3
Toxicology

As in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994; hereafter referred to as VAO), Veterans and Agent Orange: Update 1996 (IOM, 1996; hereafter, Update 1996), Veterans and Agent Orange: Update 1998 (IOM, 1999; hereafter, Update 1998), Veterans and Agent Orange: Update 2000 (IOM, 2001; hereafter, Update 2000), and Veterans and Agent Orange: Update 2002 (IOM, 2003; hereafter, Update 2002), this chapter summarizes recent experimental data that provide the scientific basis for assessment of the biologic plausibility of the effects of herbicide exposure as reported in epidemiologic studies. Establishment of biologic plausibility through laboratory studies strengthens the evidence of the effects of herbicide exposure that are believed to occur in humans. Toxic effects are influenced by dosage (magnitude and frequency of administration); by exposure to other substances, including compounds other than herbicides; by pre-existing health status; by genetic factors; and by the route and rate of the substance’s absorption, distribution, metabolism, and excretion. Attempts to extrapolate from experimental studies to human exposure must therefore carefully consider those variables.

Many chemical compounds were used by the US armed forces in Vietnam. The nature of the substances themselves is discussed in more detail in Chapter 6 of VAO (IOM, 1994). Four herbicides documented in military records were of particular concern and are examined 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 (dimenthylarsenic acid, DMA). This chapter also focuses on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin), a contaminant of 2,4,5-T, because its potential toxicity is of concern and because



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Veterans and Agent Orange: Update 2004 3 Toxicology As in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994; hereafter referred to as VAO), Veterans and Agent Orange: Update 1996 (IOM, 1996; hereafter, Update 1996), Veterans and Agent Orange: Update 1998 (IOM, 1999; hereafter, Update 1998), Veterans and Agent Orange: Update 2000 (IOM, 2001; hereafter, Update 2000), and Veterans and Agent Orange: Update 2002 (IOM, 2003; hereafter, Update 2002), this chapter summarizes recent experimental data that provide the scientific basis for assessment of the biologic plausibility of the effects of herbicide exposure as reported in epidemiologic studies. Establishment of biologic plausibility through laboratory studies strengthens the evidence of the effects of herbicide exposure that are believed to occur in humans. Toxic effects are influenced by dosage (magnitude and frequency of administration); by exposure to other substances, including compounds other than herbicides; by pre-existing health status; by genetic factors; and by the route and rate of the substance’s absorption, distribution, metabolism, and excretion. Attempts to extrapolate from experimental studies to human exposure must therefore carefully consider those variables. Many chemical compounds were used by the US armed forces in Vietnam. The nature of the substances themselves is discussed in more detail in Chapter 6 of VAO (IOM, 1994). Four herbicides documented in military records were of particular concern and are examined 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 (dimenthylarsenic acid, DMA). This chapter also focuses on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin), a contaminant of 2,4,5-T, because its potential toxicity is of concern and because

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Veterans and Agent Orange: Update 2004 considerably more information is available on TCDD than is available for the herbicides. Except as noted, the laboratory studies of those compounds were done with pure formulations of the compounds. The epidemiologic studies discussed in later chapters often track exposures to mixtures. This chapter begins with a summary of major conclusions presented in past reports. The rest of the chapter consists mostly of overviews and discussions of the relevant experimental studies that have been published since Update 2002 (IOM, 2003) on 2,4-D; 2,4,5-T; picloram; cacodylic acid; and TCDD. Within the update for each substance is a review of the toxicokinetic investigations and a summary of the toxic endpoints and their underlying mechanisms of action. The process of estimating human health risk 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, Update 2000, and Update 2002 review the results of animal and in vitro studies published through 2002 that investigated the toxicokinetics, mechanisms of action, and disease outcomes of exposure to the herbicides, and the contaminant TCDD, used in Vietnam. The herbicides have not been studied extensively, but in general none of them is considered particularly toxic. High concentrations usually are required to modulate cellular and biochemical processes. In contrast, experimental data reviewed in previous Agent Orange reports led those committees to conclude that TCDD elicits a diverse spectrum of sex-, strain-, age-, and species-specific effects: 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 enzyme induction and other biochemical effects. TOXICITY PROFILE UPDATE OF 2,4-D Toxicokinetics Toxicokinetics (also called pharmacokinetics) identifies the routes and rates of uptake, tissue distribution, transformation, and elimination of a toxic substance. Those processes, in part, determine the amount of a particular substance that reaches target organs or cells to influence toxicity. Understanding the toxicokinetics of a compound is an important component for valid reconstruction of exposure.

