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Veterans and Agent Orange: Update 2000 3 Toxicology As in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994; hereafter referred to as VAO), Veterans and Agent Orange: Update 1996 (IOM, 1996; hereafter, Update 1996) and Veterans and Agent Orange: Update 1998 (IOM, 1999; hereafter, Update 1998), this review summarizes the experimental data that serve 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, including exposures to chemicals other than herbicides, 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. Most of the experimental studies of these chemicals, unless otherwise noted, are conducted with pure chemical. This is in contrast to the epidemiologic studies discussed in later chapters in which expo-
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Veterans and Agent Orange: Update 2000 sures are often to mixtures of chemicals. Some studies of herbicides are conducted using herbicide mixtures and are noted as such in the text. This chapter begins with a brief summary of major conclusions derived from the literature reviews in VAO, Update 1996, and Update 1998. This is followed by a summary of toxicological research findings as they relate to human health, and then an overview of the scientific literature published since release of Update 1998, reviewed in detail in this chapter. Note that these more general summaries do not include references to the scientific literature because they are intended to provide background for the nonspecialist. The “Toxicity Profile Updates” section then provides details of the relevant scientific studies, with references, that have been conducted on 2,4-D,2,4,5-T, picloram, cacodylic acid, and TCDD since Update 1998. The toxicity profile update for TCDD includes a section that discusses the issues involved in estimating potential health risk and factors influencing toxicity. That subsection includes a discussion of the toxic equivalency factor approach to estimating the toxicity of TCDD. It is important, when evaluating the experimental data for all of the compounds, to keep in mind the advantages, disadvantages, and limitations of various types of studies. These considerations are discussed in the final section of the chapter, “Issues in Evaluating the Evidence.” LAY SUMMARY Highlights of Previous Reports Chapter 4 of VAO and Chapter 3 of both Update 1996 and Update 1998 review the results of animal and in vitro studies published through 1997 that investigate 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 directly genotoxic and that its ability to influence the carcinogenic process is mediated via epigenetic events such as effects on 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 through 1997 can be found in VAO, Update 1996, and Update 1998.
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Veterans and Agent Orange: Update 2000 Toxicokinetics The distribution of toxicants within the body, or toxicokinetics, can determine the amounts of a particular chemical reaching potential target organs or cells. Earlier data indicate that all four of the herbicides can be absorbed into the body. No data have been published on the toxicokinetics of 2,4-D,2,4,5-T, or picloram since Update 1998. Since Update 1998, some research has been conducted that is relevant to the distribution of cacodylic acid, an organic form of arsenic, in the body. The distribution in the body and excretion out of the body of organic arsenicals were shown to be minimally affected by the dose administered. Data also indicate that some organic forms of arsenic are transferred to the fetus, and it was seen following a human poisoning that organic arsenicals preferentially distribute to organs that are high in lipids. Studies conducted in veterans of Operation Ranch Hand since Update 1998 have refined estimates of how long it takes for half of the TCDD in the body to be eliminated (i.e., its half-life); the average half-life in humans is 7.6 years. Other studies demonstrate that the distribution of TCDD can be affected by several variables; lipoidal additives in the diet may enhance TCDD excretion, the halflife of TCDD can vary between individuals, and the half-life can vary with dietary modification. Research has also been conducted on how to estimate initial exposure levels using blood measurements of TCDD years after the exposure occurred. Mechanisms of Toxic Action There is still little known about the way that herbicides produce toxic effects in animals. Since Update 1998 the ability of 2,4-D to induce mutations has been investigated using a number of assays. Mutations were seen only in one study and there only at very high concentrations of 2,4-D in vivo. 2,4-D did affect the levels of some hormones and cellular components involved in the development and functioning of brain cells. Both 2,4-D and 2,4,5-T inhibited mitochondrial benzoyl coenzyme A (benzoyl-CoA) synthetase and an organic acid transporter. 2,4,5-T also affected Neu tyrosine kinase, a tyrosine kinase receptor that has been shown in other experiments to be correlated with an increased incidence of breast cancer. The relevance of the effects of 2,4,5-T on that enzyme to the toxic effects of 2,4,5-T is unknown. Cacodylic acid can affect microtubule networks at particular points in mitosis. Research on cacodylic acid indicates that it can cause bladder hyperplasia and tumors in rats, lung cancer in mice, and promote skin cancer in mice sensitized by genetic manipulation or exposure to ultraviolet B radiation. One study in mice has demonstrated that it can cause chromosomal abnormalities. Data published to date are consistent with the hypothesis that TCDD produces most of its biological and toxic effects by binding to a protein that regulates
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Veterans and Agent Orange: Update 2000 gene expression, the aryl hydrocarbon receptor (AhR). The binding of TCDD to the AhR triggers a sequence of cellular events that involve interactions with numerous other cellular components. Research in animals that have been engineered not to express the AhR, and in animals with slightly different forms of the receptor, supports a role of the AhR in the toxicity of TCDD. Modulation of genes by AhR may have species-, cell-, and developmental stage-specific patterns, suggesting that the molecular and cellular pathways that lead to any particular toxic event are complex. Additional research demonstrates that the biochemical and biological outcomes of TCDD exposure can be modulated by numerous other proteins with which the AhR interacts. It is plausible, for example, that the AhR could divert other proteins and transcription factors from other signaling pathways; the disruption of these other pathways could have serious consequences for a number of cell and tissue processes. With respect to the mechanism underlying the carcinogenic effects of TCDD, it still appears that TCDD does not act directly on the genetic material. Effects on enzymes or hormones could be involved in the carcinogenicity of TCDD. Disease Outcomes Recent experiments demonstrated that 2,4-D can cause behavioral effects, muscle weakness, and incoordination in animals, but these effects are seen only at high doses. Reproductive and developmental effects have been seen in animals, but also only at high doses. Furthermore, a precursor of 2,4-D,4-(2,4-dichlorophenoxy)butyric acid (2,4-DB), did not cause an immunotoxic or carcinogenic response in rodents or dogs. Evidence suggests that cacodylic acid can act as a tumor promoter in mice and rats. Many effects have been observed in animals following exposure to TCDD, and this contaminant is considered more toxic than the pure components of the herbicides used in Vietnam. Sensitivity to TCDD varies among species and strains, but most species studied develop a “wasting syndrome” from acutely toxic doses. This syndrome is characterized by a loss of body weight and fatty tissue. One target of TCDD is the liver, where lethal doses of TCDD cause necrosis, but the effect is dependent on the animal species exposed. Effects on the morphology and function of the liver are seen at lower doses. A recent study demonstrated that TCDD inhibits the ability of the liver to accumulate vitamin A. TCDD may affect, directly or indirectly, many organs of the endocrine system in a species-specific manner. For example, thyroid hormone levels are altered by treatment of animals with TCDD. Some of the results in different studies of thyroid hormones are contradictory, however, making interpretation of these results difficult. The adult nervous system has been shown to be sensitive to the effects of TCDD only at high doses. After in utero exposure, however, even these high-
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Veterans and Agent Orange: Update 2000 dose effects are not straightforward, with in utero TCDD exposure decreasing performance on certain learning and memory tasks, but improving performance on other tasks. In animals, one of the most sensitive systems to TCDD toxicity is the immune system. Recent studies have demonstrated that TCDD can alter the levels of immune cells, the measured activity of these cells, and the ability of animals to fight off infection. Effects on the immune system, however, appear to depend on the species, strain, and developmental stage of animal studied. Reproductive and developmental effects have been seen in animals exposed to TCDD. For example, effects on sperm counts, sperm production, and seminal vesicle weights have been seen in male offspring of rats treated with TCDD during pregnancy. Effects on the female reproductive system have also been seen following developmental exposure to TCDD. In some recent studies, however, the effects on the male and female reproductive system were not accompanied by effects on reproductive outcomes. The mechanism underlying the reproductive effects is not known, but it is possible that they are secondary to effects on reproductive hormones. In recent studies, TCDD did not affect surgically induced endometrial lesions in rats, although effects were seen in earlier studies. Pre- and postnatal exposure of mice to TCDD increased sensitivity to endometrial lesion growth. TCDD is an extremely potent promoter of neoplasia in laboratory rats. In a recent study, there was an increase in hepatic foci at doses as low as 0.01 ng/kg/ day. This is the lowest dose of TCDD to promote tumors to date. Recent data also suggest that promotion of liver tumors by TCDD in female rats is dependent on continuous exposure to TCDD. Relevance to Human Health As indicated above, exposure to 2,3,7,8-TCDD has been associated with both cancer and noncancer end points in animals, and most 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. Animal research indicates that TCDD can cause both cancers and benign tumors, and also enhance the incidence of certain cancers or tumors in the presence of known carcinogens. However, experimental animals differ greatly in their susceptibility to TCDD-induced effects; the sites at which tumors are induced also vary from species to species. Other noncancer health effects vary according to dose and to the animal exposed. Controversy still 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 that health effects caused by Agent Orange occur through chemicals other than TCDD. Al-
