4
Toxicology

In this chapter, the results of experiments in which animals were exposed to the substances of concern and observed for particular effects are reviewed, to provide a basis for evaluating the biologic plausibility of the epidemiologic evidence associating exposures and effects described in Chapters 8-11. Assessing the biologic plausibility of the outcomes reported in epidemiologic studies would strengthen any evidence for an association between exposures and effects.

Although there is evidence that multiple chemicals were used for various purposes in Vietnam, the use of four herbicides has been documented in military records; therefore, toxicologic assessment was limited to the compounds 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid (Figure 4-1). In addition, the toxicologic properties of a 2,4,5-T contaminant that has caused a great deal of controversy, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are described. The emphasis of the chapter is on the effects of TCDD, because there is considerably more information available on TCDD than on the herbicides.

The chapter begins with an overview that describes toxicology data on TCDD and the four herbicides in nontechnical terms. The overview is followed by complete toxicity profiles of each of the five substances considered. In reading these profiles, several characteristics of animal studies should be borne in mind. First, animals are exposed to various levels of a compound through multiple routes of exposure. In addition, animals may be exposed once to a very high dose of a compound or multiple times to lower doses. Thus, an effect observed in animals may not necessarily occur



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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 4 Toxicology In this chapter, the results of experiments in which animals were exposed to the substances of concern and observed for particular effects are reviewed, to provide a basis for evaluating the biologic plausibility of the epidemiologic evidence associating exposures and effects described in Chapters 8-11. Assessing the biologic plausibility of the outcomes reported in epidemiologic studies would strengthen any evidence for an association between exposures and effects. Although there is evidence that multiple chemicals were used for various purposes in Vietnam, the use of four herbicides has been documented in military records; therefore, toxicologic assessment was limited to the compounds 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid (Figure 4-1). In addition, the toxicologic properties of a 2,4,5-T contaminant that has caused a great deal of controversy, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are described. The emphasis of the chapter is on the effects of TCDD, because there is considerably more information available on TCDD than on the herbicides. The chapter begins with an overview that describes toxicology data on TCDD and the four herbicides in nontechnical terms. The overview is followed by complete toxicity profiles of each of the five substances considered. In reading these profiles, several characteristics of animal studies should be borne in mind. First, animals are exposed to various levels of a compound through multiple routes of exposure. In addition, animals may be exposed once to a very high dose of a compound or multiple times to lower doses. Thus, an effect observed in animals may not necessarily occur

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam FIGURE 4-1 Chemical structures of the herbicides 2,4-D, 2,4,5-T, picloram, and cacodylic acid, and of the contaminant TCDD. in humans because of differences in dose, route, and timing of exposure. Second, for the most part, animals are exposed to a single agent and are generally healthy when exposure occurs. Although most of the people exposed to TCDD who are of interest in this report were healthy, they were certainly not exposed solely to TCDD. Third, the toxicity of a given compound varies widely depending on the health status (as determined by nutrition, age, infection, etc.) of the animal examined. When data are available, the contribution of nutrition, age, and other possible factors to the toxicity of the compounds is discussed. Fourth, there is a wide variability in the toxicity of TCDD depending on the species of animal tested. These differences are exemplified in the dose of TCDD required to kill 50 percent of the animals exposed (LD50) (Table 4-1).

