Veterans and Agent Orange Update 2004 (2005) / Chapter Skim
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3 Toxicology
3 Toxicology
Pages 33-117
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From page 33... ...
, Veterans and Agent Orange: Update 1998 (IOM, 1999; hereafter, Update 1998) , Veterans and Agent Orange: Update 2000 (IOM, 2001; hereafter, Update 2000)
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From page 34... ...
High concentrations usually are required to modulate cellular and biochemical processes. In contrast, experimental data reviewed in previous Agent Orange reports led those committees to conclude that TCDD elicits a diverse spectrum of sex-, strain-, age-, and speciesspecific effects: carcinogenesis, immunotoxicity, reproductive and developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight.
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From page 35... ...
The result is a higher body burden in dogs for a substantially longer period than is exhibited by other species. A recent study examining concentrations of 2,4-D and its metabolites in the urine of herbicide applicators was consistent with 2,4-D urinary half-life estimates of 1340 h for humans (Hines et al., 2003)
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Carcinogenicity and Mechanisms Related to Genotoxic Effects Previous updates indicated little experimental evidence that 2,4-D produces any carcinogenic activity. No relevant studies on its carcinogenic effects have been published since Update 2002.
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Neurotoxicity Previous updates indicated no evidence that 2,4-D causes effects on the neurologic system in adult animals at doses in the µg/kg/day range. Case reports of acute poisonings of humans exposed to large amounts of 2,4-D formulations (>20 mL)
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Several studies cited in previous updates suggested effects of 2,4-D on the developing brain, and more recent studies present concordant results. Garcia et al.
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Those data suggest that undernourishment might exacerbate the effects of 2,4-D on developing tissues. Immunotoxicity Previous updates indicated that 2,4-D has at most a weak effect on the immune system.
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Mechanism Related to Effects on Thyroid Hormones Effects of 2,4-D on serum concentrations of thyroid hormones, particularly to decreases in thyroxine, were noted in previous updates. Ishihara et al.
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In addition to being produced as an herbicide, cacodylic acid, or DMA, is a metabolic product of organic arsenic exposure in humans. The committee considered the relevance of data on inorganic arsenic to DMA.
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. DMA might act through induction of oxidative damage or damage to DNA, and exposure results in necrosis of the urinary bladder epithelium followed by regenerative hyperplasia (IOM, 2003)
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. However, DMA cultured with primary rat astroglia cells did not produce changes in cell viability or cause DNA damage at micromolar concentrations; treatment of the astroglia cells with inorganic arsenicals resulted in decreased cell viability and increased DNA damage (Jin et al., 2004)
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In animal models it is possible to control exposure and thus to test the validity of PBPK or other models. In humans, the utility of such models is determined by examining TCDD tissue and blood concentrations as related to accidental or background exposure.
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PBPK models can offer more information about tissue distribution, but it still is possible to predict elimination of TCDD with knowledge of fat content and body mass index (BMI)
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similar to that in humans, suggesting that the guinea pig could be a useful model for low-dose studies. The TCDD concentrations were higher in adipose tissue than they were in liver, suggesting that CYP1A2 might not be as effective at sequestering TCDD in guinea pigs as it is in rats or mice, or that the dose was too low to induce CYP1A2.
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From page 47... ...
As discussed in previous Updates, individual variation arises from differences in biologic variables, such as body weight, sex, and BMI, as well as from differences in metabolism rates and exposure. TCDD concentrations in Japanese adults vary greatly, ranging from 0.0025 to 0.025 pg/g lipid in blood, and from 0.036 to 1.11 pg/g lipid in liver.
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Moreover, TCDD concentrations declined from an average of 4.3 pg/g blood lipid in 1999 to an average of 0.9 pg/g in 2003. The total PCDD and PCDF concentrations followed a similar pattern.
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The analyses confirmed that the highest concentrations of TCDD were in people residing in the most highly contaminated areas, but although the average values for blood levels of TCDD in zone A residents are higher than in zone B, the levels in some zone B individuals were higher than those in some individuals from zone A Age at first exposure was the other strong predictor of TCDD serum concentration.
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Elevated TCDD concentrations in breast milk have been observed by numerous investigators over the years. The occurrence of TCDD in breast milk is important because it indicates a flux of chemical through the organ, which could have implications for effects in breast tissue.
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The objective was to determine whether blood concentrations might be used to estimate general exposure for infants. Their analyses of the somewhat limited data suggest that the concentrations of TCDD and other compounds human milk generally reflect those in blood.
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. Greater half-life in females attributed to greater body mass index.
