Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam (1994) / Chapter Skim
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4 Toxicology
4 Toxicology
Pages 111-220
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From page 111... ...
, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) , picloram, and cacodylic acid (Figure 4-11.
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From page 112... ...
These differences are exemplified in the dose of TCDD required to kill 50 percent of the animals exposed (LD:o) (Table 4-1~.
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From page 113... ...
and DBA/2 (resistant) , are very different in their sensitivity to the acute toxicity of TCDD.
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From page 114... ...
Establishing the biologic plausibility of effects due to herbicide exposure in the laboratory strengthens the evidence for any effects of the herbicides that are suspected to occur in humans. The herbicides that were used in the greatest quantities in Vietnam were 2,4-D, 2,4,5-T, picloram, and cacodylic acid.
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From page 115... ...
Some of the cacodylic acid that is absorbed is bound to red blood cells, however, and is eliminated when the red blood cells to which it is bound die naturally. Although cacodylic acid binds readily to rat red blood cells, it does not bind readily to human red blood cells.
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From page 116... ...
In rats, liver tumor formation associated with TCDD exposure is dependent on the presence of ovaries; in other words, only female rats that have not had their ovaries removed can develop liver tumors when they are exposed to TCDD. This observation indicates that complex hormonal interactions are likely to be involved in TCDD-induced carcinogenesis.
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From page 117... ...
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From page 118... ...
It is thus possible that TCDD, together with the Ah receptor, could alter the information obtained from DNA in such a way that a normal liver cell is transformed into a cancerous liver cell, although direct proof of this possibility has not been obtained. Carcinogenicity: Herbicides Several studies of the carcinogenicity of 2,4-D, 2,4,5-T, picloram, and cacodylic acid have been performed in laboratory animals.
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From page 119... ...
Tests on cacodylic acid indicate that it is toxic to DNA only at very high doses, and tests with picloram are extremely limited, but suggest that it is not toxic. None of these compounds is metabolized to reactive intermediates.
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From page 121... ...
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From page 122... ...
TCDD has been shown to have a number of effects on the immune systems of laboratory animals. Studies in mice, rats, guinea pigs, and monkeys indicate that TCDD suppresses the function of certain components of the immune system in a dose-related manner; that is, as the dose of TCDD increases, its ability to suppress immune function increases.
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From page 123... ...
Developmental toxicity can occur any time during the lifetime of the animal as a result of either parent s exposure to a toxic agent prior to conception, during the development of the fetus, or after birth until the time of puberty. For example, administration of TCDD to male rats, mice, guinea pigs, marmosets, monkeys, and chickens can elicit reproductive toxicity by affecting testicular function, decreasing fertility, and decreasing the rate of sperm production.
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From page 124... ...
The reproductive toxicity of 2,4,5T has not been evaluated, although it was toxic to fetuses when administered to pregnant rats, mice, and hamsters. Studies of the reproductive toxicity of cacodylic acid are too limited to draw conclusions.
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From page 125... ...
Some kidney toxicity has been seen in animals exposed to 2,4-D and to cacodylic acid. Exposure to 2,4-D has also been associated with effects on blood, such as reduced levels of heme and of red blood cells.
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From page 126... ...
Some of the halogenated aromatic hydrocarbons are manufactured as commercial products, but others, like TCDD, occur as contaminants in commercial products. TCDD is formed as a contaminant in the synthesis of 2,4,5-trichlorophenol, which is used to manufacture 2,4,5-T (one of the components of several of the herbicides used in defoliation and crop destruction during the Vietnam wart and hexachlorophene.
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From page 127... ...
and oils. Exposure and Pharmacokinetics The fate of experimentally administered TCDD has been studied in a variety of animal species (reviewed: Neal et al., 1982; Gasiewicz et al., 1983; Olson et al., 1983; Birnbaum, 19851.
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From page 128... ...
In animal studies, the oral exposure route is most significant because it is believed to be the primary route for human exposure. Although the actual percentage of the total orally administered TCDD dose that undergoes gastrointestinal absorption following oral administration is found to vary among mammalian species, in virtually all cases absorption from either oil vehicles or dietary supplementation is greater than 50 percent.
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From page 129... ...
