3
Toxicology

As in Veterans and Agent Orange (VAO) and Veterans and Agent Orange: Update 1996 (Update 1996), this review summarizes the experimental data that serves as a scientific basis for assessment of the biologic plausibility of health outcomes reported in epidemiologic studies. Efforts to establish the biologic plausibility of effects due to herbicide exposure in the laboratory strengthen the evidence for the herbicide effects suspected to occur in humans. Differences in chemical levels, frequency of administration, single or combined exposures, preexisting health status, genetic factors, and routes of exposure significantly influence toxicity outcomes. Thus, any attempt to extrapolate from experimental studies to human exposure must carefully consider such variables before conclusions are made.

Multiple chemicals were used for various purposes in Vietnam. 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); picloram; and cacodylic acid. In addition, the toxicologic properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), a contaminant of 2,4,5-T, are discussed. This chapter focuses to a large extent on the toxicological effects of TCDD, because considerably more information is available on TCDD than on the herbicides.

SUMMARY

Toxicokinetics

New information on the distribution of 2,4-D and the metabolism of cacodylic acid has improved understanding of how the body handles these sub-



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Veterans and Agent Orange: Update 1998 3 Toxicology As in Veterans and Agent Orange (VAO) and Veterans and Agent Orange: Update 1996 (Update 1996), this review summarizes the experimental data that serves as a scientific basis for assessment of the biologic plausibility of health outcomes reported in epidemiologic studies. Efforts to establish the biologic plausibility of effects due to herbicide exposure in the laboratory strengthen the evidence for the herbicide effects suspected to occur in humans. Differences in chemical levels, frequency of administration, single or combined exposures, preexisting health status, genetic factors, and routes of exposure significantly influence toxicity outcomes. Thus, any attempt to extrapolate from experimental studies to human exposure must carefully consider such variables before conclusions are made. Multiple chemicals were used for various purposes in Vietnam. 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); picloram; and cacodylic acid. In addition, the toxicologic properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), a contaminant of 2,4,5-T, are discussed. This chapter focuses to a large extent on the toxicological effects of TCDD, because considerably more information is available on TCDD than on the herbicides. SUMMARY Toxicokinetics New information on the distribution of 2,4-D and the metabolism of cacodylic acid has improved understanding of how the body handles these sub-

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Veterans and Agent Orange: Update 1998 stances. 2,4-D enters the brain, but only to a limited extent, and its uptake by the brain appears to be an energy-dependent process. Cacodylic acid is one of the major metabolic products of ingested arsenic in mammals. Studies using skin taken from mice report that the absorption of cacodylic acid is influenced by the substance in which it is dissolved and the length of time that cacodylic acid remains in contact with the skin. TCDD, unlike the herbicides, stays in the body for a long time. In humans about half is eliminated every 8.5 years. It is removed from the body as it is metabolized to less toxic forms that are more easily eliminated in the urine than TCDD itself. The length of time that TCDD remains in the body increases with increasing body fat. New evidence based on animal models suggests that rats and humans tend to handle TCDD in body tissues in similar ways. However, rats tend to excrete TCDD more quickly. Rats are most likely to absorb TCDD through food and air and this fact may carry over to humans. However, the types of TCDD and other dioxins that accumulate in the body may differ markedly between humans and rodents. Mechanisms of Toxic Action Little is known about the way in which the herbicides produce toxic effects in animals. Recent studies have focused on the mechanisms of cellular toxicity of 2,4,5-T. For example, some studies using animal tissues suggest that 2,4,5-T may alter nerve and muscle function by interacting with chemicals that participate in nervous system function. 2,4,5-T may induce mutations at different stages of cell development. Finally, it may alter the cellular process involved in the elimination of harmful carcinogens. To date, the consensus is that TCDD is not directly toxic to the body's genetic material. However, it may affect enzymes and hormone levels, which in turn may produce adverse effects. Recent studies confirm earlier findings that most of the toxic effects of TCDD are caused by its binding to a protein called the aryl hydrocarbon receptor (AhR). The binding of TCDD to this protein triggers various events that result in toxic sequelae. However, some tests suggest that other events, in addition to the binding of TCDD to the AhR, are involved. Studies of the AhR and its partner protein Arnt (aryl hydrocarbon nuclear translocator protein) indicate that similar proteins exist in different species and interact with a number of other proteins to produce an effect. Researchers have recently bred mice that lack the AhR protein. It is anticipated that these mice will allow more informative studies of the way TCDD reacts with the AhR to produce a toxic effect. Disease Outcomes Disease outcomes associated with herbicide exposures continue to be debated. Some cellular-level effects have been identified, although it is not clear

