Page 613 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

578 SECTION | VII Herbicides and Fungicides

VetBooks.ir Others the androgen receptor(s) (Ankley et al., 2005; Noriega
et al., 2005). The fungicide vinclozolin was shown to have
Several other antibiotic substances, thiocarbonates, and
endocrine-modulating effects in male offspring when rat
cinnamic acid derivatives are used as fungicides. Sodium
dams were treated during the last one-third of gestation
tetrathiocarbonate, a thiocarbonate fungicide, is moder-
through postnatal day 3. The anogenital distance was
ately toxic. The rat oral LD 50 is 631 mg/kg BW. It is a
reduced, and there were cleft phallus, hypospadias and
severe irritant to rabbit skin and a marked irritant to rabbit
other malformations in the offspring (Gray et al., 1994).
eyes. Another compound, cycloheximide, is extremely
Procymidone has antiandrogenic properties. Long-term
toxic, including development toxicity (Table 45.1), with
exposure of rats to procymidone had different effects on
mutagenic potential. Dimethomorph has low oral toxicity
the pituitary gonadal axis in vivo and on Leydig cell ste-
in rats, is not an irritant to rabbit skin and is a minimal
roidogenesis ex vivo. The disruption of hormonal feedback
irritant to rabbit eyes. The acute oral LD 50 of fenpyroxi-
could be due to its antiandrogenic action through activa-
mate is 245 and 480 mg/kg BW in male and female rats,
tion of the endocrine axis, thereby causing hypergonado-
respectively. The compound may cause developmental
tropic activation of testicular steroidogenesis (Svechnikov
toxicity in rats. Fludioxonil, a phenylpyrrole fungicide,
et al., 2005). From experimental studies, it has been con-
and trifloxystrobin have low acute toxicity in rats.
cluded that fungicides can disturb the reproduction and
Fludioxonil is a slight eye irritant in rabbits, but it is nei-
development processes of both males and females through
ther a skin irritant in rabbits nor a skin sensitizer in guinea
endocrine signals in organisms indirectly exposed during
pigs. On long-term exposure, it causes liver necrosis, kid-
prenatal or early postnatal life. Such effects during fetal
ney nephropathy and mild anemia, and blue coloration of
development may be permanent and irreversible. They
the urine and perineal fur. Reproductive toxicity indicates
may act through hormone receptors and enhance or dimin-
decreased pup weight gains in rats at parenterally toxic
ish the activity normally controlled by endogenous hor-
doses. Trifloxystrobin is nonirritating but may be a skin
mones. According to one estimate in 2003, eight
sensitizer. Toxic symptoms are associated with liver tox-
fungicides (benomyl, hexachlorobenzene, mancozeb, man-
icity, changes in kidney weight, atrophy of the pancreas,
eb, metriam complex, tributyltin, zineb, and ziram) were
and spleen abnormalities. Developmental toxicity indi-
identified as potentially causing endocrine disruption in
cates decreased BW gain of pups accompanied by delayed
animals. Most of these were identified accidentally rather
eye opening at parenterally toxic doses (JMPR, 2004).
than as a result of an exhaustive screening process (Pocar
et al., 2003). Recently, in an in vitro study endocrine activ-
ity of five conazole compounds solely based on potency or
ENDOCRINE DISRUPTION
interference with steroidogenesis (assay based on H295R
In both males and females, some fungicides affect repro- cells) indicated their ranking as follows:
duction through different mechanisms of action by endo-
Decreased estradiol production:
crine disruption: exogenous agents interfere with normal
prochloraz . epoxiconazole . ketoconazole
reproduction and development processes. In males, normal
propiconazole tebuconazole
reproductive function involves interaction of the
hypothalamic-pituitary-testis axis and the thyroid gland. In Decreased testosterone production:
females, increased concentrations of xenoestrogens may prochloraz . ketoconazole . tebuconazole .
affect ovarian function through the disruption of feedback epoxiconazole . propiconazole
mechanisms in the hypothalamus-pituitary-gonadal axis
Increased progesterone production:
(Flaws and Hirshfield, 1997; Bretveld et al., 2006). prochloraz . epoxiconazole 5 propiconazole .
Fungicides, like other chemicals, may disrupt all stages of
ketoconazole . tebuconazole
hormonal function of the reproductive system. In females,
during pregnancy, and to a greater extent during lactation, Aromatase inhibition:
a portion of the maternal body burden of these chemicals prochloraz . ketoconazole propiconazole
is transferred to the offspring. Fungicides that are toxic to epoxiconazole . tebuconazole.
endocrine cells and that delete germ cells are beyond the
It is therefore concluded that conazole compounds may
scope of this chapter. However, it is well established that
alter the synthesis of sex hormones (Dreisig et al., 2013).
some fungicides affect male and female reproduction
through different mechanisms of action by endocrine dis-
ruption. For example, fenarimol, prochloraz and chlorotha- TREATMENT
lonil cause infertility in male and female rats through
inhibition of CYP450 enzymes involved in steroid metabo- In some cases, there is no treatment, whereas in others
lism and alter sexual differentiation through antagonism of supportive therapy as required by condition is indicated: