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 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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Veterans and Agent Orange: Update 2002 Latchoumycandane C, Chitra KC, Mathur PP. 2002b. The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antioxidant system in mitochondrial and microsomal fractions of rat testis. Toxicology 171:127–135. Lawrence BP, Warren TK, Luong G. 2000. Fewer T lymphocytes and decreased pulmonary influenza virus burden in mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Journal of Toxicology and Environmental Health 61:39–53. Lee JE, Safe S. 2001. Involvement of a post-transcriptional mechanism in the inhibition of CYP1A1 expression by resveratrol in breast cancer cells. Biochemical Pharmacology 62:1113–1124. Lee K, Johnson VJ, Blakley BR. 2001. The effect of exposure to a commercial 2,4-D formulation during gestation on the immune response in CD-1 mice. Toxicology 165:39–49. Lee K, Johnson VJ, Blakley BR. 2000. The effect of exposure to a commerical 2,4-D herbicide formulation during gestation on urethan-induced lung adenoma formation in CD-1 mice. Veterinary and Human Toxicology 42(3):129–132. Legare ME, Hanneman WH, Barhouni R, Burghardt RC, Tiffany-Castiglioni E. 2000. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters hippocampal astroglia-neuronal gap junction communication NeuroToxicology 21:1109–1116. Levine SL, Petrulis JR, Dubil A, Perdew GH. 2000. A tetratricopeptide repeat half-site in the aryl hydrocarbon receptor is important for DNA binding and trans-activation potential. Molecular Pharmacology 58:1517–1524. Lewis BC, Hudgins S, Lewis A, Schorr K, Sommer R, Peterson RE, Flaws JA, Furth PA. 2001. In utero and lactational treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs mammary gland differentiation but does not block the response to exogenous estrogen in the postpubertal female rat Toxicological Sciences 62:46–53. Lin T-M, Ko K, Moore, RW, Buchanan DL, Cooke PS, Peterson RE. 2001. Role of the aryl hydrocarbon receptor in the development of control and 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed male mice. Journal of Toxicology and Environmental Health, Part A 64:327–342. Lin T-M, Ko K, Moore RW, Simanainen U, Oberly TD, Peterson RE. 2002. Effects of aryl hydrocarbon receptor null mutation and in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on prostate and seminal vesicle development in C57BL/6 mice. Toxicological Sciences 68:479–487. Liu PCC, Moreno-Aliaga MJ, Dunlap DY, Hu XM, Denison MS, Matsumura F. 2002. Correlation between the high expression of C/EBPb protein in F442A cells and their relative resistance to antiadipogenic action of TCDD in comparison to 3T3-L1 cells. Journal of Biochemical and Molecular Toxicology 16:70–83. Loertscher JA, Sadek CS, Allen-Hoffmann BL. 2001a. Treatment of normal human keratinocytes with 2,3,7,8-tetrachlorodibenzo-p-dioxin causes a reduction in cell number, but no increase in apoptosis Toxicology and Applied Pharmacology 175:114–120. Loertscher JA, Sattler CA, Allen-Hoffmann BL. 2001b. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters the differentiation pattern of human keratinocytes in organotypic culture. Toxicology and Applied Pharmacology 175:121–129. Luebke RW, Copeland CB, Daniels M, Lambert AL, Gilmour MI. 2001 Suppression of allergic immune responses to house dust mite (HDM) in rats exposed to 2,3,7,8-TCDD. Toxicolological Sciences 62:71–79. Lukinmaa PL. Sahlberg C, Leppäniemi A, Partanen AM, Kovero O, Pohjanvirta R, Tuomisto J, Alaluusua S. 2001. Arrest of rat molar tooth development by lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin 173:38–47. Ma Q, Baldwin KT. 2000. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced degradation of aryl hydrocarbon receptor (AhR) by the ubiquitin-proteasome pathway. The Journal of Biological Chemistry. 275:8432–8438. Ma Q, Baldwin KT, Renzelli AJ, McDaniel A, Dong L. 2001. TCDD-inducible poly (ADP-ribose) polymerase: a novel response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochemical and Biophysical Research Communications 289:499–506.

