Document B85GoJnQ1QpOL05NDYN790XpL

=1 . Arch. Toxicol. 44. M -JJO (I9R0I 7^ x / f o / T O X IC O L O G Y Review Article RECEIVED JUN 2 7 19M ' P-*ole*ooieM to Seveso* Ecclesiastes I 18 (J Q f [ _,g i^LTH SCI Bo Holmsiedt i. Department of Toxicology. Swedish Medical Research CounciL Karolinska Injiiiwci. " "S-^OTOI StockhdlmrSveden huroduclion Worldwide attraction w*as bestowed upon the accident that occurred at the ICMESA factory'in the small Italian communin' of Mcda/Scveso at 12.30 on July 10th, 1976. This has resulted in a host of publications, including halfa dozen books, at the time of writing. The pre-history of this evient is also discussed in many publications, as is the use : of the herbicide 2.4,5-T in agriculture and as. a defoliant in the Vietnam war. . .. This present account wiDnot attempt to go into detail except for some aspects of the . protohistory of Seveso and the chronology of the events occurring immediately after . ' the: xplosipn at the ICMESA factory. '*_ /-The author has interviewedseveral peopleand consuhed a number of publications *5 in an `effort to try arid t^w so m V lig h t on facts such as why the publication of the for mula of-one of^cjnosc4ooudxonipounds ever-described -and -published i|k 1957, - ~ :*tu a c tid lo very Stile attention fdr' w many years, and why the more than.20 cases of intoxication withTCDD; 'hichhad occurred prior la the Seveso (Italy) disaster, had remained relatively unknown in'-spite of information found in open literature. In the .*_case of ICMESA, representatives' have been interviewed from both the research ! .^ ^ r k e r s of the chemical companies'concerned and Italian scientists dealing with the 1-| ^problems of chemistry and toxicology' occasioned by the Seveso accidenL " The author has also takenJinformation from a report made by an independent - Swedish commission sent toSeyeso"(Italy) shortly after the accident (Kamcdo report). This commission w as triggereetby. an'organization that has the ability to send ex- pcrienced people to investigate^rithout delay; any reported medical catastrophy in the wofid.Manyletter*.sciutotbeautborwill also be quoted in this account Because ofthe : t nature of this paper relatively fewreferences will be found in the lexL Instead, the list of *references .has been partly, annotated.* The present report ^oejyopdiseuss the problem o f dioxins as contaminants in de- *^(oiiants used in the-yi.etnam qrai^thiscase tlw r a d e r is referred to the publicationsof -- -----r*_______ 1ii"o * V." ' r.7 ! * A report -riiten on bchxtf of tlw Advisory Subgroup on Toxicology of iIk Euntpc.TM McdlctiE Resurch Council* (EMRC) 0340-5761/80/0044/0221/? 04.00 212 B. Holmtiedt Mcsclsohn and Baughman. The thesis of the latter constitutes one of the best and most comprehensive treatise of the subject in general but has. unfortunately, never been printed. Nomenclature The term "chlorinated dibenzo-p-dioxins" or. more simply, "chlorinated dioxins'* refers to 75 compounds or any combination of the 75. It is theoretically possible to have 75 different chlorinated dioxins each having its own identity and special properties.The term "chlorinated dibenzo-p-dioxins*' or. more simply, "chlorinated dioxins'' refers to nil 75 compounds'or nnv combination of the group. Only very few of these 75 compounds have been synthesized and studied for their chemical and physical properties, and *only 2.3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been examined comprehensively for its toxicological effects. However, sufficient biological effects of various chlorinated dioxins have been measured to allow theories to be proposed and generally accepted that 23,7,8-TCDD is 3--1,000 times more toxic than the other tetra isomers qp any of th other, chlorinated .dioxins.. There are 22 possible isomers, of tetraefaorodibenzo-p-dioxin. TCDD has beencommonly used t m ean'2J.7.8-tetrachlorodibenzo-p-dioxin without recognizing the existence of the other 21 tetra isomers. At the time of printing all of them have beat syn thesized (Nestrick et L, 1979). Synthesis of TCDD ,, P> A T* tri' 2.de be sp Oc fir CO of prr dr . con : . in I va.-*m c j!:ro* The sequence of events that led to the synthesis of TCDD has been related by'Rappein the book Dioxin 1978, and can also be found in Table 1. The first chlorinated dioxin, the octichlorinaied compound, was prepared as far r ach' back as 1872 by two German chemists. Merz and Weith, butthe structure of this prod *ings. uct was not clear until 1957. In the 1930s a Japanese group under Tomtta started syn- - wen ihesizing chlorinated dioxins, but the}' did not prepare TCDD. -;-Safc In 1957 Gilman and Dietrich reported that they had prepared the tetrabromodiox- 'thc i in. and in the same year Sandermann et aL published the first synthesis of TCDD. mar These two compounds werej both-prepared by halogenatiorrof;the unchlorinated ; - the dioxins. In both cases the respective laboratory worker was hospitalized. . -ieN: Table 1. Chlorinated dionAi , ->f tCSO.-."r IS72 M e n and Weith 1906 Ullmann ind Sirin 1932 Tomn et tL l c?7 Gilman and Dietrich 19.