Veterans and Agent Orange Update 2012 (2014) / Chapter Skim
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4 Information Related to Biologic Plausibility
4 Information Related to Biologic Plausibility
Pages 80-127
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From page 80... ...
Experimental studies of laboratory animals or cultured cells allow observation of effects of herbicide exposure under highly controlled conditions, which is difficult or impossible to achieve in epidemiologic studies. Such conditions include genetic differences between people, and frequency and magnitude of exposure, exposure to other chemicals, and pre-existing health conditions, all of which can be controlled in a laboratory animal study.
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From page 81... ...
The rate of excretion of a chemical from the body is often limited by the rate of metabolism of the parent chemical into more water-soluble, readily excreted metabolites. Elimination is often incomplete, especially in the case of chemicals that resist biotransformation, and incomplete excretion results in the accumulation of foreign substances that can adversely affect biologic functions.
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From page 82... ...
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. PICLORAM Chemistry Picloram (Chemical Abstracts Service Number [CAS No.]
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From page 83... ...
Studies of animals indicate 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 84... ...
. No other effects of chronic exposure to picloram have been reported.
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From page 85... ...
Inorganic arsenic can be converted to organic forms. Although organic forms can be converted into inorganic forms by microorganisms in the soil, there is no evidence that this can occur in humans or other vertebrate species (Cohen et al., 2006)
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From page 86... ...
The committee contemplated the relevance of animal data collected after exposure to inorganic arsenic, leading to DMAV being formed endogenously, vs data collected after direct exposure to exogenous DMAV, which is the form of arsenic and manner of potential exposure applicable to Vietnam veterans. It has not been established -- nor can it be inferred -- that the observed effects of exposure to inorganic arsenic are caused by endogenous formation of DMAV.
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From page 87... ...
, the committee chose not to consider the literature on inorganic arsenic for this report. The reader is referred to Arsenic in Drinking Water (NRC, 1999a)
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From page 88... ...
The toxicity of inorganic arsenic is not considered relevant to veteran exposures to Agent Blue. Neurotoxicity Kruger et al.
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From page 89... ...
Gene-expression profiling of bladder urothelium after chronic exposure to DMAV in drinking water showed significant increases in genes that regulate oxidative stress (Sen et al., 2005) , whereas hepatic gene-expression profiling showed that DMAV exposure induced changes consistent with oxidative stress (Xie et al., 2004)
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From page 90... ...
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) can induce mutations in mammalian cells at concentrations below those required to produce oxidative stress after in vitro exposure (Klein et al., 2008)
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From page 91... ...
some dioxin of O Chapter of contaminants, even some with of 2,4-D and 2,4,5-Tbut the fractiontheirTCDD is The herbicidal properties dioxin-like activity, are related to of ability to comparatively very small, as illustrated in Chapter 4. mimic the plant growth hormone indole acetic acid.
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From page 92... ...
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 93... ...
The immunotoxicity of 2,4,5-T has not been evaluated in laboratory animals. The carcinogenicity of 2,4-D and 2,4,5-T has been studied in rats, mice, and dogs after exposure in their food, direct placement in their stomachs, or exposure of their skin.
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From page 94... ...
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 95... ...
. In laboratory animals, TCDD is metabolized slowly.
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From page 96... ...
96 VETERANS AND AGENT ORANGE: UPDATE 2012 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 Breastfed infants, 0–1 year after exposure Aylward et al., 2005a < 3 years Toxicokenetic model estimates for exposures > 10,000 pg/g of serum lipid > 10 years < 50 pg/g of serum lipid Emond et al., 2005 PBPK model based on 10 Weeks Operation Ranch Hand veterans > 10 years 40,000 pg/g of serum lipid 138 pg/g of serum lipid Flesch-Janys et al., 1996 7.2 years Adult males, Boehringer cohort Geusau et al., 2002 0–3 years after exposure: 1.7 yearsb Adult female 1, 144,000 pg/g of serum lipid 3.4 yearsb Adult female 2, 26,000 pg/g of serum lipid Kumagai and Koda, 2005 Adult male, incinerator workers, 1.1–2.3 years 0–1.3 years after exposure Michalek et al., 2002 0.34 yearb Adult males, Seveso cohort, 0–3 months after exposure 6.9 years 3–16 years after exposure 9.8 years Adult females, Seveso cohort, 3–16 years after exposure 7.5 years Adult males, Operation Ranch Hand veterans, 9–33 years after exposure Needham et al., 1994 7.8 years 7.2–9.7 years Adults, Seveso cohort Pirkle et al., 1989 7.1 years 5.8–9.6 years Adult males, Operation Ranch Hand veterans, 9–23 years after exposure Milbrath et al., 2009 7.2 years Reference half-life for 48.7-year-old Sorg et al., 2009 15.4 months Victor Yushchenko: TCDD at 108,000 ppt lipid Animal studies: Monkeys Neubert et al., 1990 73.7 days 60.9–93.8 days single injection Mice DeVito and Birnbaum, 1995 15 days female B6C3F1 Gasiewicz et al., 1983 11 daysc C5BL/6J 24.4 daysc DBA/2J 12.6 daysc B6D2F1/J Koshakji et al., 1984 20 days male ICR/Ha Swiss Rats
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From page 97... ...
