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4
Information Related to Biologic Plausibility
The committee reviewed all relevant experimental studies of 2,4-dichloro-
phenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T),
4-amino-3,5,6-trichloropicolinic acid (picloram), dimethylarsinic acid (DMA,
also called cacodylic acid), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that
have been published since Update 2008 (IOM, 2009) and has incorporated the
findings, when it was appropriate, into this chapter or into the biologic-plausibility
sections of Chapters 6–11 when they are of consequence for particular health
outcomes. For each substance, this chapter includes a review of toxicokinetic
properties, a brief summary of the toxic outcomes investigated in animal experi -
ments, and a discussion of underlying mechanisms of action as illuminated by
in vitro studies. In addition, the final section of this chapter presents two newly
emerging subjects of molecular and biologic science that provide novel insight
into potential mechanisms of xenobiotic-induced disease and may increase the
biologic plausibility of the toxic actions of herbicides sprayed in Vietnam.
Establishment of biologic plausibility through laboratory studies strengthens
the evidence of a cause–effect relationship between herbicide exposure and health
effects reported in epidemiologic studies and thus supports the existence of the
less stringent relationship of association, which is the target of this committee’s
work. Experimental studies of laboratory animals or cultured cells allow observa-
tion of effects of herbicide exposure under highly controlled conditions, which
is difficult or impossible to achieve in epidemiologic studies. Such conditions
include frequency and magnitude of exposure, exposure to other chemicals, pre-
existing health conditions, and genetic differences between people, all of which
can be controlled in a laboratory animal study.
Once a chemical contacts the body, it begins to interact through the processes
76
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INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY
of absorption, distribution, metabolism, and excretion. Those four biologic pro -
cesses characterize the disposition of a foreign substance that enters the organism.
Their combination determines the concentration of the chemicals in the body and
how long each organ is exposed to it and thus influences its toxic or pharmaco-
logic activity.
Absorption is the entry of a substance into an organism, normally by uptake
into the bloodstream via mucous surfaces, such as the intestinal walls of the di -
gestive tract during ingestion. Low solubility, chemical instability in the stomach,
and inability to permeate the intestinal wall can all reduce the extent to which a
substance is absorbed after being ingested. The solubility of a chemical in fat and
its hydrophobicity influence the pathways by which it is absorbed and its relative
potential to be metabolized (structurally transformed) and ultimately whether it
persists in the body or is excreted. Absorption is a critical determinant of a chemi-
cal’s bioavailability, that is, the fraction of it that reaches the systemic circulation.
In addition to ingestion routes of exposure experienced by free-ranging humans
are inhalation (entry via the airways) and dermal exposure (entry via the skin).
Animal studies may involve additional routes of exposure that are not ordinarily
encountered by humans, such as intravenous or intraperitoneal injection, in which
a chemical is injected into the bloodstream or abdominal cavity, respectively.
Distribution refers to the travel of a substance from the site of entry to the
tissues and organs where they will have their ultimate effect or be sequestered.
Distribution takes place most commonly via the bloodstream.
Metabolism is the breaking down that all substances begin to experience as
soon as they enter the body. Most metabolism of foreign substances takes place
in the liver by the action of a number of enzymes, including cytochrome P-450s,
which catalyze the oxidative metabolism of many chemicals. As metabolism oc -
curs, the initial (parent) chemical is converted to new chemicals called metabo -
lites, which are often more water-soluble (polar) and thus more readily excreted.
When metabolites are pharmacologically or toxicologically inert, metabolism
deactivates the administered dose of the parent chemical, reducing its effects on
the body. Metabolism may activate a chemical to a metabolite that is more potent
or more toxic than it is.
Excretion, also referred to as elimination, is the removal of substances or
their metabolites from the body, most commonly in urine or feces. The rela -
tive rate of excretion of a chemical from the body is often limited by the rate
of metabolism of the parent chemical into more water soluble, readily excreted
metabolites. Excretion is often incomplete, especially in the case of chemicals
that resist metabolism, and incomplete excretion results in the accumulation of
foreign substances that can adversely affect biologic functions.
The routes and rates of absorption, distribution, metabolism, and excretion
of a toxic substance collectively are termed toxicokinetics (or pharmacokinetics).