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Veterans and Agent Orange: Update 1998 what impact these may have on living organisms. Other studies suggest disease effects including neurotoxicity and kidney, liver, and muscle damage at certain high dose levels in particular animal species; however, translating these results to the exposures experienced by veterans and others remains problematic. 2,4-D appears to affect the membrane sheath around nerve cells. Other studies support the view that 2,4-D may disrupt cellular processes in the liver, and reports of kidney and muscle damage have been published. Results from studies indicate that high doses of 2,4-D are necessary to produce these effects. A case-control study of dogs exposed to 2,4-D in addition to other pesticides used in yard work, reported an increase in lymphomas associated with exposure. The limited evidence published during the past two years suggest that cacodylic acid may promote cancer in rats. Several recent studies have examined the role of TCDD in producing certain disease outcomes in animals, including acute toxicity, dermal toxicity, liver toxicity, neurotoxicity, immunotoxicity, reproductive and developmental toxicity, and cancer. A prominent symptom of the acute toxicity of TCDD is the loss of fat tissue and body weight, a phenomenon known as wasting syndrome. Several mechanisms are under investigation including inhibition by TCDD of sugar transport activity, effects on fat cell differentiation, and effects on certain receptors and enzymes. There is some evidence to suggest that gender differences exist in the response of fat cells to TCDD. TCDD has also been shown to affect the development of skin cells by binding to the AhR. This effect is antagonized by retinoids. Liver enlargement has been shown to occur following high doses of TCDD. The mechanism by which TCDD affects the liver is still under investigation. Recently, it has been shown to inhibit DNA synthesis of liver cells, decrease certain receptors in liver cell membranes, and inhibit liver enzymes. Animal and test-tube studies continue to emphasize the importance of alterations in neurological systems as underlying mechanisms of TCDD-induced behavioral dysfunction. TCDD can affect the metabolism of serotonin, a substance in the brain that can modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. In certain brain cells, there is evidence that TCDD may increase the uptake of calcium. It is known that TCDD exposure causes a broad range of immunologic effects in experimental animals. Recent studies support earlier data that TCDD decreases immunity and host resistance to pathogenic microorganisms. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear. TCDD immunotoxicity appears to be mediated primarily through the AhR, but some components of immunosuppression have been shown to act independently of this receptor.

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Veterans and Agent Orange: Update 1998 Low doses of TCDD administered to experimental animals alter reproductive development and fertility of the offspring. When TCDD is administered to pregnant rats, malformations of the external genitalia are observed in female offspring. Functional reproductive alterations in female offspring are also observed after TCDD exposure, including decreased fertility rates and reduced fecundity. Studies in male rats and hamsters have shown that decreased daily sperm production is one of the most sensitive effects of exposure to TCDD in the womb and through breast milk. Results also suggest that TCDD exposures selectively impair rat prostate growth and development. TCDD has been shown to affect blood serum hormone levels. This outcome is thought to be due partially to the action of TCDD on the pituitary gland. Several reports published during the reference period focused on the mechanism by which TCDD induces cleft palates in experimental animals. Evidence suggests that this effect involves the AhR. There have also been reports of developmental defects in the cardiovascular system of TCDD-treated animals. Evidence suggests that cells lining the blood vessels are a primary target of TCDD-induced developmental cardiovascular toxicity. Studies continue to focus on the mechanism by which TCDD induces cancer in animals. Although there is considerable evidence that TCDD-induced cancer is mediated by the AhR, it does not appear to be solely responsible. There is also evidence that the mechanism by which TCDD induces tumor promotion may involve reactive molecules containing oxygen, which are known as oxygen radicals. It is hypothesized that a release of oxygen radicals by TCDD causes DNA damage that could lead to mutation and cancer. There is also evidence that TCDD tumor promotion may be due to its ability to interfere with intercellular communications. Inconsistencies reported in the molecular basis of dioxin' s actions reflect the degree of tissue, cell, and gene specificity that characterizes the toxic response. Relevance To Human Health Exposure to 2,3,7,8-TCDD, a contaminant in some of the herbicides used in Vietnam, has been associated with both cancer and noncancer end points in animals. Studies in animals indicate that TCDD effects are mediated through the AhR. Although structural differences in the AhR have been identified, it operates in a similar manner in animals and humans, and a connection between TCDD exposure and human health effects is, in general, considered biologically plausible. Evidence has also begun to accumulate for non-AhR mediated effects. Animal research indicates that TCDD can both cause cancers or tumors and enhance the incidence of certain cancers or tumors in the presence of known carcinogens. However, experimental animals greatly differ in their susceptibility to TCDD-induced effects, and the sites at which tumors are induced also varies