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Veterans and Agent Orange: Update 2002 Mace K, Bowman ED, Vautravers P, Shields PG, Harris CC, Pfeifer AMA. 1998. Characterization of xenobiotic metabolizing enzyme expression in human bronchial mucosa and peripheral lung tissues. European Journal of Cancer 34:914–920. Machala M, Vondracek J, Blaha L, Ciganek M, Neca J. 2001. Aryl hydrocarbon receptor-mediated activity of mutagenic polycyclic aromatic hydrocarbons determined using in vitro reporter gene assay Mutation Research 497:49–62. Maier A, Dalton TP, Puga A. 2000. Disruption of dioxin-inducible phase I and phase II gene expression patterns by cadmium, chromium, and arsenic. Molecular Carcinogenesis 28:225–235. Mandal PK, McDaniel LR, Prough RA, Clark BJ. 2001. 7,12-dimethylbenz[a]anthracene inhibition of steroid production in MA-10 mouse Leydig tumor cells is not directly linked to induction of CYP1B1. Toxicology and Applied Pharmacology 175:200–208. Manz A, Papke O, Baur X. 2001. Transfer at home of 2,3,7,8-tetrachlorodibenzo-p-dioxin and β-hexachlorocyclohexane. Gesundheitswesen 63:398–403. Markowski VP, Zareba G, Stern S, Cox, C, Weiss B. 2001. Altered operant responding for motor reinforcement and the determination of benchmark doses following perinatal exposure to lowlevel 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Health Perspectives 109:621–627. Markowski VP, Cox C, Preston R, Weiss B. 2002. Impaired cued delayed alteration behavior in adult rat offspring following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on gestation day 15. Neurotoxicology and Teratology 24:209–218. Mass MJ, Tennant A, Roop BC, Cullen WR, Styblo M, Thomas DJ, Kligerman AD. 2001. Methylated trivalent arsenic species are genotoxic. Chemical Research in Toxicology 14:355–361. Masten SA, Shiverick KT. 1995. The Ah receptor recognizes DNA binding sites for the B cell transcription factor, BSAP: A possible mechanism for dioxin-mediated alteration of CD19 gene expression in human B lymphocytes. Biochemical and Biophysical Research Communications 212:27–34. Mathieu M-C, Lapierre I, Brault K, Raymond, M. 2001. Aromatic hydrocarbon receptor (AhR)-AhR nuclear translocator- and p53-mediated induction of the murine multidrug resistance mdr1 gene by 3-methylcholanthrene and benzo(a)pyrene in hepatoma cells. The Journal of Biological Chemistry 276:4819–4827. Matikainen TM, Moriyama T, Morita Y, Perez GI, Korsmeyer SJ, Sherr DH, Tilly JL. 2002. Ligand activation of the aromatic hydrocarbon receptor transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells. Endocrinology 143:615–620. Matthews M, Heimler I, Fahy M, Radwanska E, Hutz R, Trewin A, Rawlins R. 2001. Effects of dioxin, an environmental pollutant, on mouse blastocyst development and apoptosis. Fertility and Sterility 75:1159–1162. McNulty WP. 1985. Toxicity and fetotoxicity of TCDD, TCDF and PCB isomers in rhesus macaques (Macaca mulatta). Environmental Health Perspectives 60:77–88. Mhin BJ, Lee JE, Choi W. 2002. Understanding the congener-specific toxicity in polychlorinated dibenzo-p-dioxins: Chlorination pattern and molecular quadrupole moment. Journal of the American Chemical Society 124:144–148. 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 12:44– 53. Miniero R, De Felip E, Ferri F, di Domenico A. 2001. An overview of TCDD half-life and its correlation to body weight. Chemosphere 43:839–844. Moran FM, Chen TJ, Santos S, Cheney A, Overstreet JW, Lasley BL. 2001. Effect of dioxin on ovarian function in the cynomogus macaque (M. fascicularis). Reproductive Toxicology 15: 377–383. Morita K, Nakano T. 2002. Seaweed accelerates the excretion of dioxin stored in rats. Journal of Agricultural and Food Chemistry 50:910–917.

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Veterans and Agent Orange: Update 2002 Morita, K, Ogata M, Hasegawa T. 2001. Chlorophyll derived from Chlorella inhibits dioxin absorption from the gastrointestinal tract and accelerates dioxin excretion in rats Environmental Health Perspectives 109:289–294. Muller GF, Dohr O, El-Bahay C, Kahl R, Abel J. 2000. Effect of transforming growth factor-beta1 on cytochrome P450 expression inhibition of CYP1 mRNA and protein expression in primary rat hepatocytes Archives of Toxicology 74:145–152. Murante FG, Gasiewicz TA. 2000. Hemopoietic progenitor cells are sensitive targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J mice. Toxicological Sciences 54:374–383. Nagashima H, Matsumura F. 2002. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induced downregulation of glucose transporting activities in mouse 3T3-L1 preadipocyte. Journal of Environmental Science and Health B37:1–14. Nayyar T, Zawia NH, Hood DB. 2002. Transplacental effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the temporal modulation of Sp1 DNA binding in the developing cerebral cortex and cerebellum. Experimental Toxicologic Pathology 53:461–468. Nazarenko DA, Dertinger SD, Gasiewicz TA. 2001. In vivo antagonism of AhR-mediated gene induction by 3'-methoxy-4'-nitroflavone in TCDD-responsive lacZ mice. Toxicological Sciences 61:256–264. Nebert DW, Roe AL, Dieter MZ, Solis WA, Yang Y, Dalton TP. 2000. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis Biochemical Pharmacology 59:65–85. Needham LL, Gerthoux PM, Patterson DG Jr, Brambilla P, Pirkle JL, Tramacere PL, Turner WE, Beretha C, Sampson EJ, Mocarelli P. 1994. Half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in serum of Seveso adults. Interim report. Organohalogen Compounds 21:81–85. Neubert D, Wiesmuller T, Abraham K, Krowke R, Hagenmaier H. 1990. Persistence of various polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) in hepatic and adipose tissue of marmoset monkeys. Archives of Toxicology 64:431–442. Nie M, Blankenship AL, Giesy JP. 2001. Interactions between aryl hydrocarbon receptor (AhR) and hypoxia signaling pathways. Environmental Toxicology and Pharmacology 10:17–27. Nilsson CB, Hoegberg P, Trossvik C, Azais-Braesco V, Blaner WS, Fex G, Harrison EH, Nau H, Schmidt CK, van Bennekum AM, Hakansson H. 2000. 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases in serum and kidney retinoic acid levels and kidney retinal esterification in the rat. Toxicology and Applied Pharmacology 169:121–131. Nishimura N, Miyabara Y, Suzuki JS, Sato M, Aoki Y, Satoh M, Yonemoto J, Tohyama C. 2001. Induction of metallothionein in the livers of female Sprague Dawley rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Life Sciences 69:1291–1303. Noda Y, Suzuki T, Kohara A, Hasegawa A Yotsuyanagi T, Hayashi M, Sofuni T, Yamanaka K, Okada S. 2002. In vivo genotoxicity evaluation of dimethylarsinic acid in Muta TM Mouse. Mutation Research 513:205–212. Nohara K, Fujimaki H, Tsukumo S, Ushio H, Miyabara Y, Kijima M, Tohyama C, Yonemoto J. 2000. The effects of perinatal exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin on immune organs in rats. Toxicology 154:123–133. Nohara K, Fujimaki H, Tsukumo S-I, Inouye K, Sone H, Tohyama C. 2002a. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on T cell-derived cytokine production in ovalbumin (OVA)-immunized C57Bl/6 mice. Toxicology 172:49–58. Nohara K, Izumi H, Tamura SI, Nagata R, Tohyama C. 2002b. Effect of low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on influenza A virus-induced mortality in mice. Toxicology 170:131–138. NRC (National Research Council). 1999. Arsenic in Drinking Water. Washington, DC: National Academy Press. NRC. 2001. Arsenic in Drinking Water: Update 2001. Washington, DC: National Academy Press.