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Veterans and Agent Orange: Update 2004 Several studies have examined the pharmacokinetics and metabolism of 2,4-D in animals and humans since the publication of Update 2002. Those data support the previous conclusions that metabolism and elimination of 2,4-D are relatively rapid and that tissue uptake is small. Van Ravenzwaay et al. (2003) compared the metabolism and elimination of 2,4-D in rats and in dogs to explain dogs’ greater sensitivity. Elimination of 2,4-D from rat plasma was significantly faster than in dogs after oral doses of 5 or 50 milligrams per kilogram (mg/kg) body weight. In the rat, excretion essentially was complete after 24 hours (h) for the low dose and after 48 h for the high dose. For the dog, only about half the dose was eliminated in 5 days. Thus, for an equivalent dosage, the body burden of 2,4-D is significantly higher in dogs, and that finding is consistent with the increased sensitivity of dogs to 2,4-D. Notably, an interspecies pharmacokinetic analysis by Timchalk (2004) suggested that the dog is not a relevant animal for comparative evaluation of human health risk attributable to 2,4-D exposure. The plasma half-life for 2,4-D in dogs (92–106 h) is substantially longer than in rats (~1 h) or in humans (~12 h) because dogs have less efficient renal clearance mechanisms. The result is a higher body burden in dogs for a substantially longer period than is exhibited by other species. A recent study examining concentrations of 2,4-D and its metabolites in the urine of herbicide applicators was consistent with 2,4-D urinary half-life estimates of 13–40 h for humans (Hines et al., 2003). Three studies reported that use of sunscreen and chronic consumption of alcohol could significantly increase dermal penetration of 2,4-D. Pont et al. (2004) determined that the total percentages of 2,4-D penetrating excised hairless mouse skin within a diffusion chamber in 24 h ranged from 55% for the no-sunscreen control to 87% in skin treated with sunscreen. All but one of the ingredients tested led to a significant increase in 2,4-D penetration. Penetration enhancement also occurred for human skin (Pont et al., 2004). Brand et al. (2002) observed that of nine sunscreen formulations tested, six led to significant increases in the dermal penetration of 2,4-D in hairless mice. In one case, the penetration was more than twice that of the control. The same laboratory investigated the dermal penetration of 2,4-D through the skin of rats fed either an ethanol-containing or a control diet for 6–8 weeks (Brand et al., 2004). Ethanol consumption more than doubled the rate of 2,4-D penetration. Those studies imply that people who regularly use sunscreens or consume ethanol could be at increased risk for internal exposure to and toxicity from 2,4-D. Durkin et al. (2004) describe the development of a physiologically based pharmacokinetic (PBPK) model to estimate risk to workers who use backpack pesticide sprayers. There was good correspondence between modeled and observed elimination rates of 2,4-D in rats and humans. Although it might underestimate variability because of a lack of consideration of interindividual differences in the kinetics of 2,4-D, with further refinement, the model could result in

