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4 Information Related to Biologic Plausibility
Pages 93-132

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From page 93...
... Experimental studies of laboratory animals or cultured cells make it possible to observe the effects of herbicide exposure under highly controlled conditions, which is difficult or impossible to do in epidemiologic studies. The conditions that are controlled include the genetic differences among people, the frequency and magnitude of exposure, exposure to other chemicals, 93
From page 94...
... When the resulting metabolites are pharmacologically or toxicologically inert, metabolism has deactivated the administered dose of the parent chemical and thus reduced its effects on the body. Metabolism may, however, generate a chemical that is more potent or more toxic than the parent compound.
From page 95...
... INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY 95 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 Toxicokenetic model estimates for exposures: < 3 years   > 10,000 pg/g of serum lipid > 10 years   < 50 pg/g of serum lipid Emond et al., 2005 PBPK model based on 10 Ranch Hand veterans: Weeks   40,000 pg/g of serum lipid >10 years   138 pg/g of serum lipid Flesch-Janys et al., 1996 7.2 years Adult males, Boehringer cohort Geusau et al., 2002 1.7 yearsb 0–3 years after exposure: 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 1.1–2.3 years Adult male, incinerator workers, 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, 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: 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 continued
From page 96...
... Understanding the toxicokinetics of a chemical is useful for assembling a valid reconstruction of a human exposure, but it is most important in assessing the risk of effects from exposure to a chemical by determining the concentration of the active chemical in target tissues. The principles involved in toxicokinetics are similar from chemical to chemical, although the degree to which different processes influence distribution depends on the structure and other inherent properties of a particular chemical.
From page 97...
... 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.]
From page 98...
... 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.
From page 99...
... . No other effects of chronic exposure to picloram have been reported.
From page 100...
... . See Figure 4-2 for the chemical structures of selected arsenic-containing compounds; sodium arsenite, which contains AsIII, is generally considered to be the most toxic of these arsenic compounds.
From page 101...
... The old hypothesis that methylation of inorganic arsenic was a detoxifying mechanism has been dispelled by newer studies. Direct treatment of laboratory animals with these metabolic products has demonstrated them to be linked to increased incidence of cancers and non-cancer health outcomes, but there are no studies of health effects in humans following direct exposure to DMA that could provide epidemiologic evidence of association for DMA as required by the Agent Orange Act.
From page 102...
... , but these models have limited relevance for assessing potential harm to Vietnam veterans who are presumed to have been directly exposed to DMAV. Although epidemiologic studies of direct exposure to DMAV are not available, investigations into the relationship between health outcomes and the metabolic profiles of humans exposed to inorganic arsenic provide some insight into the roles of the individual metabolites in producing adverse outcome.
From page 103...
... Toxicity Profile This section discusses the toxicity associated with organic forms of arsenic, most notably DMAV because it is the active ingredient in Agent Blue. The toxicity of inorganic arsenic is not considered relevant to veteran exposures to Agent Blue.
From page 104...
... 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)
From page 105...
... . Increased urothelial cell proliferation was also found following DMA exposure via the drinking water (Wei et al., 2002)
From page 106...
... . There may also be epigenetic effects involved in DMA carcinogenicity, as suggested by a study in humans in which there was a significant association between global DNA methylation and urinary DMA levels (Tellez-Plaza et al., 2014)
From page 107...
... in that mimic the plant growth hormone indole acetic acid. They are selective IC IC herbicides in affect monocots, such as wheat, corn, and rice.
From page 108...
... 2,4-D is also an irritant of the gastrointestinal tract, causing nausea, vomiting, and diarrhea. Chronic exposure to 2,4-D at relatively high concentrations has been shown to produce a variety of toxic effects, including hepatic and renal toxicity, neurotoxicity, and hematologic changes.
From page 109...
... 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.
From page 110...
... found that lymphocytes from smokers show genotoxic damage after exposure to 2,4-D, whereas lymphocytes from non-smokers do not, which suggests that although 2,4-D may not be a carcinogen, it may influence the activity of known carcinogens. 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN Chemistry TCDDs are polychlorinated dibenzo-p-dioxins that have a triple-ring structure consisting of two benzene rings connected by an oxygenated ring with four attached chlorine atoms; in the case of the dioxin congener of greatest concern, 2,3,7,8-TCDD (commonly called simply TCDD)
From page 111...
