Veterans and Agent Orange Update 2010 (2012) / Chapter Skim
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4 Information Related to Biologic Plausibility
4 Information Related to Biologic Plausibility
Pages 76-119
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From page 76... ...
In addition, the final section of this chapter presents two newly emerging subjects of molecular and biologic science that provide novel insight into potential mechanisms of xenobiotic-induced disease and may increase the biologic plausibility of the toxic actions of herbicides sprayed in Vietnam. Establishment of biologic plausibility through laboratory studies strengthens the evidence of a cause–effect relationship between herbicide exposure and health effects reported in epidemiologic studies and thus supports the existence of the less stringent relationship of association, which is the target of this committee's work.
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From page 77... ...
The rela tive 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. Excretion is often incomplete, especially in the case of chemicals that resist metabolism, and incomplete excretion results in the accumulation of foreign substances that can adversely affect biologic functions.
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From page 78... ...
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 79... ...
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 80... ...
also reported a dose-related increase in liver weights, hepatocellular hypertrophy, and changes in centrilobular tinctorial properties in male and female F344 rats exposed to picloram at 150 mg/kg per day and higher in the diet for 13 weeks. In a 90-day study, cloudy swelling in the liver cells and bile duct epithelium occurred in male and female F344 rats given 0.3% or 1.0% technical picloram in the diet (EPA, 1988c)
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From page 81... ...
Mechanisms No well-characterized mechanisms of toxicity for picloram are known. CACODYLIC ACID Chemistry Arsenic (As)
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From page 82... ...
Inorganic arsenic can be converted to organic forms. While 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 83... ...
, the committee chose to not consider the literature on inorganic arsenic in this report. The reader is referred to Arsenic in Drinking Water (NRC, 1999a)
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From page 84... ...
Cancer has been induced in the urinary bladder, kidneys, liver, thyroid glands, and lungs of laboratory animals exposed to high concentrations of DMA. In a 2-year bioassay, rats exposed to DMAV developed epithelial carcinomas and papillomas in the urinary bladder and nonneoplastic changes in the kidneys (Arnold et al., 2006)
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From page 85... ...
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 exposures (Klein et al., 2008)
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From page 86... ...
Cacodylic Acid [75-60-5] Toxicokinetics CI NH 2 O HO Several studies have examined the absorption, distribution, metabolism, and excretion of 2,4-D and 2,4,5-T in animals and humans.
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From page 87... ...
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 88... ...
At high doses that produced clini cal toxicity, suppression of the antibody response was observed, whereas other measures of immune function were normal. The immunotoxicity of 2,4,5-T has not been evaluated in laboratory animals.
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From page 89... ...
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 90... ...
. In laboratory animals, TCDD is metabolized slowly.
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From page 91... ...
91 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY TABLE 4-1 Continued Confidence Half-Lifea Reference Interval Comment Flesch-Janys et al., 1996 7.2 years Adult males, Boehringer cohort 1.5 yearsb Geusau et al., 2002 Adult female, severe exposure, 0–3 years after exposure 2.9 yearsb Adult female, severe exposure, 0–3 years after exposure 0.34 yearb Michalek et al., 2002 Adult males, Seveso cohort, 0–3 months after exposure 6.9 years Adult males, Seveso cohort, 3–16 years after exposure 9.8 years Adult females, Seveso cohort, 3–16 years after exposure 7.5 years Adult males, Ranch Hands, 9–33 years after exposure Needham et al., 1994 7.8 years 7.2–9.7 years Adults, Seveso cohort Pirkle et al., 1989 7.1 years 5.8–9.6 years Adult males, Ranch Hands, 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: Neubert et al., 1990 73.7 days 60.9–93.8 days Monkeys, single injection DeVito and Birnbaum, 1995 15 days Mice, female B6C3F1 11 daysc Gasiewicz et al., 1983 Mice, C5BL/6J 24.4 daysc Mice, DBA/2J 12.6 daysc Mice, B6D2F1/J Koshakji et al., 1984 20 days Mice, male ICR/Ha Swiss Hurst et al., 1998 8 days Rats, Long-Evans, excretion from liver 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 aHalf-lives of TCDD in humans based on measurement of TCDD in serum samples. bShorter half-lives measured in humans during first months after exposure or in severely contami nated persons consistent with nonlinear elimination predicted by physiologically-based pharmaco kinetic (PBPK)
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From page 92... ...
in very high TCDD exposures. Two metabolites of TCDD (2,3,7-trichloro-8-hydroxydibenzo-p-dioxin and 1,3,7,8-tetrachloro-2hydroxydibenzo-p-dioxin)
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From page 93... ...