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Veterans and Agent Orange: Update 2000 though concerns have been raised about nondioxin contaminants of herbicides, far too little is known about the distribution and concentration of these compounds in the formulations used in Vietnam to draw conclusions concerning their impact. Considerable uncertainty remains about how to apply mechanistic information from non-human studies to an evaluation of the potential health effects in Vietnam veterans of herbicide or dioxin exposure. Therefore, 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. A great deal of research on biological mechanisms has been and continues to be conducted, especially on TCDD. No single mechanism has been established as underlying the toxic effects of TCDD, and with the many different effects seen, more than a single mechanism might exist. It is hoped that as the cellular mechanisms of these compounds are discovered, subsequent VAO updates will have better information on which to base conclusions and to aid in determining the relevance of experimental data to effects in humans. OVERVIEW OF THE SCIENTIFIC LITERATURE IN UPDATE 2000 Toxicokinetics Since Update 1998, no data have been published that add to the information available on the toxicokinetics of 2,4-D,2,4,5-T, or picloram. Research has been conducted on the distribution of cacodylic acid, an organic form of arsenic that was used as an herbicide in small quantities in Vietnam. Research in mice demonstrates that the administered dose minimally affects the distribution and excretion of organic arsenicals. In humans it was observed that at least some organic forms of arsenic are transferred to the fetus and that organic arsenicals are distributed more to organs that are high in lipids. In contrast, a great deal of research conducted since Update 1998 improves the understanding of the processes that affect the distribution of TCDD to different parts of the body. Studies continue to demonstrate that an enzyme, cytochrome P450 1A2 (CYP1A2), plays an important role in the distribution of TCDD. CYP1A2 is expressed at high levels in the liver and binds TCDD. Because of this binding, the levels of TCDD in the liver are more dependent on CYP1A2 levels than on liver lipid content, but this is highly dependent on the concentration of TCDD. Experiments in mice that do not express the Cyp1A2 gene (Cyp1A2 knockout mice) in the liver further demonstrate the importance of CYP1A2 protein in the distribution of TCDD. A greater amount of TCDD is distributed to other organs, and urinary excretion is increased in knockout animals. In addition to CYP1A2 levels, other polyhalogenated aromatic hydrocar-
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Veterans and Agent Orange: Update 2000 bons (PHAHs) can affect the toxicokinetics of TCDD; there is decreased retention of TCDD in the presence of other PHAHs. Studies have been conducted investigating the length of time that TCDD remains in the body and the factors that can influence this. Follow-up examinations in Operation Ranch Hand veterans indicate that TCDD has a mean half-life of 7.6 years and elimination is inversely proportional to bodyfat content, but that age does not have an observable effect on elimination. A study in non-Ranch Hand Vietnam veterans, however, shows that age has a weak effect on the elimination rate of TCDD, and a study in an occupationally exposed cohort also indicates that the elimination rate changes with age, but this may, in part, reflect changes in body composition with age. These studies converge on a consistent estimate of half-life but are inconsistent on the effect of age. TCDD is also excreted in breast milk, causing both a decrease in maternal TCDD levels and the transfer of TCDD to breast-fed infants. Recent studies show that the volume of breast milk produced can affect the rate at which TCDD is eliminated from the mother. In addition, the concentration of TCDD in breast milk decreases over time with continued breast feeding. Modeling the residue kinetics in infants indicates that the TCDD initially accumulated in infants following exposure from breast feeding is substantially decreased by 2 years of age. Dietary factors also can affect the absorption and excretion of TCDD. The amount of fat in the diet can greatly affect absorption and excretion. Ingestion of a nonabsorbed dietary fat substitute (olestra) increased the fecal excretion of a very high dose of TCDD. It is important to know whether the TCDD levels measured in blood are representative of levels in target tissues because TCDD is often measured in blood in human studies. Autopsy studies of human tissues indicate that there is a correlation between the levels of TCDD measured in the blood lipids and the levels measured in adipose, kidney, spleen, liver, and brain tissue, but not in muscle and lung tissue. A study in rodents demonstrates that concentrations of TCDD in the fetal compartment are comparable to the levels in maternal blood. Mechanisms of Toxic Action Since Update 1998, the actions of 2,4-D,2,4,5-T, cacodylic acid, and TCDD at the molecular and cellular level have been investigated. These studies enhance our understanding of the actions of these chemicals, particularly TCDD, but the exact mechanisms by which these chemicals are toxic still are not established. No new research has been published that provides data on the mechanisms underlying the toxic effects of picloram. 2,4-D has previously been shown to have low oncogenic potential, with genotoxic effects seen only at high concentrations. Recent evidence is consistent with these earlier data. Only a high concentration of 2,4-D was genotoxic in a wing spot test. There was no evidence of genotoxicity in assays testing for re-
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Veterans and Agent Orange: Update 2000 combination; bacterial gene mutation; chromosomal aberrations; forward mutations in the hypoxanthine-guanine phosphoribosyl transferase gene (HGPRT) locus; and induction of DNA damage, repair, and unscheduled synthesis, as well as in tests of the frequency of micronucleated polychromatic erythrocytes in mice. Research continues to demonstrate effects of 2,4-D on hormone levels and the function of the nervous system. 2,4-D decreased serum thyroxine concentrations, testosterone concentrations in serum and gonads, and serum concentrations of lutenizing hormone, follicle-stimulating hormone, prostaglandin I2, and prostaglandin E2. 2,4-D also inhibited neurite extension in primary cultures of cerebellar granule cells. This effect is accompanied by a reduction in cellular microtubules, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. It also inhibits the polymerization of purified tubulin. Although the biological relevance of these affects is not established, it is possible that the effects on hormones and the nervous system are involved in the reproductive and neurological toxicity seen at high doses of 2,4-D. Both 2,4-D and 2,4,5-T have inhibitory effects on the formation and renal transport of benzylglycine. These compounds inhibit the mitochondrial enzyme benzoyl-CoA synthetase and competitively inhibit an organic acid transporter, inhibiting the secretion of benzoylglycine. 2,4,5-T also activated Neu tyrosine kinase in a cell-free system, stimulated the enzyme in MCF-7 cells, and stimulated foci formation of MCF-7 cells. Although activation of Neu tyrosine kinase has been found to be correlated with an increased incidence of breast cancer in animal models, how these cellular and biochemical effects are related to any toxic end point is unknown. Most research indicates that cacodylic acid can act as a promoter in the carcinogenic process, and one study has demonstrated that it can cause aneuploidy. It also can disrupt cell growth by affecting the microtubule network. Evidence indicates that it decreases liver glutathione levels, as well as pulmonary and hepatic ornithine decarboxylase levels. Studies published since Update 1998 are consistent with the hypothesis that TCDD produces its biological and toxic effects by binding to the AhR. For example, recent data indicate that TCDD has only minimal teratogenicity, if any, in AhR knockout mice compared to wild-type mice. Data from knockout mice also suggest that the AhR plays an important, but as yet unknown, developmental and physiological role. Many of the recent data published are consistent also with the notion that cellular processes involving growth, maturation, and differentiation are sensitive to TCDD-induced effects. Findings in animals indicating that reproductive, developmental, and oncogenic end points appear to be sensitive to TCDD are consistent with this notion, and the cellular data provide biologic plausibility for similar end points of toxicity in exposed humans. However, many of the responses to TCDD are tissue- and species-specific and the mechanistic basis for these differences is not completely understood.