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. Differences in elimination rates have been observed among Ranch Hands, and those variations would relate to differences in cumulative dose; that is, to an accurate calculation of the area under the curve for total internal exposure.
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It will be important to continue to refine PBPK models for evaluating tissue distribution in humans. The information on TCDD toxicokinetics is expanding, and new studies tend to support the conclusions of earlier work.
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To make such estimates usually requires researchers to work backwards from current blood concentrations in exposed subjects. Although differences in dioxin concentrations in blood serum obtained years or decades after external exposure could relate to differences in that exposure, individual differences in elimination rates could be substantial.
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Therefore, although the text below cites related work published since Update 2002 that was identified by the committee, closer attention is given only to studies that add substantial new information, particularly as it might be relevant to the exposure of Vietnam veterans. As discussed in Update 2002, it is important to consider exposure and species sensitivity when discussing animal data and their relevance to humans.
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Plasma TCDD concentrations showed a negative association with induced cytochrome P450 (CYP) 1A1-mediated enzyme activity after exposure of lymphocytes from those persons to TCDD in vitro (Baccarelli et al., 2004; Landi et al., 2003)
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(2003a) used a variety of human cell lines to show that several polycyclic aromatic hydrocarbons, including TCDD, induced the expression of the AhRR gene, but in a compound- and cell-specific manner.
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Those data are particularly relevant because TCDD exposure in animals is known to affect estrogen-dependent responses in several tissues, especially those involved in reproduction. Chemicals Other Than TCDD That Affect AhR Function As indicated in previous updates, data on the ability of various dioxin-like chemicals to bind to the AhR and cause toxicity show that the AhR can mediate the toxicity of those substances; newer information supports that conclusion.
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AhR-Mediated Alterations of Gene Expression Much of our current understanding of the mechanism of TCDD action is based on analysis of the induction of particular genes and altered intracellular signaling pathways. Several genes that are modulated by TCDD and by dioxin-like compounds in a variety of biologic systems, including human cells, are listed in Table 3-2, which includes citations to papers published since Update 2002.
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TOXICOLOGY 61 TABLE 3-2 Genes and Proteins Known to Be Modulated by TCDD and/or Dioxin-like Chemicals Reference Genes Genes and Proteins Directly Regulated by AhR Thomsen et al., 2004 hairy and enhancer of Split homolog-1 (HES-1) Son and Rozman, 2002 plasminogen activator inhibitor-1 Baba et al., 2001 aryl hydrocarbon receptor repressor (AhRR)
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62 VETERANS AND AGENT ORANGE: UPDATE 2004 TABLE 3-2 Continued Reference Genes Other Genes Reported, Since Update 2002, to Be Altered by AhR Ligand Exposure Adachi et al., 2004 ADP ribosylation factor 4; basic transcription factor 2 34 kDa subunit; cadherin 2; CDC-like kinase; complement component 5; cyclin-dependent kinase inhibitor 1A; cyclin dependent kinse 1; CYP19A1; DNA mismatch repair protein; early growth response protein; 110-kDa heat-shock protein; heat shock factor-binding protein 1; heat shock protein 60-kDa protein; insulin-like growth factor-binding protein 10; insulin-like growth factor binding protein 1; insulin-like growth factor II; integrin ; interleukin 1 receptor type 1; 45-kDa interleukin enhancer-binding factor 2; NEDD5 protein homolog; Niemann-Pick C disease protein; retinoblastoma-binding protein 3; Rab geranylgeranyl transferase subunit; RNA polymerase II elongation factor SIII p15 subunit; Sec61-; sex determining region Y box-containing gene 9; short/ branched chain-specific acyl-CoA dehydrogenase; solute carrier family 2 member 2; T-complex protein 1 and subunits; thyroid receptor-interacting protein 15; topoisomerase I and II ; transcription factor HTF4; translation initiation factor 4E 25-kDa subunit Fisher et al., 2004 Bcl-2 family genes bik, bid, Hrk, bok/mtd, mcl-1, bcl-x, and bcl-w; IAP family genes X-linked IAP, NAIP1, and NAIP5; Myd88; p21; p53; RIP; TNFR family genes OX40, Fas, CD30, Lt-R, and TNFR1; TNF family genes LIGHT, OX40L, and Bar-like; TRAF2 Johnson et al., 2004 actin ; Ahr; alcohol dehydrogenase 1, complex; angiopoietin-like 4; angiotensinogen; brain derived neurotrophic factor; cadherin 16; calbindin-28k; carbonic anhydrase 3; carboxylesterase 3; Cd44 antigen; coagulation factor II; cytokine receptor-like