*" Sandermann. Stockmann and Cancr. Synthesize octachlocodioxin jtrueture elucidated oflJy in 1957 Synthesize urvchloriruled dioxin Synthesize, chlorinated dioxini but not TCDD Synthesize halofenaicd dioxins but not TCDD tetrabromodibenxdioxines/TBD.D^'ft. ho^evet. s>nthc-; 4-|: sited Synthesize TCDD anal; One.eider com with :: respe- ' dcath thatn *Frolcfomcni 10 Scvcwo ' Accidents 213 TCDD'can also be prepared by pyrolysis of 2.4,5-trichlorophcnol (TP) and 2.4,5* trichlorophenoxy acids. Uncontrolled conditions during the industrial preparation of2,4.5-trichJorophenol from 1.2,4.5-lctrathIorobenzcnc have resulted in severe acci dents on several occasions. A list of both accidents and involuntary contamination can be found in Table 2. which also gives references. Some of these accidents deserve special comment. It is important to note that information on the toxicity as well as on the stability .-(long persistence and slow degradability) of TCDD was not available at the time the first reports of acute toxicity were observed, and no measures were taken to de contaminate the factories and control the residue levels ofTCDD. In fact, the presence of this and related substances was not even suspected. Workers, therefore, were probably exposed for a considerable lime following the first observations of acute toxic 'effects*,, usiially^hloracne. flitro, West Virginia, USA 1949 Tite first reported cases of industrial poisoning, due to the formation ofTCDD in un controlled exothermic reactions occurring durinc-the manufacture of TCP. were seen `in!194 9 at a 2.4.5-T-producing factory in Nitro. West Virginia. USA. The temperature in one of the reactors containing tetrachlorobcnzene, methanol and sodiumhydrodide .arose, a relief valve opened and the contents of the vessel was discharged into the inte rior of the building and over a wide area outside of the building. Two hundred twenty`eight persons were affected. ' " Symptoms included chloracne. nausea, vomiting, headaches, severe, muscular j aches and pains, fatigue, emotional instability and intolerancelo cold. Laboratory find-logs showed raised total lipids and raised prothrombin lime. Among Ibosefaflcctcd .werenot_only.*bfkmenrbgtaiso iaboraior?*pdrsonneCmcci*c&r personnel. BndeVen.the Safety Director wbo visited the area of exposure; Several wives-who had never visited the plant also developed acne, usually at the same time as their employee husbands. A man from the nearby town who purchased-a truck which was.parked in-the vicinity of r the accident at. the time it .occurred, and his child, also developed chloracne. The 'disabling symptoms which kept men from their jobs foras long as 2 years were severe 'aches and pains and fatiguability. the manifestations .of peripheral neuropathy. Liver Jtcsts were negative 4 years later. Mild residue of acne were, however.'common.. * - . * Very tittle was heard about this accident'it the time but a standardized mortality analysis has recently been conducted on the workers (Zacfc and Suskind.* 1980). One-hundred-twenty-one workers who developed chloracne resulting from-this, mc`odent on March 8, 1949, were selected for study. Follow-up of this group was ! 00% -complete. The standardized mortality ratio for al(causes.ofdeathwas shorwhto be 6.69 i with 32 deaths observed and 46.41 expected Fori,the calegor^s?of rnaUgnanf heoplasms and circulatory diseases, the standardized moatlity.ratios w ax l.OOand 0.68, /respectively. Because ofthesmall size of the cohort and lhe rdaUvdy smBll riurfiber of * .deaths observetLthe results of this study cannot be coi^uriyei.However.lt is impdftant that no apparent excess in total mortality or in deaths from malignant neoplasms op dis- ut), or Ihe FMh Sci. .) ( 1_U. U g J Q ^ ___ Table .2. Induttrial incidenti nisncinied uHlh the manufacture cf clitorinnled phenol*. Esicntnlly after Voimp et ni.. War l'tniiiiry Manufacturer'LocaIoii* Pnxluclion/ Primary Protlnc)*1 source of exposure Number nf cases 1040 United Sinici Monianlo/ Nitro. West Virginia TCP Rapi iloti * . i<uq '* l;cileial Republic of Gcririan PCP. TCP .* 'h *>i Nordrhcln-Weitfnkn * : *; \ Federai Kcpttbltc ofOermny Y . ' >= TCP l'iM- 105.1 t*nierai Republic of Germany ilochrlnger/ TCP Occt pntlonnl Occi pallonai i j V Occupational . l'ii.l 1 ' 105.1-1071 ' -- Federal Rr public of Germany ,, nSAF/ . >'; TCP \ l.udwtgshafeli . .ti: Trance > , T i r ' i Rhone 1. - Pufcnc/Greooblc * t * If Fokral Repubtkofkrniany nocnrln|tr. 'TCP - TCP -, ' ' , ' : Ingdhciffi/llambtirs ( 2.4,5 T ! Rxpkkkm * . KVa 'L** . Occupational : IndexpkrtRm Occupational 1956 **rj/ l5f, : Unheil Staici Uniteli Sinici . V1 ,1 \ Diamond Alkalni/ 2.4-D. : Newark. New Jersey . ; 2.U -T ' ' ** 1looker/ : 'X TCP Occupa) tonai '\Occupalkmal 1050 V. IKfl lui y United Staici 1itdusirie Chimiche TP F Mclcgnanesl Saronto Diamond TCP Shamrock/ Occupational Occt^mlkmnl I9AJ Netherlands Philip*-Duphar/ Amsterdam TCP : 1 19M USSR 11 M Untied State Dow Chemical/ Midland. Mlchl(in ' _i 2,4,3-T 2.4.3-T -- L .. Occupatlonnl Occupational 223 17 m 37 73 17 31 29 Many S Many, 1faul 100 I2R 30 *" fKrr, bili 'idi iimililicnuoiin Ycnr* frwu inciilcm lo1.1H nl^crvnlion* HcCvrcncc* io 128. 30. 39. 1 i -- U k 1 fi 1.11 MI I2.H 121.22. .10. 61. 62| l Il (il l.lft. 37. J7A1 ,13 -- 1231 ' 20 1251 - 12.1] M |6, IX 14. 501 _ |2fl. 601 fi 119. 621 vj i .V?r.ij j cuU^xA till i f ]it. ^ ihfM ylW ::*' I9B 1970 CichotfovaVta / *.- .'A :v . '.. * '" United Kingdom Japan Spoiling, ( !* \ ' \ '/ > ,:" '. Coalite'^pd Chemicals Productf/ Dolsovi Derbyshire \. 1972 USSR 1972--1973 Austria Une Nlir >gcn Work*/ 1974 Federal Republic of Oermnny . Haycr/Uclilingen 1975 United Slates ' Thompson*IIayward/ Kansas City. Kanin* 197ft Italy ICMHSA)Mdn ,*rpA UjJ, J/i'.Ufcij-JV:!.tit>3U.<.l.Aai i T e r .* -Occupational' , TCP jtlxplosion PCP 2.4.5-T TCP 2.4.5-T / Occupational Occupational Occupational no. 2 fatal 90 1 1 2i 1- 1 50 2.4.3,T TCP Occupation nl Occupational 5 - t; 1 9 3 1 - 111. j i , i j . 