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4 Information Related to Biologic Plausibility The committee reviewed all relevant experimental studies of 2,4-dichlo- rophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), pi- cloram, cacodylic acid, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that have been published since Update 2006 (IOM, 2007) and has incorporated the findings, when it was appropriate, into this chapter or into the biologic-plausibil- ity sections of Chapters 6–9 when they are of consequence for particular health outcomes. For each substance, this chapter includes a review of toxicokinetic properties, a brief summary of the toxic outcomes investigated in animal experi- ments, and a discussion of underlying mechanisms of action as illuminated by in vitro studies. To achieve the goals of this chapter more effectively, the current committee has slightly modified the presentation of toxicologic information used by previous Veterans and Agent Orange (VAO) committees. The toxicology chapter of each earlier update presented information about each of the several hundred potentially relevant toxicologic articles published in the preceding 2 years. In contrast with the committee’s responsibility to evaluate each potentially relevant epidemiologic study of the chemicals of interest published in the preceding 2 years, its charge with respect to the toxicologic literature is to distill experimental toxicologic findings to judge whether it is biologically plausible to attribute adverse health outcomes reported in epidemiologic investigations to the chemicals. The current committee recognized that for most readers of the VAO series the implications of most toxicologic results reported are not immediately obvious. Therefore, start- ing with this update, the committee will focus on integrating and interpreting the toxicologic evidence rather than delineating the entire body of new experimental findings. 6

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66 VETERANS AND AGENT ORANGE: UPDATE 2008 Establishment of biologic plausibility through laboratory studies strengthens the evidence of a cause–effect relationship between herbicide exposure and health effects reported in epidemiologic studies and thus supports the existence of the less stringent relationship of association, which is the target of this committee’s charge. Experimental studies of laboratory animals or cultured cells allow obser- vation of effects of herbicide exposure under highly controlled conditions that are difficult or impossible to control in epidemiologic studies. Such conditions include frequency and magnitude of exposure, exposure to other chemicals, pre- existing health conditions, and genetic differences between people, all of which can be controlled in a laboratory animal study. Once a chemical contacts the body, it begins to interact through the processes of absorption, distribution, metabolism, and excretion. Those four biologic pro- cesses characterize the disposition of a foreign substance that enters the organ- ism. Their combination determines the concentration of the compound in the body and how long each organ is exposed to it and thus influences its toxic or pharmacologic activity. Absorption is the entry of the substance into the organism, normally by uptake into the bloodstream via mucous surfaces, such as the intestinal walls of the digestive tract during ingestion. Low solubility, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a substance is absorbed after being ingested. The solubility of a chemical in fat and its hydrophobicity influence the pathways by which it is metabolized (structurally transformed) and whether it persists in the body or is excreted. Absorption is a critical determinant of the chemical’s bioavailability, that is, the fraction of it that reaches the systemic circulation. Other routes of absorption ex- perienced by free-ranging humans are inhalation (entry via the airways) and der- mal exposure (entry via the skin). Animal studies may involve additional routes of exposure that are not ordinarily encountered by humans, such as intravenous or intraperitoneal injection, in which the chemical is injected into the bloodstream or abdominal cavity, respectively. Distribution refers to the travel of a substance from the site of entry to the tissues and organs where they will have their ultimate effect or be sequestered. Distribution takes place most commonly via the bloodstream. The term metabo- lism is used to describe the breaking down that all substances begin to experience as soon as they enter the body. Metabolism of most foreign substances takes place in the liver by the action of oxidative enzymes collectively termed cyto- chrome P450. As metabolism occurs, the initial (parent) chemical is converted to new chemicals called metabolites. When metabolites are pharmacologically or toxicologically inert, metabolism deactivates the administered dose of the parent chemical reducing its effects on the body. Sometimes metabolism may activate the compound to a metabolite more potent or more toxic than the parent compound. Excretion, also referred to as elimination, is the removal of substances or

