3
Toxicology

The purpose of this chapter is to summarize recent experimental data that provide the scientific basis of assessment of the biologic plausibility of the effects of herbicide exposure as reported in epidemiologic studies. Establishment of biologic plausibility through laboratory studies strengthens the evidence of the effects of herbicide exposure that are believed to occur in humans. Toxic effects are influenced by dosage (magnitude and frequency of administration); by exposure to other substances, including compounds other than herbicides; by pre-existing health status; and by genetic factors. Those variables are difficult to control in epidemiologic studies of humans exposed to herbicides. Experimental studies using laboratory animals or cultured cells allow observation of effects of herbicide exposure under conditions that control for such variables.

The routes and rates of uptake, tissue distribution, metabolism, and elimination of a toxic substance collectively are termed toxicokinetics (also pharmacokinetics). Those processes determine the amount and persistence of a particular chemical or metabolite that reaches specific organs or cells in the body. Understanding the toxicokinetics of a compound is important for valid reconstruction of exposure in humans and for assessing the risk of effects of a particular toxicant. The principles involved in toxicokinetics are similar among chemicals, although the degree to which different processes may influence the distribution depends on the structure and other inherent properties of the chemicals. Thus, properties such as the lipophilicity or hydrophobicity of a chemical influence the pathways by which it is metabolized (structurally transformed) and whether it persists in the body or is excreted. Chemical structure and pathways of metabolism also determine the reactivity and toxic potential of a chemical. Those properties differ among the chemicals of concern in this report and may differ among species as



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3 Toxicology The purpose of this chapter is to summarize recent experimental data that provide the scientific basis of assessment of the biologic plausibility of the ef- fects of herbicide exposure as reported in epidemiologic studies. Establishment of biologic plausibility through laboratory studies strengthens the evidence of the effects of herbicide exposure that are believed to occur in humans. Toxic effects are influenced by dosage (magnitude and frequency of administration); by exposure to other substances, including compounds other than herbicides; by pre-existing health status; and by genetic factors. Those variables are difficult to control in epidemiologic studies of humans exposed to herbicides. Experimental studies using laboratory animals or cultured cells allow observation of effects of herbicide exposure under conditions that control for such variables. The routes and rates of uptake, tissue distribution, metabolism, and elimina- tion of a toxic substance collectively are termed toxicokinetics (also pharmaco- kinetics). Those processes determine the amount and persistence of a particular chemical or metabolite that reaches specific organs or cells in the body. Under- standing the toxicokinetics of a compound is important for valid reconstruction of exposure in humans and for assessing the risk of effects of a particular toxicant. The principles involved in toxicokinetics are similar among chemicals, although the degree to which different processes may influence the distribution depends on the structure and other inherent properties of the chemicals. Thus, properties such as the lipophilicity or hydrophobicity of a chemical influence the pathways by which it is metabolized (structurally transformed) and whether it persists in the body or is excreted. Chemical structure and pathways of metabolism also determine the reactivity and toxic potential of a chemical. Those properties differ among the chemicals of concern in this report and may differ among species as 47

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48 VETERANS AND AGENT ORANGE: UPDATE 2006 well. Attempts to extrapolate from experimental studies to human exposure must therefore consider them carefully. Many chemical compounds were used by the US armed forces in Viet- nam. The nature of the substances themselves is discussed in more detail in Chapter 6 of Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994). Four herbicides docu- mented in military records were of particular concern and are examined here: 2,4- dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 4-amino-3,5,6-trichloropicolinic acid (picloram), and cacodylic acid (dimethyl- arsinic acid, DMA). This chapter also focuses on 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD, or 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 were done with pure compounds or formulations; the epidemiologic studies discussed in later chapters often track exposures to mixtures. This chapter begins with a discussion of major conclusions presented in reports by predecessors of the current committee: VAO (IOM, 1994); Veterans and Agent Orange: Update 1996, hereafter referred to as Update 1996 (IOM, 1996); Veterans and Agent Orange: Update 1998, or Update 1998 (IOM, 1999); Veterans and Agent Orange: Update 2000, or Update 2000 (IOM, 2001); Veter- ans and Agent Orange: Update 2002, or Update 2002 (IOM, 2003); and Veterans and Agent Orange: Update 2004, or Update 2004 (IOM, 2005). The rest of the chapter consists mostly of overviews and discussions of the relevant experimen- tal studies that have been published since Update 2004 (IOM, 2005) on 2,4-D, 2,4,5-T, picloram, cacodylic acid, and TCDD. The update for each substance includes a review of the toxicokinetic investigations and a summary of the toxic endpoints and their underlying mechanisms of action. HIGHLIGHTS OF PREVIOUS REPORTS Prior reports have reviewed the results of animal and in vitro studies pub- lished through 2004 that investigated the toxicokinetics, mechanisms of action, and disease outcomes of exposure to the herbicides used in Vietnam and TCDD, the contaminant of Agent Orange. The herbicides have not been studied exten- sively, but in general none of them is considered highly toxic. High concentra- tions usually are required to alter cellular and biochemical processes. In contrast, experimental data reviewed in previous reports led to the conclusion that TCDD elicits a spectrum of toxic effects that vary with exposure level and the age, sex, and species of the animals studied. Carcinogenicity, immunotoxicity, reproduc- tive and developmental toxicity, hepatotoxicity, and neurotoxicity have been observed in several species. The scientific consensus is that TCDD is not directly genotoxic and that its ability to influence the carcinogenic process is mediated

