Veterans and Agent Orange Update 2008 (2009) / Chapter Skim
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4 Information Related to Biologic Plausibility
4 Information Related to Biologic Plausibility
Pages 65-103
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From page 65... ...
, picloram, cacodylic acid, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that have been published since Update 2006 (IOM, 2007)
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From page 66... ...
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.
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From page 67... ...
, and cacodylic acid (dimethyl arsenic acid, DMA)
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From page 68... ...
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)
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From page 69... ...
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)
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From page 70... ...
70 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 4-1 Estimates of TCDD Half-Life in Humans and Animals Confidence Reference Half-Lifea 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 Aylward et al., 2005a < 3 years Calculated for exposures > 10,000 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 Geusau et al., 2002 1.5 yearsb Adult female, severe exposure, 0–3 years after exposure 2.9 yearsb Adult female, severe exposure, 0–3 years after exposure Michalek et al., 2002 0.34 yearb 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 Gasiewicz et al., 1983 11.0 daysc 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 Pohjanvirta and Tuomisto, 21.9 days Rats, male Han/Wistar, resistant 1990 strain Viluksela et al., 1996 20.2 days Rats, Long-Evans, TurkuAB strain 28.9 daysd Rats, Long-Evans, Charles River strain Weber et al., 1993 16.3 ± 3.0 days 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 contaminated persons consistent with nonlinear elimination predicted by physiologically based pharmacokinetic modeling (for example, by Carrier et al., 1995)
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From page 71... ...
In laboratory 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 steroids.
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From page 72... ...
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 receptors. 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.
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From page 73... ...
Mechanism of Action TCDD binds and activates the aryl hydrocarbon receptor (AHR)
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From page 74... ...
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.
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From page 75... ...
The members of the polyhalogenated 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.
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From page 76... ...
. AHR Signaling Pathway In the absence of bound ligand, the inactive AHR is retained in the cytoplasm of the cell in a complex consisting of two molecules of the heat shock protein hsp90, one molecule of prostaglandin E synthase 3 (p23)
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From page 77... ...
. Because of the presence of AHRE motif in their gene promoters, other metabolizing genes were tested and found to be induced by AHR ligands, and this led to the identification of a so-called AHR gene battery of phase I and phase II detoxification genes that code for the drug-metabolizing enzymes CYP1A1, CYP1A2, CYP1B1, NQO1, ALHD3A1, UGT1A2, and GSTA1 (Nebert et al., 2000)
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Other Toxic Health Outcomes of Dioxin There is an extensive body of evidence from experimental studies in animal model systems that TCDD, other dioxins, and several DLCs are immunotoxic. Although the available evidence on humans is scant, mechanistic considerations support the notion that chemical alterations to immune function would cause adverse health outcomes because of the critical role that the immune system
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; mobilization of calcium from intracellular sources and imported from the culture medium (Puga et al., 1995) ; and related to calcium mobilization, the induction of mitochondria oxidative stress (Senft et al., 2002)
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From page 80... ...
Summary on Biologic Plausibility of TCDD Inducing Adverse Effects in Humans Mechanistic studies in vitro and in laboratory animals have characterized the biochemical pathways and types of biologic events that contribute to adverse effects of exposure to TCDD. For example, much evidence indicates that TCDD acting via the AHR in partnership with ARNT alters gene expression.
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From page 81... ...
From a mechanistic standpoint, adverse effects identified in vitro are expected to occur in all the cells of an organism and to all the organisms that express these proteins. That generalization sets the ground rules for the concept of biologic plausibility, which relies on extrapolation from laboratory tests to human risks, and on the precautionary principle, which bases decision-making on precaution if the precise nature or magnitude of the potential damage that a substance may cause in humans is uncertain.
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From page 82... ...
Uses of 2,4-D and 2,4,5-T 2,4-D has been used commercially in the United States since World War II to control the growth of broadleaf plants and weeds on range lands, lawns, golf courses, forests, roadways, parks, and agricultural land and remains today a widely used herbicide approved for use by the European Union and the US EPA. Formulations include 2,4-D amine and alkali salts and esters, which are mobile in soil and easily absorbed through the leaves and roots of many plants.
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From page 83... ...
After a single oral dose, 2,4-D is considered to produce moderate acute toxicity with an LD50 (dose lethal to 50% of exposed animals) of 375 mg/kg in rats, 370 mg/kg in mice, and from less than 320 to 1,000 mg/kg in guinea pigs.
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From page 84... ...
2,4-D is not metabolized to reactive intermediates capable of interacting with DNA, and the evidence supports the conclusion that 2,4-D is not a carcinogen. CACODYLIC ACID Chemistry Arsenic (As)
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From page 85... ...
Inorganic arsenic can be converted to organic forms, but organic forms cannot be converted into inorganic forms (Cohen et al., 2006)
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Therefore, the literature on inorganic arsenic is not considered in this report. The reader is referred to Arsenic in Drinking Water (NRC, 1999a)
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From page 87... ...
DMAIII and DMAV have been shown to induce DNA damage by increasing oxidative stress. Chronic exposure of ddY mice to DMAV at 400 ppm in drinking water increased staining for 4-hydroxy-2-nonenal adducts, which are indicative of oxidative stress, and for 8-oxo-2′-deoxyguanosine (8-oxodG)
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From page 88... ...
Gene-expression profiling of bladder urothelium after chronic exposure to DMAV in drinking water showed significant increases in genes that regulate apoptosis, the cell cycle, and oxidative stress (Sen et al., 2005)
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From page 89... ...
In light of the significant differences in metabolism of arsenic by different species and the lack of supportive data in humans, it cannot be concluded that DMAV leads to an increase in cancer risk in humans. Mechanisms Oxidative stress is a common theme that runs through the literature on the mechanisms of action of arsenic, particularly with regard to cancer in animals, although some studies have suggested that methylated arsenicals (MMAIII and DMAIII)
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From page 90... ...
Studies of animals have indicated that picloram is sparingly toxic at high doses. Toxicity Profile The original VAO committee reviewed studies of the carcinogenicity, genotoxicity, acute toxicity, chronic systemic toxicity, reproductive and developmental toxicity, and immunotoxicity of picloram.
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From page 91... ...
. No other effects of chronic exposure to picloram have been reported.
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From page 92... ...
2001. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine.
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1997. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo.
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1999. Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export.
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2008. An evidence for regulatory cross-talk between aryl hydrocarbon receptor and glucocorticoid receptor in HepG2 cells.
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2007. Analysis of the transcriptional regulation and molecular function of the aryl hydrocarbon receptor repressor in human cell lines.
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2004. The AHR-1 aryl hydrocarbon receptor and its co-factor the AHA-1 aryl hydrocarbon receptor nuclear translocator specify GABAergic neuron cell fate in C
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From page 98... ...
induces oxidative stress, DNA strand breaks, and poly(ADP-ribose) polymerase-1 activation in human breast carcinoma cell lines.
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2006. Sustained aryl hydrocarbon receptor activity attenuates liver regeneration.
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2005. Aryl hydrocarbon receptor activation by cAMP vs.
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2002. Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor.
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2007. Dioxin affects glucose transport via the arylhydrocarbon receptor signal cascade in pluripotent embryonic carcinoma cells.
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2008. Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase.
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