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Veterans and Agent Orange: Update 2002 Nukaya M, Takahashi Y, Gonzalez FJ, Kamataki T. 2001. Aryl hydrocarbon receptor-mediated suppression of expression of the low-molecular weight prekininogen gene in mice. Biochemical and Biophysical Research Communications 287:301–304. Oakes DJ, Pollak JK. 2000. The in vitro evaluation of the toxicities of three related herbicide formulations containing ester derivatives of 2,4,5-T and 2,4-D using sub-mitochondrial particles. Toxicology 151:1–9. Oakes DJ, Webster WS, Brown-Woodman PDC, Ritchie HE. 2002a. A study of the potential for a herbicide formulation containing 2,4-D and picloram to cause male-mediated developmental toxicity in rats Toxicological Sciences 68:200–206. Oakes DJ, Webster WS, Brown-Woodman PD, Ritchie HE. 2002b. Testicular changes induced by chronic exposure to the herbicide formulation, Tordon 75D (2,4-dichlorophenoxyacetic acid and picloram) in rats Reproductive Toxicology 16:281–289. Ogi T, Mimura J, Hikida M, Fujimoto H, Fujii-Kuriyama Y, Ohmori H. 2001. Expression of human and mouse genes encoding polkappa: testis-specific developmental regulation and AhR-dependent inducible transcription Cells to Genes 6:943–953. Ohbayashi T, Oikawa K, Iwata R, Kamea A, Evine K, Isobe T, Matsuda Y, Mimura J, Fujii-Kuriyama Y, Kuroda M, Mukai K. 2001. Dioxin induces a novel nuclear factor, DIF-3, that is implicated in spermatogenesis. FEBS Letters 508:341–344. Ohsako S, Miyahara Y, Nishimura N, Kurosawa S, Sakaue M, Ishimura R, Sato M, Takeda K, Aoki Y, Sone H, Tohyama C, Yonemoto J. 2001. Maternal exposure to a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed the development of reproductive organs of male rats: Dose dependent increase of mRNA levels of 5alpha-reductase type 2 in contrast to decrease of androgen receptor in the pubertal ventral prostate. Toxicological Sciences 60:132– 143. Ohsako S, Miyabara Y, Sakaue M, Ishimura R, Kakeyame M, Izumi H, Yonemoto J, Tohyama C. 2002. Developmental stage-specific effects of perinatal 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on reproductive organs of male rat offspring. Toxicological Sciences 66:283–292. Oikawa K, Ohbayashi T, Mimura J, Fujii-Kuriyama Y, Teshima S, Rokutan K, Mukai K, Kuroda M. 2002. Dioxin stimulates synthesis and secretion of IgE-dependent histamine-releasing factor. Biochemical and Biophysical Research Communications 290:984–987. Ozaki K, Mahler JF, Haseman JK, Moomaw CR, Nicolette ML, Nyska A. 2001. Unique renal tubule changes induced in rats and mice by the peroxisome proliferators 2,4-dichlorophenoxy acetic acid (2,4-D) and WY-14643 Toxicologic Pathology 29(4):440–450. Oztas H. 2000. Effects of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) on the early stages of pancreatic carcinogenesis induced by azaserine in the rat pancreas. Turkish Journal of Medical Sciences 30:29–34. Park J-H, Lee S-W. 2002. Up-regulated expression of genes encoding Hrk and IL-3R beta subunit by TCDD in vivo and in vitro. Toxicology Letters 129:1–11. Park S, Henry EC, Gasiewicz TA. 2000. Regulation of DNA binding activity of the ligand-activated aryl hydrocarbon receptor by tyrosine phosphorylation. Archives of Biochemistry and Biophysics 381:302–312. Partridge NC, Fiacco GJ, Walling HW, Barmina OY, Jeffrey JJ, Ruh MF. 2000. Effects of dioxin and estrogen on collagenase-3 in UMR 106-01 osteocarcoma cells. Archives of Biochemistry and Biophysics 382:182–188. Petersen SL, Curran MA, Marconi SA, Carpenter CD, Lubbers LS, McAbee MD. 2000. Distribution of mRNAs encoding the arylhydrocarbon receptor, arylhydrocarbon receptor nuclear translocator, and arylhydrocarbon receptor nuclear translocator-2 in the rat brain and brainstem. The Journal of Comparative Neurology 427:428–439. Petroff BK, Gao X, Rozman KK, Terranova PF. 2000. Interaction of estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in an ovulation model: evidence for systemic potentiation and local ovarian effects. Reproductive Toxicology 14:247–255.