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49 TOXICOLOGY by epigenetic events, such as enzyme induction, cell proliferation, apoptosis, and intracellular communication. Most, if not all, of the biochemical and toxic effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR), a cellular protein that functions as a regulator of gene transcription. Studies to understand the role of AhR in normal physiology are important for understanding the risks associated with human exposure to TCDD. UPDATED TOXICITY PROFILE OF 2,4-D The herbicide 2,4-D is a synthetic chemical that mimics specific plant- growth regulators, the auxins, and interferes with their function. According to previous reports, 2,4-D is considered moderately toxic, eliciting a number of adverse effects in animal studies, including carcinogenesis, immunotoxicity, teratogenesis, endocrine disruption, renal toxicity, and hepatotoxicity. The stud- ies reported in the last 2 years continue to indicate that the toxicity of 2,4-D can involve effects on several processes. Thus, studies reviewed in Update 2006 and previous updates indicate that 2,4-D’s effects include membrane disruption, uncoupling of oxidative phosphorylation, lipid peroxidation, altered redox status, and chromosomal abnormalities. 2,4-D can be a peroxisome proliferator and can induce cytotoxic effects, including apoptosis. Those effects occur at very high doses, and the mechanisms of 2,4-D action are not understood. 2,4-D does cause changes in gene expression, so newer studies that identify pathway changes by using gene-expression profiling may provide insights into the mechanisms of 2,4-D toxicity. Toxicokinetics 2,4-D is moderately hydrophobic and is rapidly excreted as the unchanged parent compound. The half-life in animals varies from hours to weeks and in humans from less than a day to several days, depending on the route of exposure. After oral administration, most of the dose typically will be excreted within 48 hours. Since the publication of Update 2004, several studies have examined the toxicocokinetics and metabolism of 2,4-D in animals and humans. Their re- sults support the previous conclusions that metabolism of 2,4-D to its primary metabolite, 2,4-dichlorophenol (2,4-DCP), is rapid and that the elimination of 2,4-D and 2,4-DCP is relatively rapid, thus limiting the amount that is taken up into tissues. In a study in rats, Aydin et al. (2005) examined the accumulation of 2,4-D in kidney; the kidney is a target organ in subchronic studies of 2,4-D toxicity in rodents. Male and female rats were given different doses of 2,4-D in drinking water and food for 30 days, and kidney tissue was analyzed for residues of 2,4- D and 2,4-DCP. Both compounds were found in kidney with all dose regimens,

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50 VETERANS AND AGENT ORANGE: UPDATE 2006 and the amounts of metabolite exceeded the parent compound at all doses. Also in rodents, Sturtz et al. (2006) examined the distribution of 2,4-D to milk of dams after parturition. The rats were fed diets supplemented with 2,4-D at doses equivalent to 15, 25, 50, and 70 mg/kg per day for 16 days. There was a dose- dependent increase in 2,4-D content in the dams’ serum and milk and in serum collected from the pups. Analysis of the lipid composition of the milk found a dose-dependent reduction in polyunsaturated fatty acids. Two papers documented the effects of sunscreen ingredients on dermal up- take of 2,4-D, which is of concern because sunscreens may be used in agricultural or other occupational settings where exposure to herbicides might occur. The first study (Pont et al., 2003) used hairless mouse skin explants as the model. Six com- binations of sunscreen active ingredients were applied and then 2,4-D, and mate- rial that passed the dermal barrier was collected and measured at various times over 24 hours. All six formulations enhanced the penetration of 2,4-D in through the skin. Among the active ingredients, N,N-diethyl-m-toluamide (DEET) was most effective in enhancing penetration; octocrylene was the only ingredient found to antagonize 2,4-D uptake. In a related study using the same mouse skin model, the same group (Brand et al., 2003) examined the effects of the physical blockers titanium oxide (TiO2) and zinc oxide (ZnO), which are UVA absorbers, on the uptake of 2,4-D in the presence of commercially formulated sunscreens or in an alternative carrier, phenyl trimethicone. Five of nine sunscreens tested alone increased the transdermal absorption of 2,4-D. However, ZnO impeded uptake of 2,4-D, and TiO2 had no effect when phenyl trimethicone was the solvent. Thus, inert ingredients can modify the enhancing effect of active sunscreen agents. The study also included washing the skin as a variable; washing between applications resulted in the same penetration effect of a second application, and repeating the application without washing resulted in greater penetration of the second dose. Underlying Mechanisms of Toxic Action Studies of effects of 2,4-D published since Update 2004 are consistent with the earlier conclusion that 2,4-D is not acutely toxic and has only weak carcino- genic potential. Recent animal studies of disease outcomes after 2,4-D exposure and possible mechanisms are discussed below. Genotoxic Effects and Mechanisms Related to Carcinogenicity Carcinogenicity may occur as a result of mutations (genotoxicity) or epigen- etic effects involving promotion of tumor-cell proliferation and tumor growth. Studies reviewed in previous updates indicated that 2,4-D has weak genotoxic po- tential. A recent report supports the suggestion of a weak but positive association between 2,4-D exposure and genotoxic potential. Gonzalez et al. (2005) exam- ined deoxyribonucleic acid (DNA) damage and cytogenetic endpoints in Chinese