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Veterans and Agent Orange: Update 1998 from species to species. Other noncancer health effects vary according to dose and to the animal exposed. Controversy exists over whether the effects of TCDD and other exposures are threshold dependent, that is, whether some exposure levels may be too low to induce any effect. Limited information is available on the biologic plausibility of herbicide health effects not connected with TCDD. Although concerns have been raised about non-dioxin contaminants of herbicides, far too little is known about the ubiquitousness and concentration of these compounds in the formulations used in Vietnam to draw conclusions about their impact. Considerable uncertainty remains about how to apply this information to evaluation of the potential health effects in Vietnam veterans of herbicide or dioxin exposure. Scientists disagree over the extent to which information derived from animal and cellular studies predicts human health outcomes and the extent to which health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Research on biological mechanisms is burgeoning, and subsequent VAO updates may have more and better information on which to base conclusions. VAO AND UPDATE 1996—OVERVIEW Chapter 4 of VAO and Chapter 3 of Update 1996 review the results of animal and test-tube studies published until 1995 that investigated the toxicokinetics, mechanism of action, and disease outcomes of TCDD and herbicides. According to these earlier reviews, TCDD elicits a diverse spectrum of biological sex-, strain-, age-, and species-specific effects, including carcinogenicity, immunotoxicity, reproductive and developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. The scientific consensus is that TCDD is not genotoxic and that its ability to influence the carcinogenic process is mediated via epigenetic events such as enzyme induction, cell proliferation, apoptosis, and intracellular communication. The toxicity of the herbicides used in Vietnam has been poorly studied. In general, the herbicides 2,4-D, 2,4,5-T, cacodylic acid, and picloram have not been identified as particularly toxic substances since high concentrations are often required to modulate cellular and biochemical processes. A comprehensive description of the toxicological literature published until 1995 can be found in VAO and Update 1996. UPDATE OF THE SCIENTIFIC LITERATURE—OVERVIEW Toxicokinetics A limited number of studies have been published since Update 1996 that examine the biologic and toxic effects of 2,4-D. Toxicokinetic studies using rabbits suggest that uptake of 2,4-D by the brain is restricted by the developing,

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Veterans and Agent Orange: Update 1998 as well as the mature, blood-brain barrier. In hamsters, cellular 2,4-D uptake appears to be an energy-dependent process. During the reference period since the publication of Update 1996, the disposition of TCDD in humans has been investigated in two studies. Based on multiple serum measurements collected over a 10-year period from 213 veterans of Operation Ranch Hand, the mean decay rate of TCDD was estimated to be 0.0812 per year, with a corresponding half-life estimate of 8.532 years. In these veterans, half-life increased significantly with increasing body fat, but not with age or relative changes in the percentage of body fat. In another human study, the impact of breastfeeding on the body burden of dioxin-like chemicals in Arctic Inuit people was investigated. Toxicokinetic modeling revealed that breast feeding strongly influences the body burden of TCDD during childhood but not after 20 years of age. In addition, liver and adipose tissue concentrations in adults greater than 20 years of age appeared to be lower than those associated with cancer and adverse reproductive effects in laboratory animals. Using a physiologically based model that describes the distribution kinetics of dioxin-like chemicals in various mammalian species, the kinetic profile of TCDD was found to be similar in rats and humans, although the half-lives differ considerably between species. The half-life of TCDD in rats and humans is measured in weeks and years, respectively. Comparative studies of the systemic absorption of TCDD in rats following oral and inhalation exposures indicate that both exposures are significant routes of absorption—an observation that is of relevance to humans given the similarities in kinetic profiles between rats and humans. In addition, for a given body burden, the adipose tissue concentrations have been found to vary in an inversely proportional manner to the mass of adipose tissues. Despite similarities in the toxicokinetic profile of rats and humans, some data suggest that humans may bioaccumulate higher levels of certain dioxins than mice due to interspecies metabolic differences. Results from another model of the disposition of TCDD in the rat indicate that TCDD increases the enzymatic activity of UDP-glucuronosyltransferase (UGT) and the levels of blood thyroid-stimulating hormone (TSH). Calculated increases in blood TSH levels are consistent with prolonged stimulation of the thyroid and may represent an early stage in the induction of thyroid tumors identified in previous two-year bioassays. This suggests that increases in UGT activity may be a useful biomarker for tumorigenic changes in hormone levels after TCDD exposure. However, certain noncancer end points may be more significant in assessing human health risks to TCDD than cancer end points. For instance, immune suppression and enzymatic induction have been found to occur at lower doses and under conditions more relevant to general population exposure conditions. In assessing the risk of humans to dioxins, it should also be noted that recent data suggest that toxic equivalency factors (TEFs) derived from short-term assays may not adequately predict the relative potencies of this class of compounds following chronic exposure.

