The History of Chloracne and Dioxin A Skin Disease at the Crossroads of Occupational, Environmental and Political Concerns A Paradigm of Endocrine Disruption by Gérard TILLESa b c Olivier SORG & Jean-Hilaire SAURAT a Bibliothèque Henri-Feulard, Hôpital Saint-Louis, Paris b Université de Genève, Centre Médical Universitaire, Swiss Center for Applied Toxicology c Professeur émérite de dermatologie, Université de Genève. Introduction Dermatologic manifestations Seminal observations Additional cases Complementary studies of pathological alterations. Pathophysiological approach Current features Puzzling dermatoses : chloracne or not chloracne? Chloracne-associated events Chloracne : cutaneous stigmata of industrial activities Industrial electrolysis in question Chloronaphthalene and chlorobiphenyls as causal agents The “Perna Krankheit” The 1930s to 1950s outbreak First steps of an industrial “epidemic” Chloracne, “sentinel event” of systemic toxicity Additional cases of chloronaphthalene toxicity. Outbreak in the US Navy Occupational exposure to polychlorinated biphenyls Epilogue From Nitro to Seveso Monsanto plant, Nitro, West Virginia First cases Epidemiologic studies Controversies surrounding Monsanto’s reports and their reliability Nordrhein-Westfalen Badische Anilin und Soda Fabrik AG [BASF], Ludwigshafen Boehringer, Hamburg : evidence of 2,3,7,8 tetrachlorodibenzo-p-dioxin responsibility Philips-Duphar, Amsterdam Diamond Alkali, New Jersey Dow Chemical, Michigan Experiments on prisoners Additional chloracne cases Rhône-Poulenc, Pont-de-Claix, France Spolana plant, Czechoslovakia Coalite and Chemical Products Ltd, Bolsover Seveso, Italy Initial observations Further epidemiology studies Investigations on long term adverse health effects Additional cases among trichlorophenol exposed workers Miscellaneous chemicals associated with occupational chloracne Chloracne-associated food poisoning Yusho [Japan, 1968],Yucheng [Taiwan, 1979] paradigms of chloracne associate food poisoning Additional episodes of food contamination Chloracne : elusive effect of Agent Orange in the Vietnam war From domestic to tactical uses of herbicides Operation “Ranch Hand”, military aftermath of herbicides use First concerns and controversies Reassuring statements, additional concerns Veterans’ claims Further investigations. The “Ranch Hand” Program Additional veterans claims. Further debates and controversies. Political interferences Focusing on chloracne and skin diseases Evaluation of the health effects of Agent Orange : a “conflict between science and social concerns” The “almost forgotten” Vietnamese population Chloracne, dioxins and politics : the Yushchenko case Political background Timeline of a medical and detective story Evidences and denials of dioxin intentional poisoning Victor Yushchenko as a medical case How and why did VY go to Geneva Which were the organs affected ? Which specific treatments were used ? How was dioxin clearance sped up ? Chloracne, hazardous wastes and municipal solid waste incinerators Love Canal The Times Beach and Missouri episodes The Valley of Drums Municipal solid waste incinerators. Controversies in France General situation Medical investigations in the population of Maincy Concluding remarks Appendices Appendix I : Chloracne seminal observations S. von Bettmann, Heidelberg, 1897 K. Herxheimer, Frankfurt am Main, 1899 G. Thibierge, Paris, 1899 G. Thibierge, Ph. Pagniez, Paris, 1900 L. Rénon, C. L. M. Latron, Paris, 1900 H. Hallopeau, P. Lemierre, Paris, 1900 H. Hallopeau, M. Trastour, Paris, 1900 P. Fumouze, Paris, 1901 A. Jaquet, Basel, 1902 W. Wechselmann, Berlin, 1903 W. Lehmann, Freiburg, 1905 J. Nicolas, M. Pillon, Lyon, 1926 J. Nicolas, J. Lacassagne, Lyon, 1929 Appendix II : Chloracne events Appendix III : Summary of findings in occupational, environmental and veterans studies regarding the association between specific health problems and exposure to herbicides Appendix IV : Dioxins and dioxin-like chemicals Appendix V : Carcinogenicity and adverse developmental effects of dioxins : a controversial matter Cited references Abbreviations AMA American Medical Association AhR aryl hydrocarbon receptor CYP cytochrome P450 2,4-D 2,4-dichlorophenoxyacetic acid DCA 3,4-dichloroaniline DDT 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane EPA Environmental Protection Agency (US) IARC International Agency for Research on Cancer IOM Institute of Medicine I-TEQ international toxic equivalency MADISH Metabolizing acquired dioxin-induced skin hamartoma MSWI Municipal solid waste incinerators NAS National Academy of Sciences NIOSH National Institute for Occupational Safety and Health PAB p-aminobiphenyl PCB polychlorinated biphenyl PCDF polychlorinated dibenzofuran PCN polychlorinated naphthalene PCP pentachlorophenol