... In laboratory animals, oral administration of TCDD has been shown to result in absorption of 50 to 93 percent of the administered dose (Nolan et al., 1979; Rose et al., 1976)
From page 112...
... . In laboratory animals, TCDD is metabolized slowly.
From page 113...
... . A continued analysis of Yushchenko's condition has revealed putative metabolomic and transcriptomic biomarkers that may prove useful for predicting health effects in populations with significant TCDD exposures (Jeanneret et al., 2014; Saurat et al., 2012)
From page 114...
... Effects on Enzymes, Hormones, and Receptors in Laboratory Animals and Cultured Cells 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, particularly a number of enzymes. The enzymes
From page 115...
... Among the enzymes affected by TCDD, the best studied is CYP1A1, which metabolizes some 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.
From page 116...
... in the cells of virtually every tissue in the body. The ability of TCDD to bind to the AHR with high affinity is necessary -- but not sufficient -- to produce most of the adverse effects associated with TCDD exposure, including those from direct TCDD binding to and activation of the AHR and later alterations in the expression of TCDD-regulated genes as well as to those signaling pathways altered through interactions with the AHR pathway (Poland and Knutson, 1982; Safe, 1990; Schmidt and Bradfield, 1996; Whitlock, 1990)
From page 117...
... . XAP2 interacts with the carboxyl terminus of hsp90 and with the AHR nuclear-localization signal (NLS)
From page 118...
... 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)
From page 119...
... . Because of the presence of the AHRE motif in their gene promoters, other metabolizing genes were tested and found to be induced by AHR ligands, which 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)
From page 120...
... Definition of Dioxin-Like Compounds, 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. Because of their hydrophobic nature and
From page 121...
... 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. SOURCE: Adapted from van den Berg et al., 2006.
From page 122...
... 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)
From page 123...
... Although TCDD is carcinogenic in humans and laboratory animals, it is generally classified as nongenotoxic and nonmutagenic (Wassom et al., 1977)
From page 124...
... Below is a brief summary of the epigenetic effects of TCDD. More detailed information about epigenetic mechanisms in general can be found later in this chapter, particularly concerning somatic modifications in an individual, and again in Chapter 10 with respect to effects that may affect offspring of an exposed organism.
From page 125...
... 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 the adverse effects of exposure to TCDD. For example, much evidence indicates that TCDD, acting via the AHR in partnership with ARNT, alters gene expression.
From page 126...
... For example, the concentrations of TCDD used in animal studies can be many times higher than was typical in the TCDD exposures of Vietnam veterans during their military service. In addition, TCDD is a persistent organic pollutant, and this results in human exposure that occurs over a lifetime, whereas animal studies seldom exam ine chronic low-level exposure that occurs over a period of many months or years, except those that evaluate chronic toxicity or carcinogenicity.
From page 127...
... . In contrast, laboratory studies are often conducted with inbred strains of animals and under tightly controlled experimental conditions, thus possibly underestimating or overestimating the potential contribution of a single chemical exposure to disease development.
From page 128...
... . It was not until the 1970s, however, that the first molecular epigenetic factor was described: DNA methylation, the chemical addition of a methyl group to DNA (Holliday and Pugh, 1975)
From page 129...
... We also sought to review relevant data on female veterans and male veterans separately inasmuch as the epigenetic consequences of exposures could be different, particularly in the case of adverse reproductive outcomes. A relevant example is that the in vitro exposure of preimplantation embryos to TCDD alters the DNA methylation of imprinted genes (Wu et al., 2004)
From page 130...
... In summary, the ability of epigenetic mechanisms to regulate gene expression coupled with the interaction of the epigenome and the environment might underlie the ability of xenobiotic exposure to contribute to disease development and the potential for offspring to inherit the effects of the disrupted epigenetic processes. Developmental Immunotoxicity A second emerging field in the biologic sciences that may provide insight into the mechanism of xenobiotic-induced disease is developmental immunotoxicity (DIT)
From page 131...
... 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 an increased risk of disease.
From page 132...
... Early-life chemical exposure may affect the status of genes (the epigenome) in such a way that their pattern of expression in later life is affected and thereby alter immune functional capacity.


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