411 (30,3 81 14-11 l*v| 120.231 120.2)1 U3I *X ,l ; TCP Ei plosion 1.14 3 1)4.51. 32. 53.54. 551 TT*t name of the factory or company and Hi location was cited whenever h was available because considerable confusion exists in the published literature as to what Incident b addressed. The abaence of data Indicates the Information was not available ' fcTCP * irkhlorophenol, PCP/ pentachloirophenot ' Frequently Individuals involved la an hictient* and who wt re examined Initially. may have also been examined at a later date. The years that lapsed from the expo- or^tmtfltbf mot* recent'ktamfnatfon arecked la this cdu nn. The absence of a number Indicates that only an initial examination was reported in the referenced Kfawtart :11r;- " * 'v;v' .J Prolegomena to Sevrto j v. 1, 1*1 W 9W /to! f S. m. fm Vf. . Vi #"*' r 216 B. Holmtie* cases oft he circulatory system was observed in a croup of workers with a high peak ex posure to icirachlorodibcnzocJioxin followed over a period of nearly thirty years. A morbidity study of the same group is in progress. BASF. 1953 In November 1953. an accident occurred at a TCP factory in Ludwigshafen, FRG; 75 workers were exposed to the reaction products during the accident and the subse quent cleaning work. A detailed description has been given by Goldmann (1972). Most work ers were afTected by chloracne. 42 severely; 2 1'ofthe 42 suffered consequent dam age to internal organs or disturbances of the nervous system. The most relevant features were polyneuritis, sensorial impairments and liver damage. The son of one of the workers developed chloracne following contact with his father's workdothes. An additional case of poisoning occurred 5 years later concerning a worker who was involved in repair work (welding one of the autoclaves) at the contaminated'site: subsequently this worker died with necrotic pancreatitis.' AH the 75 w-orkers could be traced incohort study 25 .years later; mortahty.was * compared both with.the rcgional^nd haiion^ and with a control groupcf workers fronnhesamg'fautofyrltrthe exposed group. 17dcaths were o b se rv e ^ ]I--25 . expected depending on the contro(population): six from cancer (four or less expected), five from cardiovascular dtseasesXss expected), two from suicides (0.2--0.6 expected), one. from fiver cirrhosis, one from^a^irogcnitaJ tract disease, and two from traffic accidents (Thiess et aL, 1976.-ISIJT)- , At the beginning the injuries vw e ascribed to `'unknown toxic chlorinated hy drocarbons". Cages containing rfebitswene theiefore placed at the exposed localities;.;. | The animals put in the autoclaves'dicd of liver necrosis after many days delay. Several" kinds of cleaning and repainting were .tried in view of the recurring cases o f chloracne but unsuccessfully. Finally, it was decided to.dismantle the factory. This took place us- . . der the strictest measures of security in the winter of 1968 to the spring of 1969. The brokendown pans of the building were put into airtight chests arid deposited in a deserted saltmine. The metallic :p aru .were melted down.' ;'V Schulz, Sorvc, and Sandcrmanh ^. ' . ' " ' ... Sometime in th e .y e a r1 9S6?i^Jk, .Schuli' in the departm ^vi^derm atology .t Eppendorfer Krankenhaus. Hamburg, received a patient'with chlbracne: from the chemical company Boehringcr. Hamburg. FRG. This led him to study other workers it the same company and he identified some 30 cases with this disease. Later on. several cases of chloracne were also identified at the main plant of Bochringer in Jngclhcim, FRG. The people in question had all been handling the sodium'salt of 2.4.5-trichlorophcnoLThis compound was manufactured at the main plant of Boehringcr -in Ingelhdm. (FRG) and shipped to Hamburg for further pro cessing. in Hamburg (FRG) nbcjW pmenii received from. Ingelhrim wxrc.reloaded from barrels wi( h shgvclcw-fthoutimuch mention totbe dustcioudf arising.'No closed ` system was available and only rudimentary precautions webe taken. - -<}. Prolifcmcm to Scvrto 217 j . Jn Germany, chloracne had been known of since 1899 and epidemics of the disease hid been called "Pernakrankheit" when it was caused by PERcItloratcd NAplhuicncs. ' To study this disease experimentally, Schulz used the rabbit car test, originally de- *' veioped by Adams et aJ.(l 941). He soon found out that pure 2.4,5-irichlorophcnol and pemachlorophenol were not chloracnegenic, whereas the technical product of 2,4.5- tnchlorophenol was highly active and responsible for the symptoms observed in the workers. - i. Schulz established a collaboration over several years with Georg Sorge. who was --the chemist responsible for the local chemical laboratory of the Boehringer Company in Hamburg. FRG. Sorge played a decisive but neglected role in the subsequent developments but. for reasons of company policy, was not allowed to take pan in the publications. Schulz and Sorge tested a number of chlorinated compounds that could possibly be contaminants of the technical product. They established, e.g., that the -.