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Veterans and Agent Orange: Update 1998 Mechanisms of Toxic Action The mechanisms of cellular toxicity of 2,4,5-T have been the focus of a number of recent studies. One study presents compelling evidence that 2,4,5-T interacts with choline to generate false cholinergic messengers that alter neuronal and muscular function. Another study found that 2,4,5-T can induce mutations at different germ cell stages. Finally, there is some evidence that 2,4,5-T modulates cellular metabolism to alter the expression of membrane pumps and drug-metabolizing enzymes involved in the disposition of chemical carcinogens. Dimethylarsinic acid (cacodylic acid, DMA) is one of the major methylated metabolites of ingested arsenicals in mammals. During the reference period, toxicokinetic studies reported that the rates of in vitro dermal absorption of DMA can be influenced by both the vehicle of administration and the duration of exposure. Scientific reports published during the past two years continue to focus on the mechanism by which TCDD exerts its effects. Structural and functional studies of the AhR and Arnt indicate that both proteins are highly conserved, are found in diverse vertebrate groups, and interact with a large number of proteins to influence nuclear events. In vitro studies have confirmed in vivo findings regarding the functional binding domains of mouse AhR that interact with the heat shock protein (hsp90). Other results continue to support the view that TCDD influences patterns of gene expression by modulating transcriptional and post-transcriptional events. Such responses are often mediated by the AhR but exhibit considerable tissue and cell specificity. From a toxicologic perspective, the development of AhR knockout mice has been an important advance because it has helped establish a definitive association between the AhR and TCDD-mediated toxicities. Some studies suggest that specific patterns of Arnt expression differ in certain tissues from those of the AhR and that Arnt may have roles in normal embryonic development independent of the AhR. The recent discovery that the oxygen-regulated transcription factor HIF-1α and the AhR share a common heterodimerization partner Arnt (HIF-1β) has fueled intensive investigation into the possible crosstalk between oxygen and dioxin signal transduction pathways. Disease Outcomes While disease outcomes associated with 2,4-D exposures continue to be debated, neurotoxic effects have been reported in rats administered high acute doses, possibly as a result of neuronal demyelination. Studies on rats continue to support the view that the hepatotoxic effects of 2,4-D may involve disruption of thiol homeostasis. Reports of kidney and muscle damage have also been published. A case-control study of dogs exposed to 2,4-D in addition to other pesticides used in yard work, reported an increase in lymphomas associated with exposure. Although 2,4-D induced significant numbers of mutations in a Droso-