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6 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY their metabolites from the body, most commonly in urine or feces. Excretion is often incomplete, and incomplete excretion results in the accumulation of foreign substances that can adversely affect function. The routes and rates of absorption, distribution, metabolism, and excretion of a toxic substance collectively are termed toxicokinetics (or pharmacokinetics). Those processes determine the amount of a particular substance or metabolite that reaches specific organs or cells and that persists in the body. Understanding the toxicokinetics of a chemical is important for valid reconstruction of exposure of humans and for assessing the risk of effects of a chemical. The principles involved in toxicokinetics are similar among chemicals, although the degree to which different processes influence the distribution depends on the structure and other inherent properties of the chemicals. Thus, the lipophilicity or hydrophobicity of a chemical and its structure influence the pathways by which it is metabolized and whether it persists in the body or is excreted. The degree to which different toxicokinetic processes influence the toxic potential of a chemical depends on metabolic pathways, which often differ among species. For that reason, attempts at extrapolation from experimental animal studies to human exposures must be done with extreme care. Many chemicals were used by the US armed forces in Vietnam. The nature of the substances themselves was discussed in more detail in Chapter 6 of the original VAO report (IOM, 1994). Four herbicides documented in military records were of particular concern and are examined here: 2,4-D, 2,4,5-T, 4-amino-3,5,6- trichloropicolinic acid (picloram), and cacodylic acid (dimethyl arsenic acid, DMA). This chapter also examines 2,3,7,8-tetrachlorodibenzo-p-dioxin (referred to in this report as TCDD to represent a single, and the most toxic, congener of the tetrachlorodibenzo-p-dioxins [tetraCDDs], also commonly referred to as dioxin), a contaminant of 2,4,5-T, because its potential toxicity is of concern; considerably more information is available on TCDD than on the herbicides. Other contaminants present in 2,4-D and 2,4,5-T are of less concern. Except as noted, the laboratory studies of the chemicals of concern used pure compounds or formulations; the epidemiologic studies discussed in later chapters often tracked exposures to mixtures. TCDD Chemistry TCDD is a polychlorinated dibenzo-p-dioxin that has a triple-ring structure consisting of two benzene rings connected by an oxygenated ring (Figure 4-1); chlorine atoms are attached at the 2, 3, 7, and 8 positions of the benzene rings. The chemical properties of TCDD include a molecular weight of 322, a melting point of 305–306°C, a boiling point of 445.5°C, and a log octanol–water parti- tion coefficient of 6.8 (NTP substance profile). It is virtually insoluble in water

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68 VETERANS AND AGENT ORANGE: UPDATE 2008 Cl O Cl Cl Cl O 2,3,7,8-tetrachlorodibenzo-p -dioxin FIGURE 4-1 Chemical structure of TCDD. Figure 4-1.eps (19.3 ng/L), but is soluble in organic solvents, such as benzene and acetone. It has been suggested (EPA 2004 Draft Document) that volatilization of dioxin from water may be an important mechanism of transfer from the aqueous to the atmospheric phase. Absorption, Distribution, Metabolism, and Elimination The absorption, distribution, metabolism, and elimination of TCDD have been extensively studied in a number of animal models in the last 25 years. Given the plethora of data, this section only highlights and summarizes key find- ings. A more exhaustive review may be found at http://www.epa.gov/ncea/pdfs/ dioxin/nas-review. TCDD is absorbed into the body rapidly but is eliminated slowly. Because of the slow elimination, the concentration of TCDD in lipid or blood is thought to be in dynamic equilibrium with that in other tissue compartments and is thus considered to be reasonable for use in estimating total body burdens. Exposure of humans to TCDD is thought to occur primarily via the mouth, skin, and lungs. In laboratory animals, oral administration of TCDD has been shown to result in absorption of 50–93% of the administered dose (Nolan et al., 1979; Rose et al., 1976). Similarly, a study performed in a 42-year-old man found that 87% of the oral dose was absorbed. Dermal absorption appears to be dose-dependent, with lower absorption occurring at higher doses (Banks and Birnbaum, 1991). Studies performed in humans indicate that human skin may be more resistant to absorp- tion (Weber, 1991). After ingestion and gastrointestinal absorption, TCDD associates primarily with the lipoprotein fraction of the blood and later partitions into the cellular membranes and tissues (Henderson and Patterson, 1988). TCDD is distributed to all compartments of the body; the amounts differ from organ to organ, but most studies indicate that the primary disposition of TCDD is in the liver and adipose tissues. For example, in a human volunteer, it was found that at 135 days after ingestion, 90% of TCDD was in fat (Poiger and Schlatter, 1986); in the rhesus monkey, TCDD is very persistent in adipose tissue (Bowman et al., 1989). The