Those processes determine the amount of a particular substance or metabolite
that reaches specific organs or cells and that persists in the body. Understanding
the toxicokinetics of a chemical is important for valid reconstruction of exposure
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78 VETERANS AND AGENT ORANGE: UPDATE 2010
of humans and for assessing the risk of effects of a chemical. The principles
involved in toxicokinetics are similar among chemicals, although the degree
to which different processes influence the distribution depends on the structure
and other inherent properties of the chemicals. Thus, the lipophilicity or hydro -
phobicity of a chemical and its structure influence the pathways by which it is
metabolized and whether it persists in the body or is excreted. The degree to
which different toxicokinetic processes influence the toxic potential of a chemi -
cal depends on metabolic pathways, which often differ among species. For that
reason, attempts at extrapolation from experimental animal studies to human
exposures must be extremely careful.
Many chemicals were used by the US armed forces in Vietnam. The nature
of the substances themselves was discussed in more detail in Chapter 6 of the
original Veterans and Agent Orange: Health Effects of Herbicides Used in Viet-
nam (VAO) report (IOM, 1994). Four herbicides documented in military records
were of particular concern and are examined here: 2,4-D, 2,4,5-T, picloram, and
cacodylic acid. This chapter also examines TCDD, the most toxic congener of the
tetrachlorodibenzo-p-dioxins (tetraCDDs), also commonly referred to as dioxin,
a contaminant of 2,4,5-T, because its potential toxicity is of concern. Consider-
ably more information is available on TCDD than on the herbicides themselves.
Other contaminants present in 2,4-D and 2,4,5-T are of less concern. Except as
noted, the laboratory studies of the chemicals of concern used pure compounds or
formulations; the epidemiologic studies discussed in later chapters often tracked
exposures to mixtures.
PICLORAM
Chemistry
Picloram (Chemical Abstracts Service Number [CAS No.] 1918-02-1; see
chemical structure in Figure 4-1) was used with 2,4-D in the herbicide formu -
lation Agent White, which was sprayed in Vietnam. It is also used commonly
in Australia in a formulation with the trade name Tordon 75D®. Tordon 75D
CI NH 2
HO
CI
N
O
CI
4-amino-3,5,6-trichloropicolinic acid
FIGURE 4-1 Structure of picloram.
Figure 4-1.eps
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INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY
contains several chemicals, including 2,4-D, picloram, a surfactant diethylene-
glycolmonoethyl ether, and a silicone defoamer. A number of studies of picloram
used such mixtures as Tordon or other mixtures of 2,4-D and picloram that are
similar to Agent White.
Toxicokinetics
The original VAO committee reviewed studies of the toxicokinetics of pi-
cloram. Studies of animals showed rapid absorption through the gastrointestinal
tract and rapid elimination of picloram as the unaltered parent chemical in urine.
Nolan et al. (1984) examined the toxicokinetics of picloram in six healthy male
volunteers who were given single oral doses of 0.5 or 5.0 mg/kg and a dermal
dose of 2.0 mg/kg. Picloram was rapidly absorbed in the gavage study and rapidly
excreted unchanged in urine. More than 75% of the dose was excreted within 6
hours, and the remainder with an average half-life of 27 hours. On the basis of
the quantity of picloram excreted in urine in the skin study, the authors noted that
only 0.2% of the picloram applied to the skin was absorbed. Because of its rapid
excretion, picloram has low potential to accumulate in humans.
In general, the literature on picloram toxicity continues to be sparse. Studies
of humans and animals indicate that picloram is rapidly eliminated as the parent
chemical. Studies of animals have indicated that picloram is sparingly toxic at
high doses.
Toxicity Profile
The original VAO committee reviewed studies of the carcinogenicity, geno-
toxicity, acute toxicity, chronic systemic toxicity, reproductive and developmental
toxicity, and immunotoxicity of picloram. In general, there is limited evidence
on cancer in some rodent models but not in other species (NCI, 1978). In those
studies, there was some concern that contaminants in the picloram (in particular,
hexachlorobenzene) might be responsible for the carcinogenicity. Thus, picloram
has not been established as a chemical carcinogen.
There is also no evidence, on the basis of studies conducted by the Envi-
ronmental Protection Agency (EPA, 1988c), that picloram is a genotoxic agent.
Picloram is considered a mild irritant; erythema is seen in rabbits only at high doses.