Administration of TCDD to laboratory animals and cultured cells affects enzymes, hormones, and receptors. In addition to adversely affecting the ability of specific organs to fulfill their normal physiologic roles, TCDD has been found to alter the function and expression of essential proteins.
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From page 94... ...
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. Related enzymes, which are also increased with TCDD exposure, include CYP1B1 and CYP1A2, which with CYP1A1 are capable of biotransforming procarcinogens to potentially mutagenic and carcinogen metabolites.
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From page 95... ...
its adverse effects on the immune system and the developing fetus and its ability to promote the formation of some cancers. Mechanism TCDD binds and activates the aryl hydrocarbon receptor (AHR)
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. XAP2 interacts with the carboxyl terminus of hsp90 and with the AHR nuclear-localization signal (NLS)
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From page 97... ...
and the subsequent activation of the serine phosphorylated form of cytosolic phospholipase A2 (cPLA2) takes place within 15 minutes of TCDD exposure (Dong and Matsumura, 2008; Park et al., 2007)
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From page 98... ...
Evidence of that response, which was described above, was first observed in conjunction with the induction of Cyp1a1, which resulted from exposure to polycyclic aromatic hydrocarbons (PAHs) or TCDD and was directly related to activation of the AHR signaling pathway (Israel and Whitlock, 1983, 1984)
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From page 99... ...
Hence, it is likely that dioxin has effects that are due to disruption of endogenous AHR functions and that are unrelated to the intrinsic toxicity of some of its ligands. Definition of Dioxin-like Compounds, the Toxic Equivalence Factor, and Toxic Equivalents TCDD has the highest affinity for the AHR, but many other chemicals have dioxin-like properties: they have similar chemical structures, have similar physiochemical properties, and cause a common battery of toxic responses because of their relatively high affinity for the AHR.
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From page 100... ...
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 ABBREVIATIONS: 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., 2006.
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From page 101... ...
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 102... ...
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
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From page 103... ...
Those generalizations set the ground rules for the concept of biologic plausibility, which relies on extrapolation from animals studies to human risks and on 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 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 104... ...
Thus, although humans are generally considered less sensitive based on an AHR with a low TCDD-binding affinity, this assumption may not apply to all individuals. Complex Disease Etiology The etiology of human diseases is highly influenced by genetics, environmental factors, and gene–environment interactions; these factors can be protective as well as deleterious.
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From page 105... ...
EMERGING SUBJECTS IN DISEASE ETIOLOGY The final section of this chapter presents two newly emerging subjects of molecular and biologic science that provide novel insight into potential mecha nisms of disease etiology: epigenetics and developmental immunotoxicity (DIT)
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From page 106... ...
This type of epigenetic inheritance between generations can affect disease etiology and other biologic phenomena. 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 107... ...
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 en vironmental 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 108... ...
Toxicology and Applied Pharmacology 222(2)
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From page 109... ...
1995. Orientation of the heterodimeric aryl hydrocarbon (dioxin)
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From page 110... ...
1997. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo.
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From page 111... ...
2008. Repression of aryl hydrocarbon receptor (AHR)
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From page 112... ...
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 113... ...
1999. Evidence that the Co-chaperone p23 regulates ligand responsiveness of the dioxin (aryl hydrocarbon)
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From page 114... ...
Toxicology and Applied Pharmacology 222(3)
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From page 115... ...
2004. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer.
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From page 116... ...
1993. Role of the aryl hy drocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin)
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From page 117... ...
2004. The Caenorhabditis elegans aryl hydrocarbon receptor, AHR-1, regulates neuronal development.
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From page 118... ...
2002. Ligand-dependent and independent modulation of aryl hydrocarbon recep tor localization, degradation, and gene regulation.
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From page 119... ...
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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