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51 TOXICOLOGY hamster ovary (CHO) cells exposed to 2,4-D and to a formulation containing 2,4-D dimethylamine salt (2,4-DMA), a derivative that is used in Argentina. The chemicals were applied to cells in culture at 0, 2, 6, or 10 g/mL of media. DNA strand breaks increased in a dose-dependent manner with a doubling at the high- est dose. Mitotic indexes were decreased only at the higher doses. Comet assay showed damage by both 2,4-D and 2,4-DMA. The mechanism of the effects is not known, but it is speculated that the chemicals stimulate production of reactive oxygen species. Overall, the studies suggest only weak genotoxicity of 2,4-D. In a study of 2,4-D effects on human prostatic-cancer cells, Kim et al. (2005) examined the androgenic action of 2,4-D and of 2,4-DCP as synergists of dihy- drotestosterone (DHT) on activation of the androgen receptor (AR). Two human prostatic-cancer cell lines were exposed to the chemicals at various doses with or without the AR agonist DHT. Among endpoints examined was induction of an AR-dependent reporter gene (luciferase). Neither 2,4-D nor 2,4-DCP alone increased reporter-gene expression, but they both enhanced the agonist-mediated activation of the reporter gene by DHT. Further analysis suggested that the effect might involve facilitation of translocation of the DHT-bound AR to the nucleus. Neurotoxicity Update 2004 cited case reports of acute poisonings of humans exposed to large amounts of 2,4-D formulations, indicating neurologic manifestations of drowsiness, coma, hyperreflectivity, hypertonia, and cerebral edema (Brahmi et al., 2003). No relevant studies involving neurotoxicity in adult humans have been published since Update 2004. However, a variety of studies address neuro- logic systems in animal models, and several studies support effects of 2,4-D on the developing brain in animal models. Studies concerning neurologic effects dur- ing development are detailed in the section on developmental toxicity below. Some studies have suggested that 2,4-D has effects on brain processes (dopamine metabolism and action) and structures (such as the nigrostriatus) im- plicated in movement disorders, such as Parkinson’s disease. A study by Thiffault et al. (2001) addressed the hypothesis that 2,4-D causes damage to dopaminergic terminals and contributes to nigrostriatal degeneration. Male C57BL/6 mice 7–8 weeks old were given a single subcutaneous injection of 100 or 200 mg/kg 2,4-D methyl ester. After 7 days, dopamine and dopamine metabolites (3,4- dihydroxyphenylacetic acid and homovanillic acid) were measured in the stria- tum. Neither dose produced any change in the concentrations of dopamine. The only statistically significant change was a slight (about 15 percent) decrease in 3,4-dihydroxyphenylacetic acid at the highest dose. Challenge with 2,4-D 7 days after a 15-mg/kg dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a known dopaminergic toxicant, did not potentiate the effects of MPTP. The results do not support a link between acute exposure to 2,4-D and nigrostriatal injury in the mouse model.

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52 VETERANS AND AGENT ORANGE: UPDATE 2006 Zafeiridou et al. (2006) used nerve preparations from a nonmammalian ver- tebrate model, the frog Rana ridibunda, to address effects of 2,4-D on peripheral nerve function. The study involved isolated sciatic nerves exposed to 2,4-D in a specialized chamber that allowed the action potential to be measured as an indica- tion of proper physiologic functioning of the nerves. The effective concentration 50 percent (EC50) of 2,4-D for neurotoxicity in this preparation was determined to be 3.8 mM. Inasmuch as 2,4-D is a weak acid, pH is thought to affect its toxicity. Changing the pH in the nerve media from a physiologic pH of 7.2 to 3.3 enhanced the toxicity and reduced the EC50 to 0.24 mM. The results suggest an effect of 2,4-D on the peripheral nervous system, but the mechanisms are unknown, and the significance of the non-physiologic-pH result is not clear. Reproductive and Developmental Toxicity Previous studies have indicated that 2,4-D is embryotoxic in vivo and that the fetus may be more sensitive than adults to its toxic effects. Since Update 2004, studies continue to indicate that 2,4-D has effects in developing animals, includ- ing multiple effects on the developing central nervous system. Sameshima et al. (2004) examined the effects of 2,4-D on rat embryos maintained in culture to determine whether toxicity involved direct effects on the embryo. Embryos of Wistar rats were isolated on day 9.5 of gestation and were exposed to 2,4-D in culture media at 50, 100, 200, or 500 g/mL. Several indexes of growth (number of somites, crown-rump length, head length, and yolk sac diameter) and structure (such as eye development, ear development, neural tube defects, and forelimb development) were examined. Growth retardation and morphologic defects were progressively more severe at higher doses, and all endpoints were significantly affected at the highest dose. The results indicate that 2,4-D can directly affect the embryo in vitro, but the mechanisms for the effects are not apparent. Bortolozzi et al. (2004) examined the effects of 2,4-D on the ontogeny of dopaminergic D2 receptors in rat pups that had been exposed to 2,4-D in utero, during lactation, and after weaning. Eight female Wistar rats were exposed to 2,4-D in the diet at 70 mg/kg per day from gestation day 16 to postpartum day 23, while four control female rats were fed vehicle in the diet. After weaning, half the litters in the 2,4-D group were fed the control diet until day 90, and the others were fed the 2,4-D diet. A specific binding assay for D2 receptors was used to measure D2 receptor concentrations in striatum, prefrontal cortex, hippocam- pus, and cerebellum at various times up to postnatal day 90. There were modest statistically significant increases in D2 receptors in all four regions of brains of pups that had been fed the 2,4-D diet after weaning. However, the effect was not evident in pups that were exposed in utero and then fed a control diet after weaning. The results suggest that the effect induced in utero or during lactation was reversible on cessation of exposure.