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Veterans and Agent Orange: Update 2002 Petroff BK, Roby KF, Gao X, Son D-S, Williams S, Johnson D, Rozman KK, Terranova PF. 2001. A review of mechanisms controlling ovulation with implications for the anovulatory effects of polychlorinated dibenzo-p-dioxins in rodents. Toxicology 158:91–107. Petroff BK, Gao X, Ohshima K-I, Shi FX, Son D-S, Roby KF, Rozman KK, Watanabe G, Taya K, Terranova PF. 2002. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on serum inhibin concentrations and inhibin immunostaining during follicular development in female Sprague-Dawley rats. Reproductive Toxicology 16:97–105. Petrulis JR, Bunce NJ. 2000. Competitive behavior in the interactive toxicology of halogenated aromatic compounds. Journal of Biochemical and Molecular Toxicology 14:73–81. Petrulis JR, Hord NG, Perdew GH. 2000. Subcellular localization of the aryl hydrocarbon receptor is modulated by the immunophilin homolog hepatitis B virus X-associated protein 2. The Journal of Biological Chemistry 275:37448–37453. Pieklo Z, Grochowalski A, Gregoraszczuk EL. 2000. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters follicular steroidogenesis in a time- and cell-specific manner. Experimental and Clinical Endocrinology and Diabetes 108:299–304. Pilat-Marcinkiewicz B, Sulik M, Szynaka B, Jablonska E, Andrzejewicz A. 2000. Fetotoxic action of 2,4-dichlorophenolyacetic acid (2,4-D). II. Ultrastructural changes in rat hepatocytes. Acta Poloniae Toxicologica 8:71–79. Pimental RA, Liang B, Yee GK, Wilhelmsson A, Poellinger L, Paulson KE. 1993. Dioxin receptor and C/EBP regulate the function of the glutathione S-transferase Ya gene xenobiotic response element. Molecular and Cellular Biology 13:4365–4373. Pirkle JL, Wolfe WH, Patterson DG, Needham LL, Michalek JE, Miner JC, Peterson MR, Phillips DL. 1989. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand. Journal of Toxicology and Environmental Health 27(2):165–171. Pitt JA, Buckalew AR, House DE, Abbott BD. 2000. Adrenocorticotropin (ACTH) and corticosterone secretion by perfused pituitary and adrenal glands from rodents exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicology 151:25–35. Pitt JA, Feng L, Abbott BD, Schmid J, Batt RE, Costich TG, Koury ST, Bofinger DP. 2001. Expression of AhR and ARNT mRNA in cultured human endometrial explants exposed to TCDD. Toxicological Sciences 62:289–298. Pohjanvirta R, Vartiainen T, Uusi-Rauva A, Monkkonen J, Tuomisto J. 1990. Tissue distribution, metabolism, and excretion of 14C-TCDD in a TCDD-susceptible and a TCDD-resistant rat strain. Pharmacology and Toxicology 66:93–100. Pohjanvirta R, Korkalainen M, McGuire J, Simanainen U, Juvonen R, Tuomisto JT, Unkila M, Viluksela M, Bergman J, Poellinger L, Tuomisto J. 2002. Comparison of acute toxicities of indolo[3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive rats. Food and Chemical Toxicology 40:1023–1032. Poland A, Glover E. 1973. Chlorinated dibenzo-p-dioxins: potent inducers of δ-aminolevulinic acid synthetase and aryl hydrocarbon hydroxylase. II. Study of the struture-activity relationship. Molecular Pharmacology 9:736–747. Poland A, Knutson JC. 1982. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annual Review of Pharmacology and Toxicology 22:517–554. Pollenz RS, Barbour ER. 2000. Analysis of the complex relationship between nuclear export and aryl hydrocarbon receptor-mediated gene regulation. Molecular and Cellular Biology 20:6095–6104. Pollenz RS, Necela B, Marks-Sojka K. 2002. Analysis of rainbow trout Ah receptor isoforms in cell culture reveals conservation of function of Ah receptor-mediated signal transduction Biochemical Pharmacology 64:49–60. Porter W, Wang F, Duan R, Qin C, Castro-Rivera E, Kim K, Safe S. 2001. Transcriptional activation of heat shock protein 27 gene expression by 17β-estradiol and modulation by antiestrogens and aryl hydrocarbon receptor agonists. Journal of Molecular Endocrinology 26:31–42. Puga A, Nebert DW, Carrier F. 1992. Dioxin induces expression of c-fos and c-jun proto-oncogenes and a large increase in transcription factor AP-1. DNA Cell Biology 11:269–281.

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Veterans and Agent Orange: Update 2002 Puga A, Maier A, Medvedovic M. 2000a. The transcriptional signature of dioxin in human hepatoma HepG2 cells Biochemical Pharmacology 60:1129–1142. Puga A, Barnes SJ, Chang C-y, Zhu H, Nephew KP, Khan SA, Shertzer HG. 2000b. Activation of transcription factors activator protein-1 and nuclear factor-κB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochemical Pharmacology 59:997–1005. Quadri SA, Qadri AN, Hahn ME, Mann KK, Sherr DH. 2000. The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis Molecular Pharmacology 58:515–525. Ramakrishna G, Perella C, Birely L, Diwan BA, Fornwald LW, Anderson LM. 2002. Decrease in K-ras p21 and increase in Raf1 and activated Erk 1 and 2 in murine lung tumors initiated by N-nitrosodimethylamine and promoted by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 179:21–34. Render JA, Hochstein JR, Aulerich RJ, Bursian SJ. 2000. Proliferation of periodontal squamous epithelium in mink fed 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Veterinary and Human Toxicology 42:85–86. Render JA, Bursian SJ, Rosenstein DS, Aulerich FJ. 2001. Squamous epithelial proliferation in the jaws of mink fed diets containing 3,3',4,4',5-pentachlorobiphenyl (PCB 126) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Veterinary and Human Toxicology 43:22–26. Richter CA, Tillitt DE, Hannink M. 2001. Regulation of subcellular localization of the aryl hydrocarbon receptor (AhR). Archives of Biochemistry and Biophysics 389:207–217. Riecke K, Grimm D, Shakibaei M, Kossmehl P, Schulze-Tanzil G, Paul M, Stahlmann R. 2002. Low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin increase transforming growth factor β and cause myocardial fibrosis in marmosets (Callithrix jacchus). Archives of Toxicology 76:360–366. Rier SE, Coe CL, Lemieux AM, Martin DC, Morris R, Lucier GW, Clark