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4 Information Related to Biologic Plausibility The committee reviewed all relevant experimental studies of 2,4-dichloro- phenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 4-amino-3,5,6-trichloropicolinic acid (picloram), dimethylarsinic acid (DMA, also called cacodylic acid), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that have been published since Update 2008 (IOM, 2009) and has incorporated the findings, when it was appropriate, into this chapter or into the biologic-plausibility sections of Chapters 6–11 when they are of consequence for particular health outcomes. For each substance, this chapter includes a review of toxicokinetic properties, a brief summary of the toxic outcomes investigated in animal experi - ments, and a discussion of underlying mechanisms of action as illuminated by in vitro studies. 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. Experimental studies of laboratory animals or cultured cells allow observa- tion of effects of herbicide exposure under highly controlled conditions, which is difficult or impossible to achieve in epidemiologic studies. Such conditions include frequency and magnitude of exposure, exposure to other chemicals, pre- existing health conditions, and genetic differences between people, all of which can be controlled in a laboratory animal study. Once a chemical contacts the body, it begins to interact through the processes 76
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77 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY of absorption, distribution, metabolism, and excretion. Those four biologic pro - cesses characterize the disposition of a foreign substance that enters the organism. Their combination determines the concentration of the chemicals in the body and how long each organ is exposed to it and thus influences its toxic or pharmaco- logic activity. Absorption is the entry of a substance into an organism, normally by uptake into the bloodstream via mucous surfaces, such as the intestinal walls of the di - gestive tract during ingestion. Low solubility, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a substance is absorbed after being ingested. The solubility of a chemical in fat and its hydrophobicity influence the pathways by which it is absorbed and its relative potential to be metabolized (structurally transformed) and ultimately whether it persists in the body or is excreted. Absorption is a critical determinant of a chemi- cal’s bioavailability, that is, the fraction of it that reaches the systemic circulation. In addition to ingestion routes of exposure experienced by free-ranging humans are inhalation (entry via the airways) and dermal exposure (entry via the skin). Animal studies may involve additional routes of exposure that are not ordinarily encountered by humans, such as intravenous or intraperitoneal injection, in which a chemical is injected into the bloodstream or abdominal cavity, respectively. Distribution refers to the travel of a substance from the site of entry to the tissues and organs where they will have their ultimate effect or be sequestered. Distribution takes place most commonly via the bloodstream. Metabolism is the breaking down that all substances begin to experience as soon as they enter the body. Most metabolism of foreign substances takes place in the liver by the action of a number of enzymes, including cytochrome P-450s, which catalyze the oxidative metabolism of many chemicals. As metabolism oc - curs, the initial (parent) chemical is converted to new chemicals called metabo - lites, which are often more water-soluble (polar) and thus more readily excreted. When metabolites are pharmacologically or toxicologically inert, metabolism deactivates the administered dose of the parent chemical, reducing its effects on the body. Metabolism may activate a chemical to a metabolite that is more potent or more toxic than it is. Excretion, also referred to as elimination, is the removal of substances or their metabolites from the body, most commonly in urine or feces. 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. The routes and rates of absorption, distribution, metabolism, and excretion of a toxic substance collectively are termed toxicokinetics (or pharmacokinetics). Those processes determine the amount of a particular substance or metabolite that reaches specific organs or cells and that persists in the body. Understanding the toxicokinetics of a chemical is important for valid reconstruction of exposure