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53 TOXICOLOGY A study by the same group (Garcia et al., 2004) examined the effects of 2,4-D on tyrosine hydroxylase activity in midbrain areas (the substantia nigra and the ventral tegmental area) in neonatal rats exposed to 2,4-D only through lactation. After birth of litters, female mice were treated with 2,4-D by intraperitoneal injec- tion at 70 or 100 mg/kg per day for 16 days; control female mice received injec- tions of carrier. Pups were nursed in one of the three groups. On postnatal day 25, cellular expression of tyrosine hydroxylase (TH) and serotonin transporters (5-HTT) was determined with immunohistochemical staining and image analysis. In both brain regions, there were reductions in TH and 5-HTT in substantia nigra of both dose groups. In the ventral tegmental area, there were reductions in both in the high-dose group and of 5-HTT in the low-dose group. A similar study (Garcia et al., 2006) examined concentrations of dopamine -hydroxylase, the enzyme that synthesizes noradrenaline from dopamine, in the locus coeruleus of neonatal rats that had been exposed to 2,4-D by lactation. As in the previous study, 9-day-old primaparous female Wistar rats were exposed by intraperitoneal injection to 2,4-D at 70 or 100 mg/kg per day for 14 days (post- natal days 9–22), and control female rats received carrier. On day 22, brains were examined for dopamine hydroxylase with immunohistochemistry. Pups exposed to either dose of 2,4-D showed a pronounced and significant (p 0.001) reduc- tion (of 73–75 percent) in dopamine hydroxylase staining in the locus coeruleus. Taken together the Garcia studies indicate that the neonatal rat brain can be influenced by lactational exposure to 2,4-D. Chemicals that interact with estrogen receptors may cause reproductive problems or could affect estrogen-dependent cancers, including breast cancer. Lemaire et al. (2006) addressed possible interaction of 2,4-D with human estro- gen receptors ER and ER . Cell lines stably transfected with human ER or ER , with a luciferase reporter construct, were used to assess the interactions of 49 chemicals, including 2,4-D. 2,4-D showed no agonist activity and no antago- nist activity with either ER or ER . Immunotoxicity Previous updates concluded that 2,4-D has at most a weak effect on the im- mune system. Recent publications are consistent with that conclusion. The ability of 2,4-D to cause thymic involution was studied in C57BL/6 mice exposed to 2,4-D and another herbicide, propanil, or to mixtures of the two (de la Rosa et al., 2005). Mice 6–8 weeks old were treated by injection of either propanil or 2,4-D at 50, 100, 150, or 200 mg/kg of body weight or with 1:1 combinations of the stated doses of each chemical. Two days after treatment, thymus weight was measured, and CD4 CD8 thymocyte populations were mea- sured by flow cytometry. Thymic atrophy was observed only in the highest-dose groups, that is, with the combination of chemicals both at 150 mg/kg and with each chemical alone at 200 mg/kg. A decrease in CD4+ CD8+ and CD4– CD8+

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54 VETERANS AND AGENT ORANGE: UPDATE 2006 cells occurred at the next-lower dose. A role for glucocorticoids was assessed by determining whether thymic effects could be reversed by treatment with a gluco- corticoid receptor antagonist (RU486) 2 hours before and 12 hours after dosing. The effects of the herbicide on the thymus appeared at least partly to require the glucocorticoid receptor. A study of 2,4-D effects on antibody responses was carried out with a design similar to that used above by the same group (Salazar et al., 2005). C57BL/6 mice were exposed to 2,4-D at 150 mg/kg, to propanil, or to mixtures of the two by intraperitoneal injection within an hour of receiving an injection of heat-killed Streptococcus pneumoniae. Responses to two specific antigens were determined: a T-cell-independent type 2 antigen (phosphorylcholine) and a T-cell-dependent antigen (pneumococcal surface protein). At 3, 5, 7, 10, and 14 days after treat- ment, spleen and bone marrow cells were obtained, cell populations were ana- lyzed with flow cytometry, and antibody-secreting cells and antibody production were determined with immunoassay. The number of phosphorylcholine antigen- specific bone marrow antibody-secreting B cells was decreased by 2,4-D. How- ever, the number of antibody-secreting B cells in spleen was not changed. The response to pneumococcal surface-protein antigen A was not affected. The results suggest a modest inhibitory effect of 2,4-D on the ability to mount a humoral immune response. Mechanisms Related to Effects on Energy Metabolism or Mitochondrial Function Several reports cited in previous updates suggested that the toxicity of rela- tively high concentrations of 2,4-D might be related, at least in part, to its effect on calcium homeostasis and energy metabolism. Those effects might be mediated by a direct action on mitochondria. It is generally recognized that the toxicity of 2,4-D is not understood at the molecular level. There may be multiple avenues of toxicity, and uncovering the pathways that are affected by 2,4-D could lead to hypotheses about the mechanisms. A study by Argese et al. (2005) examined 15 phenolic and phenoxy herbi- cides, including 2,4-D, for toxic effects on mitochondrial function and the depen- dence of EC50 on structural and physicochemical properties of the chemicals. The assay used submitochondrial particles prepared from beef-heart mitochondria, and effects on NADH generation by the particles in vitro were assessed. An EC50 for the effect was determined as the concentration of herbicide that gave 50 percent inhibition of NADH generation. The EC50 for 2,4-D was 32 M. The investigators concluded that the compounds were acting by a nonspecific mode of action at the membrane. Effects of 2,4-D on metabolic enzymes of the glycolytic, citric acid, and pentose phosphate pathways involved in generating NADH and NADPH were examined by Yilmaz and Yuksel (2005). Enzyme activities were measured in

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55 TOXICOLOGY liver of offspring of females that had received injections of 2,4-D at 3.38 mg/kg of body weight (0.01 of the LD30), or ethanol or saline. The study was repeated in three generations of mice and the offspring were exposed only in utero and through lactation. Increases in malate dehydrogenase were noted, but the effects were modest and highly variable. The authors also examined chromosomal struc- ture in bone marrow cells; no abnormalities were observed. Mechanism Related to Effects on Thyroid Hormones Effects of 2,4-D on serum concentrations of thyroid hormones, particularly decreases in thyroxine, were noted in previous updates. No new studies related to possible involvement of the thyroid were identified. Mechanisms Related to Effects of Cell Stress Responses Several investigations examined the ability of 2,4-D to promote or inhibit oxidative damage to cell membranes. Together, they suggest that at high concen- trations 2,4-D is incorporated into cellular membranes and modifies membrane structure and integrity. A number of prior studies implicated oxidative stress in the mechanisms of 2,4-D toxicity. Oxidative stress was addressed further by Celik et al. (2006) in a study of serum enzymes, antioxidant defenses, and lipid peroxidation in various tissues of rats exposed to 2,4-D. Male (Sprague-Dawley) rats 4 months old (weight, 150–200 g) were given 2,4-D (of unspecified source) in drinking water ad li- bitum for 25 days. The doses amounted to an intake of about 1.5 or 3 mg/kg per day. After 25 days, serum, red blood cells, and other tissues were obtained for assay. Serum alanine aminotransferase, lactate dehydrogenase, and creatine phosphokinase were significantly increased by both doses of 2,4,D, but aspartate aminotransferase was not affected. The lipid peroxidation end product malondial- dehyde was significantly increased in liver, kidney, and heart but not in red cells or brain. Glutathione was significantly depleted in kidney and brain at both doses, and other organs variably. Other antioxidant enzymes showed varied responses in the different organs. Together, the data implicate oxidative stress as a factor in the toxicity of 2,4-D. Gene-Expression Profiling The first expression-profiling study of 2,4-D effects was that of Bharadwaj et al. (2005), who examined global gene expression in human hepatoma cells (HepG2 cells) exposed to 2,4-D at low concentrations. HepG2 cells (at four to 10 passages) were continuously cultured in a commercial formulation of 2,4-D at concentrations 0.1 nM to 4 mM, a range spanning the full spectrum of toxic and environmental concentrations. RNA isolated from control and treated cells