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam In the guinea pig (the most sensitive species to acute lethality by TCDD), the LD50 is 0.6-2.1 µg/kg. On the other hand, the LD50 of TCDD for the hamster (the least sensitive species examined) is 1,157-5,051 µg/kg. It is currently unknown where on this spectrum humans lie; however, studies are under way to determine the sensitivity of humans to a number of effects of TCDD. Lastly, individuals within a species may vary widely in their sensitivity to the effects of a chemical. For example, two strains of mice, C57Bl/6 (sensitive) and DBA/2 (resistant), are very different in their sensitivity to the acute toxicity of TCDD. Studies involving congenic mice (mice that are identical at all genetic sites except one) suggest that for many of the toxicologic TABLE 4-1 Acute Lethality of TCDD to Various Species and Substrains Species/Strain/Sex Route LD50 (µg/kg) References Guinea pig/Hartley (male) Oral 0.6-2.1 McConnell et al., 1978a; Schwetz et al., 1973 Mink/not reported (male) Oral 4.2 Hochstein et al., 1988 Chicken/not reported Oral 8 25 Greig et al., 1973 Monkey/rhesus (female) Oral ~ 70 McConnell et al., 1978b Rat/L-E (male) Intraperitoneal ~ 10 Tuomisto and Pohjanvirta, 1987 Rat/Sherman, Spartan Oral   Schwetz et al., 1973 male   22   female   13-43   Rat/Sprague-Dawley Intraperitoneal   Beatty et al., 1978 male   60   female   25   weaning male   25   Rat/Fischer Harian (male) Oral 340 Walden and Schiller, 1985 Rat/H/W/ (male) Intraperitoneal > 3,000 Pohjanvirta and Tuomisto, 1987; Pohjanvirta et al., 1988a Mouse/B6 (male) Oral 182 Chapman and Schiller, 1985 D2A/2J (male)   2,570   B6D2F1 (male)   296   Mouse/B6 Intraperitoneal 132 Neal et al., 1982 Mouse/D2   620   Mouse/B6D2F1   300   Rabbit/New Zealand white (male and female) Oral 115 Schwetz et al., 1973   Dermal 275   Rabbit/New Zealand white (male and female) Intraperitoneal ~50 Brewster et al., 1988 Hamster/golden Syrian (male and female) Oral 1,157-5,051 Henck et al., 1981 Hamster/golden Syrian (male and female) Intraperitoneal > 3,000 Olson et al., 1980b   SOURCE: U.S. EPA, 1992.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam effects described below, the differences in the sensitivity of these two strains are due to differences in the affinity of an intracellular protein—referred to as the Ah receptor—for TCDD. Although all of these considerations have implications for the interpretation of the data described below, it should be kept in mind that the primary purpose of this review is to contribute to a consideration of the biologic plausibility of the associations observed in epidemiologic studies that are relevant to herbicide exposure in Vietnam, not to resolve the continuing scientific and regulatory concerns about TCDD. OVERVIEW Information from tests in laboratory animals and other nonhuman systems is useful because it can be combined with information obtained from humans exposed to the herbicides (described in Chapters 6 and 7) to determine the biologic plausibility for health effects observed in humans (described in Chapters 8-11). Establishing the biologic plausibility of effects due to herbicide exposure in the laboratory strengthens the evidence for any effects of the herbicides that are suspected to occur in humans. The herbicides that were used in the greatest quantities in Vietnam were 2,4-D, 2,4,5-T, picloram, and cacodylic acid. Agent Orange was a one-to-one mixture of 2,4-D and 2,4,5-T. A contaminant of 2,4,5-T, 2,3,7,8-tetrachlorodibenzo-p-dioxin (commonly called TCDD or dioxin), was found at varying levels in different batches of Agents Orange, Pink, Purple, and Green. Chemistry TCDD forms as a by-product during the manufacture of 2,4,5-T. TCDD molecules contain carbon, hydrogen, oxygen, and chlorine. TCDD dissolves easily in fats and oils but not in water, and is persistent in the environment. The primary source of TCDD in the environment is combustion and industrial processes, but the primary source of human exposure is through food. 2,4-D and 2,4,5-T are called chlorophenoxy acids and are also made up of carbon, hydrogen, oxygen, and chlorine. They both dissolve in water and are very similar in structure to a natural plant hormone called auxin. As a result of this similarity, 2,4-D and 2,4,5-T can mimic the action of auxin in some plants, and this activity is thought to be the reason these chemicals are herbicidal. Cacodylic acid contains carbon, hydrogen, oxygen, and arsenic and was called Agent Blue. Picloram contains carbon, hydrogen, oxygen, chlorine,

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam and nitrogen, and was combined with 2,4-D to become Agent White. Both compounds dissolve in water. Exposure and Metabolism When exposure to a chemical occurs, its effects on the body depend on a number of factors: it can be absorbed into the body, it can be distributed to different organs in the body, it can be metabolized by enzymes that change its chemical structure, and it can be eliminated from the body. A chemical's effects ultimately depend on the rate and extent to which all of these activities occur. When TCDD is ingested by animals (e.g., through contaminated food), more than 50 percent is absorbed into the body through the gastrointestinal tract. Most of the TCDD breathed in the air is thought to be absorbed through the lungs, but this route of exposure is not well-studied. In contrast, TCDD is not absorbed well through the skin. The same pattern of absorption holds true for 2,4-D and 2,4,5-T, and probably for picloram and cacodylic acid, although much less information is available for them. After a chemical is absorbed into the body, it can be transported to different organs through the blood or lymph system. TCDD is transported by both systems of circulation, and is distributed primarily to the liver and to body fat. Following single doses of TCDD to rats, a dose-related increase occurred in the proportion of the dose that distributed to the liver as compared to the fat. This observation may be due to increased binding of TCDD to liver cells as the doses increased, as well as to the loss of body fat that occurs in rats as doses of TCDD increase. The amount of time that TCDD remains in the liver or fat is different for different species: in rats, TCDD remains in fat longer than in the liver; in mice, it stays in both for about the same time; and in monkeys, it stays in fat for a very long time. Mice and rats eliminate TCDD from the body in both urine and feces, whereas all other species studied eliminate TCDD primarily through feces. 2,4-D and 2,4,5-T are distributed widely in the body and are eliminated quickly, mostly in the urine. The distribution patterns of picloram and cacodylic acid are not known, although they are eliminated rapidly from the body, mostly in urine. Some of the cacodylic acid that is absorbed is bound to red blood cells, however, and is eliminated when the red blood cells to which it is bound die naturally. Although cacodylic acid binds readily to rat red blood cells, it does not bind readily to human red blood cells. TCDD is removed slowly from the body; as discussed later in Chapter 6, it takes more than 10 years for half of the body burden of TCDD to be removed. TCDD is metabolized by enzymes in the liver to form derivatives that can dissolve in water and thus be more easily eliminated from the body than TCDD itself, which does not dissolve in water. Water-soluble derivatives