factor 1; epiregulin; fibroblast growth factor 7; fibroblast growth factor receptor 4; follistatin; forkhead box a2 and f2; Fos-like antigen 1; glutamyl aminopeptidase; Gro1 oncogene; high mobility group at-hook 2; -2-hs-glycoprotein; hydroxysteroid 11 dehydrogenase 2; insulin-like growth factor 2; insulin-like growth factor binding proteins 3, 5, and 6; integrin 3, 6, and 4; IL-6; interferon activated gene 202a; lymphocyte antigen 6 complex, loci e, A and H; lysyl oxidase; matrix metalloproteinase 3 and 9; mitogen regulated protein proliferin 3; NADH dehydrogenase 1; osteopontin; p21; peripherin; phospholipase a2 group VII; proliferin 2; Ras-related protein; rennin 1 structural; retinol binding protein 4, plasma; RNA binding motif, single stranded interacting protein 1; secreted phosphoprotein 1; small proline-rich proteins 2b, 2c and 2f; spleen tyrosine kinase; squalene epoxidase; stratifin; thrombomodulin; TNF receptor family member 1b; tumor-associated calcium signal transducer 2
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TOXICOLOGY 63 TABLE 3-2 Continued Reference Genes Karyala et al., 2004 ADP-ribosylation-like factor 6 interacting protein 5; calcium binding protein A11; CCAAT/enhancer-binding protein; esterase 10; immediate early response 3; nicotinic acetylcholine receptor subunit 6; nuclear factor erythroid derived 2, like 2; prenylated SNARE protein; RIKEN CDNA FLJ13933 FIS, clone Y79AA1000782; RIKEN phosphogluconate dehydrogenase inhibitor; S100 calcium binding protein A4; vanin 1; Vomeronasal organ family 2, receptor, 11; distal-less homeobox 5 Moennikes et al., 2004 DEAD/H box polypeptide 3; DnaJ (hsp40) homolog, (constitutively active AhR)
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64 VETERANS AND AGENT ORANGE: UPDATE 2004 TABLE 3-2 Continued Reference Genes Martinez et al., 2002 activin receptor type II B; acyl-coenzyme A oxidase; aminoaclase 1; B-cell lymphoma protein 3; basic transcription element binding protein 1; bone morphogenic protein; -catenin; Cdc42; CDK-2 associated protein; cellular retinoic acid binding protein 1; collagen IV 3 chain; collagen VI 3; cyclin-dependent kinase 4 inhibitor C; cyclin-dependent kinase inhibitor 2B isoform; CYP27A1; discoidin receptor tyrosine kinase; E2F dimerization partner 2; early growth response 1; EGF containing fibulin-like extracellular matrix protein; ephrin A1, isoform a; epidermal growth factor receptor substrate 15; epithelial-cadherin; fibroblast growth factor; fibronectin receptor subunit; Fos-related protein; GABA A receptor; GATA binding protein 1; glucocorticoid receptor; GTPase activating protein; homospermidine synthase; hsp 70 kDa protein insulin-like growth factor 1 receptor; GABA A receptor subunit; 25 kDa GTP binding protein; l hsp 70 kDa 2; hyaluronidase 1; insulin induced protein 1; interferon-induced protein 56 and p78; interferon receptor 1; interferon regulatory factor 4; IL-6 receptor ; IL-8; Kruppel-like factor 5; lamanin B2 chain and 3b chain; leukemia inhibitor factor; low density liproprotein receptor related protein; macrophage inflammatory protein 1-; MAP kinase-activated protein kinase 2; MAP kinase phosphatase-1; matrix metalloproteinase 1 and 9; mesoderm specific transcript isoform; mitotic arrest defective protein; multifunctional DNA repair enzyme; neurotrophic tyrosine kinase; NFB p100/p49 subunits; nuclear receptor coactivator 2; ornithine cyclodeaminase; 8-oxo-dGTPase; p53; p53-binding protein Mdm4; peripheral benzodiazepine receptor; polyamine oxidase; protein kinase C ; protein kinase C-like 2; protein tyrosine phosphatase type 1; pyruvate dehydrogenase kinase; replication licensing factor; retinoic acid receptor ; RNA polymerase II; S100 calcium binding protein; serine/threonine kinase 4; serine/threonine specific protein phosphatase; serum/glucocorticoid regulated kinase; STAT1; thioltransferase; thioredoxin reductase; thrombin receptor; thrombomodulin; thymosin 10; tissue inhibitor of metalloproteinase-3; translation initiation factor 3 and 4H; transmembrane 4 superfamily member; tumor-associated calcium signal transducer 4; tyrosine-protein kinase receptor; ubiquitin-like interferon, -inducible protein; vasoactive intestinal polypeptide receptor; VEGF; vitronectin; WAP four-disulfide core domain 2, isoform 1 precursor; zinc finger protein 42
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could influence AhR activity at specific gene sites and in specific cells or tissues. There also have been several reports that TCDD exposure to cells alters the activity of enzymes such as cAMP/protein kinase A (Vogel et al., 2004)
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Although the exact biologic mechanisms of those endpoints and the observed differences are not yet understood, recent data show the possibility that at least some of the effects are mediated by TCDD's ability, through the AhR, to modulate cell cycle control, signaling pathways that lead to cell death or inappropriate cell activation, hormones and growth factors and the responses to them, or the biochemical pathways that lead to oxidative stress. Those mechanisms are implicated in many of the toxic endpoints discussed below.