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Veterans and Agent Orange: Update 2000 The presence of the AhR and ARNT in a variety of tissues from different animal species and strains is well documented. Detailed analysis of variant forms has provided much information associating structure and expression levels with function. Furthermore, experiments in species and strains expressing different forms of the AhR suggest that differences in specific regions of the AhR may be in part responsible for differential sensitivity to TCDD. Evidence continues to indicate that the sequence of the AhR in humans is highly conserved among different individuals. Research has shown that the association of several proteins with newly synthesized AhR may modulate AhR function. For example, association with 90 kDa heat shock protein (HSP90) is important to maintain the AhR in a conformation that can bind ligand. Recent data are consistent with a mechanism in which HSP90 is released from the ligand-bound AhR following nuclear localization concomitant with ARNT-AhR dimerization. One study, however, demonstrated that dissociation of HSP90 is not required for nuclear translocation of the AhR but is essential for dimerization with ARNT. Many of the more recent investigations have focused on identifying and characterizing factors that may modulate, by either activation or repression, the ability of the activated AhR-ARNT complex to alter gene expression. In addition, several studies have noted the ability of a variety of AhR ligands to act as receptor antagonists. Studies have investigated the roles of immunophilin proteins, nuclear accessory proteins or coactivators, repression by as yet unidentified cellular factors specific to certain cell types, nuclear factor κB (NF-κB), and histone acetylators and deacetylators. Investigations into the endogenous ligand for the AhR continue. Although several endogenous compounds which bind to the AhR have been described, it is not yet clear whether any of these have any physiological significance. Naturally occurring ligands for the receptor include resveratrol, curcumin, tryptophan metabolites, galangin, the dietary flavonols quercetin and kaempferol, lipoxin A4, and products of heme metabolism. Details of the many studies investigating the cellular and molecular effects of TCDD are summarized later in this chapter. Disease Outcomes Studies published since Update 1998 are consistent with the previous view that 2,4-D is relatively nontoxic and has weak oncogenic potential. Decreased motor activity, muscle weakness, motor incoordination, decreased weight gain, and serum alterations were seen only at doses greater than 100 mg/kg. Reversible and permanent behavioral alterations have also been seen in rats following treatment with high doses of 2,4-D from gestational day 16 to postnatal day 23. These observations are consistent with previous studies suggesting that 2,4-D could have neurotoxic effects. Exposure to 2,4-D had no effect on lymphocyte blasto-
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Veterans and Agent Orange: Update 2000 genesis, immunoglobulin M (IgM) antibody production in response to sheep red blood cells, expression of lymphocyte cell surface markers, or phagocytic function of peritoneal macrophages. Only mild, reversible effects on the skin were observed following 2,4-D treatments. Developing fetuses appear to be the most sensitive to the effects of 4-(2,4–2,4-dichlorophenoxy)butyric acid (2,4-DB), of which 2,4-D is the major metabolite, but even these effects occur at relatively high concentrations. There was no evidence of an oncogenic response in studies of rodents and dogs treated with 2,4-DB. The ability of 2,4,5-T to produce myelotoxicity was examined using the mouse granulocyte-macrophage (GM) colony-forming unit (CFU) assay and the 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) test for inhibition of proliferation. The concentration that caused a 50 percent inhibition in the assays (i.e., the IC50) was at least 202 µM, indicating a relatively weak potency of 2,4,5-T to produce myelotoxicity. No other studies were found that investigate disease outcomes following exposure to 2,4,5-T. The pulmonary carcinogenic activity of cacodylic acid (dimethylarsinic acid, DMA) was examined in mice; treated mice developed more pulmonary neoplasms (number per mouse) than untreated mice. Exposure to DMA for 2 years produced bladder hyperplasia and tumors in rats. In other studies, DMA acted as a skin cancer promoter in transgenic mice sensitive to carcinogens and in hairless mice irradiated with ultraviolet B radiation. There are no recent studies investigating toxic effects following exposure to picloram; one study looking at oxidative functions showed effects of Tordon 75D (a mixture of the triisopropanolamine salts of 2,4-D and picloram) and attributed these effects to the surfactant in the mixture, not picloram. Many effects have been observed in animals following exposure to TCDD. The classic symptoms of the “wasting syndrome” (i.e., extreme loss of body weight, decreased food consumption with an increase in consumption prior to death, and bloody stool) were observed in female mink treated with TCDD. Thermoregulatory control is affected by TCDD. A study in rats indicates that the thermoregulatory centers in the hypothalamus are not permanently altered by TCDD. Neurotoxic effects have been observed after developmental exposure to TCDD, with some learning and memory tasks being affected in rats. Of the many organ systems affected by TCDD, one of the most sensitive is the immune system. Increased parasitic larval burdens occurred in rats following TCDD exposure; there was some indication that age increased the sensitivity of humoral immunity to TCDD exposure. TCDD has been shown to decrease delayed-type hypersensitivity responses, decrease the total percentage of CD4+ cells and the percentage of the CD4+ cells cycling following repeated exposure, and stimulate the production of interleukin-2 (IL-2) and increase the percentage of CD4+ and CD8+ cells in the S and G2M phase of lymphocyte cycling in primed rats. Although there are considerable species and strain differences in immune
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Veterans and Agent Orange: Update 2000 responses to TCDD, some evidence indicates that TCDD compromises (suppresses) the immune system of laboratory animals. Developmental effects on the male reproductive system have been seen following exposure to TCDD. Male offspring of rats gavaged on gestational day 15 with TCDD had significantly decreased body and seminal vesicle weights, and decreased epithelial branching and differentiation in the seminal vesicles. In another study, the number of sperm per cauda epididymis and daily sperm production were decreased, and sperm transit rate was affected at puberty and adulthood in male offspring of female rats treated with TCDD. In the highest-TCDD-exposure group, serum testosterone concentration was decreased at adulthood. In this study, however, reproductive outcomes of those males were not affected. Similarly, female offspring of pregnant female hamsters treated with TCDD on gestational day 15 showed effects on the reproductive system, but reproductive outcomes in female progeny were not reported. In recent studies TCDD did not affect surgically induced endometrial lesions in rats, although effects were seen in earlier studies. The lesions were increased in mice only with a combination of perinatal and adult exposure to TCDD. Some researchers suggest that TCDD blocks the ability of progesterone to prevent experimental endometriosis, which correlates with its ability to inhibit progesterone-associated transforming growth factor-β2 (TGF-β2) expression and endometrial matrix metalloproteinase suppression. In utero and lactational exposure of rats to TCDD decreased prostate weight without inhibiting testicular androgen production or decreasing serum androgen concentrations. Additional studies showed that the prostatic epithelial budding process was impaired, suggesting that in utero and lactational TCDD exposure interferes with prostate development by decreasing early epithelial growth, delaying cell differentiation, and producing alterations in epithelial and stromal cell histological arrangement and the spatial distribution of androgen receptor expression. Data are conflicting as to whether TCDD induces cellular apoptosis. This may be highly dependent on cell type. TCDD failed to induce apoptosis in Fas-deficient and Fas-ligand-defective mice at the lower doses tested, compared to control wild-type mice, suggesting that Fas-Fas ligand interactions may play a role in the TCDD-mediated induction of apoptosis. TCDD is an extremely potent promoter of neoplasia in laboratory rats. TCDD significantly increased the volume fraction and number of altered hepatic foci at the highest dose. Increases in the number of guanosine 5'-triphosphatase (GTPase) and adenosine 5'-triphosphatase (ATPase) deficient altered hepatic foci per cubic centimeter also occurred at doses as low as 0.01 ng/kg/day. This is the lowest dose of TCDD to promote tumors to date. Recent data also suggest that promotion of liver tumors by TCDD in female rats is dependent on continuous exposure to TCDD.