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56 VETERANS AND AGENT ORANGE: UPDATE 2006 was prepared and hybridized to Human 1.7k-Expressed Sequence Tag microar- rays. At least 87 genes showed significant changes (two-fold threshold), which were evenly divided between those showing upregulation and those showing downregulation. Changes began to appear at a 2,4-D concentration of 1.0 nM. The affected genes included genes involved in cell-cycle control, stress response, immune function, and DNA repair. Bharadwaj et al. (2005) concluded that “the cellular response to 2,4-D is complex” and ostensibly associated with altered expression of many genes. UPDATED TOXICITY PROFILE OF 2,4,5-T Commercial production of 2,4,5-T resulted in the formation of TCDD as a contaminant. This section summarizes the toxicity of 2,4,5-T itself. TCDD toxic- ity is summarized later in this chapter. The herbicide 2,4,5-T is an auxin mimic. It is similar to 2,4-D in its mode of action. VAO and the updates concur that 2,4,5-T is only weakly toxic or carci- nogenic. Updates have indicated that 2,4,5-T has only weak mutagenic potential but that it might alter the profile of enzymes involved in the metabolism of pro- carcinogens. Earlier reports indicated that 2,4,5-T could interfere with the forma- tion of the neurotransmitter acetylcholine, which could be involved in effects on growth and the nervous system. Earlier studies also indicated membrane disrup- tion and possibly oxidative stress as effects of 2,4,5-T. A few studies relevant to mechanisms of toxicity of 2,4,5-T have been published since Update 2004; most of them included assessment of 2,4-D as well as 2,4,5-T, and those studies are discussed in the sections on each of these herbicides. Toxicokinetics 2,4,5-T is moderately hydrophobic and, like 2,4-D, is generally rapidly ex- creted, largely as the unchanged parent compound although some is conjugated to amino acids. The half-life in animals varies from hours to weeks and in humans from less than a day to several days, depending on the route of exposure. No relevant studies on the toxicokinetics of 2,4,5-T in experimental animals or humans after exposure to 2,4,5-T were identified in the search for Update 2006. Mechanisms of Toxic Action Neurotoxicity The study by Zafeiridou et al. (2006), described in the section on 2,4-D tox- icity, also addressed the effects of 2,4,5-T on peripheral nerve function. Isolated sciatic nerve preparations from a frog model (Rana ridibunda) were exposed to 2,4,5-T in a specialized chamber that allowed the action potential to be measured

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57 TOXICOLOGY as an indication of nerve vitality. Adding 2,4,5-T to this preparation at various concentrations resulted in a dose-dependent decrease in the time to reduce the amplitude of the action potential relative to saline. An EC50 of 0.9 mM was de- termined for 2,4,5-T. Because 2,4,5-T also is a weak acid, changing the pH in the nerve media from physiologic (7.2) to 3.3 reduced the EC50 to 0.2 mM. The results suggest an effect of 2,4,5-T on the peripheral nervous system, but the mechanisms of the effect are unknown. Cell Stress Responses One report describing cellular effects of 2,4,5-T and its metabolite 2,4,5- trichlorophenol (2,4,5-TCP) on human erythrocytes has been published (Bukowska, 2004a). The study examined the effects of 2,4,5-T and 2,4,5-TCP on indexes of oxidative stress in human red blood cells (RBCs). Exposure of RBCs to the chemicals was in buffered saline, in which RBCs constituted 5 percent of the volume. Superoxide dismutase, catalase, reduced and total glutathione, glutathione reductase, and adenylate energy charge were measured in the RBCs. Modest decreases in superoxide dismutase and catalase were observed in cells ex- posed to 2,4,5-TCP at 250 ppm but not in those exposed to 2,4,5-T. The decrease in catalase activity was pronounced at a dose of 1,000 ppm. (In comparison, at that dose, 2,4-D and its metabolite 2,4-DCP did not affect RBC catalase activity.) Both 2,4,5-T and 2,4,5-TCP elicited modest decreases in the content of reduced glutathione but did not affect total glutathione. The two compounds also caused changes in RBC structure that suggested effects on membrane integrity. Energy Metabolism or Mitochondrial Function Argese et al. (2005) used SMPs prepared from beef heart to assay effects of 2,4,5-T on NADH generation as a measure of toxicity. Effects on mitochondrial respiratory functions were considered in relation to structural and physicochemi- cal properties of 2,4,5-T and other chemicals in the study. The EC50 of 2,4,5-T for inhibition of NADH generation determined with this assay was 21 M. Com- paring effects of a number of chemicals in relation to their chemical properties, the investigators concluded that 2,4,5-T had a nonspecific mode of action at the membrane. Reproductive and Developmental Toxicity Chemicals that interact with estrogen receptors can impair reproduction. Lemaire et al. (2006) addressed possible interaction of 2,4,5-T with estrogen re- ceptors. Cell lines stably transfected with human ER or ER , with a luciferase reporter construct, were used to assess the interaction of 49 chemicals, including 2,4,5-T, with the receptors. 2,4,5-T did not show any agonist activity with either ER or ER . However, 2,4,5-T showed antiestrogenic activity in the ER cells. A 2,4,5-T concentration of 10 M inhibited the response induced by E2, an ovarian