GC. 2001a. Increased tumor necrosis factor-α production by peripheral blood leukocytes from TCDD-exposed Rhesus monkeys. Toxicological Sciences 60:327–337. Rier SE, Turner WE, Martin DC, Morris R, Lucier GW, Clark GC. 2001b. Serum levels of TCDD and dioxin-like chemicals in Rhesus monkeys chronically exposed to dioxin: correlation of increased serum PCB levels with endometriosis. Toxicological Sciences 59:147–159. Rivera SP, Saarikoski ST, Hankinson O. 2002. Identification of a novel dioxin-inducible cytochrome P450. Molecular Pharmacology 61:255–259. Roberts EA, Harper PA, Wong JMY, Wang Y, Yang S. 2000. Failure of Ah receptor to mediate induction of cytochromes P450 in the CYP1 family in the human hepatoma line SK-Hep-1. Archives of Biochemistry and Biophysics 384:190–198. Robinson SW, Clothier B, Akhtar RA, Yang AL, Latour I, Van Ijperen C, Festing MFW, Smith AG. 2002. Non-Ahr gene susceptibility loci for porphyria and liver injury induced by the interaction of “dioxin” with iron overload in mice. Molecular Pharmacology 61:674–681. Roby KF. 2001. Alterations in follicle development, steroidogenesis, and gonadotropin receptor binding in a model of ovulatory blockade. Endocrinology 142:2328–2335. Rogan W, Gladen B, Hung K, Koong S, Shih L, Taylor J, Wu Y, Yang D, Ragan N, Hsu C. 1988. Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 241:334-336. Rogers JM, Denison MS. 2002. Analysis of the antiestrogen activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in human ovarian carcinoma BG-1 cells. Molecular Pharmacology 61:1393–1403. Rosso SB, Garcia GB, Madariaga MJ, de Duffard AME, Duffard RO. 2000. 2,4-Dichlorophenoxyacetic acid in developing rats alters behavior, myelination and regions in brain gangliosides pattern. Neurotoxicology 21(1–2):155–164. Roth W, Voorman R, Aust SD. 1988. Activity of thyroid hormone-inducible enzymes following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 92:65–74. Rushing SR, Denison MS. 2002. The silencing mediator of retinoic acid and thyroid hormone receptors can interact with the aryl hydrocarbon (Ah) receptor but fails to repress Ah receptordependent gene expression. Archives of Biochemistry and Biophysics 403:189–201.

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Veterans and Agent Orange: Update 2002 Sahlberg C, Pohjanvirta R, Gao Y, Aluluusua S, Tuomisto J, Lukinmaa P-L. 2002. Expression of the mediators of dioxin toxicity, aryl hydrocarbon receptor (AhR) and the AhR nuclear translocator (ARNT) is developmentally regulated in mouse teeth. International Journal of Developmental Biology 46:295–300. Salvan A, Thomaseth K, Bortot P, Sartori N. 2001. Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). Science of the Total Environment 274:21–35. Santiago-Josefat B, Pozo-Guisado E, Mulero-Navarro S, Fernandez-Salguero PM. 2001. Proteasome inhibition induces nuclear translocation and transcriptional activation of the dioxin receptor in mouse embryo primary fibroblasts in the absence of xenobiotics. Molecular and Cellular Biology 21:1700–1709. Santini RP, Myrand S, Elferink C, Reiners JJ Jr. 2001. Regulation of CYP1A1 induction by dioxin as a function of cell cycle Journal of Pharmacology and Experimental Therapeutics 299:718–728. Savouret JF, Antenos M, Quesne M, Xu J, Milgrom E, Casper RF. 2001. 7-Ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor. The Journal of Biological Chemistry 276(5):3054–3059. Schaufler K, Haslmayer P, Jager W, Pec M, Thalhammer T. 2002. The environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin induces cytochrome P450 activity in high passage PC 3 and DU 145 human prostate cancer cell lines. International Journal of Molecular Medicine 9:411–416. Schecter A, McGee H, Stanley JS, Boggess K, Brandt-Rauf P. 1996. Dioxins and dioxin-like chemicals in blood and semen of American Vietnam veterans from the state of Michigan. American Journal of Industrial Medicine. 30:647–654. Schnoor TM, Lawson CC, Whelan EA, Dankovic DA, Deddens JA, Piacitelli LA, Reefhuis J, Sweeney MH, Connally B, Fingerhut, MA. 2001. Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Health Perspectives 109(11):1127–1132. Schrader TJ, Cooke GM. 2000. Examination of selected food additives and organochlorine food contaminants for androgenic activity in vitro. Toxicological Sciences 53:278–288. Schrey P, Wittsiepe J, Ewers U, Exner M, Selenka F. 1993. Polychlorinated dibenzo-p-dioxins and dibenzofurans in human blood. Bundesgesundheitsblatt 11:455–463. Scott MA, Tarara RP, Hendrichs AG, Benirschke K, Overstreet JW, Lasley BL. 2001. Exposure to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces squamous metaplasia in the endocervix of cynomolgus macaques. Journal of Medical Primatology 30:156–160. Seidel SD, Winters GM, Rogers WJ, Ziccardi MH, Li V, Keser B, Denison MS. 2001. Activation of the Ah receptor signaling pathway by prostglandins. Journal of Biochemical and Molecular Toxicology 15:187–196. Seike N, Wanibuchi H, Morimura K, Nishikawa T, Kishida H, Nakae D, Hirata K, Fukushima S. 2002. Lack of promoting effect due to oral administration of dimethylarsinic acid on rat lung carcinogenesis initiated with N-bis(2-hydroxypropyl)nitrosamine Cancer Letters 175:113–119. Senft AP, Dalton TP, Nebert DW, Genter MB, Hutchinson RJ, Shertzer HG. 2002. Dioxin increases reactive oxygen production in mouse liver mitochondria Toxicology and Applied Pharmacology 178:15–21. Sewall CH, Clark GC, Lucier GW. 1995. TCDD reduces rat hepatic epidermal growth factor receptor: comparison of binding, immunodetection and autophosphorylation. Toxicology and Applied Pharmacology 132:263–272. Shehin SE, Stephenson RO, Greenlee WF. 2000. Transcriptional regulation of the human CYP1B1 gene. Evidence for involvement of an aryl hydrocarbon receptor response element in constitutive expression. Journal of Biological Chemistry 275:6770–6776. Shepherd DM, Dearstyne EA, Kerkvliet NI. 2000. The effects of TCDD on the activation of ovalbumin (OVA)-specific DO11.10 transgenic CD4(+) T cells in adoptively transferred mice Toxicological Sciences 56:340–350.