-djbenzofurans wfitthighly active in the rabbit ear test, although they could not be found as impurities in the technical 2,4,5-trichIorophenoI. This is how things stood when another case of dermatitis, type hyperkeratosis and . chloracnc, was admitted into the department of dermatology. Eppcndorier Kran- kenhausin Hamburg. FRG. The person in question was an assistant of Professor San- _dennann in the institute of wood chemistry. Sandermann and co-worker had svn- .. .thesizetLno.lessthan 20 g ofTCDDduring their studies of chlorophenols as wood pre servatives. The assistant had become contaminated on the face by a cloud ofTCDD when opening a desiccator. This unlikely coincidence gave the clue to the possible im purity in the chemical product produced by Boehringer. FRG. ' TCDD was previously unknown. Sorgc immediately understood that it could be the 'contaminant responsible for the chloracne among the workers. Although it has nev- - er-bcen published, he managed to isolate and identify TCDD in the technical product .He also synthesized TCDD in his fairly primitive laboratory' and compared it to the iso- --ated product,-establishing unequjvocally -hs presence as a contam inant/' : ' ' T C D D wxs-found-'bv'Schutz to be highly active irithcrabbitcar testi Schulz also -a ^ Ik d -th e `im p o u n d to a spot on his left'krwcr underarm and in 2 weeks Seveloped hyperkeratosis and chloracne.' Theskm o fthe spot wasexrised, studied histologically, and. showed' thetypical lesions. 1 -r: - ;;r ' ' ' '"Sandermahn and co-workers published their synthesis in 1957. and in the same " yfcar Schulz summarized the tox*cbtogy"of,'TCDD (Kimmig and Schulz. Die ' i^xuirwissenschafxen, 1957). It was pointed .out that pure 2,4,5-trichlorophenol and *pchuchlorophenol were not cfioracnegenic^ that TCDD was both the most toxic -and the most-powerful chloracnegenic agent of the series of compounds studied, that .peroral doses Of 0.1--0.5 mg/kg bodywdgbt in the rabbit were lethal in 1--2 weeks .-and that the animals, .upon autopsy, showed- necroses and fatty liver. This succinct summary, although taken notice of by some toxicologists did not lead to any action generally. .1; ~ . . Sorge understood the temperature dependence for the formation of TCD D in the process, and developed a.low-temperaturepcocedurc for the synthesis nnd production in dosed system. Thus; Boebringer's product became more expensive but the manufac- .ture.less danecrous-fTable !,c *, * :/r. -sFor:5-^.yt2irt-?aIhbatdicarproducedrby'' Boehringer TFRG) were continuously controlled forpurity4jy th crim p k rabbit ear test- The old factory in Hamburg (FRG) 2 1R i Table J. Tcclmt*)*y Tor *ymlu.*M* of lrichlortphenol Method Cond(ioni of synthesis Pnw Chemical llijh temperature "without pressure' 200*C litltylencflyeot NaOH Bnclirin^tfr lph pressure in autoclaves 19J atm. t5 rc - Methanol NnOM B. Holmsiedt Comments In ICMESA NaOH was added to tetrx* chlorobenzene. In the presence of traces of heavy metals possible condensation to polyethyleneplyeol. Exothermal reaction Reaction under conditions of controlled temperature. Possibly isothermal `i * 1 1f t 1 ! } V i ti , ; The DOW procedure is economically more advantageous. The necessary temperature is reached in the ethyleneglycol without pressure was broken, up and destroyed. .After the occurrence of the cases o fchloracncat BMhrmger CFRG i^ithciniroducd& n.of the low temperature procedure, there have reportedly ocnrrred^A 'ipp-s pf rfrioracne. v-' n y.; , It is quitc.remarleablc,that som ^of the accidents could happen sufecoucntlv. in spite f all the warnings. Inf1957 the Bochrinacr Company t f K.G) informed other pro-_ ~5uccrs using the nigh temperature method for the manufacture o f TGF<about the risks ! and how they couldJ?e>successfully avoided, ,, , " _ - '' ' ~* M: . V* Philips-Duphar, i 963 v V; An accident occurred-ajt-.this 2.4J-T -produdng factory in Amsterdam; The Nether lands. during March: 963*-'After the-siart of the synthesis, the reaction became uncontrollable. An explosion blew the safetyvalve as well as the lid of an autoclave; and the contents of the vesselcontaminated the inside of the 4,000 mJ building,-which be came covered with-^oo'Nobody was injured by th e -explosion and-there was no fire. . .* ' *`* **: ' . - * - At the PhjTips-Dupbar.2-4.5-T factor}' sodium trichlorophenate was synthesized by the hydrolysis of t^44^eu*ach]orobenzene using 20^ ^ Jtvdirxude^ehdmethanol' . at a temperiture of j^rojrimitcly 170-C a e d i pressurc^approxim ately;2Ilatn^ It - was estimated that the final temperature in the autoclave was 4 0 0 -;4S0o.C and the pressure > 80 atm. Concerning the cause of the accident, no mechanical failure could be found, but a mistake on the part of the operators could not be excluded. Hundred and six men are likely to have been exposed to TCDD as they were in the building where the accident occurred during the subsequent period,;March--July, 1963. These workers were factory employees, a clean-up crew (non-factory personnel) and plumbing, painting and insulating personnel (non-factory workers). The personnel has been carefully investigated and it.was found .that chlpracne. was the most mihoh.'ariu'prtiminent ierion observed following cxpoiiirt-Liy$ifonction tests did not indicate liver damagc.A'few men complained of fatigue.