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Veterans and Agent Orange: Update 2004 more accurate and complete assessments of risk to those who use backpack sprayers and to others who are exposed to 2,4-D. Chemically reactive metabolites of 2,4-D are believed to mediate the hepatotoxicity of 2,4-D observed in some animal species. Li et al. (2003) determined that 2,4-dichlorophenoxyacetyl-S-acyl-CoA, a metabolite of 2,4-D, binds covalently to human serum albumin and to proteins in rat hepatocytes after in vitro incubation. The authors suggested that the metabolite contributes to induced hepatotoxicity. Toxic Endpoints and Underlying Mechanisms of Toxic Action Studies of disease outcomes published since Update 2002 are consistent with the earlier conclusion that 2,4-D is relatively non-toxic and has weak carcinogenic potential. The developing fetus appears to be the most sensitive for several toxic endpoints after maternal exposure. Recent animal studies of disease outcomes of 2,4-D exposure and possible mechanisms are discussed below. Carcinogenicity and Mechanisms Related to Genotoxic Effects Previous updates indicated little experimental evidence that 2,4-D produces any carcinogenic activity. No relevant studies on its carcinogenic effects have been published since Update 2002. Studies reviewed in previous updates indicated that 2,4-D has no genotoxic potential, or that potential is weak, at best. Several more recent reports, however, suggest a weak but positive association between 2,4-D exposure and genotoxic potential in some biologic-model systems. Whereas no effects were observed with pure 2,4-D, in some cases commercial mixtures produced dose-related responses. In others, genotoxicity was observed only when there was evidence of cytotoxicity. Although overall the studies suggest only a weak genotoxicity for 2,4-D, they suggest that the constituents of commercial formulations (like Agent Orange) enhance the toxicity—and, specifically, the genotoxicity—of 2,4-D. Grabińska-Sota et al. (2002) tested a commercial formulation of 2,4-D in several strains of bacteria. Some genotoxicity was observed, but only at very high concentrations. The genotoxicity of 2,4-D in fish was evaluated by Ateeq et al. (2002), who assessed the induction of micronuclei and erythrocyte alterations in catfish exposed to 2,4-D at concentrations of as much as 75 parts per million (ppm) in water. The formation of micronuclei and cytotoxicity (vacuolization and echinocyte formation) was concentration dependent. Essentially the same results with similar exposures were observed in a freshwater air-breathing fish, Channa punctatus (Abul Farah et al., 2003). Arias (2003) evaluated the induction of sister chromatid exchange (SCE) and altered cell cycle kinetics in 4-day-old chick embryos

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Veterans and Agent Orange: Update 2004 exposed either to a commercial herbicide preparation containing 37% 2,4-D or to pure 2,4-D. Pure 2,4-D failed to induce a statistically significant change in SCE frequency, and the commercial product produced a change only at the highest dose. It was suggested that genotoxic effects observed with some 2,4-D preparations could be attributable to impurities or adjuvants in the technical-grade products. In these studies, both types of exposure inhibited the mitotic index, but only at the two highest doses (2 and 4 mg/embryo). Since the last update, two studies have examined the genotoxic effects of 2,4-D exposure in human lymphocytes. Zeljezic and Garaj-Vrhovac (2004) treated cultured lymphocytes with two concentrations (0.4 and 4.0 micrograms per milliliter [µg/mL]) of a commercial formulation of 2,4-D with and without a metabolic activator (rat liver microsomes; S9). The lower concentration of 2,4-D is the acceptable daily intake recommended by the World Health Organization (1–4 picogram/body weight). Both concentrations induced increases in chromatid and chromosome breaks, in the number of micronuclei, and in the number of nuclear buds. Metabolic activation increased the number of chromatid breaks and micronuclei. The investigators also suggested that the genotoxicity could be attributable to compounds other than 2,4-D within the formulation. A similar study (Holland et al., 2002) examined the effects of exposure to pure and commercial formulations of 2,4-D. Induction of micronuclei was observed in both whole blood and isolated lymphocytes only at a cytotoxic concentration (0.3 milli molar [mM]) of pure or commercial 2,4-D. The replicative index, a measure of cell division kinetics, was decreased at this cytotoxic level, but at a lower concentration (0.005 mM) showed a slight increase which was more pronounced for the commercial formulation. The commercial formulation contained 9.4% pure 2,4-D, which suggests that other ingredients might be responsible for or enhance the effect of 2,4-D on the replicative index. The authors concluded that the genotoxicity of 2,4-D as measured by the micronucleus assay is negligible at environmentally relevant concentrations, but that it might be enhanced in the presence of other chemicals. Neurotoxicity Previous updates indicated no evidence that 2,4-D causes effects on the neurologic system in adult animals at doses in the µg/kg/day range. Case reports of acute poisonings of humans exposed to large amounts of 2,4-D formulations (>20 mL) indicated neurologic manifestations of drowsiness, coma, hyperreflectivity, hypertonia, and cerebral edema (Brahmi et al., 2003). One case of ingestion of an unknown quantity of 2,4-D resulted in death. No other relevant studies involving neurotoxicity in adult humans have been published since Update 2002.

