Page 591 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

556 SECTION | VII Herbicides and Fungicides

VetBooks.ir The dermal penetration in monkeys is relatively slow. and lack of relevance to humans for the nasal turbinate,
Substituted anilines are well absorbed in rats orally.
stomach and/or thyroid oncogenic effects produced in
rats. The data support grouping of alachlor, acetochlor,
The metabolism of alachlor in rats is complex due to
extensive biliary excretion, intestinal microbial metabo- and butachlor with respect to a common mechanism of
lism and enterohepatic circulation of metabolites. The toxicity for nasal turbinate and thyroid tumors, and
main routes of excretion are urine and feces, and nearly grouping of alachlor and butachlor for stomach tumors
90% of the dose is eliminated in 10 days. Dimethenamid, (Heydens et al., 2010).
an amide derivative, is slowly but well absorbed after oral The mechanism of action of paraquat and diquat is
administration (90% in rats) and is extensively metabo- very similar at the molecular level and involves cyclic
lized in rats. The maximum concentration in blood is not reduction oxidation reactions, which produce reactive
achieved until approximately 72 h. Excretion is primarily oxygen species and depletion of nicotinamide adenine
via bile. By 168 h after treatment, an average of 90% of dinucleotide phosphate hydrogen (NADPH). However,
the administered dose is eliminated. In rats, the triazolo- the critical target organ differs for the two compounds, so
pyrimidine compounds are rapidly absorbed and urinary the mammalian toxicity is quite different. Although both
elimination is rapid, with half-lives ranging from 6 to herbicides affect kidneys, paraquat is selectively taken up
12 h. Excretion is mainly through urine, and small in the lungs. Paraquat causes pulmonary lesions as a result
amounts are excreted in feces. of type I and type II pneumocytosis. The primary event in
the mechanism of toxicity within cells is paraquat’s abil-
ity to undergo a single electron reduction from the cation
MECHANISM OF ACTION
to form a free radical that is stable in the absence of
There are a number of biochemical changes or free oxygen. If oxygen is present, a concomitant reduction of
2
radical-mediated processes; some may also be produced oxygen takes place to form superoxide anion (O ).
2
by other mechanisms that have been used to assess tissue Superoxide radical, in turn, is nonenzymatically converted
injury. For example, the loss of tissue GSH may reflect to singlet oxygen, which attacks polyunsaturated lipids
alkylation reactions, not oxidation. Furthermore, some associated with cell membranes to form lipid hydroperox-
free radical-mediated changes that may cause injury are ides. Lipid hydroperoxides are normally converted to
also the result of injury. In most situations, it is difficult nontoxic lipid alcohols by the selenium-containing GSH-
to pinpoint the exact mechanism of action. The mecha- dependent enzyme, GSH peroxidase. Selenium deficiency,
nism of action of phenoxy derivatives, triazines, triazolo- deficiency of GSH, or excess lipid hydroperoxides allows
pyrimidines, imidazolinones, dinitroaniline, and many the lipid hydroperoxides to form lipid-free radicals. Lipid
other classes of herbicides is not precisely known. hydroperoxides are unstable in the presence of trace
However, phenoxy compounds are known to depress ribo- amounts of transition metal ions and decompose to free
nuclease synthesis, uncouple oxidative phosphorylation radicals, which in turn cause further peroxidation of poly-
and increase the number of hepatic peroxisomes. The unsaturated lipid in a process that is slowed by vitamin E.
relationship of these biochemical changes to clinical Peroxidation of the membranes could in turn cause cellu-
effect is not clear. In dogs, these herbicides may directly lar dysfunction and hence lead to cell damage or death
affect muscle membranes (Sandhu and Brar, 2000). (Smith, 1997). Genes associated with oxidative stress,
Herbicides such as 2,4-D, 2,4,5-trichlorophenoxyacetic redox cycling and apoptosis have been shown to play a
acid (2,4,5-T) and dicamba act as peroxisome prolifera- key role in the development of lung fibrosis (Tomita
tors. Oxadiazinon causes hepatic porphyria in both mice et al., 2007; Lock and Wilks, 2010). The neurotoxicity of
and rats. The phenyl urea herbicides linuron and monuron paraquat is under debate (Lock and Wilks, 2010), but
are rodent liver carcinogens. Chloroacetanilide and meto- its involvement in neurodegenerative diseases like
lachlor have shown weak hepatocarcinogenicity in female Parkinson’s is well established (Jones et al., 2014). A
rats and are nongenotoxic, suggesting a tumor-promoting schematic diagram incorporating these elements of the
action. The dinitro compounds markedly stimulate respi- mechanism of paraquat-induced lung toxicity is shown in
ration while simultaneously impairing adenosine triphos- Fig. 44.3.
phate synthesis. The main toxic action is uncoupling of The mechanism of action of diquat differs somewhat
oxidative phosphorylation, converting all cellular energy from that of paraquat because it undergoes alternate
in the form of heat and causing extreme hyperthermia. reduction followed by reoxidation—a process known as
In addition, the gut flora in ruminants is able to further redox recycling. Like paraquat, diquat can redox cycle,
reduce the dinitro compounds to diamine metabolites, with the major difference being that diquat can more
which are capable of inducing methemoglobinemia. readily accept an electron than can paraquat (Gage,
The available information on substituted anilines indi- 1968). The major target organs are the GI tract, the liver
cates that there is a nongenotoxic mechanism of action and the kidneys. Unlike paraquat, diquat shows no special