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69 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY disposition and elimination of TCDD depend on the tissue examined, the time that has elapsed since exposure, total exposure, and other factors. For example, the concentration of cytochrome P450 1A2 (CYP1A2) (Poland et al., 1989) in the liver is increased by TCDD. Direct binding of TCDD to the CYP1A2 is thought to result in sequestration of TCDD in the liver and to inhibit its distribution to other tissues. The importance of CYP1A2 concentrations for the toxic actions of TCDD has also been shown in studies performed in laboratory animals in which maternal hepatic CYP1A2 was found to sequester TCDD and protect the fetus against TCDD-induced teratogenesis (Dragin et al., 2006). In addition, distribu- tion of TCDD is age-dependent, as shown by studies in which young animals displayed the highest concentration of TCDD in the liver and older animals the highest concentrations in kidney, skin, and muscle (Pegram et al., 1995). Finally, the elimination rate of TCDD, in particular after low exposures, depends heavily on the amount of adipose tissue mass (Aylward et al., 2005; Emond et al., 2005, 2006). In laboratory animals and humans, metabolism of TCDD occurs slowly. It is eliminated primarily in feces as both the parent compound and its more polar metabolites. However, elimination appears to be dose-dependent; at low doses, about 35% of the administered dose of TCDD was detected in the feces; at higher doses, about 46% was observed (Diliberto et al., 2001). The dose-dependent occurrence of TCDD metabolites in the feces is thought to be due to increased expression of metabolizing enzymes at higher doses. A measure of elimination is half-life, which is defined as the time required for the plasma concentration or the amount of a chemical in the body to be reduced by one-half. The half-life of TCDD in humans varies with body mass index, age, sex, and concentration and has been found to vary from 0.4 to over 10 years (Table 4-1). In light of the variables discussed above and the effect of differences in physiologic states and metabolic processes, which can affect the mobilization of lipids and possibly of compounds stored in them, complex models known as physiologically based pharmacokinetic models have been developed to integrate exposure dose with organ mass, blood flow, metabolism, and lipid content to predict the movement of toxicants into and out of each organ. A number of recent modeling studies have been performed in an effort to understand the relevance of animal experimental studies to exposures that occur in human populations (Aylward et al., 2005a,b; Emond et al., 2005). Toxicity Profile The administration of TCDD to laboratory animals affects many tissues and organs. The effects of TCDD in laboratory animals have been observed in a number of species (rats, mice, guinea pigs, hamsters, monkeys, cows, and rabbits) after the administration of a variety of doses and after periods that represent acute (less than 24 hr), subchronic (more than 1 day up to 3 months), and chronic (more

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0 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 4-1 Estimates of TCDD Half-Life in Humans and Animals Confidence Half-Lifea Reference Interval Comment Human studies: Leung et al., 2006 0.4 year Breast-fed infants, 0–1 year after exposure Kumagai and Koda, 2005 1.1–2.3 years Adult male, incinerator workers, 0–1.3 years after exposure 10,000 Aylward et al., 2005a pg/g of serum lipid > 10 years Calculated for exposures < 50 pg/g of serum lipid Flesch-Janys et al., 1996 7.2 years Adult males, Boehringer cohort 1.5 yearsb Geusau et al., 2002 Adult female, severe exposure, 0–3 years after exposure 2.9 yearsb Adult female, severe exposure, 0–3 years after exposure 0.34 yearb Michalek et al., 2002 Adult males, Seveso cohort, 0–3 months after exposure 6.9 years Adult males, Seveso cohort, 3–16 years after exposure 9.8 years Adult females, Seveso cohort, 3–16 years after exposure 7.5 years Adult males, Ranch Hands, 9–33 years after exposure Needham et al., 1994 7.8 years 7.2–9.7 Adults, Seveso cohort years Pirkle et al., 1989 7.1 years 5.8–9.6 Adult males, Ranch Hands, 9–23 years years after exposure Animal studies: Neubert et al., 1990 73.7 days 60.9–93.8 Monkeys, marmoset, single injection days DeVito and Birnbaum, 1995 15 days Mice, female B6C3F1 11.0 daysc Gasiewicz et al., 1983 Mice, C5BL/6J 24.4 daysc Mice, DBA/2J 12.6 daysc Mice, B6D2F1/J Koshakji et al., 1984 20 days Mice, male ICR/Ha Swiss Hurst et al., 1998 8 days Rats, Long-Evans, excretion from liver 21.9 days Rats, male Han/Wistar, resistant Pohjanvirta and Tuomisto, strain 1990 Viluksela et al., 1996 20.2 days Rats, Long-Evans, TurkuAB strain 28.9 daysd Rats, Long-Evans, Charles River strain 16.3 ± 3.0 days Weber et al., 1993 Rats, male Sprague-Dawley a Half-livesof TCDD in humans based on measurement of TCDD in serum samples. b Shorter half-lives measured in humans during first months after exposure or in severely contami- nated persons consistent with nonlinear elimination predicted by physiologically based pharmacoki- netic modeling (for example, by Carrier et al., 1995). Greater half-life in females attributed to greater body-mass index. c Total cumulative excretion of 3H-TCDD-derived radioactivity.