However, within days the majority of TCDD redistributes to the liver and adipose tissue, the primary sites of TCDD deposition. This general profile of distribution for TCDD has been observed in a variety of animal species including mice, rats, nonhuman primates, guinea pigs, and hamsters (Rose
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From page 130... ...
Similarly, following administration of single doses of TCDD, a dose-related increase was observed in the proportion of TCDD distributed to the liver as compared to adipose tissue (Poiger et al., 19891. Although the mechanism for this phenomenon is unclear, it may be partially related to the fact that rats also exhibit a concomitant and dose-dependent loss of adipose tissue.
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From page 131... ...
In nonhuman primates such as the rhesus monkey, TCDD is exceptionally persistent in adipose tissue (Bowman et al., 1989~. Adding to this complexity of TCDD retention are biodisposition studies suggesting that the rate of TCDD decay from liver, adipose tissue, and other tissue may not remain constant with time (Birnbaum et al., 1980; Olson et al., 1980a; Birnbaum, 1986; Pohjanvirta et al., 1990; Neubert et al., 1990a)
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From page 132... ...
This premise is supported by a number of different studies using a variety of approaches. For example, bile extracts from TCDD-treated dogs administered to guinea pigs were found to be 100 times less toxic than orally administered TCDD itself (Weber et al., 1982~.
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From page 133... ...
In virtually all rodent studies, results indicate that all of the TCDD excreted in urine and bile is in the form of TCDD metabolites. In the rat, hamster, and mouse, approximately 15-35 percent of TCDD in feces is unmetabolized, whereas in the guinea pig, approximately 81 percent was unmetabolized in feces (Olson et al., 1980a; Neal et al., 1982; Gasiewicz et al., 1983; Olson, 1986~.
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From page 134... ...
Crossbreeding studies indicate that the sensitive phenotype segregates as an autosomal dominant phenotype. Further genetic studies identified the "Ah locus" as the area of the genome that encodes for the Ah receptor (Poland and Knutson, 1982; Nebert, 1989~.
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From page 135... ...
There is good correlation between the binding affinities of various TCDD congeners for the Ah receptor and the induction of enzyme (aryl hydrocarbon hydroxylase, AHH) activity (Poland et al., 1979~.
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TCDD may either induce a gene for a growth factor and directly affect tissue proliferation, or induce the gene for the growth factor receptor and increase the sensitivity of the cell to the growth factor
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Linearity of Response or Threshold Scientists hold vastly different opinions about the existence of a threshold effect, that is, whether there is a point below which no effect of the chemical exists, for the activity of TCDD. There are those who argue that all events that occur up to and including the induction of gene transcription have a linear dose-response curve; others argue that more complex events that require the concordance of two or more events, such as cell proliferation, may have a threshold.
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From page 138... ...
bioassay of TCDD is the most cited and that on which the Environmental Protection Agency cancer potency estimate is based. Groups of male and female Sprague-Dawley rats received 0, 0.001, 0.01, or 0.1 log TCDD/kg body weight/day in the diet for two years.
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From page 139... ...
Other positive results included increased rates of thyroid follicular cell adenoma in male rats at all dose levels, of combined adenomas and carcinomas of the adrenal gland in high-dose female rats, of subcutaneous fibrosarcomas in high-dose rats and female mice, and of lymphoma in high-dose female mice. National Toxicology Program (NTP, 1982 bJ Male Swiss-Webster mice received doses of 0.001 ~g TCDD applied to the skin 3 days per week for
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From page 141... ...
(1987) Groups of male and female B6C3F~ and B6CF~ mice received intraperitoneal doses of 0, 1, 30, or 60 fig TCDD/kg body weight in corn oil once weekly for 5 weeks, starting at 10 days of age.
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From page 142... ...
Female mice received 0.005 log TCDD per application. Half the animals received a single application of 50 log dimethylbenzanthracene one week prior to beginning TCDD treatment.
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From page 143... ...
Liver In a bioassay reported by Pilot and colleagues (1980) , female Sprague-Dawley rats received an initiating dose of diethylnitrosamine followed by 0.14 or 1.4 log TCDD/kg body weight subcutaneously once every two weeks for seven months (equivalent to 10 and 100 ng/kg/day, the same as the medium and high doses in the Kociba et al.
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From page 144... ...
