Toxicological profiles - Hexachlorobenzene


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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.

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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.

T3DB: Hexachlorobenzene

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.

Studies of the reproductive toxicity of the herbicides are thus too limited to draw conclusions about their effects on male or female fertility. Studies of the developmental toxicity of the herbicides suggest that they can be toxic to developing animals, but high doses are required. TCDD has been reported to elicit several other kinds of toxicity in laboratory animals besides those described above. For example, the liver is a target organ for TCDD-induced toxicity in sensitive species.

Effects of TCDD on the liver include increasing the rate at which liver cells multiply, increasing the rate of liver cell death, increasing fat levels in liver cells, decreasing bile flow, and increasing the levels of protein and of substances that are precursors to heme synthesis. TCDD also increases the levels of certain enzymes in the liver, but this effect is not considered toxic.

Mice and rats are susceptible to TCDD-induced liver toxicity, but guinea pigs and hamsters are not. It is possible that liver toxicity is associated with susceptibility to liver cancer. Other toxic effects of TCDD that have been reported in laboratory animals include reduced blood glucose levels and starvation, increased rates at which cells in the gastrointestinal tract multiply, and changes in skin cells. The herbicides used in Vietnam have also been reported to elicit adverse effects in a number of organs in laboratory animals.

The liver is a target organ for toxicity induced by 2,4-D, 2,4,5-T, and picloram, with changes reportedly similar to those induced by TCDD. Some kidney toxicity has been seen in animals exposed to 2,4-D and to cacodylic acid. Exposure to 2,4-D has also been associated with effects on blood, such as reduced levels of heme and of red blood cells. The chemical structure of some of these compounds is shown in Figure These chemicals are usually considered together because 1 their chemical structures are similar; and 2 they produce similar patterns of toxicity although they differ in potency; Poland and Knutson, As will be discussed further below, the greatest biologic potency is associated with halogenation at three or more lateral positions that gave the molecule a relatively planar configuration Safe, Although there are.

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In addition to TCDD, commercial formulations of chlorophenoxy herbicides contain a series of other polychlorinated dibenzodioxins PCDDs and dibenzofurans. Although studies have been conducted on many of these structurally similar molecules, such as polyhalogenated dibenzofurans and polyhalogenated biphenyls, these studies are not covered in this report because of the extensive literature base.

Some of the halogenated aromatic hydrocarbons are manufactured as commercial products, but others, like TCDD, occur as contaminants in commercial products. TCDD is formed as a contaminant in the synthesis of 2,4,5-trichlorophenol, which is used to manufacture 2,4,5-T one of the components of several of the herbicides used in defoliation and crop destruction during the Vietnam war and hexachlorophene. The degree of TCDD contamination is dependent on the temperature and pressure of the reaction conditions Lilienfeld and Gallo, Johnston Atoll inventory, a.

NCBC, Gulfport inventory, c. Eglin AFB archived sample d. Due to their chemical stability and lipophilicity, the chemicals are persistent in the environment and are magnified in the food chain. The primary source of dioxins for human exposure is the food supply Travis et al. The main ultimate sources of dioxins are industrial processes and combustion. As stated, the syntheses of some organic chemicals are known to yield dioxins U.

EPA, The use of products contaminated with dioxins and waste disposal from these production processes are two major sources of dioxin exposure U. Since , the practices that led to the dispersal of dioxins have been greatly reduced. It is insoluble in water, but is soluble in many organic solvents e. The fate of experimentally administered TCDD has been studied in a variety of animal species reviewed: Neal et al.

Drug disposition studies such as these provide important information in developing models that can predict the biodistribution and elimination of TCDD following human exposure. Ultimately, the disposition of TCDD, like all agents, is influenced by many factors—including the rate of drug absorption, distribution, metabolism, and elimination, and its sequestration and storage in various tissues—all of which have the potential for having an impact on the magnitude of toxicity produced.

The amount of bioavailable TCDD i. In animal studies, the oral exposure route is most significant because it is believed to be the primary route for human exposure. Although the actual percentage of the total orally administered TCDD dose that undergoes gastrointestinal absorption following oral administration is found to vary among mammalian species, in virtually all cases absorption from either oil vehicles or dietary supplementation is greater than 50 percent. A similar percentage of the total dose was absorbed when rats were repeatedly administered low doses of TCDD 0.