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Veterans and Agent Orange: Update 2004 Reproductive and Developmental Toxicity Stebbins-Boaz et al. (2004) examined the in vitro sensitivity of amphibian oocytes to 10 mM 2,4-D. Treatment caused depolymerization of perinuclear microtubules and altered cell morphology that was blocked with cotreatment with cytochalasin B, a microfilament inhibitor. 2,4-D treatment also blocked progesterone-induced maturation of the oocytes. Those data indicated that 2,4-D disrupts amphibian oocyte maturation through effects on cytoskeletal organization. Another study (Greenlee et al., 2004) examined the effects of 2,4-D on mouse preimplantation embryo development—a period that corresponds in humans to the first 5–7 days after conception. The 2,4-D exposure of embryos at 10 ng/mL in vitro increased the percentage of cellular apoptosis but had no effect on the development of the embryo to the blastocyst stage or on the mean cell number per embryo. Another group reported that exposure of pregnant mice to herbicide mixture containing low concentrations of 2,4-D (0.01 and 0.1 mg/kg/day), mecoprop (0.004 and 0.04 mg/kg/day), and dicamba (0.0009 and 0.009 mg/kg/day) resulted in significant reductions in implantation sites and live births (Cavieres et al., 2002), but no significant fetotoxicity was observed. Together, those data suggest that the preimplantation embryo might be especially sensitive to 2,4-D. Additional in vivo studies using 2,4-D exclusively are necessary. Sulik et al. (2002) examined kidney morphology of newborn rats exposed before and after birth to 2,4-D. Dams were exposed to a daily dose of 250 mg/kg (one-third the LD50, the dose that is lethal in 50% of test subjects) in drinking water for 2 months before fertilization and during pregnancy and lactation. Varying degrees of damage to kidney tubules were observed that were more intense after exposure in pregnancy than in the postnatal period. After withdrawal of 2,4-D, the more severe changes observed in the fetus regressed. Several studies cited in previous updates suggested effects of 2,4-D on the developing brain, and more recent studies present concordant results. Garcia et al. (2001) exposed pregnant rats to 70 mg 2,4-D/kg/day from gestation day 16 through postnatal day 23. Some of the pups were maintained on this exposure until postnatal day 90. Exposure during pregnancy and lactation produced an increased serotonin neuronal area and increased serotonin immunoreactivity in the mesencephalic nuclei. For pups exposed until postnatal day 90, only the serotonin neuronal area from the dorsal raphe nucleus was increased. Changes also were observed in the presence of reactive astrocytes in the mesencephalic nuclei and hippocampus areas; those changes differed with treatment. Those data provide evidence that 2,4-D exposure alters the serotoninergic system during brain development. Another study with the same design also sought to determine whether 2,4-D affected lateralization in the monoamine systems of the basal ganglia and whether there was any correlation with behavioral changes (Bortolozzi et al., 2003). Asymmetrical variations in brain concentrations of dopamine and serotonin were observed that were dependedent on brain region

