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Veterans and Agent Orange: Update 2002 3 Toxicology As in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hearafter referred to as VAO; IOM, 1994), Veterans and Agent Orange: Update 1996 (hearafter Update 1996; IOM, 1996), Veterans and Agent Orange: Update 1998 (hearafter Update 1998; IOM, 1999), and Veterans and Agent Orange: Update 2000 (hearafter Update 2000; IOM, 2001), this review summarizes the recent experimental data that serve as a scientific basis of assessment of the biologic plausibility of health outcomes reported in epidemiologic studies. Efforts to establish the biologic plausibility of effects of herbicide exposure in the laboratory strengthen the evidence of the herbicide effects suspected to occur in humans. Toxic outcomes are influenced by differences in dosage (magnitude and frequency of administration); by exposure to other chemicals, including chemicals other than herbicides; by pre-existing health status; by genetic factors; and by the route and rate of absorption, distribution, metabolism, and excretion. Any attempt to extrapolate from experimental studies to human exposure must therefore carefully consider such variables before conclusions are made. Multiple chemicals were used for various purposes in Vietnam. The chemical nature of the substances themselves is discussed in more detail in Chapter 6 of VAO. Four herbicides documented in military records were of particular concern and are addressed here: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 4-amino-3,5,6-trichloropicolinic acid (picloram), and cacodylic acid (dimethylarsenic acid, DMA). In addition, this chapter focuses to a large extent on a contaminant of 2,4,5-T, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin) because its potential toxicity is of concern and considerably more information is available on it than on the herbicides. Most of the
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Veterans and Agent Orange: Update 2002 experimental studies of those chemicals, unless otherwise noted, were conducted with pure chemicals, in contrast with the epidemiologic studies discussed in later chapters, in which exposures were often to mixtures of chemicals. This chapter begins with a brief summary of major conclusions presented in previous Veterans and Agent Orange reports regarding the toxicology of the compounds of interest. That summary is followed by what makes up the majority of the chapter, overviews and discussions of the relevant experimental studies that have been published on 2,4-D, 2,4,5-T, picloram, cacodylic acid, and TCDD since Update 2000. Within the update for each of the chemicals, the experimental studies investigating the toxicokinetics, mechanisms of action, and disease outcomes of exposure to the chemical are discussed. Where appropriate, the mechanisms of action are discussed as they relate to a particular endpoint. Estimating potential human health risks on the basis of the animal data is then discussed. HIGHLIGHTS OF PREVIOUS REPORTS Chapter 4 of VAO and Chapter 3 of Update 1996, Update 1998, and Update 2000 review the results of animal and in vitro studies published through 2000 that investigate the toxicokinetics, mechanism of action, and disease outcomes of the herbicides used in Vietnam, and the contaminant TCDD. The toxicity of the four herbicides has not been studied extensively, but in general they are not considered particularly toxic because high concentrations are usually required to modulate cellular and biochemical processes. In contrast, the toxicity of TCDD has been studied extensively. On the basis of the experimental data reviewed in previous Agent Orange reports, the committees concluded that TCDD elicits a diverse spectrum of sex-, strain-, age-, and species-specific effects, including carcinogenesis, immunotoxicity, reproductive and developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. The scientific consensus is that TCDD is not directly genotoxic and that its ability to influence the carcinogenic process is mediated by epigenetic events, such as enzyme induction, cell proliferation, apoptosis, and intracellular communication. Most, if not all, of TCDD's effects are mediated through the aryl hydrocarbon receptor (AhR), which interacts with other proteins, binds to DNA and results in biochemical effects, including enzyme induction. TOXICITY PROFILE UPDATE OF 2,4-D Toxicokinetics Toxicokinetics (also referred to as pharmacokinetics) pertains to the routes and rates of uptake, tissue distribution, transformation, and elimination of a toxicant. Those processes, in part, determine the amount of a particular chemical that reaches potential target organs or cells and thereby influences toxicity to organs