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78 VETERANS AND AGENT ORANGE: UPDATE 2010 of humans and for assessing the risk of effects of a chemical. The principles involved in toxicokinetics are similar among chemicals, although the degree to which different processes influence the distribution depends on the structure and other inherent properties of the chemicals. Thus, the lipophilicity or hydro - phobicity of a chemical and its structure influence the pathways by which it is metabolized and whether it persists in the body or is excreted. The degree to which different toxicokinetic processes influence the toxic potential of a chemi - cal depends on metabolic pathways, which often differ among species. For that reason, attempts at extrapolation from experimental animal studies to human exposures must be extremely careful. Many chemicals were used by the US armed forces in Vietnam. The nature of the substances themselves was discussed in more detail in Chapter 6 of the original Veterans and Agent Orange: Health Effects of Herbicides Used in Viet- nam (VAO) report (IOM, 1994). Four herbicides documented in military records were of particular concern and are examined here: 2,4-D, 2,4,5-T, picloram, and cacodylic acid. This chapter also examines TCDD, the most toxic congener of the tetrachlorodibenzo-p-dioxins (tetraCDDs), also commonly referred to as dioxin, a contaminant of 2,4,5-T, because its potential toxicity is of concern. Consider- ably more information is available on TCDD than on the herbicides themselves. Other contaminants present in 2,4-D and 2,4,5-T are of less concern. 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.] 1918-02-1; see chemical structure in Figure 4-1) was used with 2,4-D in the herbicide formu - lation Agent White, which was sprayed in Vietnam. It is also used commonly in Australia in a formulation with the trade name Tordon 75D®. Tordon 75D CI NH 2 HO CI N O CI 4-amino-3,5,6-trichloropicolinic acid FIGURE 4-1 Structure of picloram. Figure 4-1.eps
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79 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY contains several chemicals, including 2,4-D, picloram, a surfactant diethylene- glycolmonoethyl ether, and a silicone defoamer. A number of studies of picloram used such mixtures as Tordon or other mixtures of 2,4-D and picloram that are similar to Agent White. Toxicokinetics The original VAO committee reviewed studies of the toxicokinetics of pi- cloram. Studies of animals showed rapid absorption through the gastrointestinal tract and rapid elimination of picloram as the unaltered parent chemical in urine. Nolan et al. (1984) examined the toxicokinetics of picloram in six healthy male volunteers who were given single oral doses of 0.5 or 5.0 mg/kg and a dermal dose of 2.0 mg/kg. Picloram was rapidly absorbed in the gavage study and rapidly excreted unchanged in urine. More than 75% of the dose was excreted within 6 hours, and the remainder with an average half-life of 27 hours. On the basis of the quantity of picloram excreted in urine in the skin study, the authors noted that only 0.2% of the picloram applied to the skin was absorbed. Because of its rapid excretion, picloram has low potential to accumulate in humans. In general, the literature on picloram toxicity continues to be sparse. Studies of humans and animals indicate that picloram is rapidly eliminated as the parent chemical. Studies of animals have indicated that picloram is sparingly toxic at high doses. Toxicity Profile The original VAO committee reviewed studies of the carcinogenicity, geno- toxicity, acute toxicity, chronic systemic toxicity, reproductive and developmental toxicity, and immunotoxicity of picloram. In general, there is limited evidence on cancer in some rodent models but not in other species (NCI, 1978). In those studies, there was some concern that contaminants in the picloram (in particular, hexachlorobenzene) might be responsible for the carcinogenicity. Thus, picloram has not been established as a chemical carcinogen. There is also no evidence, on the basis of studies conducted by the Envi- ronmental Protection Agency (EPA, 1988c), that picloram is a genotoxic agent. Picloram is considered a mild irritant; erythema is seen in rabbits only at high doses. The available information on the acute toxicity of picloram is also paltry. Some neurologic effects—including hyperactivity, ataxia, and tremors—were reported in pregnant rats exposed to picloram at 750 or 1,000 mg/kg (Thompson et al., 1972). Chronic Systemic Toxicity Several studies have reported various effects of technical-grade picloram on the livers of rats. In the carcinogenicity bioassay conducted by Stott and col -
