Dioxin: Biological Toxicity

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EXECUTIVE SUMMARY

Dioxin is considered to be one of the most toxic substances known to the human race. The history of dioxin in the United States is filled with controversy and debate. Questions regarding whether dioxin causes cancer, as well as myriad other diseases, and the nature of the risk associated with these diseases abound in the media and literature. A wealth of evidence has shown that dioxin causes carcinogenic, neurological, reproductive, developmental, physiological, and immunotoxic effects in various animal models, yet very little evidence exists to implicate dioxin as a cause of human disease. Scientists currently lack important information pertaining to the biological mechanisms of dioxin's actions and consequently cannot properly assess the chemical's health risks. In this paper, I will summarize the biological effects that have been shown to result dioxin exposure and discuss current views regarding the biological mechanisms responsible for these effects.

BACKGROUND

Dioxins represent a family of 75 toxic chemicals, none of which occur naturally, nor have they been intentionally produced for any useful purpose. Dioxins are byproducts of the modern industrial age. ,,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most thoroughly studied and the most toxic of the 75 dioxin isomers. As a pure solid, TCDD is colorless, odorless, lipid-soluble and only sparingly soluble in water (Williams, 001).

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TCDD is created by solid and hazardous waste incinerators, the manufacture of chlorine bleached paper, the combustion of wood in the presence of chlorine, cement kilns, metal smelting, burning chlorinated benzenes and biphenols (PCBs), and the manufacture of certain pesticides and herbicides (,4,5-T) (Williams, 001).

Dioxin bioaccumulates in adipose tissue and can be found in most people. Because TCDD bioaccumulates in the food chain, the major route of human exposure is through the ingestion of food containing TCDD, especially fish, meat and dairy products. It has been estimated that food accounts for 8 percent of total adult exposures (Poindexter, 1).

Dioxin has received much media attention in the past few decades and thus has become a public concern. Dioxin has a reputation of being extremely toxic, which is based primarily on tests performed on guinea pigs, the most dioxin-sensitive mammalian species. By comparison, the hamster is 5,000 to 10,000 times more resistant in similar toxicity tests (Poindexter, 1).

1. PHYSIOLOGICAL EFFECTS

Dioxin is toxic to some animal species, but the evidence for corresponding toxicity in humans has not been established. No deaths due to systemic dioxin toxicity in humans have been reported. Only two clinical effects have been repeatedly observed in exposed populations chloracne and transient hepatic effects. Epidemiological evidence suggests that dioxin may play a role in heart disease, hypothyroidism, and diabetes. (Williams, 001).

Chloracne

Chloracne is the only overt effect of dioxin exposure in human populations Acneiform lesions may appear as early as one to three weeks after dioxin exposure. The lesions are small, pale yellow cysts, which are the result of altered differentiation of acinar sebaceous basal cells into keratinocytes. The lesions primarily involve the face, especially the periorbital, temporal and malar areas, as well as the upper body (Poindexter, 1).

A genetic basis for the dermal responses to dioxin has been defined in selected laboratory animals. In experiments performed on mice, scientists observed strain-specific differences in the cutaneous reactions of haired and hairless mice to the topical application of dioxin (Joseph, Burton, Michalek, & Alton, 18).

Hepatic Effects

Although hepatotoxicity from TCDD exposure has been observed in a variety of animal species, there is no evidence that TCDD causes long-term hepatotoxicity in humans. Some studies have shown a transient increase in hepatic enzyme levels without clinical disease. Studies involving victims of the Seveso, Italy and Times Beach, Mo. incidents suggested subclinical hepatic effects (Poindexter, 1).

Animal studies have revealed potential mechanisms for dioxin's action upon the liver. One toxicology study, using rats, showed that dioxin may cause changes in enzymes of oxidated stress in the liver resulting in hepatic effects (Kern, Fishman, Song, Brown, & Fonseca, 00) Another experiment, performed on mice, showed that dioxin increases mitochondrial respiration-dependent reactive oxygen production, which may play an important role in dioxin-induced toxicity and disease (Seneft, et al., 00).

Heart Disease

A study involving 1,18 German workers in a pesticide factory found a dose-dependent relationship to deaths from heart disease, as well as cancer, among workers exposed to dioxin. Exposed workers showed an increase in death due to ischemic heart disease, a narrowing of the arteries, causing a reduction of blood flow resulting in heart attack (Williams, 001).