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Veterans and Agent Orange: Update 2002 or cells. Understanding the toxicokinetics of a compound is important for valid reconstruction of exposure to it. Since Update 2000, several studies have examined the pharmacokinetics and metabolism of 2,4-D in animal species. Recent data support the conclusions of previous updates that metabolism and elimination of 2,4-D are relatively rapid and that tissue uptake is small. Kim et al. (2001) constructed a physiologically based pharmacokinetic (PBPK) model to describe and predict the kinetic behavior of 2,4-D in rats after long-term exposures to low doses. The model was tested with experimental data from rats that were given 2,4-D at 1 or 10 mg/kg body weight per day by subcutaneous infusion for 7, 14, and 28 days. In general, the experimental data fell within the range of 2,4-D concentrations predicted by the PBPK model for the blood and different brain regions. The model supports the concept that uptake of the chemical into brain was limited primarily by the membrane components of the blood–brain barrier. In another study (Barnekow et al., 2001) the elimination and metabolism of 2,4-D following oral administration were evaluated in laying hens dosed with 2,4-D at 18 mg/kg body weight for 7 days and in lactating goats dosed with 2,4-D at 483 mg/kg body weight for 3 days. More than 90% of the total dose was eliminated within 24 h of the final dose. Individual tissue residues accounted for less than 0.1% of the dose. The most abundant residue was 2,4-D; a minor metabolite, 2,4-dichlorophenol, was also present. Overall, those studies suggest that in the species used 2,4-D is eliminated relatively rapidly and that uptake and metabolism by most tissues are low. A study by Dickow et al. (2000) attempted to correlate plasma concentrations with observed clinical effects in dogs after a dose of twice the reported LD50 (the lowest dose that kills half the animals that receive it), 2,4-D at 100 mg/kg body weight. All dogs survived, but vomiting and diarrhea were observed. The mean total and unbound plasma 2,4-D concentrations were 511 mg/L and 129 mg/L, respectively. As discussed in previous updates, studies suggest that although 2,4-D is relatively nontoxic, the developing nervous system might be a target after exposure to high concentrations. Sturtz et al. (2000) therefore investigated the lactational transfer of 2,4-D by measuring it in tissues of rats whose dams received 2,4-D at 50, 70, and 100 mg/kg body weight during nursing. 2,4-D residues in tissues depended on dose and exposure time. At the highest dose, there was impaired body growth, low tissue weights, and diminished stomach contents of the offspring. The analysis of tissues indicated that 2,4-D was transferred to the neonates during nursing and that, at least at the highest maternal dose, the toxicity might be explained by diminished milk intake or direct toxic effects on the neonate. When 2,4-D treatment was discontinued, the residues remained in the stomach contents of the neonates for at least a week.
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Veterans and Agent Orange: Update 2002 Mechanisms of Toxic Action Mechanisms Related to Genotoxic Effects Several studies reviewed in Update 2000 indicate a relatively weak or no genotoxic potential of 2,4-D. Two studies published since then are consistent with a lack of genotoxicity. A study by Venkov et al. (2000) demonstrated a lack of mutagenic action of 2,4-D by using tests in yeast, transformed hematopoietic cells, and mouse bone marrow cells. Charles et al. (2000) also demonstated a lack of genotoxicity after exposure to 4-(2,4-dichlorophenoxy) butyric acid, of which 2,4-D is a metabolite, by looking at gene mutation in bacteria and cultured mammalian cells, cytogenetic abnormalities in mammalian cells, and induction of DNA damage and repair in rat hepatocytes. A study by Amer and Aly (2001), however, observed increased genotoxity after oral exposure to 2,4-D at 3.3 mg/kg body weight for 3 and 5 consecutive days; a significant increase in the percentage of chromosomal aberrations in bone marrow and spermatocytes was observed with both regimens. The genotoxic effects of 2,4-dichlorophenol, a metabolite of 2,4-D, were also investigated in that study and were much weaker. Only the highest