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80 VETERANS AND AGENT ORANGE: UPDATE 2010 leagues (1990), treatment-related hepatomegaly, hepatocellular swelling, and altered tinctorial properties in the central regions of the liver lobules were noted in the groups exposed at 60 and 200 mg/kg per day. In addition, males and females exposed at the high dose had higher liver weights than controls. The no-observed- effect level (NOEL) was 20 mg/kg per day, and the lowest observed-effect level was 60 mg/kg per day for histologic changes in centrilobular hepatocellular tissues. According to the Environmental Protection Agency (EPA), hexachloro - benzene (at 197 ppm) was probably not responsible for the hepatic effects (EPA, 1988c). Gorzinski and colleagues (1987) 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). Hepatic effects have also been reported in dogs exposed to picloram: increased liver weights were reported in beagles that received 35 mg/kg per day or more in the diet for 6 months (EPA, 1988c). No other effects of chronic exposure to picloram have been reported. Reproductive and Developmental Toxicity The reproductive toxicity of picloram was evaluated in a two-generation study; however, too few animals were evaluated, and no toxicity was detected at the highest dose tested, 150 mg/kg per day (EPA, 1988c). Some developmental toxicity was produced in rabbits exposed to picloram by gavage at 400 mg/kg per day on days 6–18 of gestation. Fetal abnormalities included single-litter inci - dences of forelimb flexure, fused ribs, hypoplastic tail, and omphalocele (John- Greene et al., 1985). Some maternal toxicity was observed at that dose, however, and EPA concluded on the basis of the low-litter incidence of the findings that the malformations were not treatment-related (EPA, 1988c). No teratogenic effects were produced in the offspring of rats given picloram by gavage at up to 1,000 mg/kg per day on days 6–15 of gestation, although the occurrence of bilateral accessory ribs was significantly increased (Thompson et al., 1972). Immunotoxicity Studies of the potential immunotoxicity of picloram included dermal sen - sitization and rodent immunoassays. In one study, 53 volunteers received nine 24-hour applications of 0.5 mL of a 2% potassium picloram solution on the skin of both upper arms. Each volunteer received challenge doses 17–24 days later. The formulation of picloram (its potassium salt) was not a skin sensitizer or an irritant (EPA, 1988c). In a similar study, a 5% solution of picloram (M-2439, Tordon 101 formulation) produced slight dermal irritation and a sensitization response in 6 of the 69 volunteers exposed. When the individual components of
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81 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY M-2439—picloram, triisopropanolamine (TIPA) salt, and 2,4-D TIPA salt—were tested separately, no sensitization reaction occurred (EPA, 1988c). Tordon K+, but not technical-grade picloram, was also found to be a skin sensitizer in guinea pigs (EPA, 1988c). CD1 mice exposed to Tordon 202C (94% 2,4-D and 6% picloram) had no consistent adverse effects on antibody responses (Blakley, 1997), but the lack of a consistent response may be due to the fact that CD1 mice are outbred. Mechanisms No well-characterized mechanisms of toxicity for picloram are known. CACODYLIC ACID Chemistry Arsenic (As) is a naturally occurring element that exists in a trivalent form (As+3 or AsIII) and a pentavalent form (As+5 or AsV). The AsIII in sodium arsenite is generally considered to be the most toxic—see Figure 4-2 for chemical struc - tures of selected arsenic-containing compounds. FIGURE 4-2 Structures of selected arsenic-containing compounds. Figure 4-2.eps
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82 VETERANS AND AGENT ORANGE: UPDATE 2010 Arsenic is commonly present in drinking-water sources associated with volcanic soils and can reach high concentrations (over 50 ppb). Numerous hu- man health effects have been attributed to drinking-water exposure, particularly bladder, skin, and lung cancers and vascular diseases. Arsenic exists in both inorganic and organic (methylated) forms and is read - ily metabolized in humans and other species. 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). Cacodylic acid (CAS No. 75- 60-5) has a valence of +5 and is commonly referred to as dimethylarsinic acid (DMAV). Cacodylic acid, disodium methanearsonate, and monosodium methane- arsonate are herbicides that EPA approved for use in the United States, where they are occasionally applied on golf courses and large open spaces. Cacodylic acid was the form of arsenic used in Agent Blue, one of the mixtures used for defoliation in Vietnam; DMAV made up about 30% of Agent Blue. Agent Blue was chemically and toxicologically unrelated to Agent Orange, which consisted of phenoxy herbicides contaminated with dioxin-like compounds. As shown in Figure 4-3, DMAIII and DMAV, as well as monomethyl arsonic acid (MMAIII and MMAV) are metabolic products of exposure to inorganic arsenic. Methylation of inorganic arsenic used to be considered a detoxification process associated with increased excretion (Vahter and Concha, 2001). However, some of the methylated metabolic intermediates, especially MMAIII, have been found to be more toxic MMAIII iAsV MMAV Limited cellular DMAs DMAV uptake 60–80% of human urinary excretion iAsIII iAsIII DMAIII TMA Extensive cellular uptake TMAO TMAO MMAs None found in human urine, 10–20% of human 5–10% of rat urinary excretion urinary excretion FIGURE 4-3 General pathways of arsenic metabolism after exposure to inorganic arsenic (iAs). SOURCE: Adapted with permission from Cohen et al., 2006. Figure 4-3.eps
