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| Names | |
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| IUPAC name
IUPAC
4,5,11,12-tetrachloro-8-oxatricyclo[7.4.0.0²,⁷]trideca-1(13),2,4,6,9,11-hexaene
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| Other names
2,3,7,8-tetrachlorodibenzofuran
2,3,7,8-Tetrachloro-dibenzofuran | |
| Identifiers | |
3D model (JSmol)
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| ChEMBL | |
| ChemSpider | |
| KEGG | |
PubChem CID
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| Properties | |
| C12H4Cl4O | |
| Molar mass | 305.96 g·mol−1 |
| Appearance | Colorless Crystals |
| Melting point | 227 °C (441 °F; 500 K) |
| 6.92e-07 mg/mL at 26 °C | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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2,3,7,8-tetrachlorodibenzofuran (TDCF) is a polychlorinated dibenzofuran with a chemical formula of C12H4Cl4O. 2,3,7,8-tetrachlorodibenzofuran is part of the chlorinated benzofuran (CDF) family that contain 1-8 chlorines attached to the parent dibenzofuran chain. The CDF family includes 135 compounds of which only a few have been studied.
TCDF was discovered in the mid- 20th century along with other CDFs. It was found to be an unwanted by-product in the manufacturing of chlorinated compounds; it is not commercially used or produced itself. TDCF is directly released into the environment via emissions of waste incineration, fires with PCB transformers, vehicle exhausts using leaded fuel, and bleaching of industrial products.
Research in TDCF has found that it is highly toxic and interferes with the endocrine, immune and reproductive system of humans and animals. Historically, the Yusho and Yu-Cheng incidents, in 1968 and 1979 respectively, where thousands were poisoned with rice oil contaminated with PCBs and CDFs, have given a lot of data to study the toxic effects of this molecule.
TDCF and other CDFs are known to have a lasting impact on the environment. TDCF can exist as both a gas and particles in the atmosphere, which result in deposition in the soil. It has an estimated half-life of around 60 days in the soil and atmosphere. This molecule can easily accumulate in the food chain leading to potential human exposure. TDCF is listed as a hazardous air pollutant in the Clean Air Act of the 1990s. Monitoring programmes are established to keep track of the levels on TDCF in various environmental compartments to avoid damaging ecosystems.
Carcinogenicity 3, not classifiable as to its carcinogenicity to humans
Synthesis edit
TDCF is not purposefully manufactured. It is formed as a by-product of industrial manufacturing processes involving organic compounds with chlorine atoms present. In certain favorable reaction conditions like alkaline medium with a temperature over 150°C, UV light and radical forming substances. In the production of chlorinated pesticides CDFs are formed as byproducts by intermolecular condensation of ortho-chlorophenols. Intramolecular cyclization reactions of predibenzofurans also result in CDFs. In thermal waste treatment processes CDFs are produced by combustion and pyrolysis (non)organochlorine compounds in the presence of chlorides. The recycling of metal cables also leads to the formation of CDFs as chlorine is formed by burning the insulator polyvinylchloride which causes new CDFs. From PCBs, the production of CDFs happen by loss of two ortho clorines, loss of ortho as well as chlorine, loss of an ortho hydrogen and chlorine with an additional shift of chlorine from the 2 to 3 position, and loss of two ortho hydrogens.
Available forms edit
TCDF is not made industrially and there are no commercial uses for it. TCDF can be found in the environment as an unwanted by-product therefore it can be found in the soil, water, sediments but also airborne. It is released into the air as vapour after burning of hazardous waste, gas exhausts using leaded gasoline, fires involving PCB mixtures and a byproduct of bleaching pulp. Some of this vapour remains in the air as particles but some of it gets deposited into the soil as well as water. Most of the exposure and available forms is through the air and the consumption of high fat meats that were exposed to the 2,3,7,8-Tetrachloro-dibenzofuran (National Center for Biotechnology Information, 2024).
Mechanism of action edit
TCDF elicits adverse effects though the chronic activation of the aryl hydrocarbon receptor (AhR). Binding to AhR triggers key protein kinase which increases activation of transcription factors, specifically those for lipid metabolism.