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Veterans and Agent Orange: Update 2000 Hong SJ, Grover CA, Safe SH, Tiffany-Castiglioni E, Frye GD. 1998. Halogenated aromatic hydrocarbons suppress CA1 field excitatory postsynaptic potentials in rat hippocampal slices. Toxicology and Applied Pharmacology 148(1):7–13. Huang W, Koller LD. 1998. 2,3,7,8-Tetrachlorodibenzo-p-dioxin co-stimulates staphylococcal enterotoxin b (SEB) cytokine production and phentype cell cycling in Long-Evans rats. International Journal of Immunopharmacology 20(1–3):39–56. Huang W, Koller LD. 1999. Effects of a single or repeated dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on T-cell subpopulations in the Long-Evans rat. Toxicology Letters 109(1– 2):97–104. Huff J. 1993. Chemicals and cancer in humans: first evidence in experimental animals. Environmental Health Perspectives 100:201–210. Huff J, Lucier G, Tritscher A. 1994. Carcinogenicity of TCDD: experimental, mechanistic, and epidemiologic evidence. Annual Review of Pharmacology and Toxicology 34:343–372. Hughes MF, Kenyon EM. 1998. Dose-dependent effects on the disposition on monomethylarsonic acid and dimethylarsinic acid in the mouse after intravenous administration. Journal of Toxicology and Environmental Health 53(2):95–112. Hughes MF, Kenyon EM, Edwards BC, Mitchell CT, Thomas D. 1999. Strain-dependent disposition of inorganic arsenic in the mouse. Toxicology 137(2):95–108. Hughes MF, Del Razo LM, Kenyon EM. 2000. Dose-dependent effects on tissue distribution and metabolism of dimethylarsinic acid in the mouse after intravenous administration. Toxicology 143(2):155–166. Hurst CH, Abbott BD, DeVito MJ, Birnbaum LS. 1998. 2,3,7,8-Tetrachlorodibenzo-p-dioxin in pregnant Long Evans rats: disposition to maternal and embryo/fetal tissues. Toxicological Sciences 45(2):129–136. Hurst CH, DeVito MJ, Setzer RW, Birnbaum LS. 2000. Acute administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in pregnant Long Evans rats: association of measured tissue concentrations with developmental effects. Toxicological Sciences 53(2):411–420. Hushka LJ, Williams JS, Greenlee WF. 1998. Characterization of 2,3,7,8-tetrachlorodibenzfurandependent suppression and AH receptor pathway gene expression in the developing mouse mammary gland. Toxicology and Applied Pharmacology 152(1):200–210. Iida T, Hirakawa H, Matsueda T, Nagayama J, Nagata T. 1999. Polychlorinated dibenzo-p-dioxins and related compounds: correlations of levels in human tissues and in blood. Chemosphere 38(12):2767–2774. Ikuta T, Egushi H, Tachibana T, Yoneda Y, Kawajiri K. 1998. Nuclear localization and export signals of the human aryl hydrocarbon receptor. Journal of Biological Chemistry 273(5):2895– 2904. Ikuta T, Tachibana T, Watanabe J, Yoshida M, Yoneda Y, Kawajiri K. 2000. Nucleocytoplasmic shuttling of the aryl hydrocarbon receptor. Journal of Biochemistry 127(3):503–509. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. Jana NR, Sarkar S, Yonemoto J, Tohyama C, Sone H. 1998. Strain differences in cytochrome P450 1A1 gene expression caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver: role of the aryl hydrocarbon receptor and its nuclear translocator. Biochemical and Biophysical Research Communications 248(3):554–558. Jana NR, Sarkar S, Ishizuka M, Yonemoto J, Tohyama C, Sone H. 1999a. Role of estradiol receptora in differential expression of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible genes in the RL95– 2 and KLE human endometrial cancer cell lines. Archives of Biochemistry and Biophysics 368(1):31–39.
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Veterans and Agent Orange: Update 2000 Jana NR, Sarkar S, Ishizuka M, Yonemoto J, Tohyama C, Sone H. 1999b. Cross-talk between 2,3,7,8-tetrachlorodibenzo-p-dioxin and testosterone signal transduction pathways in LNCaP prostate cancer cells. Biochemical and Biophysical Research Communications 256(3):462– 468. Kamath AB, Nagarkatti PS, Nagarkatti M. 1998. Characterization of phenotypic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocytes in vivo and its effect on apoptosis. Toxicology and Applied Pharmacology 150(1):117–124. Kamath AB, Camacho I, Nagarkatti PS, Nagarkatti M. 1999. Role of Fas-Fas ligand interactions in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity: increased resistance of thymocytes from Fas-deficient (lpr) and Fas ligand-defective (gld) mice to TCDD-induced toxicity. Toxicology and Applied Pharmacology 160(2):141–155. Karchner SI, Powell WH, Harm, ME. 1999. Identification and functional characterization of two highly divergent aryl hydrocarbon receptors (AHR1 and AHR2) in the teleost Fundulus heteroclitus. Evidence for a novel subfamily of ligand-binding basic helix loop helix-per-ARNT-Sim (bHLH-PAS) factors. Journal of Biological Chemistry 274(47):33814–33824. Kashani M, Steiner G, Haitel A, Schaufler K, Thalhammer T, Amann G, Kramer G, Marberger M,Scholler A. 1998. Expression of the aryl hydrocarbon receptor (AhR) and the aryl hydrocarbon receptor nuclear translocator (ARNT) in fetal, benign hyperplastic, and malignant prostate. Prostate 37(2):98–108. Kato K, Yamanaka K, Hasegawa A, Okada S. 1999. Dimethylarsinic acid exposure causes accumulation of Hsp72 in cell nuclei and suppresses apoptosis in human alveolar cultured (L-132) cells. Biological and Pharmaceutical Bulletin 22(11):1185–1188. Kaya B, Yanikoglu A, Marcos R. 1999. Genotoxicity studies on the phenoxyacetates 2,4-D and 4-CPA in the Drosophila wing spot test. Teratogenesis, Carcinogenesis, and Mutagenesis 19(4): 305–312. Kazlauskas A, Poellinger L, Pongratz I. 1999. Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (aryl hydrocarbon) receptor. Journal of Biological Chemistry 274(19):13519–13524. Kelley SK, Nilsson CB, Green MH, Green JB, Hakansson H. 1998. Use of model-based compartmental analysis to study effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on vitamin A kinetics in rats. Toxicological Sciences 44(1):1–13. Kim JE, Sheen YY. 2000. Inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-stimulated Cyp1a1 promoter activity by hypoxic agents. Biochemical Pharmacology 59(12):1549–1556. Kim W, Hwang S, Lee H, Song H, Kim S. 1999. Panax ginseng protects the testis against 2,3,7,8-tetrachlorodibenzo-p-dioxin induced testicular damage in guinea pigs. BJU International 83(7): 842–849. Kimura T, Kuroki K, Doi K. 1998. Dermatotoxicity of agricultural chemicals in the dorsal skin of hairless dogs. Toxicologic Pathology 26(3):442–447. Klinge CM, Bowers, JL, Kulakosky PC, Kamboj KK, Swanson HI. 1999. The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements. Molecular and Cellular Endocrinology 157(1–2):105–119. Klinge CM, Kaur K, Swanson HI. 2000. The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TF1 and ERRalpha1. Archives of Biochemistry and Biophysics 373(1):163–174. Kohle C, Gschaidmeier H, Lauth D, Topell S, Zitzer H, Bock KW. 1999. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells. Archives of Toxicology 73(3):152–158. Kolluri SK, Weiss C, Koff A, Gottlicher M. 1999. p27Kip1 induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells. Genes and Development 13(13):1742–1753.