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128 VETERANS AND AGENT ORANGE: UPDATE 2006 Kuznetsov NV, Andersson P, Gradin K, Stein P, Kieckmann A, Pettersson S, Hanberg A, Poellinger L. 2005. The dioxin/aryl hydrocarbon receptor mediates downregulation of osteopontin gene expression in a mouse model of gastric tumourigenesis. Oncogene 24(19):3216–3222. 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 of the National Academy of Sciences of the Unites States of America 97(19):10442–10447. Lai KP, Wong MH, Wong CK. 2005a. Effects of TCDD in modulating the expression of Sertoli cell secretory products and markers for cell-cell interaction. Toxicology 206(1):111–123. Lai KP, Wong MH, Wong CK. 2005b. Inhibition of CYP450scc expression in dioxin-exposed rat Leydig cells. Journal of Endocrinology 185(3):519–527. Larsen MC, Brake PB, Pollenz RS, Jefcoate CR. 2004. Linked expression of Ah receptor, ARNT, CYP1A1, and CYP1B1 in rat mammary epithelia, in vitro, is each substantially elevated by specific extracellular matrix interactions that precede branching morphogenesis. Toxicological Sciences 82(1):46–61. Lemaire G, Mnif W, Mauvais P, Balaguer P, Rahmani R. 2006. Activation of alpha- and beta-estrogen receptors by persistent pesticides in reporter cell lines. Life Sciences 79(12):1160–1169. Lensu S, Miettinen R, Pohjanvirta R, Lindén J, Tuomisto J. 2006. Assessment by c-Fos immunostain- ing of changes in brain neural activity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and leptin in rats. Basic and Clinical Pharmacology and Toxicology 98:363–371. Leung HW, Kerger BD, Paustenbach DJ. 2006. Elimination half-lives of selected polychlorinated dibenzodioxins and dibenzofurans in breast-fed human infants. Journal of Toxicology and Environmental Health, Part A 69(6):437–443. Li B, Liu H-Y, Dai L-J, Lu J-C, Yang Z-M, Huang L. 2006. The early embryo loss caused by 2,3,7,8- tetrachlorodibenzo-p-dioxin may be related to the accumulation of this compound in the uterus. Reproductive Toxicology 21(3):301–306. Lin P, Chang H, Ho WL, Wu MH, Su JM. 2003. Association of aryl hydrocarbon receptor and cytochrome P4501B1 expressions in human non-small cell lung cancers. Lung Cancer 42(3):255–261. Lin TM, Rasmussen NT, Moore RW, Albrecht RM, Peterson RE. 2004. 2,3,7,8-Tetrachlorodibenzo- p-dioxin inhibits prostatic epithelial bud formation by acting directly on the urogenital sinus. Journal of Urology 172(1):365–368. Lind PM, Eriksen EF, Sahlin L, Edlund M, Örberg J. 1999. Effects of the antiestrogenic environmental pollutant 3,3 ,4,4 ,5-pentachlorobiphenyl (PCB 126) in rat bone and uterus: Diverging effects in ovariectomized and intact animals. Toxicology and Applied Pharmacology 154(3):236–244. Lind PM, Larsson S, Oxlund H, Hakansson H, Nyberg K, Eklund T, Örberg J. 2000a. Change in bone tissue composition and impaired bone strength in rats exposed to 3,3 ,4,4 ,5-pentachlorobiphenyl (PCB 126). Toxicology 150:41–51. Lind PM, Örberg J, Edlund U-B, Sjöblom L, Lind L. 2000b. Bone tissue composition, dimensions and strength in rats an increased dietary level of vitamin A or exposed to 3,3 ,4,4 ,5-pentachloro- biphenyl (PCB 126) alone or in combination with vitamin C. Toxicology 151:11–23. Lindén J, Korkalainen M, Lensu S, Tuomisto J, Pohjanvirta R. 2005. Effects of 2,3,7,8-tetrachloro- dibenzo-p-dioxin (TCDD) and leptin on hypothalamic mRNA expression of factors participat- ing in food intake regulation in a TCDD-sensitive and a TCDD-resistant rat strain. Journal of Biochemical and Molecular Toxicology 19(3):139–148. Liu PC, Matsumura F. 2006. TCDD suppresses insulin-responsive glucose transporter (GLUT-4) gene expression through C/EBP nuclear transcription factors in 3T3-L1 adipocytes. Journal of Biochemical and Molecular Toxicology 20(2):79–87. Loertscher JA, Lin T-M, Peterson RE, Allen-Hoffman BL. 2002. In utero exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin causes accelerated terminal differentiation in fetal mouse skin. Toxicological Sciences 68:465–472.