Halogenated dibenzofurans, similarly bind to AhR, increasing the activation of transcription in the xenobiotic response element (XRE) promoter region. The bounded AhR and halogenated dibenzofurans translocates to the nucleus together with hydrocarbon nuclear translocator (ARNT) and xenobiotic responsive element (XRE). In turn, this increases the expression of CYP1A1 and aryl hydrocarbon hydroxylase (CYP1B1). The increased signaling of AhR signaling has a number of effects. Firstly, it promotes the conversion of arachidonic acid to prostanoids via cyclooxygenase-2. This alters the Wnt/beta-catenin signaling by downregulating Sox9 and changes the signaling of receptors for inflammatory cytokines. Additionally, AhR signaling atlers proteasomal degradation of steroid hormone receptors, cellular response to UVB stress and changes the differentiation of certain T-cell subsets. Overall, the ranging activations and alterations caused by AhR signaling contributes to body weight loss, cancer and thymic atrophy.
Metabolism edit
Cytochrome P4501A1, or CYP1A1, is the enzyme responsible for the metabolism of TCDF. Additionally, TCDF metabolism increases significantly in the liver, kidney, and lungs of rats when pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 4-hydroxy-2,3,7,8-TCDF was the major metabolite produced by rat CYP1A1. Human liver microsomes and recombinant yeast microsomes that expressed human CYP1A1 metabolizes TCDF. However, yeast microsomes expressing human CYP1A2 don't metabolize TCDF. The rate of TCDF metabolism is faster in rats compared to humans. This may be due to the fact that humans have a slower metabolism compared to rats and therefore TCDF may stay longer in humans.
Indications edit
Exposure to CDFs can occur through inhalation, dermal contact as well as oral ingestion. When exposed, CDFs can affect the gastrointestinal tract by inducing vomiting and diarrhea. Additionally, exposure to CDFs can cause anemia, due to interference with hematopoiesis, more specifically by disrupting the function and development of erythroid progenitor cells. When inhaled, the person affected is more susceptible to lung infections as well. Finally, the more acute symptoms following exposure to CDFs are, depending on exposure route, skin and eye irritations, severe acne, darkened skin color and swollen eyelids with discharge. The acute symptoms, which are dermatitis, skin appendages, diarrhea and vomiting are the most obvious health effects of the CDF poisoning.
Efficacy and side effects edit
Efficacy edit
The concept of efficacy, in the context of toxic substances, is related to the dose-response relationship. When a smaller dose is needed to produce a toxic effect indicates higher toxicity. That being said, TCDF can have significant biological effects even when exposed to a very low dose, making it a dangerous compound both for humans and the environment, due to its bioaccumulation effectiveness. The bioaccumulation factor was investigated in aquatic environments and the values were found to range between the values of 1000 to 184.000 l/kg.
Adverse effects edit
TCDF has been associated with an increased risk of various cancers in animal testing. Additionally, exposure to TCDF can often lead to reproductive issues, both with conception as well as birth defects. Exposure to high levels of TCDF can also cause skin disorders such as chloracne which are acne-like lesions which can persist for an extended period of time. Finally, TCDF can induce liver toxicity, as it is the hub of detoxification in the body, and due to the TCDF’s chemical stability and lipid solubility, it is highly resistant to metabolic breakdown.
Toxicity edit
TCDF is one of the most toxic congeners (naturally occurring compounds other than ethanol after the process of distilling and fermentation) of the polychlorinated dibenzofurans (Weber, et al 1984) Its toxicity is associated with fatty liver disease (Yuan, et al., 2020). Mainly the toxicity of TCDF has been recorded through testing of breast milk, adipose tissue and blood serum. It is at this moment not yet classifiable as to its carcinogenicity to humans, classified therefore as type 3 of the IARC (International Agency for Research on Cancer classification). Toxicity levels and baselines are not yet known in humans but are being tested on animals, more on this at Effects on Animals (The Metabolomics Innovation Centre, 2014).