Thyroid

Dioxin is structurally similar to the thyroid hormone. Some of its toxic effects resemble hypothyroidism, a reduced functioning of the thyroid gland. Deficiencies of thyroid hormone during fetal life or early infancy can lead to mental impairment, hearing loss, and speech problems. Even when IQs measure in the normal range, thyroid deficiency can result in language comprehension problems, impaired learning and memory, and hyperactive behavior (Williams, 001).

Diabetes

Dioxin alters glucose tolerance and interferes with the hormone, insulin. A ten-year follow-up study of 55 exposed workers found half to be diabetic or with abnormal glucose tolerance tests, an early sign of diabetes. The risk of diabetes appears to rise 1% for every 100 picogram dioxin/gram (pg/g) of lipid in the blood (Williams, 001).

Toxicology studies using animal models also support a link between dioxin and diabetes. Cranmer, et al., found that high blood dioxin levels may result in insulin resistance (Cranmer, Louie, Kennedy, Kern, & Fonseca, 000). Kern, et al., found that dioxin stimulated tumor necrosis factor and inhibited glucose transport and lipoprotein lipase in adipose cells, providing a possible physiologic mechanism for epidemiologic studies that link dioxin to diabetes (Kern, Dicker-Brown, Said, Kennedy, & Fonseca, 00).

BIOLOGICAL MECHANISMS PHYSIOLOGICAL EFFECTS

Dioxin may interfere with normal endocrine function by disrupting natural hormones. Estrogen, glucocorticoid, prolactin, insulin, gastrin, melatonin, and other hormones are affected by dioxin, either by its activity on the hormone or receptor. Further studies are needed to determine the exact mechanisms of disruption (EPA, 000).

The available data indicates an involvement of dioxin in processes regulating cellular differentiation and proliferation, as well as those controlling endocrine homeostasis. Physiological effects related to dioxin exposure are presumed to be mediated through interaction with a specific protein called the Ah receptor. This process involves the binding of TCDD to the receptor, followed by the binding of the receptor-ligand complex to DNA recognition sites. This leads to the expression of specific genes and translation of their protein products, which then mediate their biological effects. Differences in toxicity may result from countless variations related to this chain of events (EPA, 000).

. NEUROLOGICAL EFFECTS

Although dioxins have produced neurotoxic results in laboratory animals, data from human studies have been inconsistent and inconclusive. In one epidemiological study, peripheral nervous system involvement was studied six years after the Seveso accident in 15 persons with chloracne. No case of peripheral neuropathy was found; however, subclinical peripheral nerve impairment was reported in 16 persons (EPA, 000) In another human study involving Dutch children, it was found that neurotoxic effects of prenatal dioxin exposure may persist into school age, resulting in subtle cognitive and motor developmental delays (Vreugdenhil, Lanting, Mulder, Boersma, & Weisglas-Kuperus, 00).

BIOLOGICAL MECHANISMS NEUROLOGICAL EFFECTS

Several toxicological studies have been done to elucidate the neurotoxic effects of dioxin in animals. Johansen, et al., performed an experiment using rats that provided evidence that dioxin causes hyperactivity and impulsive behavior similar to behavior in human children with ADHD and that the mechanism involves the inhibition of dopamine synthesis and deficient vesicular storage or release (Johansen, Aase, Meyer, & Sagvolden, 00). Nayyar, et al., found that the transcription factor Sp 1, responsible for growth and differentiation in the developing brain of rats, is developmentally regulated and expressed very highly in actively developing brain regions, and a potential consequence of the transplacental effect of dioxin to the fetus is in utero neurotoxicity (Nayyar, Zawia, & Hood, 00).

. IMMUNOTOXIC EFFECTS

Concern over the potential toxic effects of chemicals on the immune system arises from the critical role of the immune system in maintaining health. Based on studies involving many animal species, scientists have demonstrated the ability of dioxin to impair the immune system by directly reducing the number of B cells (formed in the bone marrow), and T cells (formed in the thymus). As an immune suppressant, dioxin interferes with the bodys ability to fight disease. It is also capable of up regulating the immune system to become hypersensitive, leading to autoimmunity and allergies. The past few decades have seen a marked increase in the numbers of people suffering with allergies and a variety of autoimmune diseases (Williams, 001).