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1 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY than 3 months) exposures. Some differences are observed in the different species, particularly with respect to their degree of sensitivity, but in general the effects observed are qualitatively similar. Relatively high exposures of TCDD affect a variety of organs and result in organ dysfunction and death. The specific organ dysfunction that constitutes the lethal event, however, is not known. A character- istic of TCDD exposure is a wasting syndrome with loss of adipose and muscle tissues and severe weight loss. In most rodents, exposure to TCDD affects the liver, as indicated by hepatic enlargement, the presence of hepatic lesions, and impaired hepatic function. The thymus is also sensitive. Finally, in both humans and nonhuman primates, TCDD exposure results in chloracne and associated dermatologic changes. As will be discussed in more detail in Chapters 6–9, stud- ies performed in animal models have indicated that exposure to TCDD adversely affects the heart, the skin, and the immune, endocrine, and reproductive systems, and increases the incidence of cancers of the liver, skin, thyroid, adrenal cortex, hard palate, nasal turbinates, tongue, and respiratory and lymphatic systems (Huff et al., 1994). When TCDD has been administered to pregnant animals, such birth defects as cleft palate, malformations of the reproductive organs of the male and female progeny, and abnormalities in the cardiovascular system have been observed. The administration of TCDD to laboratory animals and cultured cells affects enzymes, hormones, and receptors. In addition to adversely affecting the ability of specific organs to fulfill their normal physiologic roles, TCDD has been found to alter the function and expression of essential proteins. Some of the proteins are enzymes, specialized proteins that increase the rates of chemical reactions and aid in the body’s ability to convert chemicals into different molecules. The metabolism of foreign chemicals often changes their biologic properties and in some cases increases the body’s ability to eliminate them in urine. The enzymes that are most affected by TCDD are ones that act on or metabolize xenobiotics and hormones. Xenobiotics are chemicals that are not expected to be present in the body, and hormones are made by the body and serve as chemical messengers that transport a signal from one cell to another. Among the enzymes affected by TCDD, the best studied is CYP1A1, which metabolizes xenobiotics. In labora- tory animals, exposure to TCDD commonly results in an increase in the CYP1A1 present in most tissues; CYP1A1 therefore is often used as a marker of TCDD exposure. Other enzymes that are affected by TCDD are ones that metabolize hormones such as thyroid hormones, retinoic acid, testosterone, estrogens, and adrenal ste- roids. Those hormones transmit their signals by interacting with specific proteins called receptors and in this manner initiate a chain of events in many tissues of the body. For example, binding of the primary female sex hormone, estrogen, to the estrogen receptor promotes the formation of breasts and the thickening of the endometrium and regulates the menstrual cycle. Exposure to TCDD can increase

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2 VETERANS AND AGENT ORANGE: UPDATE 2008 the metabolism of estrogen, and this leads to a decrease in the amount of estrogen available for binding and activating the estrogen receptor. The ultimate effect of TCDD is an interference with all the bodily functions that are regulated by estro- gens. Similarly, the actions of TCDD on the adrenal steroids can adversely affect their ability to regulate glucose tolerance, insulin sensitivity, lipid metabolism, obesity, vascular function, and cardiac remodeling. In addition to changing the amount of hormone present, TCDD has been found to interfere with the ability of receptors to fulfill their role in transmitting hormone signals. Animal models have shown that exposure to TCDD can increase the amounts of enzymes in the body and interfere with the ability of hormones to activate their specific hormone re- ceptors. Those actions of TCDD on enzymes and hormone receptors are thought to underlie, in part, observed developmental and reproductive effects and cancers that are hormone-responsive. TCDD alters the paths of cellular differentiation. Research performed primarily in cultured cells has shown that TCDD can affect the ability of cells to undergo such processes as proliferation, differentiation, and apoptosis. During the pro- liferative process, cells grow and divide. When cells are differentiating, they are undergoing a change from less specialized to more specialized. Cellular dif- ferentiation is essential for an organism to mature from a fetal to an adult state. In the adult, proper differentiation is required for normal functions of the body, for example, in maintaining a normally responsive immune system. Processes of controlled cell death, such as apoptosis, are similarly important during develop- ment of the fetus and are necessary for normal physiologic functions in the adult. Apoptosis is a way for the body to eliminate damaged or unnecessary cells. The ability of a cell to undergo proliferation, differentiation, and apoptosis is tightly controlled by an intricate network of signaling molecules that allows the body to maintain the appropriate size and number of all the specialized cells that form the fabric of complex tissues and organs. Disruption of that network that alters the delicate balance of cell fate can have severe consequences, including impair- ment of the function of the organ because of the absence of specialized cells. Alternatively, the presence of an excess of some kinds of cells can result in the formation and development of tumors. Thus, the ability of TCDD to disrupt the normal course of a specific cell to proliferate, differentiate, or undergo apoptosis is thought to underlie (at least in part) its adverse effects on the immune system and the developing fetus and its ability to promote the formation of certain cancers. Definition of Dioxin-like Compounds and TEF and TEQ Terminology Many compounds have dioxin-like properties: they have similar chemical structure, have similar physiochemical properties, and cause a common battery of toxic responses. Because of their hydrophobic nature and resistance to me-