^Thclatempcriod < tc^omcru 10 Scveto 2 IV .ween exposure and the appearance of chloracnc. characterised by comedones, slides and cysies on. the face a.nd,,someiimes on other parts of the body, was proximaiely 4--6 weeks. A follow up' study of the exposed personnel is under v. Immediately after the accident, the building was closed. Animal experiments were jicd sidcc the management knew of problems encountered with 2,4,5-T production Lhc USA and in the Federal Republic of Germany. Rodents died from dust, peeled ofT jnt. etc: In March 1963. the compound TCDD was said to be unknown to the plant magement in spite of reference to the work in Germany! No mention is made of hull's 957 paper. Spectrophotometric analysis was oflittle use but in 1966. a GLC rthod for TCDD analysis, developed by Dow Chemical Co, the Netherlands, was in duced. It was estimated that 200--500 g TCDD were released in the building. The activities in the building included removal of paint from machinery, walls, etc. : the"-end of 1963-a-fiaaI decision was reached to close the building since de* numihauon was deemed impossible. After the unsuccessful dccontaminalionrihe ant remained closed for 1-0 years. In 1973 the factory building was dismantled, nbedded in concrete and dumped in the Atlantic Ocean. A question in the Dutch par:mcat'remains*the only official document concerning this accident in the middle of a orld_dty-(NTagel, 1972). Two extremdy-detailed reports regarding.safety measures have been published by aJderup {1-974).' The workers were using fully protective clothing (air supplied suits). ie report shows that in this case advantage was taken of the experience in Gerany. "For the particular purpose with which it all started we received much advice from e medical.and safety services ofthe BASF in Ludwigsh&feri arri Rhein. FRG. where a milar factory building had been disposed of without untoward events a few years T,;TVe*re much indebted to Dr. P. J. Goldmann' and' the-chief safety engineer Bifkh'ifrn for their kind exjx^^n^working procedures and preventive measures, ac- to* docurnenla5oS*such as films ahd'pbotographs, 7and useiul advice." * The aaual demolition ofthefactory was carried but in April ihrough-the first halfof me. 1573L'An impression of theamounts to be disposed o f produced from a building f IS x 1X5 x 11.5 m withfiiU process equipment together with tools, protective gear id erer^ h in g th it is to be considered contaminaied, can be given from the tonnage of icjlumjrships. Three ships of a b d ^ 3 3 p t6hS*^fe'fiBed:trpto fun tonnage, which ieans 80o bfthe available volume ftll former equipment removed). A harbour had cs- edallr to be made for these ships arid in such a w i/th a t they could be moored parallel >thelongest walls-and separated fronrthe nearest wallby the crane track (lhc floor of a on-com&minated wing ofthe building); A pontoon was used as a windbreaker leaving xjm for; rwo of the s h ^ togcthcr. ^ '* ^ -/* . Dtiderup's paperi are Tull ofth* most detailed and curious information such as: _ i-workingteam, and spepiifllytfor~tKc firiefffi&ung -itn lffib jrtc rg tp e to itfe fri& u ld be discussed and greed upon. Since the suitshad the t ipperbh the back.nobody could free himself wiih: 220 8. Holmucdt out help. Therefore, permission was given to keep a knife within the suit to make a direct escape possible. No one actually took the knife with him.*' It even goes as far as to discuss "unexpected events to be expected'*. Coalite, England, 90S Coalite & Chemicals (England) had been manufacturing 2.4.5-trichlorophenol since 1965 and the solvent in this case was ethylene glycol. A detailed description has been given by May. 1973. 1.2.4.5.-letrachlorobenzenc and ethylene glycol were charged to the reactor together with ortho dichlorobenzene and caustic soda solution. The vessel was heated by oil and reaction look place at about ISO. C with an arbitrary upper limit of 200 C. Since about 1966-1967 caustic soda flake had been charged directly to the reactor, no water being added at this stage. At midnight on 23rd April 1968. the reaction temperature reached 175. C and thereafter it rose continuously for 50 min. When it had reached a point somewhere in excess of 250 C an, explosion of considerable violence occurred and the*supervising chcmisl was killed by falling m asonry., ' _V The manufacturing procedure at (foalite (England) did not utilize either pressure or _ agitatlion in tbc^uLoclaxc.stage. Explosions elsewhere, of which therattujch staffVere nwnrec. usedhath hut at a lower temperature. It was believed that the Coaute (England) -. method could not produce an explosion and. further more, in the event of an unforeseen icmpcralurc'-rise, "that there would.be* fewer and less dangerous toxic by ;prod- ..j ' Ucts" ! * ` '. ; * J The workers were immediately subjected to a clinical examination -but-nolhing m; particular was found. rrview ofthese "satisfactory findings" the building n u re o p e a e d ^ . after 10 days. AD damaged and obviously dirty areas were sealed off to be dcco.rv- - taminated properly and at leisure, while the remainder ofthe building wassubjected to a., thorough spring dean. Production was then resumed in the greater p an .of.tbe.plant- .. j For a time worit continued normally. Process operators were watched partkulariy. . , carefully but (hey all remained well However, certain men, all of whom had been in . \ Fine Chemicls-Unt (England), developed a mild but peculiar skin coodnkra. This took the form of a sflghtmaltr erythema and the eruption of tiny vesides around thebdrdert j of the pinnae. The conditions developed and the diagnosis quickly established itself as . ,,,] chloracme. It:tbecamc. widespread. These, skin conditions deyetoped .a m o n g < ^ ..e ^ '.j : ployces b e tw ^ M a y and Decembertof 1968 and 79 cascSjofc^Lpracne `: Within the n t x i i ^ S months theireater majority `(cases made ah a l i n p ^ c c m ^ S t ^ ^ ^ : .r covery. ` ; `' i; The Fine Chemicals Unit (England) was again closed and no one was allowed into ii without special protective clothing, including full face mask, gloves and boots. U was obvious that the entire building would have to be thoroughly cleaned and resurfaced. Heavy and expensive equipment which had been alTecied by blast or was badly contaminated* was buried 45 m deep at the base of an opencast coal mine. Two unexplained cases of chlorncnc indicating retnfestaiion occurred when new factory was ro n stru ^ at/th ejiitc.: ,/j;- . . . .