The available information on the acute toxicity of picloram is also paltry. Some
neurologic effects—including hyperactivity, ataxia, and tremors—were reported in
pregnant rats exposed to picloram at 750 or 1,000 mg/kg (Thompson et al., 1972).
Chronic Systemic Toxicity
Several studies have reported various effects of technical-grade picloram
on the livers of rats. In the carcinogenicity bioassay conducted by Stott and col -
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80 VETERANS AND AGENT ORANGE: UPDATE 2010
leagues (1990), treatment-related hepatomegaly, hepatocellular swelling, and
altered tinctorial properties in the central regions of the liver lobules were noted in
the groups exposed at 60 and 200 mg/kg per day. In addition, males and females
exposed at the high dose had higher liver weights than controls. The no-observed-
effect level (NOEL) was 20 mg/kg per day, and the lowest observed-effect level
was 60 mg/kg per day for histologic changes in centrilobular hepatocellular
tissues. According to the Environmental Protection Agency (EPA), hexachloro -
benzene (at 197 ppm) was probably not responsible for the hepatic effects (EPA,
1988c). Gorzinski and colleagues (1987) also reported a dose-related increase in
liver weights, hepatocellular hypertrophy, and changes in centrilobular tinctorial
properties in male and female F344 rats exposed to picloram at 150 mg/kg per
day and higher in the diet for 13 weeks. In a 90-day study, cloudy swelling in
the liver cells and bile duct epithelium occurred in male and female F344 rats
given 0.3% or 1.0% technical picloram in the diet (EPA, 1988c). Hepatic effects
have also been reported in dogs exposed to picloram: increased liver weights
were reported in beagles that received 35 mg/kg per day or more in the diet for
6 months (EPA, 1988c). No other effects of chronic exposure to picloram have
been reported.
Reproductive and Developmental Toxicity
The reproductive toxicity of picloram was evaluated in a two-generation
study; however, too few animals were evaluated, and no toxicity was detected at
the highest dose tested, 150 mg/kg per day (EPA, 1988c). Some developmental
toxicity was produced in rabbits exposed to picloram by gavage at 400 mg/kg
per day on days 6–18 of gestation. Fetal abnormalities included single-litter inci -
dences of forelimb flexure, fused ribs, hypoplastic tail, and omphalocele (John-
Greene et al., 1985). Some maternal toxicity was observed at that dose, however,
and EPA concluded on the basis of the low-litter incidence of the findings that the
malformations were not treatment-related (EPA, 1988c). No teratogenic effects
were produced in the offspring of rats given picloram by gavage at up to 1,000
mg/kg per day on days 6–15 of gestation, although the occurrence of bilateral
accessory ribs was significantly increased (Thompson et al., 1972).
Immunotoxicity
Studies of the potential immunotoxicity of picloram included dermal sen -
sitization and rodent immunoassays. In one study, 53 volunteers received nine
24-hour applications of 0.5 mL of a 2% potassium picloram solution on the skin
of both upper arms. Each volunteer received challenge doses 17–24 days later.
The formulation of picloram (its potassium salt) was not a skin sensitizer or an
irritant (EPA, 1988c). In a similar study, a 5% solution of picloram (M-2439,
Tordon 101 formulation) produced slight dermal irritation and a sensitization
response in 6 of the 69 volunteers exposed. When the individual components of
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INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY
M-2439—picloram, triisopropanolamine (TIPA) salt, and 2,4-D TIPA salt—were
tested separately, no sensitization reaction occurred (EPA, 1988c). Tordon K+, but
not technical-grade picloram, was also found to be a skin sensitizer in guinea pigs
(EPA, 1988c). CD1 mice exposed to Tordon 202C (94% 2,4-D and 6% picloram)
had no consistent adverse effects on antibody responses (Blakley, 1997), but the
lack of a consistent response may be due to the fact that CD1 mice are outbred.
Mechanisms
No well-characterized mechanisms of toxicity for picloram are known.
CACODYLIC ACID
Chemistry
Arsenic (As) is a naturally occurring element that exists in a trivalent form
(As+3 or AsIII) and a pentavalent form (As+5 or AsV). The AsIII in sodium arsenite
is generally considered to be the most toxic—see Figure 4-2 for chemical struc -
tures of selected arsenic-containing compounds.
FIGURE 4-2 Structures of selected arsenic-containing compounds.