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83 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY than the parent sodium arsenite (Aposhian et al., 2000). The methylation pathway of inorganic arsenic results in the formation of pentavalent DMA (DMAV) and trivalent DMA (DMAIII). The committee contemplated the relevance of animal data following expo- sure to inorganic arsenic, where DMAV is formed endogenously, vs data follow- ing direct exposure to exogenous DMAV, as would have been the form of arsenic to which Vietnam veterans were potentially exposed. 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. Furthermore, recent studies would suggest that there is an increased incidence of cancer in individuals that gener- ate less DMAV endogenously (Huang SK et al., 2008). Finally, because there is no evidence that DMA is demethylated to inorganic arsenic in humans or other animals (Cohen et al., 2006), 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) and Arsenic in Drinking Water: 2001 Update (NRC, 2001). Thus, the committee only considered and reviewed those toxicological studies in which animals were directly exposed to DMAV. Toxicokinetics The metabolism and disposition of DMAV has recently been reviewed (Cohen et al., 2006; Suzuki et al., 2010). In general, DMAV is rapidly excreted mostly unchanged in the urine of most animal species after systemic exposure. However, rats are unique in that a small percentage (10%) of DMAV binds to hemoglobin in red blood cells and that leads to a longer half-life in blood (Cui et al., 2004; Suzuki et al., 2004). The binding of DMAV to hemoglobin is 10 times higher in rats than in humans (Lu et al., 2004). Chronic exposure of normal rat hepatocytes to DMAV resulted in reduced uptake over time and in acquired cytotoxic tolerance (Kojima et al., 2006); the tolerance was mediated by induction of glutathione- S- transferase activity and of multiple-drug–resistant protein expression. Adair et al. (2007) recently examined the tissue distribution of DMA in rats after dietary exposure for 14 days and found that it was extensively metabolized to trimethyl - ated forms that may play a role in toxicity. Recently, a physiologically based pharmacokinetic model (PBPM) for in - travenous and ingested DMAV has been developed on the basis of mouse data (Evans et al., 2008). Similar models have been developed for humans on the basis of exposure to inorganic arsenic (El-Masri and Kenyon, 2008), but these models have limited utility in considering the toxicity of DMAV exposures that are relevant to Vietnam veterans. 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 toxic-
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84 VETERANS AND AGENT ORANGE: UPDATE 2010 ity of inorganic arsenic is not considered relevant to veteran exposures to Agent Blue. Neurotoxicity Kruger et al. (2006) found that DMAIII and DMAV significantly attenu- ated neuronal ion currents through N-methyl-D–aspartate receptor ion channels whereas only DMAV inhibited ion currents through α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors. The data suggest that those methyl - ated forms of arsenic may have neurotoxic potential. Immunotoxicity Previous studies have shown that a low concentration of DMAV (10–7 M) could increase proliferation of human peripheral blood monocytes after their stimulation with phytohemagglutinin whereas it took a high concentration (10 –4 M) to inhibit release of interferon-g. This suggested that immunomodulatory ef- fects of DMAV are concentration-specific (Di Giampaolo et al., 2004). Genotoxicity and Carcinogenicity Both DMAIII and DMAV are genotoxic, increasing oxidative stress and caus- ing DNA damage. Gómez et al. (2005) demonstrated that DMAIII induced a dose-related increase in DNA damage and oxidative stress in Jurkat cells. DMAIII was considerably more potent than DMAV in inducing DNA damage in Chinese hamster ovary cells (Dopp et al., 2004), and this was associated with a greater uptake of DMAIII into the cells. An additional study showed that DMAV is poorly membrane-permeable, but when forced into cells by electroporation it can induce DNA damage (Dopp et al., 2005). Gene-expression profiling of bladder uro- thelium after chronic exposure to DMAV in drinking water showed significant increases in genes that regulate oxidative stress (Sen et al., 2005), while hepatic gene-expression profiling showed that DMAV exposure induced changes consis- tent with oxidative stress (Xie et al., 2004). In vivo, DMAV-induced prolifera- tion of the urinary bladder epithelium could be attenuated with the antioxidant N-acetylcysteine (Wei et al., 2005). Both DMAIII and DMAV are also carcinogenic. 