concentration tested, 2,4-D at 180 mg/kg body weight, induced a significant percentage of effects after intraperitoneal injection (Amer and Aly, 2001). Mechanisms Related to Effects on Energy Metabolism or Mitochondrial Function Several reports cited in previous updates suggest that the toxicity of 2,4-D might be related, at least in part, to its effect at relatively high concentrations on calcium homeostasis and energy metabolism. Those actions might be mediated by a direct action on mitochondria. A study discussed in Update 2000 indicated that the mitochondrial effects of some herbicide preparations, including those containing 2,4-D, might be due primarily to the surfactant in the formulations and not to 2,4-D itself. A similar study by Oakes and Pollak (2000) confirmed that as much as 50% of the effects of several formulations, including Agent Orange, on oxidative functions of submitochondrial particles is due to “inert” components. A molecular study by Di Paolo et al. (2001) isolated a single protein contained in rat liver mitochondria to which radiolabeled 2,4-D or one of its metabolites was covalently bound. Although the identity of the protein is not known, the investigators suggest that the alteration of its function may be related to known alterations in mitochondrial function produced by 2,4-D. Previous updates noted that 2,4-D is a peroxisome proliferator, that is, it causes an increase in the number and size of peroxisomes in several tissues of susceptible species. Such chemicals are nonmutagenic carcinogens in the livers of rodents. Humans and hamsters are considered to be relatively resistant to the effects of peroxisome proliferators. A study by Ozaki et al. (2001) observed distinct morphologic changes in the kidneys of rats and mice chronically exposed
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Veterans and Agent Orange: Update 2002 to 2,4-D and WY-14643 (a known peroxisome proliferator) for up to 3 months. The changes were characterized by alteration in tubule structures, long brush borders of tubule cells, and reduced volume and number of mitochondria. Those changes were not observed in hamsters. The authors indicate that although 2,4-D is considered a weak peroxisome proliferator in the rodent liver, it appeared to be more effective in inducing renal changes. Kaioumova et al. (2001) determined that the dimethylammonium salt of 2,4-D (up to 3 mM) caused concentration-and time-dependent apoptosis in peripheral lymphocytes of healthy people and in vitro in Jurkat T cells. Further examination of the mechanism indicated that those effects were mediated by direct action of the chemical on mitochondria. Hepatocyte ultrastructural changes were observed in rats whose mothers received the sodium salt of 2,4-D in drinking water (at a daily dose of 2,4-D at 250 mg/kg body weight) before fertilization and during pregnancy and lactation; the changes were consistent with effects of 2,4-D on mitochondria and energy metabolism (Pilat-Marcinkiewicz et al., 2000). Mechanisms Related to Effects on Thyroid Hormones Effects of 2,4-D on serum concentrations of thyroid hormones, particularly decreases in thyroxine, were noted in previous updates. A recent report by Kobal et al. (2000) likewise observed decreased serum concentrations of thyroxine and triiodothyronine after oral exposure of male and female rats to 2,4-D at 11 and 110 mg/kg body weight per day for 10 days. Chemical-induced alterations in thyroid homeostasis can adversely affect the development of many organ systems including the nervous and reproductive systems. Most of these effects are caused by lack of thyroid hormone alone rather than by increases in TSH. Mechanisms Related to Effects on Cell Stress Responses Stress proteins (for example, heat-shock proteins) are most often induced in a variety of cells in response to environmental and chemical stressors and have been proposed as markers of the presence of stressors. Two studies examined the ability of 2,4-D to increase heat-shock proteins in bacteria and a human cell line. 2,4-D exposure induced several heat-shock proteins in bacteria (Cho et al., 2000), but did not induce the hsp70 promoter in a HeLa cell line (Ait-Aissa et al., 2000). An additional study determined that a single exposure to 1 mM 2,4-D diminished growth and total protein in all E. coli strains tested; successive exposures to 0.01 mM 2,4-D also had a toxic effect on cell growth (Balague et al., 2001). Disease Outcomes Studies of disease outcomes published since Update 2000 are consistent with the previous conclusion that 2,4-D is relatively nontoxic and has weak oncogenic