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam of TCDD are thought to be much less toxic to animals than TCDD itself, although at present, no significant correlations have been made between the distribution, metabolism, and elimination of TCDD and its toxicity in different species. 2,4-D, 2,4,5-T, and cacodylic acid are not metabolized to any significant extent in the body. It is not known whether picloram is metabolized. Carcinogenicity: TCDD The ability of TCDD to cause cancer in animals has been studied using rats, mice, and hamsters exposed to TCDD for between one and two years. In these studies, TCDD was fed to animals, applied to their skin, injected under their skin, or injected into their abdominal cavities. Table 4-2 summarizes the results of the different studies that have been performed in animals to evaluate the ability of TCDD to cause cancer. As the table shows, increased tumor rates have been reported to occur at several different sites in the body in different studies, although the liver was consistently a site of tumor formation in different studies and different species. In studies in which liver cancer occurred, other toxic changes in the liver also occurred. Other organs in which increased cancer rates were observed in animals exposed to TCDD include the thyroid and adrenal glands, the skin, and the lung. Organs in which decreased cancer rates were seen in animals exposed to TCDD include the uterus, pancreas, and the pituitary, mammary, and adrenal glands. In addition to increasing cancer rates in animals by itself, TCDD can increase tumor formation by other chemicals. For example, when a single dose of a known carcinogen is applied to the skin of mice and that dose is followed by multiple doses of TCDD over a period of several months, more skin tumors are seen than would be expected from the single dose of carcinogen alone. Similar results are obtained in rat livers when a single dose of a liver carcinogen is followed by multiple doses of TCDD. In rats, liver tumor formation associated with TCDD exposure is dependent on the presence of ovaries; in other words, only female rats that have not had their ovaries removed can develop liver tumors when they are exposed to TCDD. This observation indicates that complex hormonal interactions are likely to be involved in TCDD-induced carcinogenesis. Mechanism of Action TCDD has a wide range of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells. TCDD may thus play a number of different roles that could affect tumor formation. Understanding how TCDD affects tumor formation in