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). Similarly, Wang et al. (2009) found that DMAV exposure in drinking water given to F344 rats resulted in a change in the urinary bladder epithelium, but there were no changes in DNA re - pair capacity. In another study, Cohen et al. (2007a) exposed F344 rats to DMAV
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85 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY in the diet for 2 years and found an increase in bladder tumors; they postulated that trimethylated forms of arsenic may be responsible for bladder cancer in rats. In the mouse lung, DMAV acted act as a tumor initiator (Yamanaka et al., 2009) and as a tumor promoter (Mizoi et al., 2005). Additionally, DMAV can act as a complete carcinogen inducing lung tumors in susceptible strains of mice, includ - ing those with deficient DNA repair activity (Hayashi et al., 1998; Kinoshita et al., 2007). Yamanaka et al. (2009) suggest that DMAIII can act as a tumor promoter through the formation of a DMAIII radical after reduction of DMAV. 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). Recent studies have shown that mice deficient in DNA-repair enzymes associated with oxidative stress are highly susceptible to formation of tumors, particularly lung tumors, induced by DMAV (Kinoshita et al., 2007). The chemical reaction of arsenicals with thiol groups in sensitive target tissues, such as red blood cells and kidneys, may also be a mechanism of action of organic arsenicals (Naranmandura and Suzuki, 2008). The variation in the susceptibility of various animal species to tumor forma- tion caused by inorganic and organic arsenic is thought to depend heavily on differences in metabolism and distribution. Thus, genetic differences may play an important role. Numerous investigators are examining potential human suscepti - bility factors and gene polymorphisms that may increase a person’s risk of cancer and other diseases induced by arsenicals. Several such studies have been under- taken (Aposhian and Aposhian, 2006; Hernandez et al., 2008; Huang SK et al., 2008; Huang YK et al., 2008; McCarty et al., 2007; Meza et al., 2007; Steinmaus et al., 2007, 2010), but it is not yet possible to identify polymorphisms that may contribute to a person’s susceptibility to DMA-induced cancer or tissue injury. PHENOXY HERBICIDES: 2,4-D AND 2,4,5-T Chemistry 2,4-D (CAS No. 94-75-7) is an odorless and, when pure, white crystalline powder (Figure 4-4); it may appear yellow when phenolic impurities are present. The melting point of 2,4-D is 138°C, and the free acid is corrosive to metals. It is soluble in water and in a variety of organic solvents (such as acetone, alcohols, ketones, ether, and toluene). 2,4,5-T (CAS No. 93-76-5) is an odorless, white to light-tan solid with a melting point of 158°C. 2,4,5-T is noncorrosive and is
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86 VETERANS AND AGENT ORANGE: UPDATE 2010 Phenoxy Herbicides 2,4-D [ 94-75-7] 2,4,5-T [ 93-76-5] CI O CI O O CI O CI OH CI OH FIGURE 4-4 Structures of 2,4-D and 2,4,5-T. MCPA [ 94-74-6] Silvex [ 93-72-1] CI soluble in alcohol and water. It reacts with organic and inorganic bases to form O CI O salts and with alcohols to form esters. O CI O OH Uses of 2,4-D and 2,4,5-T OH CI 2,4-D has been used commercially in the United States since World War MCPP [ 93-65-2] Dicamba range lands, II to control the growth of broadleaf plants and weeds on [1918-00-9] lawns, golf courses, forests, roadways, parks, and agricultural land O remains today and CI a widely used herbicide approved for use by the European Union O and the US EPA. Formulations includeO2,4-D amine and alkali salts and esters, which are CI O mobile in soil and easily absorbed through the leaves and roots of many plants. OH Like 2,4-D, 2,4,5-T was developed and marketed as a herbicide during World OH War II. However, the registration for 2,4,5-T was canceled byCI EPA in 1978 when it became clear that it was contaminated with TCDD during the manufacturing process. It is recognized that the production of 2,4-D also involves the generation 2,3,7,8-TCDD [1746-01-6] of some dioxin contaminants, even some with dioxin-like activity, but the fraction CI of TCDD is comparatively very small, as illustrated in CI Chapter 4. O The herbicidal properties of 2,4-D and 2,4,5-T are related to their ability to mimic the