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Veterans and Agent Orange: Update 2004 and sex. Some changes appeared to be irreversible, and serotonin changes in left and right striata appeared to correlate with the behavioral alterations (spontaneous circling activity) previously reported. Ferri et al. (2003) examined the effect of 2,4-D exposure on iron, zinc, and copper concentrations in the brain, serum, and liver of well-nourished and undernourished developing rats. Those metals are known to be essential for normal-brain development. Metal concentrations in tissues were found to be altered only at the highest dose (100 mg/kg) to the dam in well-nourished pups exposed through dams’ milk. A lower dose (70 mg/kg) produced no alterations. However, undernourished pups displayed greater sensitivity to the lower dose of 2,4-D, as indicated by altered metal concentrations and decreased tissue weight. Those data suggest that undernourishment might exacerbate the effects of 2,4-D on developing tissues. Immunotoxicity Previous updates indicated that 2,4-D has at most a weak effect on the immune system. Recent publications are consistent with this. One study reported a possible beneficial effect of exposure to low concentrations of 2,4-D (Balagué et al., 2002). Some studies suggest a relationship between the frequency of errors in antigen receptor gene assembly and an increased risk of lymphoid malignancy. That correlation has been reported for agricultural workers exposed to pesticides (Lipkowitz et al., 1992). Knapp et al. (2003) examined the effects of 2,4-D exposure to mice on the frequency of errors in V(D)J recombination (that is, recombination of the V-gamma and J-beta segments of the T-cell receptor) in thymocytes. At doses of 3–100 mg/kg/day for 4 days, no significant increase in aberrant V(D)J rearrangements was observed. Alterations to bone marrow B-cell populations after exposure of mice to single doses of 50–200 mg/kg were studied by de la Rosa et al. (2003). Decreases in the pre-B and IgM+ B-cell populations were observed 7 days after treatment for the highest dose of 2,4-D. Escherichia coli is responsible for many urinary tract infections in humans. Weak acids, such as salicylate, that interfere with interaction betweeen bacteria and epithelial cells are sometimes used to treat those infections. Balagué et al. (2002) reported that daily low doses (2.6 and 25 mg/kg) of 2,4-D (also a weak acid) for 20 days significantly decreased or eliminated bacterial cells in mouse bladder and kidneys. A higher dose (70 mg/kg) was not effective after 9 days of treatment. The authors suggested that low exposure to 2,4-D might have a protective effect against urinary tract infections. Several previous investigations (IOM, 2001, 2003) reported kidney toxicity for high 2,4-D concentrations in several animal species. More recent reports detail effects in fish (Gómez et al., 2002).

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Veterans and Agent Orange: Update 2004 Mechanisms Related to Effects on Energy Metabolism or Mitochondrial Function Several reports cited in previous updates suggested that the toxicity of relatively high concentrations of 2,4-D might be related, at least in part, to its effect on calcium homeostasis and energy metabolism. Those actions might be mediated by a direct action on mitochondria. Some publications suggest it might be attributable to the surfactant in the formulations and not to the 2,4-D itself. However, two recent studies are consistent with the hypothesis that 2,4-D itself causes mitochondrial damage. De Moliner et al. (2002) and Tuschl and Schwab (2003) reported that the exposure of rat cerebellar granule cells and human hepatoma cells, respectively, to 1–16 mM concentrations of 2,4-D elicited cell cycle alterations and apoptotic cell death. Their studies also suggested that the events were caused by a direct effect on mitochondrial membrane potential. Mechanism Related to Effects on Thyroid Hormones Effects of 2,4-D on serum concentrations of thyroid hormones, particularly to decreases in thyroxine, were noted in previous updates. Ishihara et al. (2003) examined the effects of industrial and agricultural chemicals on the binding of 3,5,3-L-triiodothronine (T3) to serum thyroid hormone binding proteins (THBPs) and thyroid hormone receptors (TRs). 2,4-D had little or no effect on the binding to THBPs from several species, including humans, or to TRs from chicken or bullfrog. Mechanisms Related to Effects of Cell Stress Responses Several investigations examined the ability of 2,4-D to promote or inhibit oxidative damage to cell membranes. Together they suggest that, at high concentrations, 2,4-D is incorporated into cellular membranes to modify membrane structure and integrity. Duchnowicz and Koter (2003) reported that exposure of isolated erythrocytes to 1 mM 2,4-D resulted in a small but significant increase in hemolysis and in membrane lipid peroxidation. Increased hemolysis was not observed at 0.1 mM (Kleszczyńska et al., 2003). This might be related to a noted concentration-dependent decrease in erythrocyte glutathione (Bukowska, 2003). However, concentrations of 0.5 and 1 mM 2,4-D were found to protect erythrocyte membranes against partial peroxidation induced by ultraviolet irradiation (Bonarska et al., 2003). Özcan Oruç et al. (2004) examined oxidative stress responses in the gills, brains, and kidneys of fish exposed to 2,4-D. Although no significant changes in tissue malondialdehyde, a measure of lipid peroxidation, were observed, there were significant changes in the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GST), and catalase. GST activity in the liver was