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam TABLE 4-2 Summary of Carcinogenicity Bioassays of TCDD Reference Species/Strain/Sex Protocol Results Van Miller et al., 1977 Sprague-Dawley rats, male, 10/group 0.001-1,000 ppb (0.0003-500 µg/kg/wk) in feed for 78 weeks; observed for 17 weeks High mortality, poor reporting; total tumors increased in all but lowest dose group; possible increase in lung tumors and liver tumors; no tumors in controls Kociba et al., 1978 Sprague-Dawley rats, male and female, 86/control group, 50/treated groups 21-2,200 ppt (0.001-0.1 µg/kg/day) in feed for 2 years Males: increased tumors of tongue, nose/palate; females: increased tumors of lung, liver, nose/palate Toth et al., 1979 Swiss mice, male, 100/control group, 45/treated groups 0.007-7.0 µg/kg/wk by gavage for 1 year; observed for life spans Liver tumors in 0.7 group; none in 0.007 group; higher dose died NTP, 1982a Osborne-Mendel rats, male and female, 75/control group, 50/treated groups 0.0014-0.071 µg/kg/day by gavage for 2 years Males: increased tumors of thyroid and skin; females: increased tumors of skin, liver, and adrenal gland NTP, 1982a B6C3F1 mice, male and female, 75/control group, 50/treated groups Males: 0.0014-0.071 µg/kg/day; females: 0.0057-0.29 µg/kg/day; by gavage for 2 years Males: increased tumors of lung and liver; females: increased lymphoma and tumors of liver, thyroid gland, skin NTP, 1982b Swiss-Webster mice, male and female, 45/control group, 30/treated groups 0.001-0.005 mg/dermal application, 3 times weekly for 2 years Males: no effect; females: increased skin fibrosarcomas Della Porta et al., 1987 B6C3F1 mice, male and female, 42-50/group 2.5-5.0 µg/kg/week by gavage for 52 weeks; observed until 78 weeks Both sexes: increased hepatocellular carcinoma   B6C3F1 and B6CF1 mice, male and female, 89-106/group 1-30 µg/kg/week by intraperitoneal injection for 5 weeks; observed until 78 weeks All: increased lymphoma; B6C3F1 males: increased hepatocellular adenomas and carcinomas Rao et al., 1988 Syrian golden hamsters, male 100 µg/kg by intraperitoneal injection; 2-6 treatments over a 4-week period; observed until 12-13 months Increased squamous cell carcinoma of facial skin     50-100 µg/kg by subcutaneous injection; 2-6 treatments over a 4-week period; observed until 12-13 months Increased squamous cell carcinoma of facial skin   SOURCE: Adapted from Huff, 1992.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam laboratory animals may help us understand whether TCDD would affect tumor formation in humans. For example, when a chemical's ability to induce tumors in animals is tested, it is administered at doses much higher than those to which humans are normally exposed in the environment. High doses of chemicals can cause toxic effects in animals that may increase their sensitivity to carcinogenesis; in other words, cancer can occur at high doses because of effects that would not occur at low doses (Cohen and Ellwein, 1990). In this case, it would not be appropriate to conclude that a chemical that caused cancer in laboratory animals would do so in humans. Understanding how a chemical causes cancer is thus a very important consideration when using information obtained in the laboratory to evaluate effects in humans. A normal cell can be transformed into a cancer cell when the information that is coded into the DNA of the cell is changed in critical places. Such changes are called mutations and may result from the direct interaction of a chemical with DNA. TCDD is not considered toxic to DNA; that is, tests of its ability to alter the structure of DNA have been negative. Another way that a normal cell can be transformed into a cancer cell is when changes occur in the regulation of the manner in which the information encoded in DNA is expressed, and incorrect information is received by the cell. Regulation of DNA is performed by proteins called receptors, which interact both with other molecules and with specific sites on DNA. There is a receptor in liver cells (and probably other cells as well), called the Ah receptor, that can interact with TCDD and then with sites on DNA. Binding of TCDD and the Ah receptor to each other and then to DNA results in a number of biologic effects such as increasing the activity of certain enzymes and affecting the levels of hormones and of molecules that control tissue growth. For example, TCDD treatment can increase the rate at which liver cells multiply; both this effect and TCDD-induced liver tumor formation are dependent on the presence of ovaries. It is thus possible that TCDD, together with the Ah receptor, could alter the information obtained from DNA in such a way that a normal liver cell is transformed into a cancerous liver cell, although direct proof of this possibility has not been obtained. Carcinogenicity: Herbicides Several studies of the carcinogenicity of 2,4-D, 2,4,5-T, picloram, and cacodylic acid have been performed in laboratory animals. In general they have produced negative results, although some were not performed using rigorous criteria for the study of cancer in animals, and some produced equivocal results that could be interpreted as either positive or negative. The studies and their results are summarized in Table 4-3.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 2,4-D was administered to rats, mice, and dogs in their food, by injecting it under their skin, or by placing it directly into their stomachs. All the results were negative, except for one study that found an increased rate of brain tumors in male rats, but not female rats, receiving the highest dose. These tumors also occurred in the control group and might have occurred spontaneously and not as a result of 2,4-D exposure, however. In another study, the occurrence of cancer of the lymph system (malignant lymphoma) among dogs kept as pets was found to occur more frequently when owners used 2,4-D on their lawns than when they did not (although this test had limitations). These dogs were exposed to other chemicals in addition to 2,4-D, however. Another test using dogs exposed to 2,4-D in the laboratory produced negative results, so it is not clear whether 2,4-D was responsible for the lymphomas in dogs. 2,4,5-T has been tested in rats and mice in their food, in their drinking water, by injecting it under their skin, or by placing it directly into their stomachs. Cacodylic acid has been tested in a very limited study in mice both in their food and by placing it directly into their stomachs. Picloram has been tested in rats and mice in their food. Results of all of these studies were uniformly negative, with the exception of one study using picloram in which liver tumors appeared but were attributed to the presence of hexachlorobenzene as a contaminant. Mechanism of Action In the absence of any compelling evidence that the herbicides used in Vietnam are carcinogens in animals, it is difficult to draw conclusions regarding their mechanisms of action as such. The mechanisms of action of the herbicides have not been studied to the same extent as TCDD. Neither 2,4-D nor 2,4,5-T is considered toxic to DNA; that is, they do not interact directly with or change the structure of DNA. Tests on cacodylic acid indicate that it is toxic to DNA only at very high doses, and tests with picloram are extremely limited, but suggest that it is not toxic. None of these compounds is metabolized to reactive intermediates. They do not accumulate in the body. Thus there is as yet no convincing evidence of, or mechanistic basis for, the carcinogenicity in animals of any of the herbicides used in Vietnam. Immunotoxicity: TCDD The immune system is a complex network of cells and molecules that play an important role in the maintenance of health and resistance to infection. Suppressing the activity of the immune system could lead to an increase in the incidence and severity of infectious disease and an increase in