plant growth hormone indole acetic acid. They are selective herbicides O in that they affect the growth of only broadleaf dicots (which include most weeds) IC IC and do not affect monocots, such as wheat, corn, and rice. Picloram [1918-02-1] 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. Data As both compounds on CI are consistent among species and support the conclusion that absorption of oral or N O inhaled doses is rapid and complete. Absorption through the skin is much lower OH CI but may be increased with the use of sunscreens or alcohol (Brand et al., 2002; Pont et al., 2004). After absorption, 2,4-D and 2,4,5-T are distributed widely in the body but are eliminated quickly, predominantly in unmetabolized form in urine (Sauerhoff et al., 1977). Neither 2,4-D nor 2,4,5-T is metabolized to a great Figure 2-1.eps
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109 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY Arnold EK, Beasley VR, Parker AJ, Stedelin JR. 1991. 2,4-D toxicosis II: A pilot study of clinical pathologic and electroencephalographic effects and residues of 2,4-D in orally dosed dogs. Veterinary and Human Toxicology 33:446–449. Arnold LL, Eldan M, Nyska A, van Gemert M, Cohen SM. 2006. Dimethylarsinic acid: Re- sults of chronic toxicity/oncogenicity studies in F344 rats and in B6C3F1 mice. Toxicology 223(1-2):82–100. ATSDR (Agency for Toxic Substances and Disease Registry). 1998. Toxicological profile for chlori - nated dibenzo-p-dioxins. US Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux PM, Brambilla P, Mocarelli P. 2005a. Concentration-dependent TCDD elimination kinetics in humans: Toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. Journal of Exposure Analysis and Environment Epidemiology 15(1):51–65. Aylward LL, Brunet RC, Starr TB, Carrier G, Delzell E, Cheng H, Beall C. 2005b. Exposure recon - struction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination. Risk Analysis 25(4):945–956. Bacsi SG, Reisz-Porszasz S, Hankinson O. 1995. Orientation of the heterodimeric aryl hydrocarbon (dioxin) receptor complex on its asymmetric DNA recognition sequence. Molecular Pharma- cology 47(3):432–438. Banks YB, Birnbaum LS. 1991. Absorption of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) after low dose dermal exposure. Toxicology and Applied Pharmacology 107(2):302–310. Barker DJ, Gelow J, Thornburg K, Osmond C, Kajantie E, Eriksson JG. 2010. The early origins of chronic heart failure: Impaired placental growth and initiation of insulin resistance in childhood. European Journal of Heart Failure 12(8):819–825. Beaudouin R, Micallef S, Brochot C. 2010. A stochastic whole-body physiologically based pharma - cokinetic model to assess the impact of inter-individual variability on tissue dosimetry over the human lifespan. Regulatory Toxicology and Pharmacology 57(1):103–116. Birnbaum LS. 1994. Evidence for the role of the Ah receptor in response to dioxin. Progress in Clini- cal and Biological Research 387:139–154. Birnbaum L, Harris M, Stocking L, Clark A, Morrissey R. 1989. Retinoic acid and 2,3,7,8–tetra - chlorodibenzo-p-dioxin selectively enhance teratogenesis in C57BL/6N mice. Toxicology and Applied Pharmacology 98:487–500. Blakley BR. 1997. Effect of Roundup and Tordon 202C herbicides on antibody production in mice. Veterinary and Human Toxicology 39(4):204–206. Blevins RD. 1991. 2,3,7,8-tetrachlorodibenzodioxin in fish from the Pigeon River of eastern Tennes - see, USA: Its toxicity and mutagenicity as revealed by the Ames Salmonella assay. Archives of Environmental Contamination and Toxicology 20:366–370. Boutros P, Moffat ID, Franc MA, Tijet N, Tuomisto J, Pohjanvirta R, Okey AB. 2004. Dioxin- responsive AHRE–II gene battery: Identification by phylogenetic footprinting. Biochemical and Biophysical Research Communications 321(3):707–715. Boverhof DR, Burgoon LD, Tashiro C, Sharratt B, Chittim B, Harkema JR, Mendrick DL, Zacharewski TR. 2006. Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicological Sciences 94(2):398–416. Bowman RE, Schantz SL, Weerasinghe NCA, Gross ML, Barsotti DA. 1989. Chronic dietary intake of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 5 and 25 parts per trillion in the monkey: TCDD kinetics and dose–effect estimate of reproductive toxicity. Chemosphere 18:243–252. Brand RM, Spalding M, Mueller C. 2002. Sunscreens can increase dermal penetration of 2,4-dichlo - rophenoxyacetic acid. Journal of Toxicology–Clinical Toxicology 40(7):827–832. Carrier G, Brunet RC, Brodeur J. 1995. Modeling of the toxicokinetics of polychlorinated dibenzo- p-dioxins and dibenzofurans in mammalians, including humans. II. Kinetics of absorption and disposition of PCDDs/PCDFs. Toxicology and Applied Pharmacology 131(2):267–276.
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