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Veterans and Agent Orange: Update 2002 potential. Also as previously indicated, the developing fetus appears to be most sensitive to the effects of 2,4-D for a number of toxic end points. One recent investigation yielded no evidence that paternal exposure to a herbicide formulation containing 2,4-D and picloram caused birth defects or any other adverse reproductive outcome (Oakes et al., 2002a). Recent animal studies of disease outcomes of 2,4-D exposure are discussed below. Neurotoxicity Bortolozzi et al. (2001) studied the effects of nonphysiologic, direct, intracebral administration of 2,4-D (2,4-D at 50 or 100 µg/rat) on behavior and neurochemical alterations in the rat brain. 2,4-D induced a regionally specific neurotoxicity in the basal ganglia, but the neurotoxic effects depended on the location of injection, the dose, and the length of time since the injection. Those data suggest that 2,4-D has the ability to produce direct effects on the brain if high enough concentrations can be achieved. In another study, 2–4 mM 2,4-D directly affected the viability of isolated frog sciatic nerve (Kouri and Theophilidis, 2002). Garabrant and Philbert (2002) reviewed the scientific evidence relevant to neurologic effects of 2,4-D. Although high doses in experimental animals have been found to produce myotonia and alterations in gait and behavioral indexes, there is no evidence of effects on the neurologic system at doses in the microgram-per-kilogram-per-day range. That information is consistent with the conclusion of this and previous Agent Orange updates. Reproductive and Developmental Toxicity Several studies have examined the developmental toxicity of 2,4-D. Charles et al. (2001) examine the potential for 2,4-D and its salts and esters to induce developmental toxicity in rats and rabbits. In both species, effects on maternal body weight manifest with 2,4-D at 30 mg/kg maternal body weight per day. At higher doses, body weights and feed consumption were more severely affected. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was about 10 mg 2,4-D/kg body weight per day. Significantly decreased fetal body weights and fetal variations were seen in rats only at doses greater than 90 mg 2,4-D/kg body weight per day. At maternally toxic doses in rabbits, embryonal and fetal development were unaffected. Those data suggest that those end points in the developing rat and rabbit are not uniquely sensitive to 2,4-D or its salt and ester forms. Postnatal measures were not examined in that study. A study by Fofana et al. (2000) examined maternal and fetal toxicity after exposure of pregnant dams to 2,4-D at daily doses of 50, 70, 110, or 150 mg/kg maternal body weight on gestational days 6–10, 6–15, or 11–15. There was significant maternal weight loss in all experimental groups and a dose-related embryolethality. Kidney and urogenital malformations were found in the fetuses. A later study by Fofana et al.
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Veterans and Agent Orange: Update 2002 (2002) reported similar findings except that impaired growth of the unaffected offspring was not observed. Two studies examined brain development in rats and concluded that exposure to 2,4-D may produce alterations in brain development. Ferri et al. (2000) injected dams with 2,4-D (at 100 mg/kg body weight per day) or vehicle during lactation (on postnatal day 9–15 or 9–25). No overt signs of toxicity were observed in the dams, but significant differences were observed in the development of the brain monoaminergic system of neonates exposed to 2,4-D through mother's milk. There was an increase in 5-hydroxyindolacetic acid and serotonin in brains of 25-day-old pups. Alterations in serotonin, dopamine, and norepinephrine were also seen in several brain areas. Rosso et al. (2000) exposed neonatal rats to 2,4-D at 100 mg/kg body weight per day on postnatal days 7–25 or 2,4-D at 70 mg/kg body weight per day on postnatal days 12–25. Decreased body and brain weights were noted only at the higher dose regimen, but both regimens decreased the amount of brain myelin gangliosides and myelin deposition. Alterations in muscular force and motor activity were also seen. Another study investigated whether 2,4-D alters sensitivity to amphetamine by altering the number of D2-like receptors, a subtype of dopamine receptors in the brain (Bortolozzi et al., 2002). Rats exposed to 2,4-D at 70 mg/kg body weight per day from gestational