POP persistent organic pollutant SMR standardized mortality ratio STS soft-tissue sarcoma 2,4,5-T 2,4,5-trichlorophenoxyacetic acid TCAB 3,3',4,4’-tetrachloroazobenzene TCAOB 3,3',4,4’-tetrachloroazoxybenzene TCB 1,2,4,5-tetrachlorobenzene TCP 2,4,5-trichlorophenol TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin TEF toxicity equivalency factor TEQ toxic equivalent VA Veterans Administration/Affairs VAVA Vietnam Association of Victims of Agent Orange VY Victor Yushchenko Introduction to chloracne history It seems logical to consider that dermatology is the oldest medical discipline, since the skin is the only organ directly visible. Indeed, records exist for the description of skin diseases by the Ancient Egyptians dating back to 2000 BC. However, modern dermatology, involving a systematic description and classification of skin diseases, with an attempt to deduce a treatment, only started to develop during the second half of the 18th century. The skin is the largest organ of the body and, with an external surface of 1.7-2m2, any morphological change (following / due to?) various environmental or systemic stresses will be fully visible. The skin is in direct contact with the environment, and hence will be the first target organ following exposure to pathogenic microorganisms, xenobiotic chemicals or physical stressors. Pathophysiological changes of the skin may also be the consequence of diseases of the internal organs. The possibility of observing the skin directly renders dermatology a (distinctive?) medical discipline, and dermatologists have developed a rich teminology to describe the various skin (manifestations / diseases and disorders?). It has been known for a long time that the appearance of the skin may be affected by various conditions. These changes can manifest themselves as a rash, erythema, discoloration, (atrophic changes / atrophy?) or inflammation. A skin rash (is observed following / can follow?) exposure to heavy metals, such as lead, mercury or thallium, as well as during viral, bacterial or fungal infections, such as zona, syphilis or mallasezia. Other metals, such as nickel, chromium and cobalt, may induce contact dermatitides, whereas arsenic may induce hyperpigmentation, hyperkeratosis and squamous cell carcinoma. Sunburn, solar urticaria and actinodermatitis are common following acute exposure to the sun, whereas photoageing is the consequence of long-term exposure to the sun. All these conditions have been observed since the beginning of the Christian era, although their description has evolved over time, becoming progressively more precise with the development of dermatology over the last 200 years. Acne vulgaris is a very common skin condition that has probably affected most adolescents for millennia. It seems, however, that it has been considered as a true disease only since the 6th century, when Aetius Amidenus, a physician in Constantinople, named “ionthos” (ίονθωξ,) or “acnae” the lesions occurring on the face at the “acme” (ἀκμή) of life, which at that time might have referred to puberty. At the turn of the 20th century, strange cases of acne began to appear in workers engaged in the production of caustic soda or potash by the electrolysis of sodium or potassium chloride, with the release of chlorine gas. In the first decades of the 20th century, such acneiform eruptions appeared in workers on the sites of production of chlorinated pesticides, in particular polychlorinated naphthalenes. When considering the conditions leading to these strong acne-like eruptions not related to puberty, it appeared that the common denominator was the presence of chlorine gas, chlorination reagents and/or chlorinated organic compounds. In 1899, Karl Herxheimer, Professor of Skin and Venereal Diseases at the new University of Frankfurt (Germany), was the first to establish relationships between chlorine in a large sense and the development of these strange acneiform eruptions, and so introduced the term “chloracne” for this new skin condition. Since the middle of the 20th century, several industrial accidents involving the production or the use of 2,4,5-trichlorophenol [TCP] (why square brackets?), as well the use of TCP-related herbicides by the US army during the Vietnam War, , pointed to the by-product 2,3,7,8- tetrachlorodibenzo-p-dioxin [TCDD] as the causative agent for the development of chloracne. More recently, the team led by Professor Jean-Hilaire Saurat at Geneva University Hospital, during the medical care of the former Ukrainian president Victor Yushchenko, who had been poisoned by TCDD during his presidential campaign, (made a better characterisation / provided a better description?) of chloracne lesions, which are not true acne lesions, and not necessarily induced by chlorine or chlorinated