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Veterans and Agent Orange: Update 2004 increased at all times from 24–96 h after 2,4-D exposure; SOD activity was increased only at 72 and 96 h (Özcan Oruç and Üner, 2002). It was suggested that tissues adapt to protect cells against oxidative stress elicited by toxins such as 2,4-D. The authors also suggested that increases in tissue SOD and GST activity might serve as good biologic markers of oxidative stress. Orfila et al. (2002) reported that administration of the maximum recommended daily doses of vitamins E and C was ineffective for preventing or altering liver damage produced in rats orally dosed with 200 mg/kg 2,4-D amine daily for 15 days. 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 2002. Several previous reports indicated that 2,4,5-T has only weak mutagenic potential but that it might alter the profile of enzymes involved in the metabolism of procarcinogens. Previous reports concur that 2,4,5-T is only weakly toxic or carcinogenic. TOXICITY PROFILE UPDATE OF CACODYLIC ACID Toxicokinetics Cacodylic acid was present at 4.7% in a herbicide used for defoliation in Vietnam. Cacodylic acid is DMA, which also is a metabolic product of exposure to inorganic arsenic. Methylation of inorganic arsenic generally has been considered a detoxification process: it produces less acutely toxic methylated species (monomethyl arsenic (MMA) and DMA), and it increases excretion of arsenic. More recently, however, some of the methylated metabolic intermediates have been thought to be more toxic than is the parent compound. The methylation pathway of inorganic arsenic results in the formation of pentavalent DMA (DMAv) and trivalent DMA (DMAIII) (IOM, 2003). DMAv appears to be less toxic than DMAIII (IOM, 2003); about 80% of DMA is excreted unchanged and more rapidly than is inorganic arsenic (reviewed in Duzkale et al., 2003). DMAIII in fingernails and DMAv in fingernails and hair can serve as biologic markers of arsenic exposure (Mandal et al., 2003). Endpoints and Underlying Mechanisms of Toxic Action Since Update 2002, the only new literature concerning the toxic activity of cacodylic acid addressed genotoxicity, a major mechanism of carcinogenesis. In addition to being produced as an herbicide, cacodylic acid, or DMA, is a metabolic product of organic arsenic exposure in humans. The committee considered the relevance of data on inorganic arsenic to DMA. Although inorganic arsenic is