day 16 to postnatal day 23 and acutely challenged with amphetamine exhibited increased sensitivity to amphetamine and an increase in D2-like receptor density. The increased density depended more on the particular brain region and the sex of the animal than on the timing of the 2,4-D exposure. A reversal to basal density of D2-like receptors did not occur after cessation of 2,4-D exposure. A recent study investigated the male-mediated reproductive toxicity of a mixture of 2,4-D and picloram similar to Agent White called Tordon 75D® (Oakes et al., 2002b). Male rats were exposed by gavage (5 days/week for 9 weeks) to Tordon 75D® (2.5%, 5%, and 10% solutions, corresponding to approximate Tordon 75D® doses of 37, 75, and 150 mg/kg body weight per day) and then mated with untreated females at various times during the treatment and after an 11-week recovery period. On gestational day 20, pregnant females were killed, and fetuses were weighed and examined for malformations. The positive control, cyclophosphamide, increased postimplantation fetal death, but no effects on fetal survival or malformations were observed in the herbicide-treated groups. Garabrant and Philbert (2002) reviewed the scientific evidence relevant to reproductive risks posed by 2,4-D exposure. They conclude that there is a lack of reproductive and developmental toxicity by any route of administration at 2,4-D doses that do not exceed 50 mg/kg body weight, a dose that saturates renal clearance mechanisms, and that offspring of treated pregnant animals show mild to moderate alterations in skeletal development only in the presence of overt maternal toxicity. Those conclusions are consistent with the data presented in this and previous updates.
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Veterans and Agent Orange: Update 2002 Immunotoxicity Lee et al. (2001) examined the effect of exposure to a commercial 2,4-D formulation during gestation on the immune response in mice. Pregnant mice were given the formulation in drinking water (0–1.0%, equivalent to 2,4-D at 0– 650 mg/kg body weight per day) on gestational days 6–16. Immune function in the offspring was evaluated 7 weeks after birth. Decreased body weights and minor reductions in kidney weights were seen in the two highest-dose groups (0.1 and 1.0%). Immune alterations were observed only in the highest-dose group. Suppression of the lymphocyte response to mitogens, an increase in relative B-cell counts, and reduction in the number of cytotoxic and suppressor T cells were seen. The humoral immune response, as measured by antibody production against sheep red blood cells, and peritoneal macrophage phagocytic function were not altered. The authors conclude that the effect on human and animal immune function would probably be minimal when 2,4-D is encountered after normal application in the environment. Garabrant and Philbert (2002) reviewed the scientific evidence relevant to possible effects of 2,4-D on the immune system and concluded that there is little evidence of a significant effect at any dose. That conclusion is consistent with the conclusion of this and previous updates,which note that 2,4-D has at most a weak effect on the immune system. Carcinogenicity Using a protocal similar to that discussed above, Lee et al. (2000) examined the effect of exposure to a commercial 2,4-D formulation during gestation on urethan-induced lung adenoma in mice. Female offspring of dams exposed to 2,4-D (0–1.0%) on gestational days 6 –16 were given urethan (1.5 mg/g) at the age of 7 weeks to induce pulmonary adenoma. Offspring were examined at the age of 12 weeks for formation of pulmonary adenomas. Gestational 2,4-D exposure did not affect the number of tumors produced, but it did reduce the mean tumor diameter in the highest-dose group. The authors concluded that gestational 2,4-D exposure had no persistent effect on immune cells involved in cell-mediated immunosurveillance mechanisms. Garabrant and Philbert (2002) reviewed the scientific evidence relevant to cancer risks posed by 2,4-D exposure and concluded that there was no experimental evidence that 2,4-D or any of its salts or esters damages DNA and that studies in experimental animals had demonstrated a lack of carcinogenic effects of 2,4-D. Those conclusions are consistent with the conclusions of the present and previous updates. TOXICITY PROFILE UPDATE OF 2,4,5-T No relevant studies on the toxicokinetics of 2,4,5-T or the disease outcomes seen in experimental animals after exposure to 2,4,5-T have been published since Update 2000.