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129 TOXICOLOGY Long J-R, Egan KM, Dunning L, Shu X-O, Cai Q, Cai H, Dai Q, Holtzman J, Gao Y-T, Zheng W. 2006. Population-based case–control study of AhR (aryl hydrocarbon receptor) and CYP1A2 polymorphisms and breast cancer risk. Pharmacogenetics and Genomics 16(4):237–243. Lu M, Wang H, Li XF, Lu X, Cullen WR, Arnold LL, Cohen SM, Le XC. 2004. Evidence of he- moglobin binding to arsenic as a basis for the accumulation of arsenic in rat blood. Chemical Research in Toxicology 17(12):1733–1742. Lund AK, Goens MB, Kanagy NL, Walker MK. 2003. Cardiac hypertrophy in aryl hydrocarbon receptor null mice is correlated with elevated angiotensin II, endothelin-1, and mean arterial blood pressure. Toxicology and Applied Pharmacology 193(2):177–187. Lund AK, Peterson SL, Timmins GS, Walker MK. 2005. Endothelin-1-mediated increase in reactive oxygen species and NADPH oxidase activity in hearts of aryl hydrocarbon receptor (AhR) null mice. Toxicological Sciences 88(1):265–273. Lund AK, Goens MB, Nunez BA, Walker MK. 2006. Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice. Toxicology and Applied Pharmacology 212(2):127–135. Machado FS, Johndrow JE, Esper L, Dias A, Bafica A, Serhan CN, Aliberti J. 2006. Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nature Medicine 12(3):330–334. Machemer DE, Tukey RH. 2005. The role of protein kinase C in regulation of TCDD-mediated CYP1A1 gene expression. Toxicological Sciences 87(1):27–37. Marlowe JL, Knudsen ES, Schwemberger S, Puga A. 2004. The aryl hydrocarbon receptor displaces p300 from E2F-dependent promoters and represses S phase-specific gene expression. Journal of Biological Chemistry 279(28):29013–29022. Martinez JM, Baek SJ, Mays DM, Tithof PK, Eling TE, Walker NJ. 2004. EGR1 is a novel target for AhR agonists in human lung epithelial cells. Toxicological Sciences 82(2):429–435. Matthews J, Wihlen B, Thomsen J, Gustafsson JA. 2005. Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachloro- dibenzo-p-dioxin-responsive promoters. Molecular and Cellular Biology 25(13):5317–5328. Mazina O, Park S, Sano H, Wong P, Matsumura F. 2004. Studies on the mechanism of rapid activation of protein tyrosine phosphorylation activities, particularly c-Src kinase, by TCDD in MCF10A. Journal of Biochemical and Molecular Toxicology 18(6):313–321. Miao W, Hu L, Scrivens PJ, Batist G. 2005. Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. Journal of Bio- logical Chemistry 280(21):20340–20348. Michalak M, Malkowska-Walczak B, Rubis B, Trzeciak WH, Spaczyn ski M. 2005. Expression and ´ ´ roles of aryl hydrocarbon receptor and pregnane X receptor in endometrial cancer. Polish Jour- nal of Gynaecological Investigations 8(2):56–59. Michalek JE, Pirkle JL, Needham LL, Patterson DG Jr, Caudill SP, Tripathi RC, Mocarelli P. 2002. Pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso adults and veterans of Operation Ranch Hand. Journal of Exposure Analysis and Environmental Epidemiology 12(1):44–53. Miettinen HM, Pulkkinen P, Jamsa T, Koistinen J, Simanainen U, Tuomisto J, Tuukkanen J, Viluksela M. 2005. Effects of in utero and lactational TCDD exposure on bone development in differen- tially sensitive rat lines. Toxicological Sciences 85(2):1003–1012. Miettinen HM, Sorvari R, Alaluusua S, Murtomaa M, Tuukkanen J, Viluksela M. 2006. The ef- fect of perinatal TCDD exposure on caries susceptibility in rats. Toxicological Sciences 91(2):568–575. Milstone LM, LaVigne JF. 1984. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces hyperplasia in conflu- ent cultures of human keratinocytes. Journal of Investigative Dermatology 82(5):532–534.

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130 VETERANS AND AGENT ORANGE: UPDATE 2006 Minsavage GD, Park SK, Gasiewicz TA. 2004. The aryl hydrocarbon receptor (AhR) tyrosine 9, a residue that is essential for AhR DNA binding activity, is not a phosphoresidue but augments AhR phosphorylation. Journal of Biological Chemistry 279(20):20582–20593. Mitsuhashi T, Yonemoto J, Sone H, Kosaki K, Tohyama C, Takahashi T. 2003. Effects of in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the neural progenitor cells (NPC) of the developing murine neocortex. Social Neuroscience 29:4. Mitsui T, Sugiyama N, Maeda S, Tohyama C, Arita J. 2006. Perinatal exposure to 2,3,7,8-tetrachloro- dibenzo-p-dioxin suppresses contextual fear conditioning-accompanied activation of cyclic AMP response element-binding protein in the hippocampal CA1 region of male rats. Neurosci- ence Letters 398(3):206–210. Miyamoto K. 2004. Effects of dioxin on gene expression in female reproductive system in the rat. Environmental Sciences 11(1):47–55. Mizoi M, Takabayashi F, Nakano M, An Y, Sagesaka Y, Kato K, Okada S, Yamanaka K. 2005. The role of trivalent dimethylated arsenic in dimethylarsinic acid-promoted skin and lung tumori- genesis in mice: tumor-promoting action through the induction of oxidative stress. Toxicology Letters 158(2):87–94. Mizutani T, Yoshino M, Satake T, Nakagawa M, Ishimura R, Tohyama C, Kokame K, Kangawa K, Miyamoto. 2004. Identification of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible and -suppressive genes in the rat placenta: induction of interferon-regulated genes with possible inhibitory roles for angiogenesis in the placenta. Endocrine Journal 51(6):569–577. Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C, Poellinger L, Schwarz M. 2004. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Research 64:4707–4710. Moon DG, Lee KC, Kim YW, Park HS, Cho HY, Kim JJ. 2004. Effect of TCDD on corpus caver- nosum histology and smooth muscle physiology. International Journal of Impotence Research 16(3):224–230. Mouron SA, Grillo CA, Dulout FN, Golijow CD. 2005. DNA-protein cross-links and sister chroma- tid exchanges induced by dimethylarsinic acid in human fibroblasts cells. Mutation Research 581(1-2):83–90. Mueller MD, Vigne JL, Streich M, Tee MK, Raio L, Drecher E, Bersinger NA, Taylor RN. 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases glycodelin gene and protein expression in human endometrium. Journal of Clinical Endocrinology and Metabolism 90(8):4809–4815. Mulero-Navarro S, Pozo-Guisado E, Perez-Mancera PA, Alvarez-Barrientos A, Catalina-Fernandez I, Hernandez-Nieto E, Saenz-Santamaria J, Martinez N, Rojas JM, Sanchez-Garcia I, Fernandez- Salguero PM. 2005. Immortalized mouse mammary fibroblasts lacking dioxin receptor have impaired tumorigenicity in a subcutaneous mouse xenograft model. Journal of Biological Chemistry 280(31):28731–28741. Mulero-Navarro S, Carvajal-Gonzalez JM, Herranz M, Ballestar E, Fraga MF, Ropero S, Esteller M, Fernandez-Salguero PM. 2006. The dioxin receptor is silenced by promoter hypermethylation in human acute lymphoblastic leukemia through inhibition of Sp1 binding. Carcinogenesis 27(5):1099–1104. Murphy KA, Villano CM, Dorn R, White LA. 2004. Interaction between the aryl hydrocarbon recep- tor and retinoic acid pathways increases matrix metalloproteinase-1 expression in keratinocytes. Journal of Biological Chemistry 279(24):25284–25293. Mutoh J, Taketoh J, Okamura K, Kagawa T, Ishida T, Ishii Y, Yamada H. 2006. Fetal pituitary gonadotropin as an initial target of dioxin in its impairment of cholesterol transportation and steroidogenesis in rats. Endocrinology 147(2):927–936. Myllymaki SA, Haavisto TE, Brokken LJS, Viluksela M, Toppari J, Paranko J. 2005. In utero and lactational exposure to TCDD; steroidogenic outcomes differ in male and female rat pups. Toxicological Sciences 88(2):534–544.