Inducing CYP1A2 may thus increase DNA damage by estrogens, which may play a part in TCDD-induced carcinogenesis in the female rat liver. This possibility is consistent with the observations that CYP1A2 is found only in the liver, that ovariectomy protects against TCDDinduced hepatocarcinogenesis in female rats, and that male rats are not susceptible.
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From page 145... ...
. Increased rates of cell proliferation may be related to TCDD's effects on the epidermal growth factor (EGF)
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From page 146... ...
Since a chemical may act at a given step in the generation of an immune response, the timing of exposure to the chemical or antigen to which a response is generated is critical, and must be considered in determining the applicability of animal studies on chemical exposure to epidemiologic evaluation of the effects of environmental toxicants on the human immune system. Numerous studies in several species have indicated that the immune system is highly sensitive to the effects of exposure to TCDD and related compounds.
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From page 147... ...
Either the generation of specific serum antibody titer or the number of plaque-forming cells produced after immunization with sheep red blood cells (SRBCs) , a T celldependent antigen, is markedly suppressed following TCDD exposure.
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From page 148... ...
Recent studies indicate that the hypersensitivity of TCDD-treated mice to endotoxin may be due to an increase in the production of these inflammatory cytokines (Thomas and Hinsdill, 1978, 1979; Vos et al., 1978; Loose et al., 1979; Taylor et al., 1990; Clark et al., 1991a; Hoglen et al., 1992~. In addition, the wasting syndrome and the mortality observed following exposure to TCDD were reduced after treatment of mice with pharmacologic levels of anti-TNF antibodies, suggesting a role for this inflammatory mediator in the process (Taylor et al., 1992~.
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From page 149... ...
response was the cell-mediated immune response parameter measured in rats and guinea pigs, and graft-versus-host response was measured in mice. From this study, it was shown that guinea pigs were more sensitive to the effects of TCDD than rats, which is consistent with other toxic effects of TCDD (McConnell et al., 1978a; Poland and Knutson, 1982~.
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From page 150... ...
mice, which differ in the affinity of their Ah receptor for TCDD, and mice that are congenic at the Ah locus, the generation of cell-mediated and humoral immune responses in vivo seems to be Ah receptor mediated (Silkworth and Grabstein, 1982; Vecchi et al., 1983; Kerkvliet et al., l990a,b)
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From page 151... ...
It is important to emphasize that almost without exception, structure-activity studies indicate that liver alterations produced by HAH congeners are associated with the Ah locus. The most extensive characterization of liver-associated alterations in response to TCDD and related compounds has been in rodents, primarily mice and rats; however, some hepatotoxicity data are available in other mammalian species.
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From page 152... ...
Neither the guinea pig nor the hamster displays severe morphological alterations in the liver following TCDD administration. In light of this, although liver lesions may contribute to TCDD lethality in laboratory animals, the cause of death cannot be explained on the basis of liver lesions alone.
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From page 153... ...
Cantoni and colleagues (1981) demonstrated that oral exposure of rats to 0.01, 0.1, or 1 ,ug TCDD/kg body weight/week for 45 weeks produced an increase in coproporphyrin concentrations at all dose levels.
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From page 154... ...
Acute TCDD exposure of guinea pigs and rats also produces a significant reduction in binding of LDL to its receptor on the hepatic plasma membrane (Bombick et al., 1984~. It is important to emphasize that this reduction in LDL binding was not caused
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From page 155... ...
These data suggest that TCDD and related compounds decrease bile flow. Enzyme Induction The most extensively studied biochemical effects on hepatic function associated with exposure to TCDD and related compounds are the marked changes this class of chemicals produces on enzyme activity.
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From page 156... ...
Reproductive and Developmental Toxicity Introduction TCDD has been found to have a number of effects on reproductive and developmental function in laboratory animals. Although a number of studies have addressed the effects of TCDD on the fertility of male laboratory animals, there are no data relating male animal exposure to TCDD and developmental end points such as congenital anomalies, cancer, and growth retardation, which are the end points of interest in humans.
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From page 157... ...
Female rats were untreated. Mortality was 93 percent in the high-dose group, and body weights were significantly decreased in both groups.
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From page 158... ...