. Human studies of the Operation Ranch Hand cohort have consistently found a similar relationship between increasing half-life of TCDD and increasing BMI (Michalek and Tripathi, 1999; Michalek et al., 1992, 1996)
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From page 98... ...
. Toxicity Profile Effects on Tissues and Organs of Laboratory Animals The effects of TCDD in laboratory animals have been observed in a number of species (rats, mice, guinea pigs, hamsters, monkeys, cows, and rabbits)
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From page 99... ...
Among the enzymes affected by TCDD, the best-studied is CYP1A1, which metabolizes xenobiotics. In laboratory animals, exposure to TCDD commonly results in an increase in CYP1A1 in most tissues; CYP1A1 therefore is often used as a marker of TCDD exposure.
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From page 100... ...
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 101... ...
The ability of TCDD to bind to the AHR with high affinity is considered to be necessary -- but not sufficient -- to produce the wide array of adverse effects associated with TCDD exposure. The pathologic responses associated with exposure to TCDD are thought to be due to binding to and activation of the AHR and later alterations in the expression of TCDDregulated genes and to altered signaling of biologic pathways that interact with the AHR signal-transduction mechanism (Poland and Knutson, 1982; Safe, 1990; Schmidt and Bradfield, 1996; Whitlock, 1990)
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From page 102... ...
. The canonical DNA recognition motif of the AHR–ARNT complex is referred to as the AHR-responsive element (AHRE, also referred to as the DRE or the XRE, for dioxin- or xenobiotic-responsive element, respectively)
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From page 103... ...
and the later activation of the serine phosphorylated form of cytosolic phospholipase A2 (cPLA2) takes place within 15 min of TCDD exposure (Dong and Matsumura, 2008; Park et al., 2007)
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From page 104... ...
. A second potential source of AHRmediated toxicity may be aberrant changes in global gene expression beyond those observed in the AHR gene battery.
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From page 105... ...
The recommendation is to use the TEF of the corresponding chlorinated congener as an interim TEF value for brominated congeners for human risk assessment (van den Berg et al., 2013)
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From page 106... ...
Chemical TEF Chlorinated dibenzo-p-dioxins 2,3,7,8-TCDD 1.0 1,2,3,7,8-PeCDD 1.0 1,2,3,4,7,8-HxCDD 0.1 1,2,3,6,7,8-HxCDD 0.1 1,2,3,7,8,9-HxCDD 0.1 1,2,3,4,6,7,8-HpCDD 0.01 OctoCDD 0.0003 Chlorinated dibenzofurans 2,3,7,8-TCDF 0.1 1,2,3,7,8-PeCDF 0.03 2,3,4,7,8-PeCDF 0.3 1,2,3,4,7,8-HxCDF 0.1 1,2,3,6,7,8-HxCDF 0.1 1,2,3,7,8,9-HxCDF 0.1 2,3,4,7,8,9-HxCDF 0.1 1,2,3,4,6,7,8-HpCDF 0.01 1,2,3,4,7,8,9-HpCDF 0.01 OctoCDF 0.0003 Non-ortho-substituted PCBs PCB 77 -- 3,3′,4,4′-tetraCB 0.0001 PCB 81 -- 3,4,4′,5-tetraCB 0.0003 PCB 126 -- 3,3′,4,4′,5-pentaCB 0.1 PCB 169 -- 3,3′,4,4′,5,5′-hexaCB 0.03 Mono-ortho-substituted PCBs PCB 105 -- 2,3,3′,4,4′-pentaCB 0.00003 PCB 114 -- 2,3,4,4′,5-pentaCB 0.00003 PCB 118 -- 2,3′,4,4′,5-pentaCB 0.00003 PCB 123 -- 2′,3,4,4′,5-pentaCB 0.00003 PCB 156 -- 2,3,3′,4,4′,5-hexaCB 0.00003 PCB 157 -- 2,3,3′,4,4′,5′-hexaCB 0.00003 PCB 167 -- 2,3′,4,4′,5,5′-hexaCB 0.00003 PCB 189 -- 2,3,3′,4,4′,5,5′-heptaCB 0.00003 NOTE: CB, chlorinated biphenyl; CDD, chlorinated dibenzo-p-dioxin; CDF, chlorinated dibenzofuran; PCB, polychlorinated biphenyl; TEF, toxicity equivalency factor. SOURCE: Adapted from: van den Berg et al.