BIOLOGICAL MECHANISMS IMMUNOTOXIC EFFECTS

Currently, very little is known about the mechanism by which dioxin causes immunotoxicity in humans. Evidence in mice suggests that the effects on T-cell functions appear to be related to perinatal alterations to precursor stem cells. One study, done using Jurkat T-Cells observed that dioxin caused the up-regulation of the Hrk protein and suggested this might result in T-cell suppression (Park & Lee, 00). In another study, scientists determined that compromised T-cell activation and suppressed type- cytokine production by T-cells may be involved in the impaired humoral immunity associated with TCDD exposure (Nohara, et al., 00).

Another potential mechanism for immunosuppression is the observed reduction in CD4+ T helper cells. Dearstyne and Kerkvliet hypothesized that TCDD affects T cells through the induction or augmentation of apoptosis. Their data suggested that dioxin-induced suppression of CD4+ T-cells involves, in part, increased cell death that may be mediated by Fas/FasL interaction (Dearstyne & Kerkvliet, 00).

Finally, it has been suggested that exposure to dioxin inhibits in vitro functional differentiation and maturation of blood monocyte-derived dendritic cells and that such an effect may contribute to the immunotoxicity of these environmental contaminants due to the major role that dendritic cells play as potent antigen presenting cells in the development of the immune response (Laupeze, et al., 00).

4. REPRODUCTIVE AND DEVELOPMENTAL EFFECTS

Although there is no epidemiological evidence that makes a direct association between exposure to dioxin and effects on human reproduction or development, the evidence suggests that there is such an effect. This is supported by the fact that all four manifestations of developmental toxicity, reduced viability, structural alterations, growth retardation, and functional alterations, have been observed to some degree following presumed exposure to dioxin-related agents (EPA, 000).

In animals, dioxin exposure has been observed to result in both male and female reproductive effects, as well as effects on development. These effects include increased prenatal mortality, functional alterations in learning and sexual behavior, and changes in the development of the reproductive system occur at the lowest exposure levels (EPA, 000).

In the male, dioxin exposure results in the delay of the onset of puberty, reduction in testis weight, abnormal testicular morphology, decrease spermatogenesis, and reduced fertility. There is also an alteration of normal sexual behavior and reproductive function. Males exposed to TCDD during gestation are demasculinized (Poindexter, 1).

In the female, altered cyclicity, reduced ovarian weight, decreased fertility, and shortened reproductive life span are noticed after dioxin exposure. Also, structural alterations of the genitalia and a slight delay in puberty are observed (Poindexter, 1).

BIOLOGICAL MECHANISMS REPRODUCTIVE EFFECTS

Dioxin's action as a developmental toxicant is probably achieved through interaction with the Ah receptor and occurs by one of four mechanisms. First, TCDD might activate genes that are directly involved in tissue proliferation. Second, TCDD-induced changes in hormone metabolism may lead to tissue proliferation or to altered secretion of a trophic hormone. Third, TCDD-induced changes in the expression of growth factor or hormone receptors may alter the sensitivity of a tissue to proliferative stimuli. Fourth, TCDD-induced toxicity may lead to cell death, followed by regenerative proliferation (EPA, 000).

Several mechanisms have been proposed to explain the biological action of dioxin on the development and reproduction of animals. Based upon a study of male rats, Latchoumycandane, et al., suggested that the low doses of TCDD elicit depletion of antioxidant enzymes and increase in the levels of HO and lipid peroxidation differentially in mitochondrial and microsomal fractions of rat testis, concluding that the adverse effect of TCDD on male reproduction could be due to induction of oxidative stress (Latchoumycandane, Chitra, & Mathur, 00). The author of another study speculated that TCDD acts as endocrine disruptor and ovulatory disruptor by decreasing estradiol secretion by follicular cells and progesterone secretion by luteal cells (Gregoraszczuk, 00). Finally, a study of male rats concluded that prenatal TCDD exposure produces demasculinization of male offspring sexual behavior by reducing cortical thickness in the brain and alters the normal pattern of cortical asymmetry (Zareba, et al., 00).