OCR for page 30
Veterans and Agent Orange: Update 2002 Shimba S, Hayashi M, Sone H, Yonemoto J, Tezuka M. 2000. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces binding of a 50 kDa protein on the 3' untranslated region of urokinase-type plasminogen activator mRNA Biochemical and Biophysical Research Communications 272: 441–448. Shimba S, Wada T, Tezuka M. 2001. Arylhydrocarbon receptor (AhR) is involved in negative regulation of adipose differentiation in 3T3-L1 cells: AhR inhibits adipose differentiation independently of dioxin. Journal of Cell Science 114:2809–2817. Shridhar S, Farley A, Reid FL, Foster WG, Van Vugt DA. 2001. The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on corticotrophin-releasing hormone, arginine vasopressin, and pro-opiomelanocortin mRNA levels in the hypothalamus of the cynomolgus monkey. Toxicological Sciences 63:181–188. Simanainen U, Tuomisto JT, Tuomisto J, Viluksela M. 2002. Structure-activity relationships and dose responses of polychlorinated dibenzo-p-dioxins for short-term effects in 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant and -sensitive rat strains. Toxicology and Applied Pharmacology 181:38–47. Singh SU, Casper RF, Fritz PC, Sukhu B, Ganss B, Girard B Jr, Savouret JF, Tenenbaum HC. 2000. Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol. Journal of Endocrinology 167:183–195. Slezak BP, Hatch GE, DeVito MJ, Diliberto JJ, Slade R, Crissman K, Hassoun E, Birnbaum LS. 2000. Oxidative stress in female B6C3F1 mice following acute and subchronic exposure to 2,3,7,8-tetrachlodibenzo-p-dioxin (TCDD). Toxicological Sciences 54:390–398. Slezak BP, Hamm JT, Reyna J, Hurst CH, Birnbaum LS. 2002. TCDD-mediated oxidative stress in male rat pups following perinatal exposure. Journal of Biochemical and Molecular Toxicology 16:49–52. Smart J, Daly AK. 2000. Variation in induced CYP1A1 levels: Relationship to CYP1A1, Ah receptor and CSTM1 polymorphisms. Pharmacogenetics 10:11–24. Smith AG, Clothier B, Carthew P, Childs NL, Sinclair PR, Nebert DW, Dalton TP. 2001. Protection of the CYP1A2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 173:89–98. Sordo M, Herrera LA, Ostrosky-Wegmand P, Rojas E. 2001. Cytotoxic and genotoxic effects of As, MMA, and DMA on leukocytes and stimulated human lymphocytes. Teratogenesis Carcinogenesis and Mutagenesis 21:249–260. Sparrow BR, Thompson CS, Ryu B-W, Selevonchick DP, Schaup HW. 1994. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced alterations of pyruvate carboxylase levels and lactate dehydrogenase isozyme shifts in C57BL/6J male mice. Journal of Biochemical Toxicology 9:329–335. Stanton BJ, El-Sabeawy F, Yang XF, Enan E, Lasley BL. 2001a. Interaction of estrogen and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in immature male chickens (Gallus domesticus). Comparative Biochemistry and Physiology Part C 129:35–47. Stanton B, Watkins S, German JB, Lasley B. 2001b. Interaction of estrogen and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with hepatic fatty acid synthesis and metabolism of male chickens (Gallus domesticus). Comparative Biochemistry and Physiology Part C 129:137–150. Sterling KM Jr, Cutroneo KR. 2002. Differentiation-dependent induction of CYP1A1 in cultured rat small intestinal epithelial cells, colonocytes, and human colon carcinoma cells; basement membrane-mediated apoptosis. Journal of Cellular Biochemistry 86:440–450. Sturtz N, Evangelista de Duffard AM, Duffard R. 2000. Detection of 2,4-dichlorophenoxyacetic acid (2,4-D) residues in neonates breast-fed by 2,4-D exposed dams. Neurotoxicology 21(1-2):147– 154. Styblo M, Del Razo LM, Vega L, Germolec DR, LeCluyse EL, Hamilton GA, Reed W, Wang C, Cullen WR, Thomas DJ. 2000. Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Archives of Toxicology 74:289–299.