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam TABLE 4-3 Summary of Carcinogenicity Bioassays of Herbicides Used in Vietnam Reference Species/Strain/Sex Protocol Results Bionetics, 1968a; Innes et al., 1969 Strain (C57BL/6×C3H/Anf)F1 and (C57BL/6×AKR)F1 mice, male and female, 18/group 46.4 mg 2,4-D/kg by gavage at 7 days of age, the same amount unadjusted for body weight daily until 28 days of age, then 149 mg/kg diet until 78 weeks of age No effect   Strain (C57BL/6×C3H/Anf)F1 and (C57BL/6×AKR)F1 mice, male and female, 18/group 21.5 mg 2,4,5-T/kg by gavage at 7 days of age, the same amount unadjusted for body weight daily until 28 days of age, then 60 mg/kg diet until 78 weeks of age No effect   Strain (C57BL/6×AKR)F1, male and female, 18/group 100 mg 2,4-D/kg by gavage at 7 days of age, the same amount unadjusted for body weight daily until 28 days of age, then 323 mg/kg diet until 78 weeks of age No effect   Strain (C57BL/6×C3H/Anf)F1 and (C57BL/6×AKR)F1, male and female, 18/group Single dose of 215 mg 2,4-D or 2,4,5-T/kg by gavage or subcutaneously on day 28 of age No effect Hansen et al., 1971 Osborne-Mendel rats, male and female, 25/group 0, 5, 25, 125, 625, or 1250 ppm 2,4-D in the diet for 2 years No effect Hazleton, 1986 Fischer 344 rats, male and female, 60/group 0, 1, 5, 15, or 45 mg 2,4-D/kg in the diet for 2 years Females: no effect; males: increased astrocytomas at high dose only   B6C3F1 mice, male and female, 60/group 0, 1, 15, or 45 mg 2,4-D/kg in the diet for 2 years No effect

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Hayes et al., 1991 Dogs kept as pets Case-control study, information from questionnaires and telephone interviews, no exposure data Household with dogs developing malignant lymphoma used 2,4-D more frequently than those that did not; odds ratio = 1.3 Hansen et al., 1971 Beagle dogs, male and female, 3/group 0, 10, 50, 100, or 500 ppm 2,4-D in the diet for 2 years No effect Muranyi-Kovacs et al., 1976 XVII/G mice, 20 male and 19 female; C3Hf mice, 22 male and 25 female 100 mg 2,4,5-T/l drinking water for 2 months, followed by 80 mg/kg diet for their life spans No effect Kociba et al., 1979 Sprague-Dawley rats, male and female, 60/group 0, 3, 10, or 30 mg 2,4,5-T/kg/d in the diet for 2 years No effect Innes et al., 1969 Unspecified strain mice, male and female 46.4 mg cacodylic acid/kg on day 7 of age, same amount unadjusted for body weight daily until day 28 of age, then 121 ppm (about 18 mg/kg/d) in the diet for 18 months No effect Stott et al., 1990 Fischer rats, male and female, 50/group 0, 20, 60, or 200 mg picloram/kg/d in the diet for 2 years No effect NCI, 1978 Osborne-Mendel rats, male and female 0, 10,000, or 20,000 ppm picloram (0, 500, or 1,000 mg/kg/d) in the diet for 39 weeks, then 0, 5,000, or 10,000 ppm for 41 weeks; observed for additional 33 weeks Increase in liver tumors attributed to contamination of picloram by hexachlorobenzene   B6C3F1 mice, male and female 0, 2,500, or 5,000 ppm picloram (0, 357, or 714 mg/kg/d) in the diet for 79 weeks; recovered for additional 10 weeks No effect

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