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Veterans and Agent Orange: Update 1998 phila cell line and increased mRNA levels of multidrug resistance (mdr) genes in mouse liver, cancer bioassays show no carcinogenic effect. Results from chronic and subchronic toxicity studies indicate that 2,4-D is relatively nontoxic. Limited research has been conducted on the offspring of male animals exposed to herbicides. A study of male mice fed varying concentrations of simulated Agent Orange mixtures concluded there were no adverse effects in offspring. A statistically significant excess of fused sternebra in the offspring of the two most highly exposed groups was attributed to an anomalously low rate of the defect in controls. Another study reported an increase in the incidence of mal-formed offspring of male mice exposed to subacute levels of a mixture of 2,4-D and picloram in drinking water. However, the paternal toxicity observed in the high dosage levels used and inconsistent dose-response pattern are of concern. Limited evidence presented during the past two years suggests that DMA acts as a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats. DMA induces apoptosis and sensitizes DNA to oxidative injury. TCDD has been shown to adversely affect a number of organ systems that have been or may be linked to a variety of disease outcomes. TCDD lethality has been associated with changes in brain serotonin metabolism. However, the wide interspecies differences in TCDD-induced lethality cannot be explained by changes in tryptophan metabolism or carbohydrate homeostasis. A prominent symptom of the acute toxicity of TCDD is the loss of adipose tissue and body weight, a phenomenon known as wasting syndrome. Several mechanisms are under investigation including inhibition by TCDD of glucose transport activity and hepatic phosphoenolpyruvate carboxykinase (PEPCK, the rate-limiting enzyme of hepatic gluconeogenesis); the effects of TCDD on adipocyte differentiation; and the effects of TCDD on epidermal growth factor receptor and protein-tyrosine kinase. There is some evidence to suggest that gender differences exist in the response of cells to TCDD. Glucose uptake and lipoprotein lipase activity were significantly decreased in adipose tissue in vitro after intraperitoneal (ip) injection of TCDD in male guinea pigs. No significant effect was observed in females. In addition, radiolabeled-TCDD binding affinity studies in adipose explant tissues showed that tissues from male guinea pigs and monkeys had a higher binding capacity for TCDD than female tissues. TCDD has been shown to induce differentiation in human keratinocytes, which may be initiated by TCDD binding to the AhR. This effect is antagonized by retinoids and may involve interactions between TCDD and retinoids in the regulation of epithelial differentiation. The mechanism by which TCDD induces hepatotoxicity is still under investigation. TCDD has been shown to inhibit hepatocyte DNA synthesis; decrease hepatic plasma membrane epidermal growth factor receptor; inhibit hepatic pyruvate carboxylase activity as a consequence of a reduction in pyruvate carboxylase mRNA levels (this effect was ten-fold greater than in congenic Ahb/b mice, suggesting that a competent AhR is required); and induce cytochrome P4501A1

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Veterans and Agent Orange: Update 1998 (CYP1A1) in fish and chick embryo hepatocyte cultures, resulting in porphyrin accumulation. Studies have been conducted to examine the short-and long-term effects of TCDD on rat ethoxyresorufin o-deethylase (EROD) activity and liver enzymes. Four days after oral dosing, EROD activity was considerably elevated. Hepatic PEPCK and glutamyl transpeptidase activities were inhibited and stimulated, respectively. Ninety days after dosing, liver EROD activity and PEPCK activity revealed considerable reversibility, whereas glutamyl transpeptidase activity remained elevated. Hepatomegaly has been shown to occur following high subchronic doses. Using Mardin Darvey canine kidney cells, TCDD has been shown to stimulate transcription of the PGHS-2 gene. It has been suggested that PGHS-2 expression may be involved in toxic reactions that involve inappropriate cellular growth, such as tumor promotion. Animal studies and in vitro mechanistic studies continue to emphasize the importance of alterations in neurotransmitter systems as underlying mechanisms of TCDD-induced behavioral dysfunction. Lethal doses of TCDD administered to rats affect the metabolism of serotonin, a neurotransmitter in the brain able to modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. In primary cultures of rat hippocampal neuronal cells, there is evidence that TCDD may increase the uptake of intracellular calcium. This concentration-dependent increase in calcium is associated with a decrease in mitochondrial membrane potentiation and activation of β-protein kinase C (β-PKC). TCDD and structurally related halogenated aromatic hydrocarbons cause a broad range of immunologic effects in experimental animals. Recent studies support earlier data that TCDD decreases innate immunity and host resistance to pathogenic microorganisms; impairs cell-mediated immune responses, such as the generation and lytic activity of cytotoxic T cells; and suppresses humoral immunity by inhibiting B-lymphocyte differentiation into antibody-producing cells. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear. TCDD immunotoxicity appears to be mediated primarily through AhR-dependent processes, but some components of immunosuppression have been shown to act independently of the AhR. Low doses of TCDD administered to experimental animals alter reproductive development and fertility of the progeny. Studies in male rats and hamsters have shown that decreased daily sperm production and cauda epididymal sperm number are some of the most sensitive effects of in utero and lactational TCDD exposure. However, in utero and lactational TCDD exposure does not appear to alter radiolabeled sperm transit time through the whole epididymis. Studies have been conducted to determine whether in utero and lactational TCDD exposure decreases male rat accessory sex organ weights during postnatal development and whether this effect involved decreases in testicular androgen production or changes in peripheral androgen metabolism. Results suggest that in utero and

