Dioxin - Molecule of the Month - September 2005



Dioxin - click for 3D structure



Fabio Pichierri

Tohoku University

Sendai, Japan

Molecule of the Month, September 2005.


Dioxin, the short name for 2,3,7,8-tetrachlorodibenzo-para-dioxin (2,3,7,8-TCDD), is considered to be one of the most dangerous compounds that pollute our environment. Its chemical structure is made of two aromatic rings joined through a pair of oxygen atoms, as shown in the above drawing. Four chlorine atoms, two on each aromatic ring, are attached at positions 2, 3, 7, and 8. The whole molecule is flat-like and possesses D2h symmetry. If we consider that up to eight chlorine atoms can be attached to the dibenzodioxin (DD) skeleton, then 75 chlorine-substituted DD isomers can be conceived. Dioxin is inextricably linked to environmental pollution from waste incineration and to its incidental formation in chemical plants that are devoted to the production of pesticides [Tuppurainen 2003].


A man-made disaster

Here we give a short account of the Seveso incident which happened almost thirty years ago in northern Italy and has been recounted in great detail by Prof. Paolo Mocarelli, a medical doctor and university professor that has dedicated many years of his life in studying the effects of dioxin on human health [Mocarelli 2001].


The morning of July 10th (Saturday) 1976 is an ordinary morning just like any other. At 12:37 a cloud blows out from one of the many chimneys of ICMESA, a chemical factory located near the small town of Meda, not far from the city of Seveso. On the next day the mayors of Meda and Seveso are alerted by representatives of ICMESA about the toxic cloud. Soon after, the citizens notice the leaves of trees turning yellow while small animals start to die. Even more frightening are the burns that appear on the faces of children. After more than one week from the incident, people are still wondering what is going on. The presence of dioxin in the environment is being hypothesized and subsequently confirmed on July 20. How was it possible that dioxin escaped from the chemical plant? ICMESA was producing 2,4,5-trichloro-phenol (TCP), a compound that possesses bactericidal properties and finds use as a pesticide. Its synthesis employs 1,2,4,5-tetrachloro-benzene (TCB) as the base compound:



The exothermic reaction increased excessively the pressure of the vessel containing the reactants and, as a result of the malfunctioning of a safety valve, several compounds among which about 30 Kg (!) of TCDD escaped directly into the atmosphere. In the days following the incident the authorities had to estimate the real extent of the disaster so as to quickly undertake the necessary procedures of evacuation, medical assistance, along with securing the contaminated area. Emergency procedures are always based on technical and scientific data, such as the measurement of the amount of TCDD in the blood, fruits, vegetables, and the soil. This, however, was the first large-scale environmental disaster concerned with TCDD contamination and little or no information was available at that time. As Prof. Mocarelli points out, <<Science admits its ignorance within its realm. To admit it publicly is more difficult>>.


Several committees were organized and a great deal of scientific and technical activity was undertaken. The immediate effects of TCDD on humans were (a) lesions of the skin as a result of contact with the various compounds present in the toxic cloud, and (b) chloracne, an acne-like skin condition that results from the exposure to chlorinated hydrocarbons. Chloracne manifests itself with the formation of small bumps, termed comedomes, and cysts on the cheeks and behind the ears. Statistical studies performed over several years on pregnant women did not show a significant increase in malformations although the sex ratio at birth appears being skewed toward females. Furthermore, an increase in the risk of tumors of the lymphoid system has also been observed. A comprehensive toxicological study of the Seveso incident has been published in 2003 [Pesatori et al. 2003].


Besides the medical aspects related to the incident, an important problem that had to be solved at that time was cleaning the contaminated areas near Seveso and Meda. Incineration was initially suggested and supported by both scientists and politicians. Eventually, under the pressure of the public opinion, the authorities opted for soil scarification and its disposal into specially-constructed basins. An OAK PARK was finally created onto these basins and the citizens can now be proud of the beauty and resurrection of their land. We conclude this short story with the telling words of Prof. Mocarelli: <<Seveso teaches us that we must have a perspective on our limits, i.e. on the effects that take place on natural systems that have been built over the course of thousands or millions of years, effects of our behavior that create far-reaching changes and even destruction>>.



It has been established that TCDD binds to the aryl hydrocarbon receptor (AHR) in human tissues [Mandal 2005]. From here, the AHR-TCDD complex enters the cell nucleus to interact with a specific DNA sequence. The complex is believed to act as a transcription factor of the alpha-beta-alpha family that initiates a signaling cascade which provokes the observed tissue changes (e.g. chloracne). The characterization of the 3D structure of AHR (or part of it) will greatly help in shading further light on the molecular mechanisms behind the toxicological effects of TCDD (and other chlorinated hydrocarbons) as well as in finding possible remedies (drugs, therapies, etc) for the treatment of dioxin poisoning.