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. As indicated in previous updates, TCDD inhibits the differentiation of some preadipocyte cell lines to adipocytes (fat cells)
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Down-regulation of this factor during adipose differentiation could result in suppression of Ahr gene transcription. Several investigations cited in previous updates noted that TCDD exposure alters plasma and tissue lipid content in animals.
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No relevant studies on bone have been published since Update 2002. In general, possible effects of TCDD on bone have not been thoroughly investigated.
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. Pulmonary Toxicity This and previous updates report evidence suggestive of an association between herbicide exposure in Vietnam and respiratory cancer (see Carcinogenesis below)
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Previous updates have reported that TCDD exposure in laboratory animals significantly disrupts the homeostasis of vitamin A Several recent reports are consistent with the ability of the AhR-signaling pathway to interact with the retinoid receptor pathways by different mechanisms.
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The body burdens of TCDD at 25 and 6 µg/kg observed in 2 of the subjects are among the highest ever recorded in humans and are at least 100-fold higher than body burdens in most, if not all, Vietnam veterans. However, those concentrations are comparable to the doses used in most studies with experimental animals.
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Studies cited in previous updates indicate that TCDD affects the homeostasis of vitamin A Huang et al.
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. Those new results favor the hypothesis that thymic involution observed after TCDD exposure results from direct AhRmediated toxicity to the developing thymocytes that could be exacerbated by additional effects on thymic epithelial cells.
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TOXICOLOGY 75 numbers of neutrophils in mouse spleen and blood with a growing tumor allograft also were reported by Choi et al.
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TCDD accelerated differentiation, as demonstrated by increased expression of the differentiation markers involucrin and filaggrin. TCDD also increased proliferation, as indicated by an increased production of NADHNADPH and changes in cell cycle.
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Previous reports indicate the development of lung cancer in female rats but not male rats exposed to TCDD.
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indicated that if TCDD is given to pregnant rats, the offspring are more susceptible to dimethylbenz[a] anthraceneinduced mammary cancer as adults.
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Testicular activities of superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase were decreased, and there were increased tissue concentrations of H2O2 and lipid peroxidation. Acute-exposure studies produced a similar effect of TCDD-induced oxidative stress on epididymal sperm (Latchoumycandane et al., 2003)
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(2004) reported that there is constitutive expression of CYP1A1 in immature oocytes, but not in cumulus cells, and that a significant increase in CYP1A1 occurs in both cell types after maturation.
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Previous updates reported that TCDD blocks many estrogen-induced responses in human breast cancer cells. Davis et al.
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In the National Toxicology Program study (NTP, 2004) , female Harlan Sprague-Dawley rats were administered TCDD at 3, 10, 22, 46, or 100 ng/kg body weight by gavage 5 days a week for 104 weeks.
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TOXICOLOGY 83 trations in a doseresponse fashion. Gingival squamous hyperplasia was observed in the oral mucosa, as was squamous hyperplasia of the forestomach.
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The cardiovascular system, in particular the vascular endothelium of the developing embryo, also has been identified as a primary target of TCDD toxicity in fish. Studies cited in Update 2002 concluded that circulatory failure and oxidative stress in vascular endothelial cells are primary events that mediate the toxicity.
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From page 85... ...
That effect appears to involve regulation of the Wilms's tumor suppressor gene, which is important in mesenchymalepithelial transition and differentiation during nephrogenesis, and it is consistent with the noted ability of TCDD to disrupt the process. Previous updates cited several reports indicating that development of the male reproductive system is exceptionally sensitive to in utero and lactational TCDD exposure.