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Veterans and Agent Orange: Update 1998 lactational TCDD exposure selectively impairs rat prostate growth and development without inhibiting testicular androgen production or consistently decreasing prostate dihydrotestosterone (DHT) concentration. Male mice treated with a mixture of 2,4-D, 2,4,5-T, and TCDD exhibited dose-related liver and thymus toxicity and reduced weight gain, although no significant effects were observed on sperm function, reproductive outcomes, survival of offspring, or neonatal development. In female rats, a single dose of TCDD administered on gestational day (GD) 15 results in malformations of the external genitalia in Long Evans (LE) and Holtzman rats. There was complete to partial clefting of the phallus. Treatment on GD 8 was more effective in inducing functional reproductive alterations in female progeny (e.g., decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, increased incidence of constant estrus). TCDD administered by gastric intubation altered serum hormone levels in immature female rats. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadotropin levels were increased. This effect is due partially to the action of TCDD on the pituitary and is calcium dependent. After water-borne exposure of newly fertilized eggs to TCDD, the toxicity and histopathology of TCDD in zebrafish revealed that TCDD did not increase egg mortality or affect time to hatching. However, pericardial edema and craniofacial malformations were observed in zebrafish larvae. Reports indicate that in ovo TCDD exposure of the domestic chicken, domestic pigeon, and great blue heron adversely affected the body and skeletal growth and hatchability of the domestic pigeon but had no effect on the domestic chicken or great blue heron. Studies involving human luteinizing granulose cells have shown that glucose transporting activity can be used as a sensitive biomarker to detect the very early response to TCDD in these steroid-producing cells and that the effect of TCDD on progesterone is mediated through cyclic adenosine 5'-monophosphate (cAMP)-dependent protein kinase. TCDD-induced cleft palate and hydronephrosis involve mechanisms that are AhR mediated. There are data to suggest that TCDD interacts with other signaling pathways in inducing cleft palate. For example, cross-regulation of the receptors is believed to be important in the synergistic interaction between TCDD and hydrocortisone. When female mice are treated with TCDD and retinoic acid simultaneously, palatal clefts can be observed in 100 percent of offspring at dose levels far lower than those required for either agent to produce clefting if given alone. This synergy suggests that the pathways controlled by these agents converge at one or more points in cells of the developing palate. The effects of TCDD on the estrogen-signaling system during fetal and perinatal development of peripubertal female rats has been investigated. The mechanism for the reduction in female fertility that accompanies in utero and lactational exposure to TCDD remains unknown, although it could be linked to estrogenic effects such as clefting of the phallus and hypospadias.

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Veterans and Agent Orange: Update 1998 Several reports published during the reference period describe developmental deficits in the cardiovascular system of TCDD-treated animals. Evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity. CYP1A1 is induced in mammalian endothelial cells in culture. The vascular endothelium in lake trout is also uniquely sensitive to induction of CYP1A1 by TCDD in developing animals. CYP1A1 induction in the endothelium may be linked to early lesions that result in TCDD-induced vascular derangements leading to the yolk sac, pericardial, and meningial edema associated with lake trout sac fry mortality. CYP1A1 induction has also been observed in adult quail aortic tissue. The cardiotoxicity induced by TCDD was examined in chick embryo. The spatial and temporal expression of AhR and Arnt suggests that the developing myocardium and cardiac septa are potential targets of TCDD-induced teratogenicity, and such targets are also consistent with cardiac hypertrophy and septal defects observed following TCDD exposure. DNA damage and consequent cell death in the embryonic vasculature are key physiological mediators of TCDD-induced embryotoxicity in medaka (a small Japanese freshwater fish [Oryzias latipes]). Treatment of TCDD-exposed medaka embryos with an antioxidant provides significant protection against TCDD-induced embryotoxicity and suggests that reactive oxygen species may participate in the teratogenic effects of TCDD. TCDD has been shown to significantly induce CYP1A1 mRNA levels and EROD activity in several human cancer cells. Experiments involving several strains of mice provide evidence that a functional Ah receptor is required for TCDD induction of CYP1A1 and liver tumor promotion. However, the AhR does not appear to be exclusively responsible. CYP1A1 induction in various mice strains was not directly related to the degree of tumor-promoting capability, which suggests that other undefined genetic factors may play an important role. Studies comparing liver induction in TCDD-responsive (C57BL/6J) and less responsive (DBA/2J) mice indicate that induction of CYP1B1 and CYP1A1 mRNA content is more pronounced in the former. CYP1A1 was more responsive to TCDD that CYP1B1 in both strains, suggesting that CYP1B1 mRNA expression is less inducible by TCDD but that both genes are AhR regulated. Other studies indicate that the expression of CYP1A1 and CYP1B1 is highly cell specific even though each is regulated through the AhR. However, each P450 exhibits a surprising similar pattern of hormonal regulation even though expressed in different cell types. Studies conducted to compare AhR in cultured fetal cells and adult liver tumors from TCDD-responsive (C57BL/6J) and less responsive (DBA/2J) mice indicate that the responsiveness of fetal cells is likely mediated by the AhR and is not due to a different allelic form of AhR ligand binding subunit in fetal versus adult cells.