Electronic structure

The electronic structure of molecules arises from the physics of both electrons and nuclei. Within the framework of quantum mechanics, the branch of physics devoted to the study of microscopic particles, the time-independent non-relativistic Schrödinger equation (Hy=Ey) coupled to the Born-Oppenheimer approximation (stating that the motion of electron can be decoupled from that of nuclei as a result of their different masses) represent a good starting point for modeling the electronic structure of polyatomic molecules. The figure below shows the plots of four molecular orbitals (MOs) of TCDD whose (eigen)energies are the numerical solutions of the Schrödinger equation. The MOs spanning the HOMO (highest occupied MO) and LUMO (lowest unoccupied MO) levels are those of interest to research chemists for they are related to important properties of the molecule such as its chemical reactivity. On the top-left side, the HOMO-1 level which shows two pair of "lips" arising from the combination of carbon p-type atomic orbitals lying perpendicular to the molecular plane. The HOMO level (top-right) shows the contribution of four pairs of p-type atomic orbitals of carbon atoms. Both HOMO and HOMO-1 possess anti-bonding character with respect to the central CO bonds.

On the bottom-left side, the LUMO level which arises from the p-type orbitals of eight carbon atoms and possesses anti-bonding character with respect four CC bonds. The LUMO+1 level (bottom-right) displays the contributions from the p-type orbitals of chlorine atoms and has anti-bonding character with respect to the four CCl bonds. Populating it with electrons (upon either chemical or electrochemical reduction of TCDD) might help in achieving (partial or total) de-chlorination of TCDD [the calculations were carried out by me using Stewart's PM3 semiempirical MO method as implemented in the WinMOPAC software package].


Several physico-chemical properties have been predicted from the results of electronic structure calculations (computational quantum chemistry). For example, the adiabatic electron affinity (EA) of TCDD corresponds to 0.259 eV as computed at the B3LYP/aug-cc-pvDZ level of theory [Arulmozhiraja et al. 2000]. Furthermore, theoretical calculations performed on the simple DD molecule (with hydrogen atoms in place of chlorine atoms) predict that the replacement of both oxygen atoms with sulfur and selenium produces puckered molecules characterized by high inversion barriers [Kim et al. 2003]. The results have been interpreted as being a direct consequence of the electronic structure of these molecules.



The molecular structure of TCDD has been experimentally determined by single-crystal x-ray diffraction crystallography [Boer 1973]. As shown in the figure below, the packing of TCDD in the crystal shows the herringbone motif observed in the molecular crystals of polyaromatic hydrocarbons (PAHs). The molecules in the crystal are characterized by Cl•••O contacts at 3.087 and 3.131 Å. These and other crystallographic data are available from the Cambridge Structure Database (CSD) which is being distributed by the Cambridge Crystallographic Data Centre (CCDC).




K. Tuppurainen et al., Perspectives on the Formation of Polychlorinated Dibenzo-p-dioxins and Dibenzofurans during Municipal Solid Waste (MSW) Incineration and Other Combustion Processes, Acc. Chem. Res. 36 (2003) 652-658

P. Mocarelli, Seveso: a teaching story, Chemosphere 43 (2001) 391-402

A.C. Pesatori et al., Short- and long-term morbidity and mortality in the population exposed to dioxin after the Seveso accident, Ind. Health. 41 (2003) 127-38

P.K. Mandal, Dioxins: a review of its environmental effects and its aryl hydrocarbon receptor biology, J. Comp. Physiol. B 175 (2005) 221-230

S. Arulmozhiraja et al., Electron affinities for the most toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin: a density functional theory study, J. Phys. Chem. A 104 (2000) 7068-7072

S. Kim et al., A theoretical investigation into the conformational changes of dibenzo-p-dioxin, thianthrene, and selenanthrene, J. Mol. Struct. (Theochem) 655 (2003) 451-458

F.P. Boer et al., Adv. Chem. Ser. 120 (1973) 14



Dioxins and Health, by Arnold Schecter and Thomas A. Gasiewicz, Wiley-Interscience; 2nd edition (June 20, 2003)

Mechanistic Aspects of the Thermal Formation of Halogenated Organic Compounds Including Polychlorinated Dibenzo-p-Dioxins (Current Topics in Environmental and Toxicological Chemistry), by G.G. Choudry and O. Hutzinger, Gordon & Breach Science Pub (August 1, 1983)

The Dioxin War: Truth and Lies about a Perfect Poison, by Robert Allen, Pluto Press (September 13, 2004)

La Fabbrica dei Profumi (The Fabric of Perfumes), by Daniele Biacchessi, Baldini & Castoldi, 1995. [This book recounts the story of Seveso's incident and is available in Italian only]


Useful links

The official site of the town of Seveso: http://www.sevesonline.com/

DIMESAB (Dipartimento di medicina ambientale sperimentale e biotecnologie sanitarie) at the University of Milano Bicocca: http://www.dimesab.medicina.unimib.it/

Society of Toxicology: http://www.toxicology.org/

DioxinFacts.org: http://www.dioxinfacts.org/index.html

US Environmental Protection Agency (EPA): http://www.epa.gov/

An informative home page about dioxin: http://www.ejnet.org/dioxin/

A resource guide on skin cancer awareness: https://thedermreview.com/skin-cancer-awareness-guide/

Dioxin 2004 symposium: http://www.dioxin2004.org/frameset.htm


This web page is dedicated to the memory of my dear uncle who sparked my interest for Science and the mysteries of Nature as a mean to minimize my ignorance

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