Page 659 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

624 SECTION | VIII Rodenticides

VetBooks.ir is twice that of the kidneys because of its involvement in compounds are extremely toxic to humans and animals.
Tl has been classified as the most toxic cumulative metal
enterohepatic circulation. Tl is known to pass in the milk
cation. A single dose of 15 mg Tl/kg body weight has
of poisoned female rats, mice, guinea pigs, and humans.
A significant fraction of free plasma Tl also crosses the been found to be lethal in guinea pigs, dogs, and humans.
placental barrier. A small amount of Tl can also be found The LD 50 is 15 mg/kg in rats and 16 27 mg/kg in mice.
in hair. Following chronic exposure, Tl can be deposited Of course, these values vary depending on the form of Tl
in the bones, which may account for its cumulative (Mulkey and Oehme, 1993).
toxicity. Onset of signs and symptoms of Tl poisoning is slow
(i.e., within 48 h). The signs and symptoms of Tl toxicity
(thallotoxicosis) can vary depending on the species, age,
Mechanism of Action
form of Tl, dose, and acute versus chronic exposure.
Tl produces toxicity in mammals through multiple Gastroenteritis, polyneuropathy, and hair loss are the
mechanisms. Tl 1 and K 1 have common cellular targets dominant features of Tl poisoning (Mulkey and Oehme,
and receptor sites associated with biological activity and 1993). Acutely poisoned animals show abdominal pain,
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1
toxicity. Tl replaces K in the intracellular environment, vomiting, and constipation or diarrhea. At a high-dose
1
1
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and shows a 10-fold greater affinity over K for Na /K - exposure, neurologic signs dominate with peripheral neu-
ATPase. Tl at higher concentrations competitively inhibits ropathy. Sensory disturbances include pain, ataxia, and
1
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Na /K -ATPase activity. Mitochondria have an abun- paresthesia, which progress to muscle atrophy. Muscle
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dance of Na /K -ATPase, and are particularly suscepti- fibers can show myopathic changes with abnormal central
ble to the effects of Tl. Tl inhibits the influx and efflux of nucleoli, striated transverse fibers disappearance, necrosis,
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K in mitochondria without causing any alterations in and fibrosis. Cats dosed with Tl at 4 mg/kg body weight
1
movement of Na . In addition, Tl inactivates sulfhydryl developed hypotonia and ataxia mainly due to pathologi-
groups, including those affecting the permeability of the cal changes in sensory neurons (Sager, 1994). Dogs and
outer mitochondrial membrane. As a result of mitochon- cats exposed to Tl also showed hemorrhagic gastroenteri-
drial dysfunction, a variety of morphological changes, tis and hepatic and renal damage.
including mitochondrial swelling and vacuolization, occur Surviving animals usually show signs of alopecia,
in mitochondria in kidney, liver, brain, pancreas, and bloody lesions of the skin, tremors, neuropathy (involving
other tissues of mammals. Tl compromises mitochondrial both central and peripheral nervous systems), and paraly-
energy production by inhibiting pyruvate dehydrogenase sis of muscles. In addition, Tl causes structural and func-
complex and succinate dehydrogenase by uncoupling oxi- tional changes in the heart and kidneys. Evidence from
dative phosphorylation. Tl is also known to disrupt nor- experimental animal studies suggests that the reproductive
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mal cell metabolism by stimulating several K -dependent system is highly susceptible to Tl. Humans and animals
enzymes such as phosphatase, homoserine dehydrogenase, accumulate Tl in testes, where morphological and bio-
vitamin B 12 -dependent diol dehydrogenase, L-threonine chemical changes occur. Tl is embryotoxic and terato-
dehydratase, and AMP deaminase. genic in chick embryo, causing achondroplasia, leg bone
Tl has been demonstrated to increase the levels of curvature, beak deformity, microcephaly, and decreased
hydrogen peroxide and decrease the levels of glutathione, fetal size. However, teratological investigations in mam-
which leads to enhanced lipid peroxidation, oxidative mals have produced conflicting results (Gregotti and
stress, and energy depletion primarily in the brain (Hasan Faustman, 1998). For further details on Tl toxicity, refer
and Ali, 1981; Hanzel and Verstraeten, 2005). Tl-induced to Mulkey and Oehme (1993) and Galvan-Arzate and
changes, such as cellular energy loss, depletion of flavopro- Santamaria (1998).
teins, and binding of Tl to active sulfhydryl sites of
enzymes, are the proposed mechanisms for Tl neuropathy. Diagnosis
The complexing of Tl to cysteine appears to inhibit cross-
linking of proteins, and thereby, causes inhibition of kerati- Diagnosis of Tl poisoning is based on evidence of Tl expo-
nization of hair. Tl blocks formation of the disulfide bonds sure, clinical signs, and chemical confirmation in body tis-
in keratin and, thus, leads to hair loss (Mulkey and Oehme, sue/fluid. Quantitative analysis for Tl in urine, serum,
1993). Most evidence supports direct involvement of Tl feces, saliva, or hair is performed to assess the extent of Tl
with the hair follicles as the mechanism of hair loss. exposure and to monitor treatment. Tl residue analysis at
diagnostic labs is commonly carried out using atomic
absorption spectrometer, inductively coupled plasma (ICP),
Toxicity
or ICP mass spectrometer-based methods. Tl-induced
Tl toxicity has been studied extensively in rats, mice, hematological changes may include anemia, leukocytosis,
guinea pigs, rabbits, dogs, and humans. In general, Tl eosinophilia, and lymphocytopenia. Decreased creatinine