5. CARCINOGENIC EFFECTS

Although there is no conclusive evidence for human carcinogenicity, TCDD is irrefutably an animal carcinogen. Because the exact mechanisms of action are unknown, extrapolation from animal studies to humans is impossible. Before human carcinogenic potential from TCDD can be determined, long-term epidemiologic studies in humans are necessary (Poindexter, 1)

BIOLOGICAL MECHANISMS CARCINOGENIC EFFECTS

Much evidence suggests that TCDD does not damage DNA directly through the formation of DNA adducts. Mechanisms have been proposed that support the possibility that TCDD might be indirectly genotoxic, either through the induction of CYP1 enzymes capable of producing oxidative stress or by altering the DNA-damaging potential of some endogenous compounds, including estrogens. Many of these pathways are involved in cell proliferation and differentiation and are consistent with the generally accepted conclusion that TCDD acts as a "tumor promoter" in a multistage fashion (EPA, 000).

There is a scientific consensus that most, if not all, of the biochemical and toxic effects of TCDD require an initial interaction with its receptor, the aryl hydrocarbon (Ah) receptor. The properties of the Ah receptor (AhR) and the mechanisms whereby this receptor regulates gene expression are only beginning to be understood. However, formation of the AhR-TCDD complex is only the first of many steps involved in the production of a biochemical and toxic effect (EPA, 000).

In addition, there have been numerous reports on TCDD-induced modifications of growth factor signaling pathways and cytokines in experimental animals and cell systems. Some of the altered systems include those for epidermal growth factor, transforming growth factor alpha, estrogen, glucocorticoids, tumor necrosis factor-alpha, interleukin 1-beta, plasminogen inactivating factor-, and gastrin (EPA, 000).

Several recent toxicological studies have begun to detail the molecular mechanisms involved in the formation of cancer in animals. In one study, TCDD induced CYP1A1 and CYP1B1 in hormone-independent prostate cancer cell lines, suggesting that CYP induction should be considered in patients with advanced prostate cancer (Schaufler, Haslmayer, Jager, Pec, & Thalhammer, 00). The results of another study showed the suitability of an explant culture system for examining the inducibility of human pulmonary CYP1A1 and CYP1A (Wei, Caccavale, Weyand, Chen, & Iba, 00) Andreasen, et al., identified a critical residue in AHR proteins that has an important impact on transactivation, enhancer site recognition, and regulation (Andreasen, Tanguay, Peterson, & Heideman, 00). Finally, Wang and Hankinson described the functional involvement of the brahma/SWI-related gene 1 protein in cytochrome P4501A1 transcription mediated by the aryl hydrocarbon receptor complex and implicated the importance of ATP-dependent chromatin remodeling activity on inducible gene expression mediated by AHR/ARNT (Wang & Hankinson, 00).

CONCLUSION

In 14, the Environmental Protection Agency (EPA) released a reassessment of the risks associated with exposure to dioxin and reported a ten-fold increase in the risk of cancer. The announcement initiated much controversy and received much media attention. In light of what I have discussed in this paper, however, the announcement seems very reasonable. The fields of public health science and risk assessment are dynamic and continue to evolve. As scientists acquire more information regarding the biological mechanisms underlying dioxin-associated diseases, they are better able to assess the risks associated with those diseases.

Aside from a few incidences of acute physiological effects, dioxin has not been proven to cause disease in humans. Yet, the wealth of information regarding disease in animals associated with exposure to dioxin is conclusive and undeniable. The fact that scientists have yet to diagnose these effects in humans is probably a reflection of their lack of knowledge of the biological mechanisms underpinning dioxin-related disease.

The common thread linking most, if not all, diseases associated with dioxin in animals is the Ah receptor. Dioxin binds to the Ah receptor and this may trigger subsequent disruption to DNA integrity, hormone balance, cell signaling pathways, and/or cell metabolism, resulting in a variety of effects. Further research should attempt to elucidate the molecular mechanisms associated with the chain of events following dioxin-receptor binding, in order to better understand how dioxin contributes to specific diseases.

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REFERENCES

Andreasen EA, Tanguay RL, Peterson RE, Heideman W. (00). Identification of a critical amino acid in the aryl hydrocarbon receptor. The journal of biological chemistry, 77 (15), 110-8

Burton JE, Michalek JE, Rahe AJ. (18). Serum dioxin, chloracne, and acne in veterans of Operation Ranch Hand. Archives of Environmental Health, 5 (), 1 (6)

Cranmer M, Louie S, Kennedy RH, Kern PA, Fonseca VA. (000). Exposure to ,,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with hyperinsulinemia and insulin resistance. Diabetes, 4 (5), A6

Environmental Protection Agency (EPA). (000). EPA home page=Exposure and human health reassessment of ,,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Retrieved April , 00, from http//www.epa.gov/ncea pdfs/dioxin