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 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY tabolism, these chemicals persist and bioaccumulate in fatty tissues of animals and humans. Several hundred chemicals—such as the polychlorinated dibenzo- p-dioxins, polychlorinated dibenzofurans, polybrominated dibenzo-p-dioxins, polybrominated dibenzofurans, and polychlorinated biphenyls—are described as dioxin-like compounds (DLCs), although only a few of them are thought to display dioxin-like toxicity. For most purposes, only 17 polychlorinated dibenzo- p-dioxins and polychlorinated dibenxofurans and a few of the coplanar poly- chlorinated biphenyls that are often encountered in environmental samples are recognized as being true DLCs. In the context of risk assessment, these polychlo- rinated dibenzo-p-dioxins, polychlorinated dibenxofurans, and polychlorinated biphenyls are commonly found as complex mixtures when detected in environ- mental media and biologic tissues or when measured as environmental releases from specific sources. That complicates the human health risk assessment that may be associated with exposures to varied mixtures of DLCs. To address the problem, the concept of toxic equivalency has been elaborated by the scientific community, and the toxic equivalency factor (TEF) has been developed and in- troduced to facilitate risk assessment of exposure to those chemical mixtures. On the most basic level, TEFs compare the potential toxicity of each DLC found in a mixture with the toxicity of TCDD, the most toxic member of the group. The procedure involves assigning individual TEFs to the DLCs with consideration of chemical structure, persistence, and resistance to metabolism. TEF ascribe spe- cific order-of-magnitude toxicity to each DLC relative to that of TCDD, which is assigned a TEF of 1.0. The DLCs have TEFs ranging from 0.00001 to 1.0. When several compounds are present in a mixture, the toxicity of the mixture is estimated by multiplying the TEF of each DLC in the mixture by its mass concentration and summing the products to yield the TCDD toxicity equivalent quotient (TEQ) of the mixture. Mechanism of Action TCDD binds and activates the aryl hydrocarbon receptor (AHR). The AHR is a member of a family of basic-helix-loop-helix (bHLH) transcription factors, that is, one of many proteins in the cell that controls the transfer (or transcription) of genetic information from DNA to RNA. bHLH proteins are characterized by the presence of a string of basic amino acid residues followed by two alpha helices joined by a loop. Generally, the larger of the two helices participates in binding to DNA in a specific sequence motif; the specificity is determined largely by the amino acid sequence of the helix. bHLH transcription factors are dimeric, form- ing functional heterodimers with other members of the family. By mechanisms that are poorly understood, binding of the heterodimeric complex to DNA recruits the transcriptional machinery needed to activate gene expression and results in a large increase in the rate of synthesis of mRNA molecules for the genes regulated by the complex and ultimately in a large increase in the corresponding protein.

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4 VETERANS AND AGENT ORANGE: UPDATE 2008 The best known AHR target is the expression of a mixed-function oxidase en - zyme that was termed aryl hydrocarbon hydroxylase (AHH) in the 1960s and is now better known as the CYP1A1 enzyme. Expression of this protein is an acute outcome of AHR activation and may not faithfully represent the consequences of chronic exposure to AHR ligands. In its inactive state, the AHR is found in the cytosol of the cell, where it is protected from proteolytic degradation by several chaperones and cochaperones. As a receptor, the AHR is a protein capable of receiving and forming a com- plex with specific substances, termed ligands, which confer on it the ability to perform a biologic function. In the case of the AHR, the function is to induce the transcription of specific target genes. Hence, the AHR belongs to a class of ligand-activated transcription factors. If the ligand is a chemical, such as TCDD, the AHR dissociates from the chaperones and translocates into the nucleus of the cell, where it forms a heterodimer with another bHLH protein, the AHR nuclear translocator (ARNT). This heterodimer binds to its cognate DNA motifs and recruits the macromolecular complexes needed to initiate gene transcription. AHR Functional Domains The AHR contains several regions, or domains, that perform distinct func- tions. The receptor is a member of the Per-Arnt-Sim (PAS) bHLH subfamily (Burbach et al., 1992; Fukunaga et al., 1995). The bHLH motif is found in the amino terminus of the protein and is common to all transcription factors in this subfamily (Jones, 2004). The members of the bHLH family also have several highly conserved domains with functionally distinctive biochemical roles. One of the domains is the basic region, described earlier, which is involved in the binding of AHR/ARNT complexes to DNA. Another domain is the HLH region, which facilitates the stable interaction between AHR and ARNT. A third domain is termed the PAS domain and consists of a stretch of 200–350 amino acids with high sequence relatedness to protein domains that were originally found in the Drosophila melanogaster genes period (Per) and single minded (Sim) and in the AHR’s dimerization partner ARNT; hence the name PAS. The AHR contains two PAS domains, PAS-A and PAS-B (Ema et al., 1992). The PAS domains support secondary interactions with other PAS-domain–containing proteins, with the chaperones and cochaperones, and with many other transcription factors, coacti- vators and corepressors. The ligand-binding site of AHR is in the PAS-B domain (Coumailleau et al., 1995) and contains several conserved residues critical for ligand binding (Goryo et al., 2007). A fourth important domain in the carboxyl terminus of the protein, is rich in glutamine and is involved in coregulator recruit- ment and transactivation (Kumar et al., 2001).