*.; C "^At the time^of.thc!accident it seems'that May was unaware of Schulz's 1957^T ; ' publication. ;;'VL:7 J Prolegomena 10 Seveso 221 Othir Jncidents from Table 2 Concerning most of the other incidents listed in Table 2. much scantier evidence is aviilable.Por example, it is known that a number of cases of chloracne occurred at the Dow Chemical Co. (USA) in 1964 and that this led to the termination of the high tem perature procedure and the adaption of the Bochringer technique. In connection with .thls.-V.X. Rowe carried out a number of toxicity experiments with chlorinated dioxins 'on various species and seems to have been the first person to arrive at the extraordinary toxicityfor TCDD of an LD,,eperorally in the guinea pig of 0.6 ug/kg bodyweight. The author has seen the original laboratory records and the toxicity tests have since been re pealed elsewhere. Early toxicity experiments were sometimes hampered by the long de lay between time of administration and time of death. In February, 1970, the Dow Chemical Company (USA) wrote up instructions for the safe handling of.TCQD in the laboratory. These instructions were reissued almost ivrbalirr in 1978 on October 10th. and include a description of a "*wipc lest" to be used in contaminated areas. Seveso, 1976 As is now well known the only accident where detectable' traces of TCDD have been released into the environment happened at the ICMESA plant at Meda/Seveso (Italy). 20 km north of Milan (Italy), and resulted in a most serious environmental*con tamination. On July 10th, 1976, as a result of this accident, a chemical cloud consisting primarily of 2.4.5-trichlorophenol but also containing some TCDD was released into the atmosphere and over the surrounding area. The planL produced 2.4.5-trichloriv , pbenjSl by hydrolysis of 1,2,4,5-tetrachlorobenzene with causticin ethyleneglycol tin ~ jEJeyatediemperature. Due to so far unknown reasons, a s a f^ ^ a ly e ^ p ttire d an'rer leased part" of the reactor.content. Analyris o fthcsolids from the reactor,head showed . the-presaice-ofTCDlJ. * V' - * v : The 2.4,5-trichJorophenoI was produced for use in the rynthesis of hcxachloro- phene, a bacteriddc. The process used at ICMESA was simOar to the one used m the plahLdeitroyed in'1968 at Co*hte,'EngJand:The reason v ^ y ^ e i y n ^ c ^ wcnt astray is'spH'debated and one of the main issues o f tbccpUncasc pqw in process in'Italy. .Another isstie concerns the disputed lade of information to thiwork i^jriidauthorities . _a5t.^e potential danger of the operation before and i h e r the explosion.' ; .The sequence of events during thehectic days after the discharge is difTicult to fot- low-hiit two offidaJ chronologies issued by the Region of Lombardy (Italy)'have partially deared the picture. In the following the Swiss version (Rochd Reggiani) and the Italian version (CattabenL Dept. of Pharmacology, Milan."Italy),'and the two chronologies from the Region of Lombardy (Italy) will be given consecutively for the sake of. clarity. * 'Frorfl *many interviews, unpublished and'published docum entsr.^/author has formed the following'-opinion:- ' * " r *' r'.'- - - * ICMESA is a subsidiary of HoTTman La'Roche..We are informed________ r____ _ ______________ , _ TCP iq`1972 and that the product was shipped toibcU S forite m a n u f o c lu ^ 222 B. Holmstedt chlorophenc. We are also informed that TCDD analyses were continuously performed on the batches of TCP produced. Baughman (1974) n his thesis, also mentions analysis of the American hexachlorophenc product made from the TCP shipped to Dela ware. At the time of the explosion the Medical Director of Roche, G. Reggiani, was informed about the situation. According to personal communication he did not know anything about TCDD at that time but acquired information from G. Zbinden, the tox icologist in Zurich, and also through a telephone call to Dow Chemical Company. From Zbinden he received the EPA report on dioxines (Environ. Health Perspectives. Exp. Issue No. S, 87,1973). Thus equipped, he set out for Milan, Italy. Upon arrival in Sevcso (Italy) on Friday, July 16th, 1976, he was mainly alarmed by the skin damage in children caused by the alkaline chlorophenolates. At that time no other skin damage had occurred. Before the arrival of Reggiani in Milan, Italy, some important events had taken place. The effect on the vegetation could be observed on July .13th. On July 14th the first cases of intoxications and death occurred among animals and, on the same day, several children were hospitalized with skin .lesions. July 15th, the Lord Mayor of Seveso (Italy) issued a decree prohibiting-fce consumption of all vegetables and food within the area ofthe factor}' and the selling of all provisions. On July 1Tih, thejvorkers of ICMESA stopped working and went dh strike. Regarding what happened*on July 17th, Dr. Reggiani states the following in a-letter to the author: "The physicians taking care of the children hospitalized on 16th July after the first signs of a skin lesion appeared and who had been confronted with the clinical picture of chemical bums were informed^by. me on the following day, 17th July, that the lesions were possibly caused by the potentially caustic nature of the reactor contents (sodium, hydroxide, sodium salt of ethylene glycol, trichlorophenol etc.) but that a contact with an unknown quantity ofdioxin had to be considered too. Literature on this product was. therefore handed over to them and ^requested them to keep,all organic functions of the - hospitalized children including blood count-and coagulation under dose control. They passed on the information in writing to their health authorities.