days a week, for 3 weeks at doses of 0, 0.5, 1,
system (CNS) of mammals. 5 or 10 mg/kg body wt/day. No dermal irritation was