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Veterans and Agent Orange: Update 2004 a human carcinogen, there is no evidence that direct exposure to its metabolite, DMA, produces cancer in humans. DMA also is not demethylated to inorganic arsenic. It has not been established nor can it be inferred that the effects observed from exposure to inorganic arsenic also occur from exposure to DMA. Therefore, the literature on inorganic arsenic is not considered in this report. The reader is referred to Arsenic in Drinking Water (NRC, 1999a) and Arsenic in Drinking Water: 2001 Update (NRC, 2001). Cancer has been induced in the urinary bladder, kidneys, liver, thyroid glands, and lungs of laboratory animals exposed to high concentrations of DMA (IOM, 2003). DMA might act through induction of oxidative damage or damage to DNA, and exposure results in necrosis of the urinary bladder epithelium followed by regenerative hyperplasia (IOM, 2003). Since Update 2002, further studies have investigated the potential carcinogenicity of DMA itself. In a 2-year bioassay, F344 rats were administered drinking water that contained 0, 12.5, 50, or 200 ppm DMA for 104 weeks (Wei et al., 2002). Between weeks 97 and 104, urinary bladder tumors were observed in 8 of 31 rats treated with 50 ppm DMA and in 12 of 31 rats administered 200 ppm DMA. No urinary bladder neoplasms were observed in the groups given 0 or 12.5 ppm DMA. The urinary bladder tumors had a low rate of H-ras mutations, but no alterations of the p53, K-ras, or B-catenin genes were reported. In another study, F344 rats were exposed to 100 ppm DMA for 2 weeks. DMA produced cytotoxicity and regenerative hyperplasia of the urothelium of the urinary bladder (Cohen et al., 2002). Salim et al. (2003) administered DMA in drinking water (0, 50, or 200 ppm for 18 months) to P53 heterozygous (+/-) knockout mice and wild-type (+/+) C57BL/6J mice. Treatment resulted in a significant increase in total numbers of tumors (at the 50- and 200-ppm doses) in the wild-type mice and significant earlier induction of tumors in more organs and tissues of both the p53 +/- knockout (50 and 200 ppm) and the wild-type mice (50 and 200 ppm). The lack of organ specificity or mutations in the residual allele or in wild-type alleles in both genotypes suggests that DMA is a non-genotoxic carcinogen. In an initiation–promotion experiment, carcinogenesis in F344 rats was initiated with a single injection (200 mg/kg) of diethylnitrosamine and promoted with 100 ppm DMA (Nishikawa et al., 2002). DMA treatment resulted in a significant increase in numbers and areas of GST-P positive foci (preneoplastic lesions) in the liver. Duzkale et al. (2003) found that DMA exerted differential antiproliferation and cytotoxic activity against leukemia and multiple myeloma cells, but not against normal peripheral blood progenitor cells, and induced apoptosis in the malignant cells. However, the concentrations of DMA necessary to achieve those effects were 500–1,000 times those required when arsenic trioxide was used. Other researchers have observed increased apoptosis in cell cultures exposed to DMA and noted that DMA requires intracellular reduced glutathione to induce apoptosis (Sakurai, 2003; Sakurai T et al., 2002).

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Veterans and Agent Orange: Update 2004 DNA strand breaks, a form of oxidative damage, were generated by DMA in cultured human cells and in isolated bacterial DNA (Schwerdtle et al., 2003). DMA also was cytotoxic to cultured Chinese hamster V79 cells and caused chromosome structural aberrations (Ochi et al., 2003). Nesnow et al. (2002) showed that the DNA-damaging activity of DMA is an indirect genotoxic effect mediated by reactive oxygen species formed concomitantly with the oxidation of DMAIII to DMAv. Induction of the tumor suppressor protein p53, another indicator of DNA damage, was produced by DMA in cultured human cells in a dose- and time-dependent manner (Filippova and Duerksen-Hughes, 2003). DMA also has induced chromosome aberrations in Chinese hamster ovary cells and in the SCE assay (Kochhar et al., 2003). However, DMA cultured with primary rat astroglia cells did not produce changes in cell viability or cause DNA damage at micromolar concentrations; treatment of the astroglia cells with inorganic arsenicals resulted in decreased cell viability and increased DNA damage (Jin et al., 2004). DMA was a clastogen in human lymphocytes and a mutagen at the Tk+/-locus in mouse lymphoma cells (Kligerman et al., 2003). Those authors did not consider DMA to be a gene mutagen. Coexposure of human liver ferritin and DMA resulted in more DNA damage (Plasmid pBR322) than did exposure to DMA alone (Ahmad et al., 2002). The authors proposed that iron-dependent DNA damage could be a mechanism of action of human arsenic carcinogenesis. Cacodylic acid, at doses on the order of 200 ppm, has been shown to act as a tumor promoter in the kidneys and urinary bladders of laboratory animals (IOM, 2003). TOXICITY PROFILE UPDATE OF PICLORAM The compounds 4-amino-3,5,6-trichloropicolinic acid (picloram) and 2,4-dichlorophenoxyacetic acid (2,4-D) are components of Agent White, an herbicide formulation used in Vietnam. Studies reviewed in previous updates and in VAO reported fairly rapid elimination of picloram and suggest that some carcinogenic and neurologic effects can be attributed to exposure, although only at extremely high doses. Some cellular abnormalities in liver and inconsistent developmental effects also have been reported, and there is some evidence that picloram causes male-mediated birth defects including persistent histologic effects in testes, in animals (IOM, 2003). However, blood concentrations of either agent associated with a dose that is high enough to elicit such effects were not likely to occur in occupational exposure to Agent White. No relevant studies of picloram have been published since the preparation of Update 2002.