Murray and colleagues (1979) exposed both male and female rats to 0, 0.001, 0.01, or 0.1 log TCDD/kg body weight/day in the diet over three generations.
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From page 159... ...
This effect is age dependent and is not observed in immature animals (Safe et al., 19911. Developmental Toxicity Prenatal exposure to TCDD has been associated with both increased fetal mortality and increased developmental abnormalities in laboratory animals.
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From page 160... ...
These similarities include similarities in cognitive function, learning, and memory. Because of the structural and functional similarities of the nervous system across species, extrapolation of experimentally produced neurotoxicity from laboratory animals to humans is easier than for many other end points of toxicity.
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From page 161... ...
Overall, these results indicated no significant neurological impairment in animals that developed significant decreases in body weight following TCDD exposure. Allen and colleagues (1977)
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From page 162... ...
After groups of 11 male rats were given a single high dose of TCDD (1,000 ~g/kg body weight) or corn oil (vehicle)
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From page 163... ...
In response to glucose deprivation induced by 2-deoxyglucose (400 mg/kg body weight) , TCDD-treated rats ate little, while controls increased their feed consumption 10 times.
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From page 164... ...
investigated the role of hypothalamic endorphin and mu opioid receptor levels in Sprague-Dawley rats given a high but sublethal oral dose of TCDD (50,ug/kg body weight)
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From page 165... ...
investigated hypothalamic factors that could account for the reduction of serum concentrations of prolactin in Sprague-Dawley rats given a lethal dose of TCDD (50 ~g/kg body weight)
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From page 166... ...
The 5-HT depletion did not affect the outcome of TCDD exposure, suggesting that although TCDD increases 5-HT levels in the brain, this may not be the cause of the wasting syndrome. While lethal or near lethal dose levels of TCDD may be associated with neurochemical alterations or changes in the responsiveness of neurochemical processes in the central nervous system, the changes observed may also be regulatory responses occurring secondary to changes induced in other organ systems.
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From page 167... ...
This decrease is unusual because hyperglycemia normally would be expected in the presence of hypoinsulinemia. Comparable onset kinetics were observed with respect to both decreased insulin and decreased serum glucose following TCDD treatment (Gorski and Rozman, 1987~.
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From page 168... ...
, which is stimulatory. Following TCDD treatment, rats exhibited an increase in plasma fatty acids and de novo fatty acid synthesis in liver.
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From page 169... ...
(1988c) have speculated that a decrease in T4 by TCDD may account for the decrease in de novo fatty acid synthesis in interscapular brown adipose tissue.
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From page 170... ...
exhibited decreased glucose absorption as measured in isolated perfused jejunal segments. The greatest magnitude of inhibition was measured 2 days following TCDD treatment (30 percent)
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From page 171... ...
The changes in atrial function were not secondary to loss in body weight as determined by pair-fed controls. There was no effect of TCDD exposure on the ratio of heart ventricular mass to body weight or on the activities of pyruvate kinase and citrate synthase in homogenates prepared from heart ventricular muscle.
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From page 172... ...
The alterations in insulin and the increase in corticosterone 4-8 days after TCDD administration occurred as a response to this primary defect in PEPCK activity. Although the alterations observed in insulin and corticosterone (key regulators of PEPCK activity)
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From page 173... ...
as well as humans (Jones and Krizek, 1962~. However, the skin of laboratory animals generally does not exhibit a similar sensitivity to chlorinated compounds.
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From page 174... ...
These studies show that the toxicity of TCDD can be modulated by the diet of the animal. In summary, the formation of chloracne lesions after administration of TCDD is observed in some laboratory animals.
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From page 175... ...
In addition, its distribution and elimination are dose dependent, characterized by a sigmoidal relationship; extrapolation from high to low exposure doses is thus problematic (Gehring and Betso, 1978J. A half-life in humans following single doses of 2,4-D has been estimated to be approximately 18 to 20 hours (Sauerhoff et al., 1977; WHO, 19841; a half-life in humans based on multiple doses has not been estimated with certainty (Ibrahim et al., 19911.
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From page 176... ...
No differences in tumor rates were detected compared to untreated or vehicle controls. The same investigators also administered single doses of 215 mg/kg body weight of commercial (90 percent)
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From page 177... ...