**. At the time immediately after the accident, the first and uppermost task assigned to the Givaudan laboratories for analytical chemistry in DubendorfDear Zfirich, Switzer land, was to examine the possibility that a certain amount of the contaminant TCDD had been produccdtnd .emitted.,.... .. ., The first samples of dustaixi soil .collected with the Dow.wipe test .procedure on July 14th, 16th, and 18th, ^ n < x i6 3 d i^ a U e a h d r e p n x iu ^ f e `rw ulu but thesamples of grass collected on the foDowing days allowed a good evaluation of the concentration of the dioxin and the mapping up'of the contaminaied zone. The laboratory chiefof Gi vaudan, Dr. Vatcrlaus, came down on the 19th July. In the meantime, further analytical data were coming from the laboratories in Switzerland, and with their help it was then possible for Reggiani to submit to the Italian authorities a plan for the evacuation and protection of the population. This he did on Friday. 23rd July, as follows:. *~j - TThit day I requested that .the population of the zone;Ve. were outlining be, immediately evacuated and that the people be prevented from entering i*LFurthermore, I suggested that the people evacuated-and those tiring around (he area be kept under medical control *hd weekly follow-un bate line examinations for toxic effects be r . i Prolcforncm to Scvcso 223 f. 'regularly performed, furthermore, that ail personal belongings-bereft behind in the ' houses and that fruits, vegetables or animals belonging to this1area be not consumed. Pregnant women were to" be-informed of the remote possibility of ah embryoloxic ^effect" (Reggiaai letter, 1977-02-21). Friday, July 23, represents the turning point for the event "dioxin of Scveso". In the building of the regional Authorities were convened medical specialists from the Region A '.of Lombardy, Italy, and the top officers of the provincial Health Authorities. Chaired by Domenico Amari, Prefect of Milan (Italy) and by the regional minister of health, Ri- volta, the meeting carried on the whole day, A statement was issued at the end of the 3- -meeting.-"The convention is of the opinion that no measures are required for the ^ protection of the population". The experts agreed unanimously that further steps were * neither urgent nor necessary. During the television news the Health Director, A. Rivol- $ la, declared on the same day that "everything is under control" (Mazotta, 1976). .1 The original analytical results as well as the state of the art of analysis of soil and _t " .vegetabfercafnc3 out by Givaudan have been put at the disposal of the author by Drs. * \N . Neuncr(I976) andJ. Hostynec( 1977). A copy ofthe paper to the Italian authorities < * (in French) which was submitted to the Italian authorities on Saturday morning, July I " \ 24th, and signed by Waldvogd, director ofGivaudan, is also in the possession of the au- | '*thor. Evacuation was commenced that very same day. \ " - Meantime, the scientific activities of the Italians during this period of time is closely connected with two people. Professor Cavallaro, Director of the local Laboratory of Hygiene in Milan (Italy) and Professor F. Cartabeni of the Dept, of Pharmacology of the University ofMilan (Italy). Cavallaro paid a visit to the factory' on the-16th ofJuly. On the 17th July, Cavallaro was approached by Dr. Ghetti who came to him with a sample of leaves informing him that animals were dying. This led Cavallaro to visit the ICMESA factory also on the 18th July'/ He wanted .to. enter the area of TCPjjro- .*ducriom One Mr.'Paoletii in charge of TCP production did not, however, want him to __ _ ' *1 . mVl J* * " MJ ^ *V ! !l 1 *i- I J _-fl *L? t_ ** <T*/^rvT^ first rime the:infopnatian*dn TCDD istheToDowirig:'' Chemical analysis of the' environmerrr'and'other modern techniques, j-P rogress in Analytical Chemistry, vok'S. r i l T i i i f F i ' U rAfwT, t-t !JPEm rr^'Tbe significance of pesticide origin and toxitity '( t a n a b e n r letter; 19701-30). ' However, according'to the Kamedo' R eport alrtidy on the 17th J uly the factory management .confirmed the possible formation erf1TCDD. This seems to be the first rime- TCD D ;;was brought up in Lcormecrion-with the' accident -- 7 days after the "'-explosion. C. r --' / *,, According to the official version of the Region o fLombardy (Italy) Prof. Cavalla- 3 0.-4O S ^".A . B. Holmtedt suggested TCDD and 1CMESA made the first concession to the Health Authorities that same day. However, they did not admit in an explicit wav that it was TCDD but they let it be understood that this could be the case. The Kamedo Report confirms that on July 18th. the Laboratory of Hygiene in collaboration with the Institute of Pharma cology at the University of Milan (Italy) commenced analytical work but docs not say what this consisted of. On July 19th Prof. Cavallaro and Prof, Ghetti, on the instructions of the Provincial Medical Officer and the Assessors' Council, left for Zurich (Switzerland). Givaudan's headquarters --the parent company oflQMESA --to ascertain the first results of the analyses carried out on the samples collected by ICMESA's technicians following the accident. On the 20th July they obtained TCDD-standard for analysis and at the same time got the information that a maximum of 2 kg. TCDD had been discharged (Kamedo Report). In Zurich (Switzerland) the analytical methods were demonstrated to Cavallaro and the toxicity of the dioxin was underlined. As y e t he was not fully aware or the great toxicity ofTC D D . Upon returning to Italy, various specialists were called imo-Seveso (Italy) arid the Department of Pharmacology of the University ofM ilan (Italy)-were asked to. control the results from, DGbendorif and verify the presence of-TCDD. --(Evento-ICMESA.