Page 539 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

506 SECTION | VI Insecticides

VetBooks.ir are esters of phosphorus-containing acids. Almost half a TOLERANCE DEVELOPMENT
century ago, tri-o-cresyl phosphate (TOCP) was known
Tolerance development to the toxicity of OPs was noted
to produce delayed neurotoxic effects in man and chick-
ens, characterized by ataxia and weakness of the limbs, more than half a century ago. Following prolonged expo-
sure to an OP, the physiological effects often diminish
developing 10 14 days after exposure (Johnson, 1969).
more than expected from the degree of AChE inhibition
This syndrome was called OP-induced delayed neuropa-
or repeated additions of OP give lower responses with
thy (OPIDN). In recent literature, the syndrome has been
time. Tolerance to AChE inhibiting OPs (such as DFP,
renamed OP-induced delayed polyneuropathy (OPIDP).
disulfoton, methyl parathion, and others) has been
OPIDP is characterized by distal degeneration of long
observed using different forms of administration and in
and large-diameter motor and sensory axons of both
different species, such as mice, rats, guinea pig, and man
peripheral nerves and spinal cord. Among all animal spe-
(Fonnum and Sterri, 1981, 2006; Gupta and Dettbarn,
cies the hen appears to be the most sensitive and is there-
1986; Gupta et al., 1986; Gupta, 2004).
fore used as an animal model. TOCP and certain other
Tolerance to OP toxicity can develop in several ways.
compounds have minimal or no anti-AChE property;
Most often, it occurs due to receptor changes either in the
however, they cause phosphorylation and aging (dealky-
number of receptors or by decreased affinity of the recep-
lation) of a protein in neurons called neuropathy target
tor molecule. However, it can also occur due to the pres-
esterase (NTE), and subsequently lead to OPIDP (Gupta
ence of other proteins that can bind or inactivate the
and Milatovic, 2012). Studies on the sensitivity of the tar-
inhibitor and thereby make it less readily available. Some
get enzymes of a variety of OPs showed that the compar-
of the examples for binding to the OPs are carboxyles-
ative inhibitory power of OPs against hen AChE and
terases, butyrylcholinesterases, lysophospholipase, acetyl-
NTE in vitro correlates with their comparative effects
hydrolase, or other binding proteins such as albumin
in vivo (i.e., delayed neuropathy or death). The relation-
(Sogorb and Vilanova, 2010; Mangas et al., 2017). In
ship between the degree of NTE inhibition and the sever-
addition, tolerance can be achieved through more rapid
ity of OPIDP changes according to the compound
metabolism of the OP compounds by OP-hydrolyzing
involved and the source of NTE. For example, certain
enzymes such as paraoxonases (PONs), DFPase, and
compounds cause OPIDP with a minimum of 70% NTE
somanases (Costa et al., 2006; Fonnum and Sterri, 2006).
inhibition, while others require almost complete inhibi-
ACh receptors (both mAChRs and nAChRs) are
tion to cause OPIDP. Inhibition of peripheral nerve NTE
involved in the development of tolerance to OP toxicity.
is required to develop OPIDP and no clinical deficits
Treatment with a cholinergic agonist for a prolonged time
appear if only brain NTE is inhibited. For neuropathy to
leads to a decrease in the mAChRs. This is common
occur, a second reaction called “aging” of NTE must take
for G protein-linked receptors. In some studies, OPs
place and this involves cleavage of the lateral side chain
have been found to cause a decrease in the numbers
from the phosphorylated NTE. This reaction is called
of mAChRs in the brain, while in others both the number
aging because it is a slow progressive process and the
of mAChRs and the affinity to the ligand in ileum and
product is no longer responsive to nucleophilic reactivat-
striatum.
ing agents, such as oximes. The cascade of events from
Significant reductions in nAChRs numbers (B max ),
NTE inhibition/aging to impairment of retrograde axonal
without change in affinity (K D ), have been found in brain
transport and axonal degeneration is yet to be explained
of tolerant rats treated with disulfoton (Costa and
(Moretto and Lotti, 2006; Gupta and Milatovic, 2012;
Murphy, 1983) and in skeletal muscle of rats treated with
Mangas et al., 2017). Today, many compounds, such as
DFP (Gupta et al., 1986; Gupta and Dettbarn, 1986). In
DFP, N,N -diisopropyl phosphorodiamidic fluoride (mipa-
0
tolerant rats, significant recovery of CarbEs and BuChEs
fox), tetraethyl pyrophosphate (TEPP), parathion, o-cre-
has also been found. In essence, tolerance development
syl saligenin phosphate, and haloxon, are known to
following subchronic or chronic treatment with AChE
produce this syndrome. Some OPs as well as non OP
inhibiting OPs occurs through multiple mechanisms.
inhibitors (such as carbamates and sulfonyl fluorides)
also covalently react with NTE but cannot undergo the
aging reaction. As a result, these inhibitors do not cause CONCLUDING REMARKS
OPIDP, and when given to experimental animals prior to AND FUTURE DIRECTIONS
neuropathic OP, may protect from OPIDP when they
occupy at least 30% of the NTE active site. For the OPs and CMs constitute a large number of chemicals that
details of OPIDP syndrome, readers are referred to are used in agriculture primarily as insecticides and in
Morreto and Lotti (2006) and Wu and Chang (2010). veterinary medicine as parasiticides. These chemicals
Treatment of this syndrome is symptomatic. exert a broad range of toxic effects, varying from mild