OCR for page 94
Veterans and Agent Orange: Update 2000 Korkalainen M, Tuomisto J, Pohjanvirta R. 2000. Restructured transactivation domain in hamster AH receptor. Biochemical and Biophysical Research Communications 273(1):272–281. Krig SR, Rice RH. 2000. TCDD suppression of tissue transglutaminase stimulation by retinoids in malignant human keratinocytes. Toxicological Sciences 56(2):357–364. Kuchenhoff A, Seliger G, Klonisch T, Tscheudschilsuren G, Kaltwasser P, Seliger E, Buchmann J, Fischer B. 1999. Arylhydrocarbon receptor expression in the human endometrium. Fertility and Sterility 71(2):354–360. Kumar MB, Tarpey RW, Perdew GH. 1999. Differential recruitment of coactivator RIP 140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs. Journal of Biological Chemistry 274(32):22155–22164. Lahvis GP, Bradfield CA. 1998. Ahr null alleles: distinctive or different? Biochemical Pharmacology 56(7):781–787. Review. Lahvis GP, Lindell SL, Thomas RS, McCuskey RS, Murphy C, Glover E, Bentz M, Southard J, Bradfield CA. 2000. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proceedings National Academy of Sciences USA 97: 10442–10447. LaKind JS, Berlin CM, Park CN, Naiman DQ, Gudka NJ. 2000. Methodology for characterizing distributions of incremental body burdens of 2,3,7,8-TCDD and DDE from breast milk in North American nursing infants. Journal of Toxicology and Environmental Health 59(8):605– 639. Lang DS, Becker S, Devlin RB, Koren HS. 1998. Cell-specific differences in the susceptibility of potential cellular targets of human origin derived from blood and lung following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Cell Biology and Toxicology 14(1):23–38. La Pres JJ, Glover E, Dunham EE, Bunger MK, Bradfield CA. 2000. ARA9 modifies agonist signaling through an increase in cytosolic aryl hydrocarbon receptor. Journal of Biological Chemistry 275(9):6153–6159. Lavin AL, Hahn DJ, Gasiewicz TA. 1998. Expression of functional aromatic hydrocarbon receptor and aromatic hydrocarbon nuclear translocator proteins in murine bone marrow stromal cells. Archives of Biochemistry and Biophysics 352(1):9–18. Lawrence BP, Kerkvliet NI. 1998. Role of altered arachidonic acid metabolism in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced immune suppression of C57B1/6 mice. Toxicological Sciences 42(1):13–22. Lee CA, Lawrence BP, Kerkvliet NI, Rifkind AB. 1998. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induction of cytochrome P450-dependent arachidonic acid metabolism in mouse liver microsomes: evidence for species-specific differences in responses. Toxicology and Applied Pharmacology 153(1):1–11. Lees MJ, Whitelaw ML. 1999. Multiple roles of ligand in transforming the dioxin receptor to an active basic helix-loop-helix/PAS transcription factor complex with the nuclear protein Arnt. Molecular and Cellular Biology 19(18):5811–5822. Li W, Wanibuchi H, Salim EI, Yamamoto S, Yoshida K, Endo G, Fokushima S. 1998. Promotion of NCI-Black-Reiter male rat bladder carcinogenesis by dimethylarsinic acid on organic compound. Cancer Letters 134(1):24–36. Li W, Wu WZ, Barbara RB, Schramm KW, Kettrup A. 1999. A new enzyme immunoassay for PCDD/F TEQ screening in environmental samples: comparison to micro-EROD assay and to chemical analysis. Chemosphere 38(14):3313–3318. Liu PCC, Dunlap DY, Matsumura F. 1998. Suppression of C/EBPalpha and induction of C/EBPbeta by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse adipose tissue and liver. Biochemical Pharmacology 55(10):1647–1655. Loeffler IK, Peterson RE. 1999. Interactive effects of TCDD and p,p’-DDE on male reproductive tract development in in utero and lactationally exposed rats. Toxicology and Applied Pharmacology 154(1):28–39.
OCR for page 95
Veterans and Agent Orange: Update 2000 Long WP, Perdew GH. 1999. Lack of an absolute requirement for the native aryl hydrocarbon receptor (AhR) and AhR nuclear translocator transactivation domains in protein kinase C-mediated modulation of the AhR pathway. Archives of Biochemistry and Biophysics 371(2): 246–259. Long WP, Pray-Grant M, Tsai JC, Perdew GH. 1998. Protein kinase C activity is required for aryl hydrocarbon receptor pathway-mediated signal transduction. Molecular Pharmacology 53(4): 691–700. Long WP, Chen X, Perdew GH. 1999. Protein kinase C modulates aryl hydrocarbon receptor nuclear translocator protein-mediated transactivation potential in a dimer context. Journal of Biological Chemistry 274(18):12391–12400. Lorenzen A, Okey AB. 1991. Detection and characterization of Ah receptor in tissue and cells from human tonsils. Toxicology and Applied Pharmacology 107:203–214. Luebke RW, Copeland CB, Andrews DL. 1999. Effects of aging on resistance to Trichinella spiralis infection in rodents exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology 136(1):15–26. Ma Q, Baldwin KT. 2000. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced degradation of aryl hydrocarbon receptor (AhR) by the ubiquitin-proteasome pathway. Role of the transcription activation and DNA binding of AHR. Journal of Biological Chemistry 275(12):8432–8438. Ma Q, Whitlock JP Jr. 1996. The aromatic hydrocarbon receptor modulates the Hepa 1c1c7 cell cycle and differentiated state independently of dioxin. Molecular and Cellular Biology 16(5): 2144–2150. Machala M, Drabek P, Neca J, Kolarova J, Svobodova Z. 1998. Biochemical markers for differentiation of exposures to nonplanar polychlorinated biphenyls, organochlorine pesticides or 2,3,7,8-tetrachlorodibenzo-p-dioxin in trout liver. Ecotoxicology and Environmental Safety 41(1):107– 111. Mahajan SS, Rifkind AB. 1999. Transcriptional activation of avian CYP1A4 and CYP1A5 by 2,3,7,8-tetrachlorodibenzo-p-dioxin: differences in gene expression and regulation compared to mammalian CYP1A1 and CYP1A2. Toxicology and Applied Pharmacology 155(1):96–106. Matsumura F, Enan E, Dunlap DY, Pinkerton KE, Peake J. 1997. Altered in vivo toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C-SRC deficient mice. Biochemical Pharmacology 53(10):1397–1404. Meek MD. 1998. Ah receptor and estrogen receptor-dependent modulation of gene expression by extracts of diesel exhaust particles. Environmental Research 79(2):114–121. Meek MD, Finch GL. 1999. Diluted mainstream cigarette smoke condensates activate estrogen receptor and aryl hydrocarbon receptor-mediated gene transcription. Environmental Research 80(1):9–17. Meyer BK, Perdew GH. 1999. Characterization of the AhR-hsp90-XAP2 core complex and the role of the immunophilin-related protein XAP2 in AhR stabilization. Biochemistry 38(28):8907– 8917. Meyer BK, Pray-Grant MG, Vanden Heuvel JP, Perdew GH. 1998. Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity. Molecular and Cellular Biology 18(2):978–988. Michalek JE, Tripathi RC. 1999. Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 15-year follow-up. Journal of Toxicology and Environmental Health 57(6):369–378. Michalek JE, Rahe AJ, Kulkarni PM, Tripathi RC. 1998. Levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in 1,302 unexposed Air Force Vietnam-era veterans. Journal of Exposure Analysis and Environmental Epidemiology 8(1):59–64. Miller, CA III. 1999. A human aryl hydrocarbon receptor signaling pathway constructed in yeast displays additive responses to ligand mixtures. Toxicology and Applied Pharmacology 160(3): 297–303. Mimura J, Ema M, Sogawa K, Fujii-Kuriyama Y. 1999. Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes and Development 13(1):20–25.
OCR for page 96
Veterans and Agent Orange: Update 2000 Morgulis MS, Oliveira GH, Dagli ML, Palermo-Neto J. 1998. Acute 2,4-dichlorophenoxyacetic acid intoxication in broiler chicks. Poultry Science 77(4):509–515. Morikawa T, Wanibuchi H, Morimura K, Ogawa M, Fukushima S. 2000. Promotion of skin carcinogenesis by dimethylarsinic acid in keratin (K6)/ODC transgenic mice. Japanese Journal of Cancer Research 91(6):579–581. Moser GA, McLachlan MS. 1999. A non-absorbable dietary fat substitute enhances elimination of persistent lipophilic contaminants in humans. Chemosphere 39(9):1513–1521. 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(2):374–383. Neubert D. 1992. Evaluation of toxicity of TCDD in animals as a basis for human risk assessment. Toxic Substances Journal 12:237–276. Nguyen TA, Hoivik D, Lee JE, Safe S. 1999. Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex. Archives of Biochemistry and Biophysics 367(2):250–257. Nohara K, Ushio H, Tsukumo S, Kobayashi T, Kijima M, Tohyama C, Fujimaki H. 2000. Alterations of thymocyte development, thymic emigrants and peripheral T cell population in rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology 145(2–3):227–235. Oakes DJ, Pollack JK. 1999. Effects of a herbicide formulation, Tordon 75D®, and its individual components on the oxidative functions of mitochondria. Toxicology 136(1):41–52. Ochi T, Nakajima F, Fukumori N. 1998. Different effects of inorganic and dimethylated arsenic compounds on cell morphology, cytoskeletal organization, and DNA synthesis in cultured Chinese hamster V79 cells. Archives of Toxicology 72(9):566–573. Ochi T, Nakajima F, Nasui M. 1999. Distribution of gamma-tubulin in multipolar spindles and multinucleated cells induced by dimethylarsinic acid, a methylated derivative of inorganic arsenics, in Chinese hamster V79 cells. Toxicology 136(2–3):79–88. Parrish AR, Alejandro NF, Bowes RC, Ramos KS. 1998. Cytotoxic response profiles of cultured renal epitheial and mesenchymal cells to selected aromatic hydrocarbons. Toxicology in Vitro 12:219–232. Partanen AM, Alaluusua S, Miettinen PJ, Thesleff I, Tuomisto J, Pohjanvirta R, Lukinmaa PL. 1998. Epidermal growth factor receptor as a mediator of developmental toxicity of dioxin in mouse embryonic teeth. Laboratory Investigation 78(12):1473–1481. Patandin S, Dagnelie PC, Mulder PG, Op de Coul E, van der Veen JE, Weisglas-Kuperus N, Sauer PJ. 1999. Dietary exposure to polychlorinated biphenyls and dioxins from infancy until adulthood: A comparison between breast-feeding, toddler, and long-term exposure. Environmental Health Perspectives 107(1):45–51. Perdew GH, Hollenback CE. 1995. Evidence for two functionally distinct forms of the human Ah receptor. Journal of Biochemical Toxicology 10(2):95–102. Petrick JS, Ayala-Fierro F, Cullen WR, Carter DE, Vasken Aposhian H. 2000. Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes. Toxicology and Applied Pharmacology 163 (2):203–207. 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(3):247–255. Phelan DM, Brackney WR, Denison MS. 1998. The Ah receptor can bind ligand in the absence of receptor-associated heat-shock protein 90. Archives of Biochemistry and Biophysics 353(1):47– 54. Pohjanvirta R, Wong JMY, Li W, Harper PA, Tuomisto J, Okey AB. 1998. Point mutation in intron sequence causes altered carboxyl-terminal structure in the aryl hydrocarbon receptor of the most 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant rat strain . Molecular Pharmacology 54(1): 86–93.
OCR for page 97
Veterans and Agent Orange: Update 2000 Pohjanvirta R, Viluksela M, Tuomisto JT, Unkila M, Karasinska J, Franc MA, Holowenko M, Giannone JV, Harper PA, Tuomisto J, Okey AB. 1999. Physicochemical differences in the AH receptors of the most TCDD-susceptible and the most TCDD-resistant rat strains. Toxicology and Applied Pharmacology 155(1):82–95. Pollenz RS, Santostefano MJ, Klett E, Richardson VM, Necela B, Birnbaum LS. 1998. Female Sprague-Dawley rats exposed to a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin exhibit sustained depletion of aryl hydrocarbon receptor protein in liver, spleen, thymus, and lung. Toxicological Sciences 42(2):117–128. Prell RA, Dearstyne E, Steppan LG, Vella AT, Kerkvliet NI. 2000. CTL hyporesponsiveness induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin: role of cytokines and apoptosis. Toxicology and Applied Pharmacology 166(3):214–221. Pryputniewicz SJ, Nagarkatti M, Nagarkatti PS. 1998. Differential induction of apoptosis in activated and resting T cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its repercussion on T cell responsiveness. Toxicology 129(2–3):211–226. 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, Dalton TP, Chang C, Knudsen ES, Maier MA. 2000b. Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest. Journal of Biological Chemistry 275(4):2943–2950. Quadri SA, Quadri 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, Anderson LM. 1998. Levels and membrane localization of the c-K-ras p21 protein in lungs of mice of different genetic strains and effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Aroclor 1254. Carcinogenesis 19(3):463–470. Rawlings NC, Cook SJ, Waldbillig D. 1998. Effects of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D, and pentachlorophenol on the metabolic endocrine and reproductive endocrine system in ewes . Journal of Toxicology and Environmental Health 54(1):21–36. Reiners JJ Jr., Clift RE. 1999. Aryl hydrocarbon receptor regulation of ceramide-induced apoptosis in murine hepatoma 1c1c7 cells. A function independent of aryl hydrocarbon receptor nuclear translocator. Journal of Biological Chemistry 274(4):2502–2510. Ricci MS, Toscano DG, Toscano WA Jr. 1999a. ECC-1 human endometrial cells as a model system to study dioxin disruption of steroid hormone function. In Vitro Cellular and Developmental Biology 35(4):183–189. Ricci MS, Toscano DG, Mattingly CJ, Toxcano WA Jr. 1999b. Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells. Journal of Biological Chemistry 274(6):3430– 3438. Richon VM, Rifkind RA, Marks PA. 1992. Expression and phosphorylation of the retinoblastoma protein during induced differentiation of murine erythroleukemia cells. Cell Growth and Differentiation 3(7):413–420. Riebniger D, Schrenk D. 1998. Nonresponsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin of transforming growth factor beta1 and CYP 1A1 gene expression in rat liver fat-storing cells. Toxicology and Applied Pharmacology 152(1):251–260. Roberts EA, Johnson KC, Harper PA, Okey AB. 1990. Characterization of the Ah receptor mediating aryl hydrocarbon hydroxylase induction in the human liver cell line Hep G2. Archives of Biochemistry and Biophysics 276(2):442–450. Roberts EA, Johnson KC, Dippold WG.1991. Ah receptor mediating induction of cytochrome P450IA1 in a novel continuous human liver cell line (Mz-Hep-1). Detection by binding with [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin and relationship to the activity of aryl hydrocarbon hydroxylase. Biochemical Pharmacology 42(3):521–528.
OCR for page 98
Veterans and Agent Orange: Update 2000 Roberts BJ, Whitelaw ML. 1999. Degradation of the basic helix-loop-helix/Per-ARNT-Sim homology domain dioxin receptor via the ubiquitin/proteasome pathway. Journal of Biological Chemistry 274(51):36351–36356. Robles R, Morita Y, Mann KK, Perez GI, Yang S, Matikainen T, Sherr DH, Tilly JL. 2000. The aryl hydrocarbon receptor, a basic helix-loop-helix transcription factor of the PAS gene family, is required for normal ovarian germ cell dynamics in the mouse. Endocrinology 141(1):450–453. Rogan WJ, Gladen BC, Hung KL, Koong SL, Shih LY, Taylor JS, Wu YC, Yang D, Ragan NB, Hsu CC . 1988. Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 241(4863):334–336. Rohde S, Moser GA, Popke O, McLachlan MS. 1999. Clearance of PCDD/Fs via the gastrointestinal tract in occupationally exposed persons. Chemosphere 38(14):3397–3410. Roman BL, Peterson RE. 1998. In utero and lactational exposure of the male rat to 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs prostate development. 1. Effects on gene expression. Toxicology and Applied Pharmacology 150(2):240–253. Roman BL, Pollenz RS, Peterson RE. 1998a. Responsiveness of the adult male rat reproductive tract to 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: Ah receptor and ARNT expression, CYP1A1 induction, and Ah receptor down-regulation. Toxicology and Applied Pharmacology 150(2): 228–239. Roman BL, Timms BG, Prins GS, Peterson RE. 1998b. In utero and lactational exposure of the male rat to 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs prostate development. 2. Effects on growth and cytodifferentiation. Toxicology and Applied Pharmacology 150(2):254–270. Rosso SB, Caceres AO, de Duffard AM, Duffard RO, Quiroga S. 2000. 2,4-Dichlorophenoxyacetic acid disrupts the cytoskeleton and disorganizes the Golgi apparatus of cultured neurons. Toxicological Sciences 56(1):133–140. Safe S. 1990. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Critical Reviews in Toxicology 21(1):51–88. Sakurai T, Kaise T, Matsubara C. 1998. Inorganic and methylated arsenic compounds induce cell death in murine macrophages via different mechanisms. Chemical Research and Toxicology 11(4):273–283. Sandoz C, Lesca P, Narbonne JF. 1999. Hepatic Ah receptor binding affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin: similarity between beagle dog and cynomolgus monkey. Toxicology Letters 109(1–2):115–121. Santostefano MJ, Wang X, Richardson VM, Ross DG, DeVito MJ, Birnbaum LS. 1998. A pharmacodynamic analysis of TCDD-induced cytochrome P-450 gene expression in multiple tissues: dose- and time-dependent effects. Toxicology and Applied Pharmacology 151:294–310. Sarkar S, Jana NR, Yonemoto J, Tohyama C, Sone H. 2000. Estrogen enhances induction of cytochrome P-4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin in liver of female Long-Evans rats. International Journal of Oncology 16(1):141–147. Schaldach CM, Riby J, Bjeldanes LF. 1999. Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry 38(23):7594–7600. Schecter A, Kassis I, Popke O. 1998a. Partitioning of dioxins, dibenzofurans, and coplanar PCBs in blood, milk, adipose tissue, placenta and cord blood from five American women. Chemosphere 37(9–12):1817–1823. Schecter A, Ryan JJ, Popke O. 1998b. Decrease in levels and body burden of dioxins, dibenzofurans, PCBs, DDE, and HCB in blood and milk in a mother nursing twins over a thirty-eight month period. Chemosphere 37(9–12):1807–1816. Schlezinger JJ, White RD, Stegeman JJ. 1999. Oxidative inactivation of cytochrome P-450 1A (CYP1A) stimulated by 3,3',4,4'-tetrachlorobiphenyl: production of reactive oxygen by vertebrate CYP1As. Molecular Pharmacology 56(3):588–597.