A recent study evaluated the ability of 2,4-D to enhance lung tumor initiation by urethan in mice (Blakley et al., 19923. Groups of 25 male CD1 mice received Weed-no-More in their drinking water for 15 weeks at concentrations of 0, 0.0325, 0.08125, or 0.163 percent (equivalent to doses of 0-50 mg 2,4-D/kg body weight/day)
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From page 178... ...
injection with doses of 35 or 70 mg/kg body weight (Adhikari and Grover, 1988~. Weak positive results in tests for sister chromatic exchanges in cultured human lymphocytes have also been reported (Linnainmaa, 1984; Turkula and Jalal, 1985)
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From page 179... ...
Chronic Systemic Toxicity Studies in laboratory animals have demonstrated that chronic exposure to 2,4-D can elicit effects in a number of organs. For example, chronic exposure to 2,4-D has produced a wide variety of hepatotoxic effects in rodents, including subacute toxic hepatitis, local necrosis, centrilobular atrophy, elevated peroxisomes, elevated mixed-function oxidases, and other enzyme and glycogen changes (IARC, 1977; WHO, 1984~.
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From page 180... ...
concluded that the renal toxicity of 2,4-D in rats is due to damage to the loop of Henle and not to the proximal tubule. Neurobehavioral toxicity was reported in rats that received daily subcutaneous injections of 150-250 mg 2,4-D/kg body weight over four successive 14-day periods (Schulze and Dougherty, 19889.
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From page 181... ...
administered single doses of 2,4-D butyl ester at 50-200 mg/kg body weight to female BDF~ mice by gavage and reported enhanced antibody production against SRBCs, as well as a stimulated lymphoproliferative response to lipopolysaccharide. These doses also produced clinical signs of toxicity and CNS pathology, however.
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From page 182... ...
Rates of clearance from plasma and urinary excretion depend on dose and are species specific. Doses greater than 50 mg/kg body weight saturate the renal clearance mechanism for 2,4,5-T in rats (Piper et al., 1973b)
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From page 183... ...
No differences in tumor rates were detected when compared to untreated or vehicle controls. The same investigators also administered single doses of 21.5 mg/kg body weight of commercial (98 percent pure)
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From page 184... ...
gave single oral doses of 100 mg 2,4,5-T to pigs, and reported anorexia, vomiting, diarrhea, ataxia, hemorrhagic enteritis, and congestion of the liver and kidneys. Myotonia and anorexia have also been observed in dogs that received 100 mg 2,4,5-T/kg body weight (Drill and Hiratzka, 1953~.
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From page 185... ...
Immunotoxicity No studies of the immunotoxicity of 2,4,5-T could be found. TOXICITY PROFILE OF CACODYLIC ACID Introduction Cacodylic acid (hydroxydimethylarsine oxide; dimethylarsinic acid; CAS No.
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From page 186... ...
Studies in rats indicate that cacodylic acid is absorbed more slowly following oral administration than intratracheal administration, becomes bound to red blood cells, and is excreted readily in urine. Clearance from the rat red blood cell is very slow, with the half-life of cacodylic acid in rat erythrocytes being approximately the same as that of the erythrocytes (95 days)
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From page 187... ...
The cacodylic acid was excreted relatively rapidly by the hamster (80 percent after 24 hours following oral administration', primarily in urine and feces. Some of the cacodylic acid (approximately 26 percent of the total arsenic in the whole blood)
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From page 188... ...
Female rats exposed to 6.94 mg/liter air of cacodylic acid in acute inhalation toxicity experiments developed erythematous lesions on the feet and ears (Stevens et al., 1979~. Chronic Systemic Toxicity Studies of the chronic systemic toxicity of cacodylic acid are extremely limited.
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From page 189... ...
The high dose levels at which these effects were observed suggest that there is likely to be a relatively low risk of reproductive toxicity to humans in actual exposure situations. Exposure to cacodylic acid has been associated with fetotoxicity in laboratory animals, although these effects occurred only at doses that also produced maternal toxicity.
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From page 190... ...
The authors concluded that picloram was carcinogenic to Osborne-Mendel female rats based on the increased incidence of liver neoplastic nodules in the high-dose group (NCI, 1978~. An EPA peer review committee reassessed the tumor incidence and agreed that there was a statistically significant (p < 0.05)
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From page 191... ...
