Page 589 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

554 SECTION | VII Herbicides and Fungicides

VetBooks.ir market. Nitrofen was the first Protox-inhibiting herbicide derivative herbicide. Absorption of 2,4-D occurs rapidly
2,4-D is the most extensively studied phenoxy acid
to be introduced for commercial use in 1964. This diphe-
from the gastrointestinal (GI) tract, and peak levels are
nyl ether (DPE) herbicide was eventually recognized as a
relatively weak inhibitor of Protox, but it was a lead com- reached in 10 min to 24 h depending on species, dose and
pound of an entire class of structurally related herbicides chemical form. Following oral exposure to 2,4-D, plasma
that were much more active. Subsequently, several DPE half-life ranges from 3.5 to 18 h. Dermal absorption was
herbicides have been successfully commercialized reported to occur rapidly but was usually less than 6%.
(Nandihalli et al., 1992; Anderson et al., 1994). The compound is protein bound in vivo and is rapidly dis-
Substituted aniline, an alachlor herbicide, was regis- tributed to the liver, kidneys, lung and brain. 2,4-D has
tered and introduced in 1967 for the preplant or preemer- also been reported to cross the placental barrier in labora-
gent control of a broad spectrum of grass, sedge and tory animals and pigs. 2,4-D is not metabolized to reac-
broadleaf weeds (Heydens et al., 2010). Subsequently, tive intermediates, does not accumulate in tissues and is
inhibitors of aromatic acid biosynthesis herbicides excreted predominantly as the parent compound in urine.
(organic phosphorus) such as glyphosate, broad-spectrum, However, the rate of excretion via urine is inversely pro-
nonselective, postemergent, systemic herbicide with activ- portional to dose. 2,4-D has been detected in the milk of
ity on essentially all annual and perennial plants have been lactating rats dosed with 2,4-D. The salts and esters of
developed. Monsanto discovered the herbicidal properties 2,4-D undergo acid and/or enzymatic hydrolysis to form
of glyphosate in 1970, and the first commercial formula- 2,4-D acid, and small amounts may be conjugated with
tion was introduced in 1974 under the Roundup brand glycine or taurine. Excretion can be markedly enhanced
name. Other triazine and triazole herbicides have been by ion trapping using alkaline agents because most of
extensively used in agriculture in the United States and these herbicides are organic acids (Erne, 1966a,b;
other areas of the world for more than 50 years. The tria- Pelletier et al., 1989; Kennepohl et al., 2010).
zines inhibit photosynthesis by blocking photosynthetic Another organic acid herbicide, dicamba, is rapidly
electron transport (Gysin and Knuesli, 1960; Steven and and nonselectively distributed to most of the organs; how-
Summer, 1991; Breckenridge et al., 2010). Dicamba, ever, dermal absorption is minimal. Ninety percent of
which was first registered in the United States in 1967, is excretion is through urine, and a small amount is excreted
another organic (benzoic) acid herbicide that acts by mim- in feces. Dicamba is mostly unmetabolized but may be
icking the effects of auxins (i.e., natural plant growth hor- conjugated with glucuronic acid or glycine. Elimination
mones), causing enhanced but uncontrolled growth rates, occurs rapidly, and there is no evidence of bioaccumula-
alterations in plant function homeostasis and death (Harp, tion in the mammalian system (Harp, 2010).
2010). Another class of synthetic chemical compounds Bipyridyl derivative paraquat is rapidly but incom-
called the imidazolinone herbicides was discovered in the pletely absorbed from the GI tract of laboratory animals
1970s, with the first US patent awarded in 1980 for and humans, with plasma concentration of 30 90 min,
imazamethabenzmethyl. New families of herbicides and it is poorly absorbed through contact with skin. It has
introduced since the 1970s account for increasing shares been reported that dogs absorb more paraquat than do
of use and include bipyridyl (paraquat), bentazon, fenaxa- rats, resulting in greater susceptibility of dogs toward
lactogen, oxyfluorfen, clomazone, clorpyralid, fluazifop, paraquat toxicity (Lock and Wilks, 2010). Paraquat is
and norfluorazon. Today, the use of newer compounds very poorly metabolized, and bulk is excreted unchanged
that have low toxicity is quite common (Osteen and in the urine and feces. The transport mechanism for
Padgitt, 2002). organic cations in renal proximal tubular cells is not fully
understood; however, two membrane proteins, organic
cation transporter 1 (OCT1) and organic cation transporter
TOXICOKINETICS 2 (OCT2), have been isolated from rat kidney. OCT1,
located at the basolateral membrane, transports tetraethy-
Toxicokinetics studies provide important data on the lammonium, and this can be inhibited by other organic
amount of toxicant delivered to a target as well as spe- cations such as quinine. OCT2 stimulates the uptake of
cies-, age- and gender-specific metabolism. Animals are tetraethylammonium, and this can be markedly inhibited
exposed to herbicides of different chemical classes. In by cimetidine. The transport of paraquat can be blocked
general, liver is the primary site for biotransformation and by the addition of the divalent cation quinine, cimetidine
may include activation as well as detoxification reactions and, to a lesser extent, tetraethylammonium, suggesting
through the cytochrome P450-dependent monooxygenase that paraquat may be transported by both transport sys-
system, the flavin-containing monooxygenase, esterases tems, an electro neutral organic cation/H 1 exchange and
and a variety of transferases, most notably the glutathione P-glycoprotein (Chan et al., 1998). It was found that the
(GSH) S-transferases (Hodgson and Meyer, 1997). hMATE1-mediated transport of agmatine was inhibited