Effects on animals edit
The recorded effects on animals are most commonly investigated in the house mouse as well as male guinea pigs. Exposure to TCDF has led to problems in multiple organs within mice such as its liver, jejunum, cecum, small intestine and the general intestines. In general, the liver is the main target of TCDF, which leads to induced hepatic lipogenesis (Yuan, et al 2020). When testing on female mice, the effects on embryos were recorded, showing that TCDF has the strongest effect on fetal kidneys and leads to 100% of fetuses to be teratogenic at toxicity levels which are not fatal for the mother (Weber, et al 1984). The exposure to TCDF leads to a decrease in glucose homeostasis leading to an abundance of glucose in the mouse body. It also promotes the increment in bile acid metabolic processes which leads to an increase in multiple acids such as Deoxycholic acid, Glycocholic Acid, Taurochenocdeoxycholic Acid, Tauromuricholic acid, Lithocholic acid, Chenodeoxycholic acid, Taurolithocholic acid and an abundance of bile acids and salts. As mentioned previously, it affects the liver as it results in a positive regulation of lipid biosynthetic processes leading to an abundance of unsaturated fatty acids. The baseline toxicity levels for TCDF are known for the mouse, the guinea pig and monkey, being at LD50 Guinea pig (Hartley, male, 3-4 wk old) oral 5-10 ug/kg, LD50 Mouse (C57B1/6, male, 6 wk old) oral >6,000 ug/kg and LD50 Monkey (Macaca mulatta, female, 2.0-3.7 kg) oral 1,000 ug/k (WHO, 1989).
References edit
- ^ [FRIESEN,KJ & WEBSTER,GRB (1990)]
Ioannou, Y. M., Birnbaum, L. S., & Matthews, H. B. (1983). Toxicity and distribution of 2,3,7,8-tetrachlorodibenzofuran in male guinea pigs. Journal of toxicology and environmental health, 12(4-6), 541–553. https://doi.org/10.1080/15287398309530448 Matsumura, F. (1995). Mechanism of action of dioxin-type chemicals, pesticides, and other xenobiotics affecting nutritional indexes. The American Journal of Clinical Nutrition, 61(3). https://doi.org/10.1093/ajcn/61.3.695s National Center for Biotechnology Information. (2024, March 12). 2,3,7,8-tetrachlorodibenzofuran. National Center for Biotechnology Information. PubChem Compound Database. https://pubchem.ncbi.nlm.nih.gov/compound/2_3_7_8-Tetrachlorodibenzofuran#section=Probable-Routes-of-Human-Exposure National Center for Biotechnology Information (2024). PubChem Annotation Record for , 2,3,7,8-TETRACHLORODIBENZOFURAN, Source: Hazardous Substances Data Bank (HSDB). Retrieved March 10, 2024 from https://pubchem.ncbi.nlm.nih.gov.
National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 39929, 2,3,7,8-Tetrachlorodibenzofuran. Retrieved March 10, 2024 from https://pubchem.ncbi.nlm.nih.gov/compound/2_3_7_8-Tetrachlorodibenzofuran.
Pope, C. N., & Liu, J. (202AD). Chapter 10 - Microbiome in toxicity and its modulation. In An Introduction to interdisciplinary toxicology: From molecules to man (pp. 127–138). essay, Academic Press. Tai, H. L., Mcreynolds, J. H., Goldstein, J. A., Eugster, H. P., Sengstag, C., Alworth, W. L., & Olson, J. R. (1993). Cytochrome-p4501a1 mediates the metabolism of 2,3,7,8-tetrachlorodibenzofuran in the rat and human. Toxicology and Applied Pharmacology, 123(1), 34–42. https://doi.org/10.1006/taap.1993.1218 The Metabolomics Innovation Centre (TMIC). (n.d.). 2,3,7,8-tetrachlorodibenzofuran (T3D0207). T3DB. http://www.t3db.ca/toxins/T3D0207#identification The Metabolomics Innovation Centre (TMIC). (2014, December 24). 2,3,7,8-tetrachlorodibenzofuran (T3D0207). T3DB. http://www.t3db.ca/toxins/T3D0207
Weber, H., Lamb, J. C., Harris, M. W., & Moore, J. A. (1984). Teratogenicity of 2.3.7.8-tetrachlorodibenzofuran (tcdf) in mice. Toxicology Letters, 20(2), 183–8.)
WHO; Environ Health Criteria 88: Polychlorinated Dibenzo-para-dioxins and Dibenzofurans p.276 (1989)
Yuan, P., Dong, M., Lei, H., Xu, G., Chen, G., Song, Y., Ma, J., Cheng, L., & Zhang, L. (2020). Targeted metabolomics reveals that 2,3,7,8-tetrachlorodibenzofuran exposure induces hepatic steatosis in male mice. Environmental Pollution (Barking, Essex : 1987), 259, 113820–113820. https://doi.org/10.1016/j.envpol.2019.113820