Page 608 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Toxicity of Fungicides Chapter | 45 573

VetBooks.ir of the kidney lesion to tubular adenoma and carcinoma. stimulation of the hypothalamus and pituitary (Atterwill
and Aylard, 1995). Prolonged and continuous elevation of
Initial cytotoxicity and regenerative hyperplasia within
TSH levels results in hypertrophy and hyperplasia of the
the proximal tubular epithelium are essential prerequisites
for subsequent tumor development. The proposed mode thyroid follicular cells in rats, mice, hamsters, monkeys,
of action for the induction of renal toxicity in rodents is and dogs, leading to development of follicular nodular
outlined in Fig. 45.2. hyperplasia, adenoma and/or carcinoma in rats and mice
The toxicology database supporting mechanism of (Ollinger et al., 2010). Conazoles such as propiconazole
action of carbamic acid derivatives such as EBDCs and have a phenobarbital-type mode of action, leading to cell
their common metabolite ETU has been explained using proliferation, increased liver weight, and microsomal
modern studies with mancozeb, maneb and metiram enzyme induction (JMPR, 2004).
because the principal target organ is the thyroid. These
compounds inhibit the synthesis of thyroid hormone, thy- TOXICITY
roxine (T4), and triiodothyronine (T3), leading to elevated
levels of thyroid-stimulating hormone (TSH) via feedback There is a wide and diverse spectrum of chemical struc-
tures of fungicides, covering both inorganic and organic
substances, thus leading in toxicity to livestock. Some of
Parent chlorothalonil these fungicides are believed to be obsolete or discontin-
CN ued. To date, several fungicides have been evaluated by
Cl Cl
WHO for their toxic potential and acceptable daily intake
has been recommended by the Joint Meeting on Pesticide
Cl CN
Cl Residues (JMPR). A number of livestock poisoning cases
Absorption from fungicides result from treated grains or potatoes, etc.
conjugation to GSH Most of the available toxicity data are from laboratory ani-
mals; little information is available for farm animals and
CN CN
GS Cl GS SG pets. In general, newer classes of fungicides have low
to moderate toxicity. However, the toxicity of fungi-
Liver
cides may vary due to the presence of other ingredients
Cl CN Cl CN
GS GS (e.g., surfactants and emulsifiers) present in the formu-
Biliary
excretion lation. The details of guidelines for their hazard evalua-
tion and their classification have previously been
Plasma
Plasma summarized (IPCS, 2002; Gupta, 2006). There is
metabolites
GIT increasing experimental and anecdotal evidence that
exposure to fungicides also affects at least some form
of development and/or reproduction in one or more spe-
Cysteine conjugates
cies of animals. A nonexhaustive list of fungicides that
N-Acetylase β-Lyase cause developmental toxicity in experimental animals is
Kidney presented in Table 45.1. More than 80% of all onco-
Mercapturates Thiol-derived genic risk from the use of pesticides derives from a few
conjugates
fungicides; however, only a small proportion of
Renal toxicity pesticide-related deaths from fungicides have been
reported (NAS, 1987; Costa, 1997).

Inorganic Fungicides
Urinary
excretion This class of fungicides includes potassium azide, potas-
sium thiocyanate, and titrated or sublimed sulfur. Sulfur
FIGURE 45.2 Schematic outlining potential pathways of chlorothalonil
had been in use throughout the 19th and early 20th centu-
metabolism in the rat that leads to formation of toxic metabolites within
the kidney. Following absorption from the GI tract, chlorothalonil is con- ries. Elemental sulfur and crude lime sulfur (calcium
jugated to glutathione in the liver. Further metabolic processing results polysulfide and barium polysulfide) are commonly used
in the formation of cysteine conjugates that may be detoxified via as fungicides. The most notable chemical property of sul-
N-acetylase or activated to toxic thiol-derived species. GIT, gastrointesti- fur is its tendency to spontaneously oxidize. This property
nal tract; GSH, glutathione. Reproduced with permission from Parsons,
P.P., 2010. Mammalian toxicokinetics and toxicity of chlorothalonil. is responsible for sulfur’s effects on the eyes, skin, and
In: Krieger, R. (Ed.), Hayes’ Handbook of Pesticide Toxicology, third respiratory tract. Safety concerns presented by combustion
ed., vol. 2. Elsevier, New York, NY, pp. 1951 1966. of sulfur can be mitigated by avoiding its use during