Figure 4-2.eps
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82 VETERANS AND AGENT ORANGE: UPDATE 2010
Arsenic is commonly present in drinking-water sources associated with
volcanic soils and can reach high concentrations (over 50 ppb). Numerous hu-
man health effects have been attributed to drinking-water exposure, particularly
bladder, skin, and lung cancers and vascular diseases.
Arsenic exists in both inorganic and organic (methylated) forms and is read -
ily metabolized in humans and other species. Inorganic arsenic can be converted
to organic forms. While organic forms can be converted into inorganic forms by
microorganisms in the soil, there is no evidence that this can occur in humans
or other vertebrate species (Cohen et al., 2006). Cacodylic acid (CAS No. 75-
60-5) has a valence of +5 and is commonly referred to as dimethylarsinic acid
(DMAV). Cacodylic acid, disodium methanearsonate, and monosodium methane-
arsonate are herbicides that EPA approved for use in the United States, where
they are occasionally applied on golf courses and large open spaces. Cacodylic
acid was the form of arsenic used in Agent Blue, one of the mixtures used for
defoliation in Vietnam; DMAV made up about 30% of Agent Blue. Agent Blue
was chemically and toxicologically unrelated to Agent Orange, which consisted
of phenoxy herbicides contaminated with dioxin-like compounds. As shown in
Figure 4-3, DMAIII and DMAV, as well as monomethyl arsonic acid (MMAIII and
MMAV) are metabolic products of exposure to inorganic arsenic. Methylation of
inorganic arsenic used to be considered a detoxification process associated with
increased excretion (Vahter and Concha, 2001). However, some of the methylated
metabolic intermediates, especially MMAIII, have been found to be more toxic
MMAIII
iAsV
MMAV
Limited
cellular
DMAs
DMAV
uptake
60–80% of human
urinary excretion
iAsIII
iAsIII DMAIII
TMA
Extensive
cellular
uptake
TMAO
TMAO
MMAs None found in
human urine,
10–20% of human
5–10% of rat
urinary excretion
urinary excretion
FIGURE 4-3 General pathways of arsenic metabolism after exposure to inorganic arsenic
(iAs).
SOURCE: Adapted with permission from Cohen et al., 2006.
Figure 4-3.eps
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INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY
than the parent sodium arsenite (Aposhian et al., 2000). The methylation pathway
of inorganic arsenic results in the formation of pentavalent DMA (DMAV) and
trivalent DMA (DMAIII).
The committee contemplated the relevance of animal data following expo-
sure to inorganic arsenic, where DMAV is formed endogenously, vs data follow-
ing direct exposure to exogenous DMAV, as would have been the form of arsenic
to which Vietnam veterans were potentially exposed. It has not been established,
nor can it be inferred, that the observed effects of exposure to inorganic arsenic
are caused by endogenous formation of DMAV. Furthermore, recent studies would
suggest that there is an increased incidence of cancer in individuals that gener-
ate less DMAV endogenously (Huang SK et al., 2008). Finally, because there is
no evidence that DMA is demethylated to inorganic arsenic in humans or other
animals (Cohen et al., 2006), the committee chose to not consider the literature
on inorganic arsenic in this report. The reader is referred to Arsenic in Drinking
Water (NRC, 1999a) and Arsenic in Drinking Water: 2001 Update (NRC, 2001).
Thus, the committee only considered and reviewed those toxicological studies in
which animals were directly exposed to DMAV.
Toxicokinetics
The metabolism and disposition of DMAV has recently been reviewed (Cohen
et al., 2006; Suzuki et al., 2010). In general, DMAV is rapidly excreted mostly
unchanged in the urine of most animal species after systemic exposure. However,
rats are unique in that a small percentage (10%) of DMAV binds to hemoglobin
in red blood cells and that leads to a longer half-life in blood (Cui et al., 2004;
Suzuki et al., 2004). The binding of DMAV to hemoglobin is 10 times higher in
rats than in humans (Lu et al., 2004). Chronic exposure of normal rat hepatocytes
to DMAV resulted in reduced uptake over time and in acquired cytotoxic tolerance
(Kojima et al., 2006); the tolerance was mediated by induction of glutathione- S-
transferase activity and of multiple-drug–resistant protein expression. Adair et al.
(2007) recently examined the tissue distribution of DMA in rats after dietary
exposure for 14 days and found that it was extensively metabolized to trimethyl -
ated forms that may play a role in toxicity.