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131 TOXICOLOGY Nagai H, Takei T, Tohyama C, Kubo M, Abe R, Nohara K. 2005. Search for the target genes involved in the suppression of antibody production by TCDD in C57BL/6 mice. International Immuno- pharmacology 5(2):331–343. Nayyar T, Wu J, Hood DB. 2003. Downregulation of hippocampal NMDA receptor expression by prenatal exposure to dioxin. Cellular and Molecular Biology 49(8):1357–1362. Ndebele K, Tchounwou PB, McMurray RW. 2004. Coumestrol, bisphenol-A, DDT, and TCDD modulation of interleukin-2 expression in activated CD+4 Jurkat T cells. International Journal of Environmental Research and Public Health 1(1):3–11. Needham L, Gerthoux P, Patterson D, Brambilla P, Pirkle J, Tramacere P, Turner W, Beretta C, Sampson E, Mocarelli P. 1994. Half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in serum of Seveso adults: interim report. Organohalogen Compounds 21:81–85. Negishi T, Shimomura H, Koyama T, Kawasaki K, Ishii Y, Kyuwa S, Yasuda M, Kuroda Y, Yoshikawa Y. 2006. Gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin affects social behaviors between developing rhesus monkeys (Macaca mulatta). Toxicology Letters 160(3):233–244. Neubert D, Wiesmuller T, Abraham K, Krowke R, Hagenmaier H. 1990. Persistence of various poly- chlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) in hepatic and adipose tissue of marmoset monkeys. Archives of Toxicology 64:431–442. Nishihashi H, Kanno Y, Tomuro K, Nakahama T, Inouye Y. 2006. Primary structure and organ-specific expression of the rat aryl hydrocarbon receptor repressor gene. Biological and Pharmaceutical Bulletin 29(4):640–647. Nishimura N, Yonemoto J, Nishimura H, Ikushiro SI, Tohyama C. 2005a. Disruption of thyroid hormone homeostasis at weaning of Holtzman rats by lactational but not in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicological Sciences 85(1):607–614. Nishimura N, Yonemoto J, Miyabara Y, Fujii-Kuriyama Y, Tohyama C. 2005b. Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon recep- tor-null mice. Archives of Toxicology 79(5):260–267. Nohara K, Pan X, Tsukumo S, Hida A, Ito T, Nagai H, Inouye K, Motohashi H, Yamamoto M, Fujii- Kuriyama Y, Tohyama C. 2005. Constitutively active aryl hydrocarbon receptor expressed spe- cifically in T-lineage cells causes thymus involution and suppresses the immunization-induced increase in splenocytes. Journal of Immunology 174(5):2770–2777. Nohara K, Ao K, Miyamoto Y, Ito T, Suzuki T, Toyoshiba H, Tohyama C. 2006. Comparison of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 gene expression profile in lymphocytes from mice, rats, and humans: most potent induction in humans. Toxicology 225(2-3):204–213. Nolan RJ, Freshour NL, Kastl PE, Saunders JH. 1984. Pharmacokinetics of picloram in male volun- teers. Toxicology and Applied Pharmacology 76:264–269. Nottebrock C, Riecke K, Kruse M, Shakibaei M, Stahlmann R. 2006. Effects of 2,3,7,8-tetrachloro- dibenzo-p-dioxin on the extracellular matrix of the thymus in juvenile marmosets (Callithrix jacchus). Toxicology 226(2-3):197–207. Novelli M, Piaggi S, De Tata V. 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced impairment of glucose-stimulated insulin secretion in isolated rat pancreatic islets. Toxicology Letters 156:307–314. NRC (National Research Council). 1999a. Arsenic in Drinking Water. Washington, DC: National Academy Press. NRC. 2001. Arsenic in Drinking Water: Update 2001. Washington, DC: National Academy Press. NTP (National Toxicology Program). 2004. Studies of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in Female Harlan Sprague-Dawley Rats (Gavage Study). Washington, DC: US Department of Health and Human Services, Public Health Service, National Institutes of Health (Used with permission of authors).

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