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Veterans and Agent Orange: Update 2002 Previous updates reviewed several possible mechanisms by which 2,4,5-T may affect biologic systems. Much of the available information suggests that 2,4,5-T may disrupt cellular pathways involving acetylcoenzyme A. Several reports suggested that 2,4,5-T has only weak mutagenic potential but that it may alter the profile of enzymes involved in the metabolism of procarcinogens. Two recent studies have investigated the mechanisms underlying the cellular effects of 2,4,5-T. A study by Kaya et al. (2000) examined the ability of several herbicides, including 2,4,5-T, to produce genotoxicity in the wing-spot test of Drosophila melanogaster. It was found to increase slightly the frequency of small single spots but not other types of mutant clones. Furthermore, the slight effect was observed only in a particular type of cross. Those data are consistent with a weak mutagenic potential of 2,4,5-T. A study by Yamanoshita et al. (2001) investigated whether low concentrations of 2,4,5-T affect apoptosis in PC12 cells, a cell line of rat pheochromocytoma cells. Exposure to 2,4,5-T concentrations as low as 10–12 g/L increased cell viability and inhibited DNA fragmentation induced by serum deprivation. The authors concluded that because the physiologic mechanisms leading to cell death are necessary for the normal development of tissues, the inhibitory effect of 2,4,5-T on those mechanisms might cause damage by interrupting normal cell homeostasis and differentiation. TOXICITY PROFILE UPDATE OF CACODYLIC ACID Cacodylic acid was present (at 4.7%) in a herbicide that was used in Vietnam in defoliation and crop-destruction missions. The active ingredient in cacodylic acid is dimethylarsinic acid (DMA), which is a metabolite of inorganic arsenic in humans; inorganic arsenic is known to cause cancers in humans. Because of possible concerns that the health effects seen following exposure to inorganic arsenic might be seen after exposure to cacodylic acid, the committee discussed whether studies of inorganic arsenic are relevant to its conclusions. Dimethylarsinic acid is resistant to hydrolysis, and is not demethylated to inorganic arsenic. Although dimethylarsinic acid is formed and is an active metobolite in humans following inorganic arsenic exposure, as discussed in Chapter 2, it has not been established and cannot be inferred that the effects seen following exposure to inorganic arsenic occur following exposure to cacodylic acid. Therefore, in general, the literature on inorganic arsenic is not considered in this report. The reader is referred to Arsenic in Drinking Water (NRC, 1999) and Arsenic in Drinking Water: 2001 Update (NRC, 2001) for further details on the effects of inorganic arsenic. The toxicokinetics of inorganic arsenic as they relate to cacodylic acid formation are discussed below. Toxicokinetics Arsenic forms reactive metabolites that affect cellular respiration in nearly every organ system in the body. It was thought for years that methylation of
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Veterans and Agent Orange: Update 2002 inorganic arsenic was a detoxification process, but recent studies have disputed that theory. The initial methylation of arsenic yields pentavalent monomethylarsonic acid (MMAv), which is reduced to trivalent monomethylarsonous acid (MMAIII) and further methylated to pentavalent dimethylarsinic acid (DMA v). DMA is further reduced to dimethylarsinous acid (DMAIII), which is methylated to form trimethylarsine oxide (Styblo et al., 2000). The route of excretion is primarily the urinary system. As discussed in Arsenic in Drinking Water (NRC 1999), in most animals the DMA that is formed is rapidly excreted in the urine, but in rats DMA accumulates in the red cells and tissues. The pentavalent arsenic species (MMAv and DMAv) are less toxic than the trivalent ones. MMAIII is about 4 times more toxic than inorganic arsenic following acute exposure; the toxicity of DMAIII is similar to that of arsenic III (NRC, 2001). Mechanisms of Toxic Action A primary mechanism of the acute toxicity of arsenic is interference with cellular respiration, but recent attention has been devoted mostly to understanding the carcinogenic properties and pathways of arsenic. Inorganic arsenic, a known human carcinogen, does not induce neoplasia in laboratory animals, but cancer has been induced in the urinary bladder, kidneys, liver, thyroid