Thoracic duct-cannulated rats showed that intestinal absorption of [ 14 C]-TCDD led to the transfer of the radioactive label to chylomicrons, which presumably transported the absorbed TCDD via the lymphatics into the circulation Lakshman et al. First, the percentage of the total TCDD dose absorbed decreased as the dosage increased. Second, the absolute absorbed amount of TCDD increased nonlinearly with dose. Lastly, the majority of the applied dose remained at the site of application, associated primarily with the stratum corneum, the uppermost layer of the epidermis, and did not penetrate through to the dermis.

Studies using soil-bound TCDD showed that a marked decrease occurred in the percentage of TCDD absorbed approximately 1 percent of total applied dose , compared to when methanol was used as the vehicle, as determined by the total amount of hepatic TCDD Shu et al. In an attempt to simulate dermal exposure from contaminated soil, TCDD was applied in a soil-water paste to rats for 24 hours.

Only 2 percent of the applied dosage was detected in hepatic tissues, suggesting very poor absorption Poiger and Schlatter, Studies using a number of other vehicles suggest that the percentage of TCDD absorbed dermally is dependent on formulation. Taken together, these findings indicate poor dermal absorption of TCDD. Little information is available pertaining to pulmonary absorption of TCDD; however, it is believed to be very high.

Once absorbed, the distribution of xenobiotics occurs through body fluids, primarily the lymphatics and blood, where agents either can be transported in the aqueous phase or are free to associate with various lipids and proteins that can serve as endogenous carriers. Following gastrointestinal uptake, TCDD enters the lymphatics where approximately 96 percent is found to be associated with the chylomicron fraction in thoracic duct-cannulated rats Lakshman et al. TCDD is transported in this manner into the circulation. The majority of absorbed TCDD was found to be distributed to the liver and adipose tissue.

The amount of an agent distributed to any given tissue is dependent on a number of factors, including the amount of blood flow to that tissue and overall tissue size. The primary sites of initial TCDD distribution from the blood, in terms of percentage of total administered dose, are the liver, adipose tissue, skin, and muscle during the first hour following administration. This general profile of distribution for TCDD has been observed in a variety of animal species including mice, rats, nonhuman primates, guinea pigs, and hamsters Rose.

Whole-body autoradiography has also revealed that in both mice and rats, in addition to the liver and adipose tissue, there was a distinct localization of 14 C-TCDD in the nasal olfactory mucosa Appelgren et al. The nasal olfactory mucosa was probably not identified in previous biodistribution studies because it is such an unlikely site for TCDD deposition, and therefore was most likely not previously examined.

There is evidence to suggest that the profile of TCDD tissue deposition may also be governed by the temporal kinetics of TCDD administration and the magnitude of the administered dose. Some studies suggest that TCDD tissue distribution is dose-dependent. Similarly, following administration of single doses of TCDD, a dose-related increase was observed in the proportion of TCDD distributed to the liver as compared to adipose tissue Poiger et al. Although the mechanism for this phenomenon is unclear, it may be partially related to the fact that rats also exhibit a concomitant and dose-dependent loss of adipose tissue.

Other evidence suggests that an increase in hepatic TCDD retention is mediated by a liver-associated binding species. Findings by several independent laboratories suggest that the hepatic binding species is cytochrome PA2 Voorman and Aust, , ; Poland et al. As would be expected for cytochrome PA2 involvement, Poland and coworkers a found that the TCDD-binding species was associated primarily with the microsomal fraction of the liver and was heat and trypsin sensitive, inactivated by mercurials, and liver specific. The prospect that cytochrome PA2 can act as a TCDD-binding protein is also consistent with the fact that the only other site at which this P isozyme is TCDD inducible other than the liver is the nasal olfactory mucosa, a tissue that exhibits high TCDD bioaccumulation Tuteja et al.

Contrary to the premise that cytochrome PA2 represents the TCDD hepatic binding species was the observation by Poland and colleagues b that dietary administration of the cytochrome PA2 inducer, isosafrole, did not increase hepatic uptake of TCDD. In contrast to studies describing dose-dependent tissue distribution of TCDD, findings from several other studies do not support this trend Rose et al. Species and tissue-related differences exist for TCDD retention time.

In nonhuman primates such as the rhesus monkey, TCDD is exceptionally persistent in adipose tissue Bowman et al. Adding to this complexity of TCDD retention are biodisposition studies suggesting that the rate of TCDD decay from liver, adipose tissue, and other tissue may not remain constant with time Birnbaum et al. Likewise, there is also evidence to suggest that TCDD retention in the rat liver may be cell-type specific. TCDD is biotransformed to water-soluble metabolites in a wide range of mammalian species Poiger and Schlatter, ; Ramsey et al. In a number of rodent species including the rat, mouse, hamster, and guinea pig, more than 90 percent of the TCDD that undergoes urinary and biliary excretion is in a polar biotransformed form.

In fact, excretion of absorbed TCDD is metabolism dependent, with the exception of nonabsorbed compound that undergoes direct intestinal excretion. Without pretreatment, Although the metabolism of TCDD has been somewhat enigmatic, a number of metabolites have been identified. The major metabolite was 1,3,7,8-tetrachlorohydroxydibenzo- p -dioxin.

Additionally, 3,7,8-trichlorohydroxydibenzo- p -dioxin and 1,2-dichloro-4,5-hydroxybenzene. The structure of the three remaining metabolites was not confirmed; however, it was believed that two of the metabolites were trichlorohydroxydibenzo- p -dioxins, with the third possibly being chlorinated 2-hydroxydiphenyl ether. In the rat, trichlorodihydroxydibenzo- p -dioxin and tetrachlorodihydroxydiphenyl ether were the major metabolites identified in bile Poiger and Buser, Additionally, what were believed to be glucuronide conjugates were identified in rat but not dog bile.

In vitro studies utilizing isolated rat hepatocytes in culture identified two glucuronide conjugates as the major metabolites of 2,3,7,8-TCDD Sawahata et al. It is generally believed that the major route of metabolism in the rat involves oxygenation of the unsubstituted carbon nearest the bridging oxygen in 2,3,7,8-TCDD.

Metabolic biotransformation of TCDD is generally accepted as being a detoxification reaction. This premise is supported by a number of different studies using a variety of approaches. Structure-activity relationship studies using synthesized congeners of known TCDD metabolites found those compounds to be toxicologically inactive even at very high concentrations i.

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These findings suggest that the covalent binding of TCDD to DNA is not likely to be responsible for its oncogenic effects, and further support the premise that TCDD metabolism is primarily a detoxification mechanism. The rate and primary route of TCDD excretion has been found to differ among animal species. After a single dose, TCDD undergoes a first-order elimination process exhibiting very slow excretion kinetics.

In the hamster, the half-life for elimination has been estimated at approximately 11 days. In the rat, following repeated oral dosing 0. From drug disposition studies in the rat, Rose and colleagues concluded that based on calculated steady-state values, it was unlikely that TCDD would continue to accumulate indefinitely in the tissues of animals exposed chronically to low levels of the compound.

Species differences also exist with respect to the route of elimination of TCDD. Conversely, in all other species, excretion occurs primarily through feces Piper et al. In the rat, hamster, and mouse, approximately percent of TCDD in feces is unmetabolized, whereas in the guinea pig, approximately 81 percent was unmetabolized in feces Olson et al.

Unmetabolized TCDD in feces is believed to be primarily a result of direct intestinal elimination since no parent form of the compound is normally observed in bile. Based on present data, no significant correlations have been made between metabolism and disposition of TCDD and strain- or species-specific toxicity. A great deal of research has gone into determining the mechanism of TCDD toxicity in order to determine the plausible biologic activity of the molecule.

Most of this research has focused on identification and characterization of the interaction of TCDD with an intracellular protein called the Ah receptor. Interaction with specific sites on DNA may have an effect on the regulation of DNA expression, affecting a wide range of mechanisms that regulate normal cellular activity. Receptor-mediated events are generally characterized by the following: 1 they are restricted to cells that express the receptor; 2 there is a structure-activity relationship i. The mechanism by which these effects are elicited by TCDD is currently unknown; therefore, the emphasis in this section is on effects mediated by the Ah receptor.

Early studies by Poland demonstrated that TCDD saturably binds an intracellular protein with a high affinity. Further characterization of the binding properties indicated that the ligand binding exhibited stereospecificity i. Additional studies showed that the binding affinity of various congeners for the soluble receptor correlated well with the ability of the molecules to elicit a biological response.