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 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY AHR Ligands From an environmental point of view, there are two classes of AHR ligands— synthetic and naturally occurring—that total more than 400 known ligands. Many of the first ligands to be discovered were synthetic polycyclic aromatic hydrocar- bons (PAHs), such as 3-methylcholanthrene, benzo[a]pyrene (B[a]P), benzanthra- cene, and naphthoflavone. The biologic consequences of experimental exposure of mice to those chemicals led to the prediction of a receptor-dependent mecha- nism long before the existence of the AHR was directly demonstrated. Compari- son of the effects of 3-methylcholanthrene treatment in two inbred mouse strains revealed a major difference in PAH responsiveness. Hepatic CYP1A1 enzyme increased more than 6-fold after 3-methylcholanthrene treatment in C57BL/6 mice but not in DB/2 mice. Appropriate genetic crosses between responsive C57BL/6 mice but in non-responsive DB/2 mice indicated that responsiveness in these prototype strains was inherited as a simple autosomal dominant trait. The genetic locus defined in the crosses was termed the aromatic hydrocarbon responsieness (Ahr) locus (Nebert et al., 1982). Molecular biologic studies dur- ing the next decade showed that responsive and nonresponsive mice had equally functional CYP1A1 enzymes and that the Ahr locus encoded a regulatory gene responsible for induction of the Cyp1a1 gene. The members of the polyhalo- genated aromatic hydrocarbons—such as the dibenzodioxins, dibenzofurans, and polychlorinated and polybrominated biphenyls—were recognized as AHR ligands much later, after the discovery by Poland and co-workers that dioxin was a potent inducer of hepatic AHH in the rat. At that time, it was found that high concentrations of TCDD could induce AHH activity in the nonresponsive DB/2 mouse to levels as high as those in the responsive C57BL/6 mouse. The difference between responsive and nonresponsive strains was in sensitivity to the inducer: DB/2 mice required 18 times more TCDD than C57BL/6 mice for 50% of the maximal response. Later, a receptor protein for TCDD, 3-methylcholanthrene and other PAHs, was identified, characterized in the hepatic cytosol of C57BL/6 mice, and termed Ah receptor (Poland et al., 1976). The available evidence indicated that the protein was the product of the Ahr locus, which was localized to mouse chromosome 12 and human chromosome 7, and later cloned (Burbach et al., 1992; Ema et al., 1992). Recent work has focused on naturally occurring compounds in hopes of identifying an endogenous ligand (Denison and Nagy, 2003). Several such natu- rally occurring compounds have been identified as AHR ligands, including the tryptophan derivatives indigo and indirubin (Adachhi et al., 2001), the tetrapyr- roles bilirubin (Sinal and Bend, 1997), the arachidonic acid metabolites lipoxin A4 and prostaglandin G (Seidel et al., 2001), modified low-density lipoprotein (McMillan and Bradfield, 2007), several dietary carotenoids (Denison and Negy, 2003; Probst et al., 1993), and cAMP (Oesch-Bartlomowicz et al., 2005). One assumption made in the search for an endogenous ligand is that the ligand will

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9 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY Arsenescu V, Arsenescu RI, King V, Swanson H, Cassis LA. 2008. Polychlorinated biphenyl–77 induces adipocyte differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis. Enironmental Health Perspecties 116(6):761–768. Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux PM, Brambilla P, Mocarelli P. 2005a. Concentration-dependent TCDD elimination kinetics in humans: Toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. Journal of Exposure Analysis and Enironment Epidemiology 15(1):51–65. Aylward LL, Brunet RC, Starr TB, Carrier G, Delzell E, Cheng H, Beall C. 2005b. Exposure recon- struction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination. Risk Analysis 25(4):945–956. Bacsi SG, Reisz-Porszasz S, Hankinson O. 1995. Orientation of the heterodimeric aryl hydrocarbon (dioxin) receptor complex on its asymmetric DNA recognition sequence. Molecular Pharma- cology 47(3):432–438. Banks YB, Birnbaum LS. 1991. Absorption of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) after low dose dermal exposure. Toxicology and Applied Pharmacology 107(2):302–310. Birnbaum L, Harris M, Stocking L, Clark A, Morrissey R. 1989. Retinoic acid and 2,3,7,8-tetrachloro- dibenzo-p-dioxin selectively enhance teratogenesis in C57BL/6N mice. Toxicology and Applied Pharmacology 98:487–500. Biswas G, Srinivasan S, Anandatheerthavarada HK, Avadhani NG. 2008. Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling. Proceedings of the National Academy of Sciences of the United States of America 105(1):186–191. Blakley BR. 1997. Effect of Roundup and Tordon 202C herbicides on antibody production in mice. Veterinary and Human Toxicology 39(4):204–206. Boutros PC, Moffat ID, Franc MA, Tijet N, Tuomisto J, Pohjanvirta R, Okey AB. 2004. Dioxin-re- sponsive AHRE–II gene battery: Identification by phylogenetic footprinting. Biochemical and Biophysical Research Communications 321(3):707–715. Boverhof DR, Burgoon LD, Williams KJ, Zacharewski TR. 2008. Inhibition of estrogen-mediated uterine gene expression responses by dioxin. Molecular Pharmacology 73(1):82–93. Bowman RE, Schantz SL, Weerasinghe NCA, Gross ML, Barsotti DA. 1989. Chronic dietary intake of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 5 and 25 parts per trillion in the monkey: TCDD kinetics and dose–effect estimate of reproductive toxicity. Chemosphere 18:243–252. Brand RM, Spalding M, Mueller C. 2002. Sunscreens can increase dermal penetration of 2,4- dichlorophenoxyacetic acid. Journal of Toxicology–Clinical Toxicology 40(7):827–832. Bredhult C, Backlin BM, Olovsson M. 2007. Effects of some endocrine disruptors on the prolif- eration and viability of human endometrial endothelial cells in vitro. Reproductie Toxicology 23(4):550–559. Burbach KM, Poland A, Bradfield CA. 1992. Cloning of the Ah–receptor cDNA reveals a distinctive ligand-activated transcription factor. Proceedings of the National Academy of Sciences of the United States of America 89:8185–8189. Burchiel SW, Thompson TA, Lauer FT, Oprea TI. 2008. Corrigendum to “Activation of dioxin re- sponse element (DRE)–associated genes by benzo(a)pyrene 3,6-quinone and benzo(a)pyrene 1,6-quinone in MCF-10A human mammary epithelial cells.” Toxicology and Applied Pharma- cology 226(3):345–346. Carrier G, Brunet RC, Brodeur J. 1995. Modeling of the toxicokinetics of polychlorinated dibenzo- p-dioxins and dibenzofurans in mammalians, including humans. II. Kinetics of absorption and disposition of PCDDs/PCDFs. Toxicology and Applied Pharmacology 131(2):267–276. Carver L, Bradfield C. 1997. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. Journal of Biological Chemistry 272:11452–11456. Carver L, Jackiw V, Bradfield C. 1994. The 90-kDa heat shock protein is essential for Ah receptor signaling in a yeast expression system. Journal of Biological Chemistry 269:30109–30112.

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94 VETERANS AND AGENT ORANGE: UPDATE 2008 Chiaro CR, Morales JL, Prabhu KS, Perdew GH. 2008. Leukotriene A4 metabolites are endogenous ligands for the Ah receptor. Biochemistry 47(32):8445–8455. Cohen SM, Arnold LL, Uzvolgyi E, Cano M, St John M, Yamamoto S, Lu X, Le XC. 2002. Possible role of dimethylarsinous acid in dimethylarsinic acid–induced urothelial toxicity and regenera- tion in the rat. Chemical Research in Toxicology 15(9):1150–1157. Cohen SM, Arnold LL, Eldan M, Lewis AS, Beck BD. 2006. Methylated arsenicals: The implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Critical Reiews in Toxicology 36(2):99–133. Cohen SM, Ohnishi T, Arnold LL, Le XC. 2007. Arsenic-induced bladder cancer in an animal model. Toxicology and Applied Pharmacology 222(3):258–263. Collins LL, Williamson MA, Thompson BD, Dever DP, Gasiewicz TA, Opanashuk LA. 2008. 2,3,7,8- tetracholorodibenzo-p-dioxin exposure disrupts granule neuron precursor maturation in the developing mouse cerebellum. Toxicological Sciences 103(1):125–136. Coumailleau P, Poellinger L, Gustafsson J, Whitelaw M. 1995. Definition of a minimal domain of the dioxin receptor that is associated with hsp90 and maintains wild type ligand binding affinity and specificity. Journal of Biological Chemistry 270:25291–25300. Cui X, Kobayashi Y, Hayakawa T, Hirano S. 2004. Arsenic speciation in bile and urine following oral and intravenous exposure to inorganic and organic arsenics in rats. Toxicological Sciences 82(2):478–487. Davarinos N, Pollenz R. 1999. Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. Journal of Biological Chemistry 274:28708–28715. Denison M, Nagy S. 2003. Activation of the aryl hydrocarbon receptor by structurally diverse exog- enous and endogenous chemicals. Annual Reiew of Pharmacology Toxicology 43:309–334. Dési I, Sos J, Nikolits I. 1962a. New evidence concerning the nervous site of action of a chemical herbicide causing professional intoxication. Acta Physiologica Academiae Scientiarum Hun- garicae 22:73–80. Dési I, Sos J, Olasz J, Sule F, Markus V. 1962b. Nervous system effects of a chemical herbicide. Archies of Enironmental Health 4:95–102. DeVito M, Birnbaum L. 1995. The importance of pharmacokinetics in determining the relative po- tency of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzofuran. Fundamental and Applied Toxicology 24:145–148. Di Giampaolo L, Di Gioacchino M, Qiao N, Travaglini P, D’Intino A, Kouri M, Ponti J, Castellani ML, Reale M, Gabriele E, Boscolo P. 2004. “In vitro” effects of different arsenic compounds on PBMC (preliminary study). Giornale Italiano di Medicina del Laoro Ed Ergonomia 26(3): 183–186. Diliberto JJ, Devito MJ, Ross DG, Birnbaum LS. 2001. Subchronic exposure of [3H]-2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) in female B6C3F1 mice: Relationship of steady-state levels to disposition and metabolism. Toxicological Sciences 61:241–255. Dolwick KM, Swanson HI, Bradfield CA. 1993. In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition. Proceedings of the National Academy of Sciences (USA) 90:8566–8570. Dong B, Matsumura F. 2008. Roles of cytosolic phospholipase A2 and Src kinase in the early ac- tion of 2,3,7,8-tetrachlorodibenzo-p-dioxin through a nongenomic pathway in MCF10A cells. Molecular Pharmacology 74(1):255–263. Dopp E, Hartmann LM, Florea AM, von Recklinghausen U, Pieper R, Shokouhi B, Rettenmeier AW, Hirner AV, Obe G. 2004. Uptake of inorganic and organic derivatives of arsenic associated with induced cytotoxic and genotoxic effects in Chinese hamster ovary (CHO) cells. Toxicology and Applied Pharmacology 201(2):156–165.