glands, and lungs of laboratory animals by exposure to high concentrations of the metabolite DMA (IOM, 2001; Kenyon and Hughes, 2001; NRC, 2001). The mechanisms responsible for those neoplasms remain unknown. Recent studies have suggested that DMA may act through induction of oxidative damage (Yamanaka et al., 2001) or damage to DNA (Kenyon and Hughes, 2001; Mass et al., 2001; Noda et al., 2002; Sordo et al., 2001). Another recent study demonstrated that DMA caused necrosis of the epithelium of the urinary bladder followed by regenerative hyperplasia (Cohen et al., 2001). Disease Outcomes Few animal studies are available on the noncancer health effects of cacodylic acid. Previous reports indicate that cacodylic acid is fetotoxic and teratogenic in rats and mice but only at high, maternally toxic doses (Kenyon and Hughes, 2001). Cacodylic acid acts as a tumor promotor in several organ systems. In a recent initiation-promotion study, however, cacodylic acid given in the drinking water at 220 ppm for 29 weeks did not act as a promotor of kidney tumors in male NCI-Black Reiter rats initiated with N-ethyl-N-hydroxyethylnitrosamine (Vijayaraghavan et al., 2000). In another study, a dose-dependent increase in the incidence of transitional-cell carcinoma occurred in the urinary bladder of male rats given cacodylic acid at 50 or 200 ppm in the drinking water for 104 weeks starting at the age of 10 weeks (Wei et al., 1999). The authors conclude that cacodylic acid is a weak carcinogen. In another study by Seike et al. (2002), oral
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Veterans and Agent Orange: Update 2002 administration of cacodylic acid at 400 ppm did not exert promoting effects in the lungs of male F344 rats initiated with N-bis (2-hydroxypropyl) nitrosamine. TOXICITY PROFILE UPDATE OF PICLORAM Picloram and 2,4-D are components of Agent White, a herbicide formulation used in Vietnam. Studies reviewed in previous updates and in VAO reported a fairly rapid elimination of picloram and suggest carcinogenic and some neurologic effects of exposure but only at extremely high doses. Some cellular abnormalities in liver and inconsistent developmental effects have also been reported. Two relevant studies of picloram have been published since Update 2000, both focusing on its potential reproductive effects. A study by Oakes et al. (2002b) investigated the possibility of male-mediated reproductive toxicity of a mixture of 2,4-D and picloram similar to Agent White, called Tordon 75D®. As discussed earlier, male rats were exposed to Tordon 75D® by gavage for 5 days per week for 9 weeks at 37 (low dose), 75 (medium dose), or 150 mg/kg of body weight per day (high dose). The 9-week treatment caused a reduction in testicular weight in some animals treated with the highest dose. The small testes had shrunken tubules and germ-cell depletion that was still evident in some rats after a 21-week recovery period. There were no significant differences in the serum concentration of testosterone between control animals and treated animals. In a related study by the same investigators (Oakes et al., 2002a), each of the males exposed to the three doses of herbicide was mated with two untreated females during weeks 2 and 3, 4 and 5, and 8 and 9 of treatment and with four untreated females after an 11-week recovery period. Negative control males were treated with distilled water, and positive controls with cyclophosphamide. On day 20 of gestation, litter size, fetal weight, and fetal malformation rate were all unaffected by herbicide treatment. The positive and negative controls showed the expected results. The results of those studies suggest that exposure to herbicide formulation containing 2,4-D and picloram can cause male-mediated birth defects or other adverse reproductive outcomes. TOXICITY PROFILE UPDATE OF TCDD Toxicokinetics The distribution of TCDD and other chlorodibenzo-p-dioxin congeners has been examined extensively in animal models and to a smaller extent in humans over the last two decades. Similar planar halogenated aromatic hydrocarbons (PHAHs), especially the polychlorinated dibenzofurans and non-ortho-polychlorinated biphenyls, have also been examined extensively. As discussed in numerous papers reviewed in previous reports (VAO and Updates 1996, 1998, 2000), those chemicals are hydrophobic and tend to be readily absorbed across cell membranes.
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Representative terms from entire chapter: