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 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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