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From page 107... ...
Genotoxic substances are known to be potentially mutagenic or carcinogenic. Although TCDD is carcinogenic in humans and laboratory animals, it is generally classified as nongenotoxic and nonmutagenic (Wassom et al., 1977)
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From page 108... ...
Summary of Biologic Plausibility That TCDD Induces 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,
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From page 109... ...
Those generalizations set the ground rules for the concept of biologic plausibility, which relies on extrapolation from animal studies to human risks, and for the precautionary principle, which bases decision making on minimizing exposure if the precise nature or magnitude of the potential damage that a substance may cause in humans is uncertain. LIMITATIONS OF EXTRAPOLATING RESULTS OF LABORATORY STUDIES TO HUMAN RESPONSES In some instances, toxic responses identified in laboratory-animal and cellculture studies are not detected in epidemiologic studies after human exposure to the same chemicals.
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From page 110... ...
• Toxicokinetics. The toxicokinetics -- absorption, distribution, metabo lism, and excretion -- of xenobiotics can vary widely between laboratory animals and humans. As shown in Table 4-1, the biologic half-life of TCDD varies from 8–29 days in rats and mice to about 7 years in humans even though drug-metabolizing enzymes -- including cytochrome P450 1A1, 1A2, and 1B1 -- are up-regulated or induced via TCDD-mediated activation of the AHR in both rat and human livers (Black et al., 2012)
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From page 111... ...
. It was not until the 1970s that the first molecular epigenetic factor was described: DNA methylation, the chemical addition of a methyl group to DNA (Holliday and Pugh, 1975)
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From page 112... ...
The most recently recognized epigenetic factor consists of small noncoding RNA molecules that can associate with mRNA and regulate gene expression. The interaction of all those epigenetic processes creates the epigenome, and the epigenome has a critical role in regulating gene expression independently of changes in DNA sequence (Christensen and Marsit, 2011; Cortessis et al., 2012; Skinner et al., 2010)
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From page 113... ...
However, there is a serious need for additional study of the question, particularly of the effects of the compounds of interest to this committee. In summary, the ability of epigenetic mechanisms to regulate gene expression might underlie the ability of xenobiotic exposure to contribute to disease development and the potential for offspring to inherit effects of the disrupted epigenetic processes.
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From page 114... ...
People who have particular genotypes may be at increased risk for specific chemical-induced DIT on the basis of heritable factors that affect metabolism or immune vulnerability. The heightened sensitivity of the developing immune system is due to the existence of critical developmental windows of vulnerability during which environmental interference with key steps of immune maturation can change the entire course of immune development and result in later-life immune dysfunction and increased risk of disease.
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From page 115... ...
2000. Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic.
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From page 116... ...
1997. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo.
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From page 117... ...
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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From page 118... ...
2008. Repression of aryl hydrocarbon receptor (AHR)
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From page 119... ...
2004. Ex pression of genes in the TGF-beta signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice.
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From page 120... ...
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 121... ...
2007. Elevation of 8-hydroxydeoxy guanosine and cell proliferation via generation of oxidative stress by organic arsenicals contrib utes to their carcinogenicity in the rat liver and bladder.
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From page 122... ...
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.
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From page 123... ...
2004. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer.
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From page 124... ...
2004. The Caenorhabditis elegans aryl hydrocarbon receptor, AHR-1, regulates neuronal development.
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From page 125... ...
2002. Ligand-dependent and independent modulation of aryl hydrocarbon recep tor localization, degradation, and gene regulation.
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From page 126... ...
2012. Renal, hepatic, pulmonary and adrenal tumors induced by prenatal inorganic arsenic followed by dimethylarsinic acid in adulthood in CD1 mice.
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From page 127... ...
2009. Dimethylarsinic acid in drinking water changed the morphology of urinary bladder but not the expression of DNA repair genes of bladder transitional epithelium in f344 rats.
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