In addition, genetic strains of mice were identified whose Ah receptor had a lower affinity for TCDD. These mouse strains had a decreased sensitivity to the toxic effects of TCDD. Crossbreeding studies indicate that the sensitive phenotype segregates as an autosomal dominant phenotype. Further genetic studies identified the "Ah locus" as the area of the genome that encodes for the Ah receptor Poland and Knutson, ; Nebert, Therefore, biochemical and genetic evidence indicates that the cytosolic protein Ah is the receptor for TCDD.

Although this protein has a high affinity for TCDD, recent studies have identified possible naturally occurring high affinity ligands for the receptor Gillner et al. Human cells from a variety of tissue types contain an intracellular protein that resembles the Ah receptor in animals Manchester et al. The isolated receptor was shown to have approximately the same sedimentation rate, molecular weight, and binding specificity as the murine Ah receptor Harper et al. The human Ah receptor has a binding affinity times higher than mouse nM versus 0.

In addition, human cells have a lower sensitivity to enzyme induction than murine cells Harper et al. The properties of this receptor have not been extensively characterized, but it is likely that, as in mice, the human population will be polymorphic with respect to the structure, function, and ligand affinity of the Ah receptor Nebert et al. Prior to ligand binding, the receptor is cryptic and contains the Kd heat shock protein, whose release is necessary to unmask the functional activity of the receptor Poellinger et al.

Studies were conducted to determine the ligand characteristics important for binding and eliciting a biologic response. There is good correlation between the binding affinities of various TCDD congeners for the Ah receptor and the induction of enzyme aryl hydrocarbon hydroxylase, AHH activity Poland et al. Analogous structure-activity studies implicate the Ah receptor in a broad number of biochemical, morphological, immunologic, neoplastic, and reproductive effects Poland and Knutsen, ; Safe, However, some responses do not have a clear relationship to Ah receptor binding and therefore may not be mediated by the Ah receptor Rozman et al.

The transformation of the Ah receptor into a DNA-binding form involves multiple events and interactions, including a conformational change measured by several parameters Denison et al. Evidence from a variety of sources indicates that the DNA-binding form of the receptor is composed of at least two different proteins Elferink et al. One protein, termed ''Arnt," that does not bind TCDD is associated with the liganded Ah receptor and may be either the DNA-binding component of the receptor or associated with translocation of the receptor from the cytoplasm to the nucleus Hoffman et al.

In addition, the ligand-binding portion of the Ah receptor appears to have been identified Bradfield et al. Fisher et al. For example, TCDD induces AHH activity a drug-metabolizing enzyme by stimulating the transcription of the CYP1A1 gene, which encodes for the hydroxylase protein, through a means that does not require protein synthesis and is receptor dependent. The liganded receptor binds to a transcriptional enhancer regulatory element, DRE, upstream from. This liganded receptor recognizes a specific nucleotide sequence 5'-TGCGTG-3' , which occurs in multiple copies within the enhancer region Denison et al.

Oxford Academic. Google Scholar. Michael E. Russell S. Stephen A. Raymond S. Cite Citation. Permissions Icon Permissions. Abstract Of the twelve different chlorobenzene isomers, a thorough evaluation of carcinogenicity has only been assessed on monochlorobenzene, 1,2-, and 1,4-dichlorobenzene, and hexachlorobenzene.

TABLE 1. Control and 0. Open in new tab. TABLE 2. Results are from the studies presented in this paper, or cited references. Open in new tab Download slide. To whom correspondence should be addressed. Fax: —, E-mail: ryang cvmbs. Ninth Ave. Barter, J. Benjamin, S. Cabral, J.

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Cabral, R. Carlson, G. Charbonneau, M. Chu, I. Conolly, R. DeVore, J. Statistics: The Exploration and Analysis of Data. West Publishing, New York. Diwan, B. Gustafson, D. Hasegawa, R. Hepatocarcinogenesis in the rat. In Carcinogenesis M. Waalkes and J. Ward, Eds. Raven Press, Ltd. Kitano, M. Morita, M. Nims, R. NTP U. National Toxicology Program a.

National Toxicology Program b. TR Research Triangle Park, NC. National Toxicology Program NTP TR Ogiso, T. Page, N. Peattie, M. Schrenk, D. Smith, A. Thomas, R.

INTRODUCTION

Vanden Heuval, J. Vandeputte, C. Wolff, G. Yang, R. Issue Section:.

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