Recently, a physiologically based pharmacokinetic model (PBPM) for in -
travenous and ingested DMAV has been developed on the basis of mouse data
(Evans et al., 2008). Similar models have been developed for humans on the
basis of exposure to inorganic arsenic (El-Masri and Kenyon, 2008), but these
models have limited utility in considering the toxicity of DMAV exposures that
are relevant to Vietnam veterans.
Toxicity Profile
This section discusses the toxicity associated with organic forms of arsenic,
most notably DMAV because it is the active ingredient in Agent Blue. The toxic-
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84 VETERANS AND AGENT ORANGE: UPDATE 2010
ity of inorganic arsenic is not considered relevant to veteran exposures to Agent
Blue.
Neurotoxicity
Kruger et al. (2006) found that DMAIII and DMAV significantly attenu-
ated neuronal ion currents through N-methyl-D–aspartate receptor ion channels
whereas only DMAV inhibited ion currents through α-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid receptors. The data suggest that those methyl -
ated forms of arsenic may have neurotoxic potential.
Immunotoxicity
Previous studies have shown that a low concentration of DMAV (10–7 M)
could increase proliferation of human peripheral blood monocytes after their
stimulation with phytohemagglutinin whereas it took a high concentration (10 –4
M) to inhibit release of interferon-g. This suggested that immunomodulatory ef-
fects of DMAV are concentration-specific (Di Giampaolo et al., 2004).
Genotoxicity and Carcinogenicity
Both DMAIII and DMAV are genotoxic, increasing oxidative stress and caus-
ing DNA damage. Gómez et al. (2005) demonstrated that DMAIII induced a
dose-related increase in DNA damage and oxidative stress in Jurkat cells. DMAIII
was considerably more potent than DMAV in inducing DNA damage in Chinese
hamster ovary cells (Dopp et al., 2004), and this was associated with a greater
uptake of DMAIII into the cells. An additional study showed that DMAV is poorly
membrane-permeable, but when forced into cells by electroporation it can induce
DNA damage (Dopp et al., 2005). Gene-expression profiling of bladder uro-
thelium after chronic exposure to DMAV in drinking water showed significant
increases in genes that regulate oxidative stress (Sen et al., 2005), while hepatic
gene-expression profiling showed that DMAV exposure induced changes consis-
tent with oxidative stress (Xie et al., 2004). In vivo, DMAV-induced prolifera-
tion of the urinary bladder epithelium could be attenuated with the antioxidant
N-acetylcysteine (Wei et al., 2005).
Both DMAIII and DMAV are also carcinogenic. Cancer has been induced in
the urinary bladder, kidneys, liver, thyroid glands, and lungs of laboratory animals
exposed to high concentrations of DMA. In a 2-year bioassay, rats exposed to
DMAV developed epithelial carcinomas and papillomas in the urinary bladder and
nonneoplastic changes in the kidneys (Arnold et al., 2006). Similarly, Wang et al.
(2009) found that DMAV exposure in drinking water given to F344 rats resulted in
a change in the urinary bladder epithelium, but there were no changes in DNA re -
pair capacity. In another study, Cohen et al. (2007a) exposed F344 rats to DMAV
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INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY
in the diet for 2 years and found an increase in bladder tumors; they postulated
that trimethylated forms of arsenic may be responsible for bladder cancer in rats.
In the mouse lung, DMAV acted act as a tumor initiator (Yamanaka et al., 2009)
and as a tumor promoter (Mizoi et al., 2005). Additionally, DMAV can act as a
complete carcinogen inducing lung tumors in susceptible strains of mice, includ -
ing those with deficient DNA repair activity (Hayashi et al., 1998; Kinoshita
et al., 2007). Yamanaka et al. (2009) suggest that DMAIII can act as a tumor
promoter through the formation of a DMAIII radical after reduction of DMAV.
Mechanisms
Oxidative stress is a common theme that runs through the literature on the
mechanisms of action of arsenic, particularly with regard to cancer in animals,
although some studies have suggested that methylated arsenicals (MMAIII and
DMAIII) can induce mutations in mammalian cells at concentrations below those
required to produce oxidative stress after in vitro exposures (Klein et al., 2008).