OCR for page 99
Veterans and Agent Orange: Update 2000 Schlummer M, Moser GA, McLachlan MS. 1998. Digestive tract absorption of PCDD/Fs, PCBs, and HCB in humans: mass balances and mechanistic considerations. Toxicology and Applied Pharmacology 152(1):128–137. Schrey P, Wittsiepe J, Mackrodt P, Selenka F. 1998. Human fecal PCDD/F excretion exceeds the dietary intake. Chemosphere 37(9–12):1825–1831. Schuur AG, Tacken PJ, Visser TJ, Brouwer A. 1998. Modulating effects of thyroid state on the induction of biotransformation enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Toxicology and Pharmacology 5:7–16. Sehy DW, Shao LE, Yu AL, Tsai WM, Yu J. 1992. Activin A-induced differentiation in K562 cells is associated with a transient hypophosphorylation of RB protein and the concomitant block of cell cycle at G1 phase. Journal of Cellular Biochemistry 50(3):255–265. Seo BW, Sparks AJ, Medora K, Amin S, Schantz SL. 1999. Learning and memory in rats gestationally and lactationally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicology and Teratology 21(3):231–239. Sewall CH, Flagler N, Heuvel J PV, Clark GC, Tritshcer AM, Maronpot RM, Lucier GW. 1995. Alterations in thyroid function in female Sprague-Dawley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 132 (2):237–244. Shertzer HG, Nebert DW, Puga A, Ary M, Sonntag D, Dixon K, Robinson LJ, Cianciolo E, Dalton TP. 1998. Dioxin causes a sustained oxidative stress response in the mouse. Biochemical and Biophysical Research Communications 253(1):44–48. Shimba S, Todoroki K, Aoyagi T, Tezuka M. 1998. Depletion of arylhydrocarbon receptor during adipose differentiation in 3T3-L1 cells. Biochemical and Biophysical Research Communications 249(1):131–137. 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 Biophysicals Research Communications 272(2):441–448. Shimizu Y, Nakatsura Y, Ichinose M, Takahashi Y, Kume H, Mimura J, Fujii-Kuriyama Y, Ishikawa T. 2000. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proceeding of the National Academy of Sciences 97:779–782. Sinal CJ, Bend JR. 1997. Aryl hydrocarbon receptor-dependent induction of Cyp1a1 by bilirubin in mouse hepatoma Hepa 1c1c7 cells. Molecular Pharmacology 52(4):590–599. Sirkka U, Pohjanvirta R, Nieminen SA, Tuomisto J, Ylitalo P. 1992. Acute neurobehavioural effects of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in Han/Wistar rats. Pharmacology and Toxicology 71(4):284–288. 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-tetrachlorodibenzo-p-dioxin (TCDD). Toxicological Sciences 54(2):390–398. Smeets JMW, van Holsteijn I, Giesy JP, van den Berg M. 1999. The anti-estrogenicity of Ah receptor agonists in carp (Cyprinus carpio) hepatocytes. Toxicological Sciences 52(2):178–188. Smialowicz RJ, DeVito MJ, Riddle MM, Williams WC, Birnbaum LS. 1997. Opposite effects of 2,2’,4,4’,5,5’-hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antibody response to sheep erythrocytes in mice. Fundamental and Applied Toxicology 37(2):141–149. Smith AG, Clothier B, Robinson S, Scullion MJ, Carthew P, Edwards R, Luo J, LIm CK, Toledano M. 1998. Interaction between iron metabolism and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice with variants of the Ahr gene: a hepatic oxidative mechanism. Molecular Pharmacology 53(1): 52–61. Sommer RJ, Sojka KM, Pollenz RS, Cooke PS, Peterson RE. 1999. Ah receptor and ARNT protein and mRNA concentrations in rat prostate: effects of stage of development and 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment. Toxicology and Applied Pharmacology 155(2):177–189.
OCR for page 100
Veterans and Agent Orange: Update 2000 Stahl BU, Rozman K. 1990. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced appetite suppression in the Sprague-Dawley rat is not a direct effect on feed intake regulation in the brain. Toxicology and Applied Pharmacology 106:158–162. Staples JE, Fiore NC, Frazier DE Jr, Gasiewicz TA, Silverstone AE. 1998a. Overexpression of the anti-apoptotic oncogene, bcl-2, in the thymus does not prevent thymic atrophy induced by estradiol or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 151(1): 200–210. Staples JE, Murante FG, Fiore NC, Gasiewicz TA, Silverstone AE. 1998b. Thymic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin are strictly dependent on aryl hydrocarbon receptor activation in hemopoietic cells. Journal of Immunology 160(8):3844–3854. Tanguay RL, Abnet CC, Heideman W, Peterson RE. 1999. Cloning and characterization of the zebrafish (Danio rerio) aryl hydrocarbon receptor. Biochimica et Biophysica Acta 1444:35–48. Teeguarden JG, Dragan YP, Singh J, Vaughan J, Xu YH, Goldsworthy T, Pitot HC. 1999. Quantitative analysis of dose- and time-dependent promotion of four phenotypes of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats. Toxicological Sciences 51:211–223. Thurmond TS, Gasiewiez TA, 2000. A single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin produces a time-and dose-dependent alteration in the murine bone marrow B-lymphocyte maturation profile. Toxicological Sciences 58:88–95. Thurmond TS, Silverstone AE, Baggs RB, Quimby FW, Staples JE, Gasiewicz TA. 1999. A chimeric aryl hydrocarbon receptor knockout mouse model indicates that aryl hydrocarbon receptor activation is hematopoietic cells contributes to the hepatic lesions induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 158:33–40. Thurmond TS, Staples JE, Silverstone AE, Gasiewicz TA. 2000. The aryl hydrocarbon receptor has a role in the in vivo maturation of murine bone marrow B lymphocytes and their responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 165:227–236. Tian Y, Ke S, Thomas T, Meeker RJ, Gallo MA. 1998. Regulation of estrogen receptor mRNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin as measured by competitive RT-PCR. Journal of Biochemical and Molecular Toxicology 12:71–77. Tian Y, Ke S, Denison MS, Rabson AB, Gallo MA. 1999. Ah receptor and NF-kB interactions, a potential mechanism for dioxin toxicity. Journal of Biological Chemistry 274:510–515. Tohkin M, Fukuhara M, Elizondo G, Tomita S, Gonzalez FJ. 2000. Aryl hydrocarbon receptor is required for p300-mediated induction of DNA synthesis by adenovirus E1A. Molecular Pharmacology 58:845–851. Tscheudschilsuren G, Kuchenhoff A, Klonisch T, Tetens F, Fischer B. 1999a. Induction of arylhydrocarbon receptor (AhR) expression in embryoblast cells of rabbit preimplantation blastocysts upon degeneration of Rauber’s polar trophoblast. Toxicology and Applied Pharmacology 157:125–133. Tscheudschilsuren G, Hombach-Klonsich S, Kuchenhoff A, Fischer B, Klonisch T. 1999b. Expression of the arylhydrocarbon receptor and the arylhydrocarbon receptor nuclear translocator during early gestation in the rabbit uterus. Toxicology and Applied Pharmacology 160:231– 237. Tsunamoto K, Todo S, Imashuku S. 1987. Effects of 5-bromo-2′-deoxyuridine on arachidonic acid metabolism of neuroblastoma and leukemia cells in culture: a possible role of endogenous prostaglandins in tumor cell proliferation and differentiation. Prostaglandins, Leukotrienes and Medicine 26(2):157–169. Tuomisto JT, Viluksela M, Pohjanvirta R, Tuomisto J. 1999. The AH receptor and a novel gene determine acute toxic responses to TCDD: segregation of the resistant alleles to different rat lines. Toxicology and Applied Pharmacology 155:71–81.
