Page 607 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

572 SECTION | VII Herbicides and Fungicides

VetBooks.ir primarily involving oxidation of the pyrrole ring (57% of phosphorylation. Thiamine is cleaved into its constituent
pyrimidine and thiazole moieties, rendering it inactive.
the administered dose) and a minor oxo-pyrrole metabolite
Although the biochemical and molecular mechanism(s)
(4% of the administered dose), followed by glucuronyl and
sulfate conjugation. There is no potential of accumulation by which captan and its analogs exert their cellular toxicity
in the tissues. Trifloxystrobin is rapidly absorbed (66%) in has not been fully established, captan is known to react
48 h and is widely distributed, with highest concentrations with cellular thiols to produce thiophosgene, a potent and
in blood, liver and kidney. Within 72 h, 72% 96% of the unstable chemical capable of reacting with sulfhydryl-,
administered dose is eliminated in the urine and feces. amino-, or hydroxyl-containing enzymes (Cremlyn, 1978).
Metabolism is extensive, and the compound undergoes Thiols reduce the potency of captan. A volatile product of
hydroxylation, O-demethylation, oxidation, conjugation, captan is responsible for mutagenic activity, the intermedi-
chain shortening and cleavage between glyoxylphenyl and ate being short-lived and formed more quickly at higher
trifluoromethyl moieties (JMPR, 2004). levels at an alkaline pH. There are several other mechan-
isms by which these chemicals can induce cellular toxicity.
For example, mouse tumors develop with oral administra-
MECHANISM OF ACTION
tion above a threshold if maintained for at least 6 months.
There are a series of biochemical changes or free radical- As shown in Fig. 45.1, epithelial cells that comprise the
mediated processes; some may also be produced by other villi are damaged by exposure to captan and sloughed off
mechanisms that have been used to assess tissue injury. into the intestinal lumen at an increased rate. Second, the
This is exemplified by the phenomenon of lipid peroxida- basal cells in the crypt compartment that normally divide
tion, which has been invoked as a toxic mechanism in at a rate commensurate with the normal loss of villi cells
many situations and also occurs subsequent to cell death from the tips of the villi increase, resulting in high cell pro-
and membrane lysis. However, in most situations, it is liferation, which is not carcinogenic per se but does play a
difficult to identify the exact mechanism of action. For role in tumor development. However, there appears to be
example, in fungicides containing mercury, the mercury no treatment-related duodenal tumor incidence of captan
ions inhibit the sulfhydryl group of enzymes involved in rats or dogs. Some of the data have been compiled in
in the transfer of amino acids across the blood brain bar- reviews, and a task force and framework have been evolv-
rier (BBB) and then interfere with protein synthesis. ing for evaluation of the mode of toxicity and tumorogeni-
Organomercurials can also release some mercury ions in city findings in mice bioassay and human relevance for
the body, but their toxicity is not believed to be a primary risk assessment purposes (Arce et al., 2010; Cohen et al.,
action of mercury ions (Sandhu and Brar, 2009). There are 2010; Gordon, 2010).
several theories regarding the mechanism by which sulfur Chlorothalonil fungicide is a reactive molecule toward
produces its toxic action. The oxidized sulfur theory attri- thio ( SH) groups. It is a soft electrophile with a prefer-
butes toxicity to its oxidation products, such as sulfur diox- ence for sulfur nucleophiles rather than nitrogen/oxygen
ide, sulfur trioxide, thiosulfuric acid, or pentathionic acid. nucleophiles. Such chemicals tend to show reactivity
The reduced sulfur theory ascribes toxicity to hydrogen toward proteins containing critical S electrophiles rather
sulfide. A direct action theory suggests toxicity due to than toward DNA (containing critical O and N nucleo-
crosslinking of proteins, formation of other cellular com- philes). A mechanistic interpretation for the carcinogenic-
ponents by free radicals of sulfur or polysulfides, or exten- ity of chlorothalonil has been published by Wilkinson and
sive oxidation of thiol groups leading to loss of function or Killeen (1996). Repeated administration of chlorothalonil
structural integrity of proteins. Pentachlorophenol (PCP), a causes hyperplasia in the forestomach of rats and mice.
halogenated substituted monocyclic aromatic, acts cellu- The data are consistent with a temporal sequence of
larly to uncouple oxidative phosphorylation, with the tar- events starting with increased cell proliferation, multifocal
1
1
get enzyme being Na /K -ATPase. Oxygen consumption ulceration and erosion of the forestomach mucosa, regen-
is increased, whereas adenosine triphosphate (ATP) forma- erative hyperplasia and hyperkeratosis, and ultimately
tion is decreased. The energy is lost as heat instead of progressing to the formation of gastric tumors within the
being stored as high-energy phosphate bonds. The electron forestomach. In dogs, there is no evidence of either neo-
transport chain responds by using increasingly more avail- plastic development or the occurrence of preneoplastic
able oxygen (increased oxygen demand) in an effort to lesions in the kidney or stomach. The absence of stomach
produce ATP, but much of the free energy is lost as body lesions in dogs is attributable to the anatomical differ-
heat. This leads to depletion of energy reserves (Eaton and ences between rodents and dogs: dogs do not possess a
Gallagher, 1997). Similarly, organotin compounds, partic- forestomach. Continued administration of chlorothalonil
ularly triethyltin, uncouple oxidative phosphorylation, leads to the development of a regenerative hyperplasia
whereas other agents (e.g., sulfur) in the presence of sulfit- within the renal proximal tubular epithelium. Continued
ing agents such as sulfur dioxide uncouple oxidative regenerative hyperplasia ultimately results in progression