Recent studies have shown that mice deficient in DNA-repair enzymes associated
with oxidative stress are highly susceptible to formation of tumors, particularly
lung tumors, induced by DMAV (Kinoshita et al., 2007). The chemical reaction of
arsenicals with thiol groups in sensitive target tissues, such as red blood cells and
kidneys, may also be a mechanism of action of organic arsenicals (Naranmandura
and Suzuki, 2008).
The variation in the susceptibility of various animal species to tumor forma-
tion caused by inorganic and organic arsenic is thought to depend heavily on
differences in metabolism and distribution. Thus, genetic differences may play an
important role. Numerous investigators are examining potential human suscepti -
bility factors and gene polymorphisms that may increase a person’s risk of cancer
and other diseases induced by arsenicals. Several such studies have been under-
taken (Aposhian and Aposhian, 2006; Hernandez et al., 2008; Huang SK et al.,
2008; Huang YK et al., 2008; McCarty et al., 2007; Meza et al., 2007; Steinmaus
et al., 2007, 2010), but it is not yet possible to identify polymorphisms that may
contribute to a person’s susceptibility to DMA-induced cancer or tissue injury.
PHENOXY HERBICIDES: 2,4-D AND 2,4,5-T
Chemistry
2,4-D (CAS No. 94-75-7) is an odorless and, when pure, white crystalline
powder (Figure 4-4); it may appear yellow when phenolic impurities are present.
The melting point of 2,4-D is 138°C, and the free acid is corrosive to metals. It
is soluble in water and in a variety of organic solvents (such as acetone, alcohols,
ketones, ether, and toluene). 2,4,5-T (CAS No. 93-76-5) is an odorless, white
to light-tan solid with a melting point of 158°C. 2,4,5-T is noncorrosive and is
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86 VETERANS AND AGENT ORANGE: UPDATE 2010
Phenoxy Herbicides
2,4-D [ 94-75-7] 2,4,5-T [ 93-76-5]
CI
O
CI O
O
CI O
CI OH
CI OH
FIGURE 4-4 Structures of 2,4-D and 2,4,5-T.
MCPA [ 94-74-6] Silvex [ 93-72-1]
CI
soluble in alcohol and water. It reacts with organic and inorganic bases to form
O
CI O
salts and with alcohols to form esters. O
CI O
OH
Uses of 2,4-D and 2,4,5-T OH
CI
2,4-D has been used commercially in the United States since World War
MCPP [ 93-65-2] Dicamba range lands,
II to control the growth of broadleaf plants and weeds on [1918-00-9] lawns,
golf courses, forests, roadways, parks, and agricultural land O remains today
and
CI
a widely used herbicide approved for use by the European Union O and the US
EPA. Formulations includeO2,4-D amine and alkali salts and esters, which are
CI O
mobile in soil and easily absorbed through the leaves and roots of many plants.
OH
Like 2,4-D, 2,4,5-T was developed and marketed as a herbicide during World
OH
War II. However, the registration for 2,4,5-T was canceled byCI EPA in 1978 when
it became clear that it was contaminated with TCDD during the manufacturing
process. It is recognized that the production of 2,4-D also involves the generation
2,3,7,8-TCDD [1746-01-6]
of some dioxin contaminants, even some with dioxin-like activity, but the fraction
CI
of TCDD is comparatively very small, as illustrated in CI Chapter 4.
O
The herbicidal properties of 2,4-D and 2,4,5-T are related to their ability to
mimic the plant growth hormone indole acetic acid. They are selective herbicides
O
in that they affect the growth of only broadleaf dicots (which include most weeds)
IC IC
and do not affect monocots, such as wheat, corn, and rice.
Picloram [1918-02-1] Cacodylic Acid [75-60-5]
Toxicokinetics
CI NH 2
O
HO
Several studies have examined the absorption, distribution, metabolism, and
excretion of 2,4-D and 2,4,5-T in animals and humans. Data As both compounds
on
CI
are consistent among species and support the conclusion that absorption of oral or
N
O
inhaled doses is rapid and complete. Absorption through the skin is much lower
OH
CI
but may be increased with the use of sunscreens or alcohol (Brand et al., 2002;
Pont et al., 2004). After absorption, 2,4-D and 2,4,5-T are distributed widely in
the body but are eliminated quickly, predominantly in unmetabolized form in
urine (Sauerhoff et al., 1977). Neither 2,4-D nor 2,4,5-T is metabolized to a great
Figure 2-1.eps
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