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9 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, Zimmermann U, Shokouhi B, Yadav S, Hirner AV, Rettenmeier AW. 2005. Forced uptake of trivalent and pentavalent methylated and inorganic arsenic and its cyto-/genotoxicity in fibroblasts and hepatoma cells. Toxicological Sciences 87(1):46–56. Dragin N, Dalton TP, Miller ML, Shertzer HG, Nebert DW. 2006. For dioxin-induced birth defects, mouse or human CYP1A2 in maternal liver protects whereas mouse CYP1A1 and CYP1B1 are inconsequential. Journal of Biological Chemistry 281(27):18591–18600. Dvorak Z, Vrzal R, Pavek P, Ulrichova J. 2008. An evidence for regulatory cross-talk between aryl hydrocarbon receptor and glucocorticoid receptor in HepG2 cells. Physiological Research 57(3):427–435. El-Masri HA, Kenyon EM. 2008. Development of a human physiologically based pharmacokinetic (PBPK) model for inorganic arsenic and its mono- and di-methylated metabolites. Journal of Pharmacokinetics and Pharmacodynamics 35(1):31–68. Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, Funae Y, Fujii-Kuriyama Y. 1992. cDNA cloning and structure of mouse putative Ah receptor. Biochemical and Biophysical Research Communications 184:246–253. Emond C, Michalek JE, Birnbaum LS, DeVito MJ. 2005. Comparison of the use of physiologically based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure as- sessments. Enironmental Health Perspecties 113(12):1666–1668. Emond C, Birnbaum LS, DeVito MJ. 2006. Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD. Enironmental Health Perspecties 114(9):1394–1400. EPA (US Environmental Protection Agency). 1988c. Guidance for the Reregistration of Pesticide Products Containing Picloram as the Actie Ingredient. Washington, DC: EPA, Office of Pes- ticide Programs. Evans BR, Karchner SI, Allan LL, Pollenz RS, Tanguay RL, Jenny MJ, Sherr DH, Hahn ME. 2008. Repression of aryl hydrocarbon receptor (AHR) signaling by AHR repressor: Role of DNA bind- ing and competition for AHR nuclear translocator. Molecular Pharmacology 73(2):387–398. Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ. 1996. Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced toxicity. Toxicology and Applied Pharmacology 140:173–179. Fernandez-Salguero PM, Ward JM, Sundberg JP, Gonzalez FJ. 1997. Lesions of aryl-hydrocarbon receptor-deficient mice. Veterinary Pathology 34(6):605–614. Flesch-Janys D, Becher H, Gurn P, Jung D, Konietzko J, Manz A, Papke O. 1996. Elimination of polychlorinated dibenzo-p-dioxins and dibenzofurans in occupationally exposed persons. Jour- nal of Toxicology and Enironmental Health 47(4):363–378. Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O. 1995. Identification of functional domains of the aryl hydrocarbon receptor. Journal of Biology and Chemistry 270:29270–29278. Funatake CJ, Marshall NB, Kerkvliet NI. 2008. 2,3,7,8-tetrachlorodibenzo- p-dioxin alters the dif- ferentiation of alloreactive CD8+ T cells toward a regulatory T cell phenotype by a mechanism that is dependent on aryl hydrocarbon receptor in CD4+ T cells. Journal of Immunotoxicology 5(1):81–91. Gasiewicz T, Geiger L, Rucci G, Neal R. 1983. Distribution, excretion, and metabolism of 2,3,7,8- tetrachlorodibenzo-p-dioxin in C57BL/6J, DBA/2J, and B6D2F1/J mice. Drug Metabolism and Disposition 11:397–403. Gehring PJ, Kramer CG, Schwetz BA, Rose JQ, Rowe VK. 1973. The fate of 2,4,5-trichlorophen- oxyacetic acid (2,4,5-T) following oral administration to man. Toxicology and Applied Phar- macology 26:352–361. Geusau A, Schmaldienst S, Derfler K, Päpke O, Abraham K. 2002. Severe 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) intoxication: Kinetics and trials to enhance elimination in two patients. Archies of Toxicology 76:316–325.

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