Mean body weights of the treated mice were unaffected by treatment, and no oncogenic response was observed (NCI, 1978~. Genotoxicity Information on the potential genotoxic effects of picloram is meager: it did not produce cytogenetic effects in rats exposed to single doses up to 2,000 mg/kg (U.S.
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From page 192... ...
. Tordon K+, but not technical grade picloram, was also found to be a skin sensitizer in guinea pigs (U.
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From page 193... ...
1988. Genotoxic effects of some systemic pesticides: in vivo chromosomal aberrations in bone marrow cells in rats.
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From page 194... ...
1990. 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibition of 17beta-estradiol-induced increases in rat uterine epidermal growth factor receptor binding activity and gene expression.
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From page 195... ...
1985. Cacodylic Acid: Agricultural Uses, Biologic Effects, and Envi
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From page 196... ...
1985. Cacodylic Acid: Agricultural Uses, Biologic Effects, and Environmental Fate.
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From page 197... ...
1991c. Dose response relationships for chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a rat liver tumor promotion model: 1.
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From page 198... ...
1985. Cacodylic Acid: Agricultural Uses, Biologic Effects, and Environmental Fate.
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From page 199... ...
Journal of Applied Toxicology 5: 163- 177. Fisher JM, Jones KW, Whitlock JP Jr.
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From page 200... ...
1979. 2,3,7,8-Tetrachlorodibenzo-p-dioxin tissue distribution, excretion, and effects on clinical chemical parameters in guinea pigs.
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From page 201... ...
1990. The effects of TCDD on receptors for epidermal growth factor, glucocorticoid, and estrogen in Ah-responsive and -nonresponsive congenic mice and the effects of TCDD on estradiol metabolism in a liver tumor promotion model in female rats.
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From page 202... ...
1989. Structure-dependent induction of aryl hydrocarbon hydroxylase in human breast cancer cell lines and characterization of the Ah receptor.
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From page 203... ...
1985. Cacodylic Acid: Agricultural Uses, Bio1O3ical Effects, and Environmental Fate.
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From page 204... ...
1985. Cacodylic Acid: Agricultural Uses, Biologic Effects, and Environmental Fate.
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From page 205... ...
1985. Cacodylic Acid: Agricultural Uses, Biolo~y,ic Effects, and Environmental Fate.
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From page 206... ...
1991a. Influence of the Ah locus on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic epidermal growth factor receptor.
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From page 207... ...
1988. 2,3,7,8-Tetrachlorodibenzo-p-dioxin causes an increase in protein kineses associated with epidermal growth factor receptor in the hepatic plasma membrane.
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From page 208... ...
1989. Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver: an update.
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From page 209... ...
1992. Differential elects of 2,3,7,8tetrachlorodibenzo-p-dioxin on responsiveness of male rats to androgens, estradiol, luteinizing hormone, gonadotropin-releasing hormone, and progesterone.
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From page 210... ...
1986. Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in guinea pigs.
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From page 211... ...
Excretion and tissue distribution of 2,3,7,8-tetrachlorodibenzop-dioxin in the rat. Environmental Health Perspectives 5:241-244.
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From page 212... ...
1973. Chlorinated dibenzo-p-dioxins: potent inducers of 6-aminolevulinic acid synthetase and aryl hydrocarbon hydroxylase.
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From page 213... ...
1981. The teratogenic potential of cacodylic acid in the rat and mouse.
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From page 214... ...
1989. Decreased ligand binding to the hepatic glucocorticoid and epidermal growth factor receptors after 2,3,4,7,8pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran treatment of pregnant mice.
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From page 215... ...
. Fundamental and Applied Toxicology 10:413-424.
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From page 216... ...
1977. Disposition of 14C or 74As-cacodylic acid in rats after intravenous, intratracheal, or peroral administration.
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From page 217... ...
1978. Effect of polychlorinated biphenyls on the immune responses of rhesus monkeys and mice.
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From page 218... ...
1981. Cacodylic Acid: Decision Document.
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From page 219... ...
1985. Cacodylic Acid: Agricultural Uses, Biologic Effects, and Environmental Fate.
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From page 220... ...
1973. Hematologic and clinical chemistry effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals.
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