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From page 86... ...
Several reports of studies in animals and exposed humans suggest that perinatal exposure to TCDD or to dioxin-like compounds can impair brain development. Rats exposed in utero to TCDD at 1 µg/kg maternal body weight showed deficits in spatial discriminationreversal learning (RL)
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From page 87... ...
The TCDD-treated embryos exhibited increased cell death and intracellular spaces in the neural tube. Significant decreases were observed in the n-3 (4060%)
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Several studies cited in previous updates had suggested effects of 2,4-D on developing brain and recent studies are consistent with this. Elicited changes in brain neurotransmitter content appeared to correlate with behavioral alterations, and some of those changes appeared to be irreversible.
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Because the relevance of studies of inorganic-arsenic exposure for evaluating effects of exposure to cacodylic acid has not been established and cannot be inferred (Chapter 2) , the literature on inorganic arsenic is not considered in this report.
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Studies of TCDD in Ranch Hand Vietnam veterans indicate that it has a mean half-life of 7.6 years. Recent clinical studies of two women
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The apparent correlation between TCDD half-life and body weight may actually be best explained in terms of body composition: the greater the portion of body composition represented by adipose tissue, the longer the half-life. TCDD concentrations are often measured in blood, and autopsy studies indicate that blood concentrations correlate with tissue concentrations.
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Reproductive and developmental effects have been seen in animals exposed to TCDD; TCDD exposure affects sperm count, sperm production, and seminal vesicle weights in male offspring and affects the reproductive systems of female offspring. In some recent studies, however, the reproductive-system effects were not accompanied by effects on reproductive outcomes.
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The relationship between mechanism and the shape of the doseresponse curve -- linear or non-linear -- is complex, not well understood, and could be different for different endpoints. Little information is available on the biologic plausibility of causation of health effects by Agent Orange through chemicals other than TCDD.
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From page 94... ...
2002. Plasmid DNA damage caused by methylated arsenicals, ascorbic acid and human liver ferritin.
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2002. Temporal trends in human TCDD body burden: decreases over three decades and implications for exposure levels.
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2003. Toxicokinetic modelling of 2,3,7,8-tetrachloro-p-dioxin blood concentrations in women after ingestion.
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I Nonlinear distribution of PCDD/PCDF body burden between liver and adipose tissues.
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2004. Application of PBPK model for 2,4-D to estimates of risk in backpack applicators.
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2004. Relationship of serum TCDD concentrations and age at exposure of female residents of Seveso, Italy.
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2003. The role of antioxidant enzymes in TCDD-induced oxidative stress in various brain regions of rats after subchronic exposure.
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2002. Micro nucleus frequency and proliferation in human lymphocytes after exposure to herbicide 2,4 dichlorophenoxyacetic acid in vitro and in vivo.
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1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam.
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2001. A study on the correlation between categorizations of the individual exposure levels to agent orange and serum dioxin levels among the Korean Vietnam veterans.
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104 VETERANS AND AGENT ORANGE: UPDATE 2004 Ko K, Theobald HM, Peterson RE.
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induces oxidative stress in the epididymis and epididymal sperm of adult rats. Archives of Toxicology 77(5)
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2002. Infant exposure to dioxin-like compounds in breast milk.
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2003. Diabetes mellitus and 2,3,7,8-tetrachlorodibenzo-p dioxin elimination in veterans of Operation Ranch Hand.
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in hepatic and adipose tissue of marmoset monkeys. Archives of Toxicology 64:431442.
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2004. Distribution of persistent, lipid-soluble chemicals in breast and abdominal adipose tissues: lessons learned from a breast cancer study.
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1989. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand.
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2002. An experimental model using guinea pigs to reduce accumulated dioxins in the body.
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1990. Partitioning of 2,3,7,8-chlorinated dibenzo-p-dioxins and dibenzofurans between adipose tissue and plasma lipid of 20 Massachusetts Vietnam veterans.
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2001. The effect of the arylhydrocarbon receptor on the human steroidogenic acute regulatory gene promoter activity.
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1990. Comparison of the polychlorinated dibenzo-p-dioxin and dibenzofuran in human tissue and human liver.
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2003. T cell-specific disruption of arylhydrocarbon receptor nuclear translocator (Arnt)
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2002. Carcinogenicity of dimethylarsenic acid in male F344 rats and genetic alterations in induced urinary bladder tumors.
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2003. Species-specific transcrip tional activity of synthetic flavonoids in guinea pig and mouse cells as a result of differential activation of the aryl hydrocarbon receptor to interact with dioxin-responsive elements.
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