OCR for page 30
Veterans and Agent Orange: Update 2002 Sugawara T, Nomura E, Sakuragi N, Fujimoto S. 2001. The effect of the arylhydrocarbon receptor on the human steroidogenic acute regulatory gene promoter activity. Journal of Steroid Biochemistry and Molecular Biology 78:253–260. Sugihara K, Kitamura S, Yamada T, Ohta S, Yamashita K, Yasuda M, Fujii-Kuriyama Y. 2001. Aryl hydrocarbon receptor (AhR)-mediated induction of xanthine oxidase/xanthine dehydrogenase activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochemical and Biophysical Research Communications 281:1093–1099. Suh J, Jeon YJ, Kim HM, Kang JS, Kaminski NE, Yang K-H. 2002. Aryl hydrocarbon receptor-dependent inhibition of AP-1 activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin in activated B cells. Toxicology and Applied Pharmacology 181:116–123. Sutter TR, Guzman K, Dold KM, Greenlee WF. 1991. Targets for dioxin: genes for plasminogen activator inhibitor-2 and interleukin-1 beta. Science 254: 415–418. Sutter TR, Tang YM, Hayes CL, Wo Y-Y, Jabs EW, Li X, Yin H, Cody CW, Greenlee WF. 1994. Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome 2 Journal of Biological Chemistry 269: 13092–13099. Svensson C, Lundberg K. 2001. Immune-specific up-regulation of adseverin gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin Molecular Pharmacology 60:135–142. Svensson C, Silverstone AE, Lai Z-W, Lundberg K. 2002. Dioxin-induced adseverin expression in the mouse thymus is strictly regulated and dependent on the aryl hydrocarbon receptor. Biochemical and Biophysical Research Communications 291:1194–1200. Takanaga H, Kunimoto M, Adachi T, Tohyama C, Aoki Y. 2001. Inhibitory effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on camp-induced differentiation of rat C6 glial cell line Journal of Neuroscience Research 64:402–409. Takimoto K, Lindahl R, Pitot HC. 1992. Regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible expression of aldehyde dehydrogenase in hepatoma cells. Archives of Biochemistry and Biophysics 298(2):493–497. Teraoka H, Dong W, Ogawa S, Tsukiyama S, Okuhara Y, Niiyama M, Ueno N, Peterson RE, Higaga T. 2002. 2,3,7,8-Tetrachlorodibenzo-p-dioxin toxicity in the zebrafish embryo: altered regional blood flow and impaired lower jaw development. Toxicological Sciences 65:192–199. Theobald HM, Roman BL, Lin TM, Ohtani S, Chen SW, Peterson RE. 2000. 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits luminal cell differentiation and androgen responsiveness of the ventral prostate without inhibiting prostatic 5alpha-dihydrotestosterone formation or testicular androgen production in rat offspring. Toxicological Sciences 58:324–338. Thornton AS, Oda Y, Stuart GR, Glickman BW, de Boer JG. 2001. Mutagenicity of TCDD in Big Blue® transgenic rats. Mutation Research 478:45–50. Tian Y, Ke S, Thomas T, Meeker RJ, Gallo MA. 1998. Transcriptional suppression of estrogen receptor gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Journal of Steroid Biochemistry and Molecular Biology 67:17–24. Timms BG, Peterson RE, vom Saal FS. 2002. 2,3,7,8-Tetrachlorodibenzo-p-dioxin interacts with endogenous estradiol to disrupt prostate gland morphogenesis in male rat fetuses. Toxicological Sciences 67:264–274. Tomita S, Sinal CJ, Yim SH, Gonzalez FJ. 2000. Conditional disruption of the aryl hydrocarbon receptor nuclear translocator (Arnt) gene leads to loss of target gene induction by the aryl hydrocarbon receptor and hypoxia-inducible factor 1α. Molecular Endocrinology 14:1674– 1681. Tritscher AM, Mahler J, Portier CJ, Lucier GW, Walker NJ. 2000. Induction of lung lesions in female rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicologic Pathology 28:761–769. Tsukumo SI, Iwata M, Tohyama C, Nohara K. 2002. Skewed differentiation of thymocytes toward CD8 T cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires activation of extracellular signal-related kinase pathway. Archives of Toxicology 76:335–343.

OCR for page 30
Veterans and Agent Orange: Update 2002 Tukey RH, Nebert DW. 1984. Regulation of mouse cytochrome P3-450 by the Ah receptor. Studies with a P3-450 cDNA clone. Biochemistry 23: 6003–6008. Tuomisto JT, Viluksela M, Pohjanvirta R, Tuomisto J. 2000. Changes in food intake and food selection in rats after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Pharmacology Biochemistry and Behavior 65:381–387. Uchida T, Yoshida S, Inui Y, Takeda K. 2002. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on testosterone production in isolated murine testicular cells. Journal of Health Science 48:292– 295. Uno S, Dalton TP, Shertzer HG, Genter MB, Warshawsky D, Talaska G, Nebert DW. 2001. Benzo[a]pyrene-induced toxicity: paradoxical protection in CYP1A1 (-/-) knockout mice having increased hepatic BaP-DNA adduct levels Biochemical and Biophysical Research Communications 289:1049–1056. Van Birgelen APJM, van den Berg M. 2000. Toxicokinetics. Food Additives and Contaminants 17:267–273. Van der Molen GW, Kooijman SALM, Slob W. 1996. A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD. Fundamental and Applied Toxicology 31:83–94. Van der Molen GW, Kooijman SALM, Wittsiepe J, Schrey P, Flesch-Janys D, Slob W. 2000. Estimation of dioxin and furan elimination rates with a pharmacokinetic model. Journal of Exposure Analysis and Environmental Epidemiology 10:579–585. van der Plas SA, Lutkeschipholt I, Spenkelink B, Brouwer A. 2001. Effects of subchronic exposure to complex mixtures of dioxin-like and non-dioxin-like polyhalogenated aromatic compounds on thyroid hormone and vitamin A levels in female Sprague-Dawley rats. Toxicological Sciences 59:92–100. Venkov P, Topashka-Ancheva M, Georgieva M, Alexieva V, Karanov E. 2000. Genotoxic effect of substituted phenoxyacetic acids. Archives of Toxicology 74:560–566. Vijayaraghavan M, Wanibuchi H, Yamamoto S, Hakoi K, Nakae D, Konishi Y, Fukushima S. 2000. Lack of promoting potential of dimethylarsinic acid in kidney of male NCI-Black Reiter rats. Journal of Toxicologic Pathology 13:87–91. Viluksela M, Duong TV, Stahl BU, Li X, Tuomisto J, Rozman KK. 1996. Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in two substrains of male Long-Evans rats after intravenous injection. Fundamental and Applied Toxicology 31:184–191. Vogel C, Abel J. 1995. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on growth factor expression in the human breast cancer cell line MCF-7. Archives of Toxicology 16:259–265. Vorderstrasse BA, Kerkvliet NI. 2001. 2,3,7,8-Tetrachlorodibenzo-p-dioxin affects the number and function of murine splenic dendritic cells and their expression of accessory molecules. Toxicology and Applied Pharmacology 171:117–125. Vorderstrasse BA, Steppan LB, Silverstone AE, Kerkvliet NI. 2001. Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression Toxicology and Applied Pharmacology 171:157–164. Wagner E, Frank MM, Smialowicz RJ. 2001. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and natural immunity: lack of an effect on the complement system in a guinea pig model. Toxicology 159:107– 113. Walker MK, Heid SE, Smith SM, Swanson HI. 2000. Molecular characterization and developmental expression of the aryl hydrocarbon receptor from the chick embryo. Comparative Biochemistsry and Physiology Part C 126:305–319. Walker NJ, Tritscher AM, Sills RC, Lucier GW, Portier CJ. 2000. Hepatocarcinogenesis in female Sprague-Dawley rats following discontinuous treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicological Sciences 54:330–337. Wang F, Samudio I, Safe S. 2001. Transcriptional activation of cathepsin D gene expression by 17β-estradiol: mechanism of aryl hydrocarbon receptor-mediated inhibition Molecular and Cellular Endocrinology 172:91–103.