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Veterans and Agent Orange: Update 1998 Diliberto JJ, Jackson JA, Birnbaum LS. 1996. Comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disposition following pulmonary, oral, dermal, and parenteral exposures to rats. Toxicology and Applied Pharmacology 138:158-168. Dohr O, Sinning R, Vogel C, Munzel P, Abel J. 1997. Effect of transforming growth factor-betal on expression of aryl hydrocarbon receptor and genes of Ah gene battery: clues for independent down-regulation in A549 cells. Molecular Pharmacology 51 (5):703-710. Dohr O, Vogel C, Abel J. 1995. Different response of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive genes in human breast cancer MCF-7 and MDA-MB 231 cells. Archives of Biochemistry and Biophysics 321 (2):405-412. Dolwick KM, Swanson HI, Bradfield CA. 1993. In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition. Proceedings of the National Academy of Sciences (USA) 90:8566-8570. Duffard R, Garcia G, Rosso S, et al. 1996. Central nervous system myelin deficit in rats exposed to 2,4-dichlorophenoxyacetic acid throughout lactation. Neurotoxicology and Teratology 18:691-696. Dunn RT II, Ruh TS, Burroughs LK, Ruh MF. 1996. Purification and characterization of an Ah receptor binding factor in chromatin. Biochemical Pharmacology 51(4):437-445. Ema M, Ohe N, Suzuki M, Mimura J, Sogawa K, Ikawa S, Fujii-Kuriyama Y. 1994. Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. Journal of Biological Chemistry 269(44):27337-27343. Enan E, Matsumura F. 1995a. Evidence for a second pathway in the action mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Significance of Ah-receptor mediated activation of protein kinase under cell-free conditions. Biochemical Pharmacology 49(2):249-261. Enan E, Matsumura F. 1995b. Regulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) of the DNA binding activity of transcriptional factors via nuclear protein phosphorylation in guinea pig adipose tissue. Biochemical Pharmacology 50:1199-1206. Enan E, Matsumura F. 1996. Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochemical Pharmacology 52:1599-1612. Enan E, Lasley B, Stewart D, Overstreet J, Vandevoort CA. 1996a. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) modulates function of human luteinizing granulosa cells via cAMP signaling and early reduction of glucose transporting activity. Reproductive Toxicology 10:191-198. Enan E, Moran F, VandeVoort CA, Stewart DR, Overstreet JW, Lasley BL. 1996b. Mechanism of toxic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in cultured human luteinized granulosa cells. Reproductive Toxicology 10:497-508. Enan E, Overstreet JW, Matsumura F, VandeVoort CA, Lasley BL. 1996c. Gender differences in the mechanism of dioxin toxicity in rodents and in nonhuman primates. Reproductive Toxicology 10:401-411. Fan F, Rozman KK. 1995. Short-and long-term biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Long-Evans rats. Toxicology Letters 75:209-216. Fan F, Pinson DM, Rozman KK. 1995. Immunomodulatory effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin tested by the popliteal lymph node assay. Toxicologic Pathology 23(4):513-517. Fan F, Wierda D, Rozman KK. 1996. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on humoral and cell-mediated immunity in Sprague-Dawley rats. Toxicology 106(1-3):221-228. Fan F, Yan B, Wood G, Viluksela M, Rozman KK. 1997. Cytokines (IL-lbeta and TNFalpha) in relation to biochemical and immunological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. Toxicology 116(1-3):9-16. Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS, Kimura S, Nebert DW, Rudikoff S, Ward JM, Gonzalez FJ. 1995. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor [see comments]. Science 268(5211):722-726.

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