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Veterans and Agent Orange: Update 2004 Michalek JE, Tripathi RC. 1999. Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 15-year follow-up. Journal of Toxicology and Environmental Health, Part A 57(6):369–378. Michalek JE, Pirkle JL, Needham LL, Patterson DG Jr, Caudill SP, Tripathi RC, Mocarelli P. 2002. Pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso adults and veterans of Operation Ranch Hand. Journal of Exposure Analysis and Environmental Epidemiology 12(1):44–53. Michalek JE, Ketchum NS, Tripathi RC. 2003. Diabetes mellitus and 2,3,7,8-tetrachlorodibenzo-p-dioxin elimination in veterans of Operation Ranch Hand. Journal of Toxicology and Environmental Health, Part A 66:211–221. Miettinen HM, Alauluusua S, Tuomisto J, Viluksela M. 2002. Effect of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on rat molar development: the role of exposure time. Toxicology and Applied Pharmacology 184:57–66. Miettinen HM, Huuskonen H, Partanen AM, Miettinen P, Tuomisto JT, Pohjanvirta R, Tuomisto J. 2004. Effects of epidermal growth factor receptor deficiency and 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal development in mice. Toxicology Letters 150(3):285–291. Minegishi T, Hirakawa T, Abe K, Kishi H, Miyamoto K. 2003. Effect of IGF-1 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the expression of LH receptors during cell differentiation in cultured granulosa cells. Molecular and Cellular Endocrinology 202(1-2):123–131. Miniero R, De Felip E, Ferri F, di Domenico A. 2001. An overview of TCDD half-life and its correlation to body weight. Chemosphere 43(4-7):839–844. Minsavage GD, Vorojeikina DP, Gasiewicz TA. 2003. Mutational analysis of the mouse aryl hydrocarbon receptor tyrosine residues necessary for recognition of dioxin response elements. Archives of Biochemistry and Biophysics 412(1):95–105. Mizuyachi K, Son DS, Rozman KK, Terranova PF. 2002. Alteration in ovarian gene expression in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin: reduction of cyclooxygenase-2 in the blockage of ovulation. Reproductive Toxicology 16(3):299–307. Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C, Poellinger L, Schwarz M. 2004. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Research 64:4707–4710. Moran FM, Lohstroh P, VandeVoort CA, Chen J, Overstreet JW, Conley AJ, Lasley BL. 2003a. Exogenous steroid substrate modifies the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on estradiol production of human luteinized granulosa cells in vitro. Biology of Reproduction 68(1):244–251. Moran FM, VandeVoort CA, Overstreet JW, Lasley BL, Conley AJ. 2003b. Molecular target of endocrine disruption in human luteinizing granulosa cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin: inhibition of estradiol secretion due to decreased 17alpha-hydroxylase/17,20-lyase cytochrome P450 expression. Endocrinology 144(2):467–473. Moran FM, Hendrickx AG, Shideler S, Overstreet JW, Watkins SM, Lasley BL. 2004. Effects of 2,3,7,8-tetrachlorodizenzo-p-dioxin (TCDD) on fatty acid availability and neural tube formation in cynomolgus macaque, Macaca fascicularis. Birth Defects Research, Part B 71:37–46. Moriguchi T, Motohashi H, Hosoya T, Nakajima O, Takahashi S, Ohsako S, Aoki Y, Nishimura N, Tohyama C, Fujii-Kuriyama Y, Yamamoto M. 2003. Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse. Proceedings of the National Academy of Sciences of the United States of America 100(10):5652–5657. Morita K, Tobiishi K. 2002. Increasing effect of nori on the fecal excretion of dioxin by rats. Bioscience, Biotechnology, Biochemistry 66(11):2306–2313. Morrow D, Qin C, Smith R, Safe S. 2004. Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell growth and hormone-induced transactivation. Journal of Steroid Biochemistry and Molecular Biology 88(1):27–36.

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