OCR for page 30
Veterans and Agent Orange: Update 2002 Wang S, Hankinson O. 2002. Functional involvement of the Brahms/SWI2-related gene 1 protein in cytochrome P4501A1 transcription mediated by the aryl hydrocarbon receptor complex. Journal of Biological Chemistry 277:11821–11827. Wang X, Santostefano MJ, DeVito MJ, Birnbaum LS. 2000. Extrapolation of a PBPK model for dioxins across dosage regimen, gender, strain and species. Toxicological Sciences 56:49–60. Weber LW, Ernst SW, Stahl BU, Rozman K. 1993. Tissue distribution and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats after intravenous injection. Fundamental and Applied Toxicology 21:523–534. Wei M, Eanibuchi H, Yamamoto S, Li W, Fukushima S. 1999. Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats. Carcinogenesis 20:1873–1876. Wei C, Cacavale RJ, Kehoe JJ, Thomas PE, Iba MM. 2001. CYP1A2 is expressed along with CYP1A1 in the human lung. Cancer Letters 171:113–120. Wong JMY, Harper PA, Meyer UA, Bock KW, Morike K, Lagueux J, Ayotte P, Tyndale RF, Sellers EM, Manchester DK, Okey AB. 2001a. Ethnic variability in the allelic distribution of human aryl hydrocarbon receptor codon 554 and assessment of variant receptor function in vitro. Pharmacogenetics 11:85–94. Wong JMY, Okey AB, Harper PA. 2001b. Human aryl hydrocarbon receptor polymorphisms that result in loss of CYP1A1 induction. Biochemical and Biophysical Research Communications. 288:990–996. Wormke M, Castro-Rivera E, Chen I, Safe S. 2000a. Estrogen and aryl hydrocarbon receptor expression and crosstalk in human Ishikawa endometrial cancer cells. Journal of Steroid Biochemistry and Molecular Biology 72:197–207. Wormke M, Stoner M, Saville B, Safe S. 2000b. Crosstalk between estrogen receptor alpha and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes. FEBS Letters 478:109–112. Wu Q, Ohsako S, Baba T, Miyamoto K, Tohyama C. 2002. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on preimplantation mouse embryos. Toxicology 174:119–129. Wyde ME, Seely J, Lucier GW, Walker NJ. 2000. Toxicity of chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in diethylnitrosamine-initiated ovariectomized rats implanted with subcutaneous 17β-estradiol pellets. Toxicological Sciences 54:493–499. Wyde ME, Wong VA, Kim AH, Lucier GW, Walker NJ. 2001a. Induction of hepatic 8-oxy-deoxyguanosine adducts by 2,3,7,8-tetrachlorodibenzo-p-dioxin in Sprague-Dawley rats is female-specific and estrogen-dependent Chemical Research in Toxicology 14:849–855. Wyde ME, Eldridge SR, Lucier GW, Walker NJ. 2001b. Regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced tumor promotion by 17β-estradiol in female Sprague-Dawley rats. Toxicology and Applied Pharmacology 173:7–17. Wyde ME, Cambre T, Lebetkin M, Eldridge SR, Walker NJ. 2002. Promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 17β-estradiol in male Sprague-Dawley rats. Toxicology and Applied Pharmacology 68:295–303. Wyman A, Lavin AL, Wilding GE, Gasiewicz TA. 2002. 2,3,7,8-Tetracholodibenzo-p-dioxin does not directly alter the phenotype of maturing B cells in a murine coculture system. Toxicology and Applied Pharmacology 180:164–177. Yamanaka K, Takabayashi F, Mutsumi M, An Y, Hasegawa A, Okada S. 2001. Oral exposure of dimethylarsinic acid, a main metabolite of inorganic arsenics, in mice leads to an increase in 8-oxo-2'-deoxyguanosine level, specifically in the target organs for arsenic carcinogenisis Biochemical and Biophysical Research Communications 287:66–70. Yamonoshita O, Saito T, Takahashi K, Hosokawa T, Okabe M, Ito K, Kurasaki M. 2001. 2,4,5-Trichlorophenoxyacetic acid inhibits apoptosis in PC12 cells Life Sciences 69:403–408. Yang D, Li Y, Yuan X, Matoney L, Yan B. 2001. Regulation of rat carboxylesterase expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): A dose-dependent decrease in mRNA levels but a biphasic change in protein levels and activity. Toxicological Sciences 64:20–27.