Therefore, each profile begins with a Public Health Statement that summarizes in nontechnical language, a substance's relevant properties. You may download that program for free from this link to Adobe and then use it to access open the files below that are labeled as PDF files. Complete Profile, Preface, 3 MB. Public Health Statement , KB. Relevance to Public Health, KB. Health Effects, 9. Chemical and Physical Information, 2. Potential for Human Exposure, KB. Analytical Methods, KB. Regulations, Advisories and Guidelines, KB. 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.
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 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. It is not known whether picloram is metabolized.
Usage in South East Asia
In these studies, TCDD was fed to animals, applied to their skin, injected under their skin, or injected into their abdominal cavities. Table 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.
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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.
ATSDR's Toxicological Profiles on CD-ROM, Version 5: 2003
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.
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. 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. Males: increased tumors of thyroid and skin; females: increased tumors of skin, liver, and adrenal gland. Males: 0. Males: increased tumors of lung and liver; females: increased lymphoma and tumors of liver, thyroid gland, skin.
All: increased lymphoma; B6C3F 1 males: increased hepatocellular adenomas and carcinomas. 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, 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. 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. 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. 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 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. 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.
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. 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. 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. Case-control study, information from questionnaires and telephone interviews, no exposure data. Increase in liver tumors attributed to contamination of picloram by hexachlorobenzene. Increasing the activity of the immune system could result in the development of allergies and of autoimmune diseases.
TCDD has been shown to have a number of effects on the immune systems of laboratory animals. Studies in mice, rats, guinea pigs, and monkeys indicate that TCDD suppresses the function of certain components of the immune system in a dose-related manner; that is, as the dose of TCDD increases, its ability to suppress immune function increases. TCDD suppresses the function of cells of the immune system such as lymphocytes cell-mediated immune response , as well as the generation of antibodies by B cells humoral immune response.
Increased susceptibility to infectious disease has been reported following TCDD administration. In addition, TCDD increased the number of tumors that formed when mice were injected with tumor cells. The effects of TCDD on the immune system appear to vary among species, although most studies used different treatments and are not completely comparable. Studies indicate, however, that some species are more sensitive to the effects of TCDD on the immune system than others.
It is not known whether humans would be more or less sensitive than laboratory animals. Studies of the mechanism of TCDD-mediated effects on the immune system are conflicting. Most studies indicate that the presence of the Ah receptor is required for TCDD-induced immunotoxicity, but other studies indicate that it is not.
It is possible that the Ah receptor could play a role in some types of immunotoxicity and not in others. Additional studies indicate that an animal's hormonal status may contribute to its sensitivity to immunotoxicity. There is not enough information available on the mechanisms of TCDD-mediated immunotoxicity in laboratory animals to be able to predict whether it would be immunotoxic in humans, but the fact that TCDD induces such a wide variety of effects in animals suggests that it is likely to have some effect in humans as well.
The potential immunotoxicity of the herbicides used in Vietnam has been studied to a very limited extent. Effects on the immune system of mice have been reported for 2,4-D administered at doses that were high enough to produce clinical toxicity, but these effects did not occur at low doses. The potential for picloram to act as a contact sensitizer produces an allergic response on the skin was tested, but other aspects of immunotoxicology. The immunotoxicity of 2,4,5-T and cacodylic acid has not been evaluated in laboratory animals.
TCDD has been reported to have a number of effects on the reproductive and developmental functions of laboratory animals. Reproductive toxicity is defined as the occurrence of adverse effects on the male or female reproductive system, whereas developmental toxicity is defined as the occurrence of adverse effects on the developing animal. Developmental toxicity can occur any time during the lifetime of the animal as a result of either parent's exposure to a toxic agent prior to conception, during the development of the fetus, or after birth until the time of puberty.
For example, administration of TCDD to male rats, mice, guinea pigs, marmosets, monkeys, and chickens can elicit reproductive toxicity by affecting testicular function, decreasing fertility, and decreasing the rate of sperm production. TCDD has also been found to decrease the levels of hormones such as testosterone in rats. These effects generally occur only at doses that are high enough to produce clinical toxicity, however, and are much less common at low doses. The reproductive systems of adult male laboratory animals are considered to be relatively insensitive to TCDD because high doses are required to elicit effects.
Potential developmental toxicity following exposure of male animals to TCDD has not been studied. Studies in female animals are limited but demonstrate reduced fertility, decreased ability to remain pregnant throughout gestation, decreased litter size, increased fetal death, impaired ovary function, decreased levels of hormones such as estradiol and progesterone, and increased rates of fetal abnormalities.
Most of these effects may have occurred as a result of TCDD's general toxicity to the pregnant animal, however, and not as a result of a TCDD-specific mechanism that acted directly on the reproductive system. Little information is available on the cellular and molecular mechanisms of action that mediate TCDD's reproductive and developmental effects in laboratory animals. Evidence from mice indicates that the Ah receptor may play a role: mice with Ah receptors that have a relatively high affinity for TCDD respond to lower doses than mice with a relatively low affinity.
Other as yet unidentified factors also play a role, however, and it is possible that these effects occur only secondarily to TCDD-induced general toxicity. Extrapolating these results to humans is not straightforward because. Several studies have evaluated the reproductive and developmental toxicity of herbicides in laboratory animals. Results indicate that 2,4-D does not affect male or female fertility and does not produce fetal abnormalities, but it did reduce the rate of growth of offspring and increase their rate of mortality when pregnant rats or mice were exposed. Very high doses were required to elicit these effects, however.
The reproductive toxicity of 2,4,5-T has not been evaluated, although it was toxic to fetuses when administered to pregnant rats, mice, and hamsters. Studies of the reproductive toxicity of cacodylic acid are too limited to draw conclusions. Studies of its developmental toxicity indicate that it is toxic to rat, mouse, and hamster fetuses at high doses that are also toxic to the pregnant mother. Very limited data indicate that picloram is not a reproductive toxicant, although it may produce fetal abnormalities in rabbits at doses that are also toxic to the pregnant animal.