OCR for page 101
Veterans and Agent Orange: Update 2000 U.S. EPA (U.S. Environmental Protection Agency). 2000. Draft Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds. Office of Research and Development. U.S. Environmental Protection Agency. [Online]. Available: http://www.epa.gov/ncea/pdfs/dioxin/dioxreass.htm. (Last updated Nov. 14, 2000). U.S. EPA. 1985. Health Assessment Document for Polychlorinated Dibenzo-p-Dioxins. Washington, DC. EPA/600/3–84/014F. Unkila M, Pohjanvirta R, Tuomisto J. 1998. Body weight loss and changes in tryptophan homeostasis by chlorinated dibenzo-p-dioxin congeners in the most TCDD-susceptible and the most TCDD-resistant rat strain. Archives of Toxicology 72:769–776. van den Berg M, Birnbaum LS, Bosveld BTC, Brunström B, Cook P, Feeley M, Giesy JP, Hanberg A, Hasegawa R, Kennedy SW, Kubiak T, Larsen JC, van Leeuwen FXR, Liem AKD, Nolt C, Peterson RE, Poellinger L, Safe S, Schrenk D, Tillitt D, Tysklind M, Younces M, Waern F, Zacharewski T. 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environmental Health Perspectives 106(12):775–792. Van der Molen GW, Kooijman S, Michalek JE, Slob W. 1998. The estimation of elimination rates of persistent compounds: a re-analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in Vietnam veterans. Chemosphere 37:1833–1844. Van der Plas SA, de Jongh J, Faassen-Peters M, Scheu G, van den Berg M, Brouwer A. 1998. Toxicokinetics of an environmentally relevant mixture of dioxin-like PHAHs with or without a non-dioxin-like PCB in a semi-chronic exposure study in female Sprague-Dawley rats. Chemosphere 37:1941–1955. Viluksela M, Unkila M, Pohjanvirta R, Tuomisto JT, Stahl BU, Rozman KK, Tuomisto J. 1999. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose hemeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains. Archives of Toxicology 73:323–336. Vogel C, Schuhmacher US, Degen GH, Bolt HM, Pineau T, Abel J. 1998. Modulation of prostaglandin H synthase-2 mRNA expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice. Archives of Biochemistry and Biophysics 351:265–271. Walker NJ, Miller BD, Kohn MC, Lucier GW, Tritscher AM. 1998. Differences in kinetics of induction and reversibility of TCDD-induced changes in cell proliferation and CYP1A1 expression in female Sprague-Dawley rat liver. Carcinogenesis 19:1427–1435. Walker NJ, Portier CJ, Lax SF, Crofts FG, Li Y, Lucier GW, Sutter TR. 1999. Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-Dawley rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 154:279–286. 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 X, Santostefano MJ, Evans MV, Richardson VM, Diliberto JJ, Birnbaum LS. 1997. Determination of parameters responsible for pharmacokinetic behavior of TCDD in female Sprague-Dawley rats. Toxicology and Applied Pharmacology 147:151–168. Wang X, Santostefano MJ, DeVito MJ, Birnbaum LS. 2000. Extrapolation of a PBPK model for dioxin across dosage regimen, gender, strain and species. Toxicological Sciences 56(1):49–60. Wanner R, Zober A, Abraham K, Kleffe J, Henz BM, Wittig B. 1999. Polymorphism at codon 554 of the human Ah receptor: different allelic frequencies in Caucasians and Japanese and no correlation with severity of TCDD- induced chloracne in chemical workers. Pharmacogenetics 9:777– 780. Warren TK, Mitchell KA, Lawrence BP. 2000. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses the humoral and cell-mediated immune responses to influenze A virus without affecting cytolytic activity in the lung. Toxicological Sciences 56:114–123.
OCR for page 102
Veterans and Agent Orange: Update 2000 Wei M, Wanibuchi H, Yamamoto S, Li W, Fukushima S. 1999. Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats. Carcinogenesis 20:1873–1876. Wei YD, Rannug U, Rannug A. 1999. UV-induced CYP1A1 gene expression in human cells is mediated by tryptophan. Chemico-Biological Interactions 118:127–140. Willey JJ, Stripp BR, Baggs RB, Gasiewicz TA. 1998. Aryl hydrocarbon receptor activation in genital tubercle, palate and other embryonic tissue in 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive lacZ mice. Toxicology and Applied Pharmacology 151:33–44. Wittsiepe J, Kullmann Y, Schrey P, Selenka F, Wilhelm M. 1999. Peroxidase-catalyzed in vitro formation of poly chlorinated dibenzo-p-dioxins and dibenzofurans from chlorophenols. Toxicology Letters 106:191–200. Wolf CJ, Ostby JS, Gray LE Jr. 1999. Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) severely alters reproductive function of female hamster offspring. Toxicological Sciences 51:259–264. Wolfle D. 1998. Interactions between 2,3,7,8-TCDD and PCBs as tumor promoters: limitations of TEFs. Teratogenesis, Carcinogenesis, and Mutagenesis. 17:217–224. Wolfle D, Marotzki S, Dartsch D, Schafer W, Marquardt H. 2000. Induction of cyclooxygenase expression and enhancement of malignant cell transformation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Carcinogenesis 21:15–21. Worner W, Schrenk D. 1998. 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppreses apoptosis and leads to hyperphosphorylation of p53 in rat hepatocytes. Environmental Toxicology and Pharmacology 6:239–247. 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. Yamanaka K, Katsumata K, Ikuma K, Hasegawa A, Nakano M, Okada S. 2000. The role of orally administered dimethylarsinic acid, a main metabolite of inorganic arsenics, in the promotion and progression of UVB-induced skin tumorigenesis in hairless mice. Cancer Letters 152(1):79– 85. Yang AL, Smith AG, Akhtar R, Clothier B, Robinson S, MacFarlane M, Festing MFW. 1999. Low levels of p53 are associated with resistance to tetrachlorodibenzo-p-dioxin toxicity in DBA/2 mice. Pharmacogenetics 9:183–188. Yang JH. 1999. Expression of dioxin-responsive genes in human endometrial cells in culture. Biochemical and Biophysical Research Communications 257:259–263. Yang JH, Vogel C, Abel J. 1999. A malignant transformation of human cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin exhibits altered expressions of growth regulatory factors. Carcinogenesis 20:13–18. Yang JZ, Agarwal SK, Foster WG. 2000. Subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates the pathophysiology endometriosis in the cynomolgus monkey. Toxicological Sciences 56:374–381. Zaher H, Fernandez-Salguero PM, Letterio J, Sheikh MS, Fornace AJ Jr, Roberts AB, Gonzalez FJ. 1998. The involvement of aryl hydrocarbon receptor in the activation of transforming growth factor-beta and apoptosis. Molecular Pharmacology 54(2):313–321.
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