-Region-of-Lombardy^Italy). TTie sample o f.T C B O .g i^ n to Cavallaro probably got.mto the hands of Cattabeni on July 22nd or somewhaieriier. .(Cattabcni interview). . ... ;j On Thursday. 22nd July, Cavallaro contacted Cattabcni who luckily mastered the massfragmentographi technique and had access to an instrument. He was. however, as ignorant about the toxicity .and chemical properties ofTCDD.as was Reggini in the beginning.-Cvllfo wantcd to know whether a sample ofleayes/rom a tree^close to. the exhaust contained TOD D. He said it was dioxin but gave no formula or other infor mation. A technician from.Cavallaro's lab. came 2 h after with a paper about TCDD. The general ignorance about these types of compounds is evidenced-by the actions of another scientist who collected leaves with his bare hands 23--24 July and who still suf fers from chloracne. -Before the arrival of CavaHaro's technician Cattabeni had already recorded a mass spectrum without observing any precautions whatsoever. From its fragmentation pattern and the characteristic molecular duster he nearly arrived at constructing the correct formula.- as evidenced by . documents shown to the present author/ 7. ! .. A t 23r 00-h on tirtf23hl ofJuly; Cavallaro was able to give-thJlcstrcsults obtained from the Department-of Pharmacology concerning TCDD. a n riy j^ 'a b o u t vegctation and ground in. the vicinity of 1CMESA. Since this date more than IO.OO-deter minations ofTC D D in soil have been carried oul strangely enough in a department of pharmacology. i Comments Jn hind sight-man\cl^ n p .c a n b e le a rn e d from Seyeso(Italy) and.previous accidents. . The word "catastrDphy'? is usually associated with sudden (or violent) denih cy.in- jury.--The Seveso(Italy) incident illustrates a completely difTeremiypc of catastrophy -- *- J ------ -/T'--- nf-ciusinc iniurics G ): PrvVfr.Tiena to'Sevcift with a latency varying from months to decades --organic injuries withtcMtologic. canccrocenic and genetic manifestations. A discharge of this character is therefore similar co- that of radioactive material' *.......... - Based upon the many human accidental exposures, it is fair to assume that-TCDD has a low acute toxicity to man compared to certain animal species e.g. the guinea pig. The Scveso (Italy) incident confirms this but the delayed appearance of chloracne indicates that man is a sensitive species and the development of this lesion is a sensitive indicator of exposure. The high animal toxicity and general properties of TCDD were clearly pointed out cy 6>chuiz in 1957. Yet in 1976 many scientists were ignorant about the extreme toxicity and even the existence of this compound. Serious work on the mechanism of union started around the 70's and was then prompted more by the discussion of the use cf defoliants in the Vietnam war than by accidental exposure in factories. The lack of knowledge about SchuizTs paper can only partly be explained by the fact that it was a short-note written irTCerman. The many accidents mentioned in Table 2. some of which have been commented . upon in this paper, did not seem to create the necessary awareness outside some specialists in toxicology, industrial hygiene and dermatology. On the other hand, one has tokeep in mind the fact that the awareness of the general public with regard locnvi'rorrmemal pollution was not great when these accidents occurred, neither was the legislation the same as it is now in most of the countries concerned. It is inconceivable to think that at the present time a factory in a major city could remain closed, con taminated with a deadly poison, for 10 years and then become dismantled and dumped into the .sea without the authorities, the general public and the news media, becoming aware of the fact. Thy overall information to scientists about potential toxic compounds is also di.Tcrcnt now.*in fact, it is almost overwhelming in.its indiscriminate magnitude. There _-js`_diarjy a case for more cooperation between .scientists in the various fielcfc of toxicology. particularly to-digest the literature.and present conclusions in a form suitable for_jhe_nom-specmirsu_5.g^' industrial dtienuitsL. - . Although some toxicologists took; careful notice o f Schulz's - 1957 paper, the problem, was that no consequences were drawn and no effective distribution of the mes sage.`wasjorganized. Somehowthey were unable, or did not feel called upon, to make pfopex.use of their knowledge in terms of eflecdve.warning. The lesson to be learned is improvement of the channels for the distribution o f knowledgeabout, and recognition *q compounds with outstanding toxic potentials. In the future a roster of people with ~bp:h_irdetailed and broad toxicological knowledge, managed by an international . organization like (he WHO. would serve a useful purpose provided that it is kept up to date.contjnuously. As, will be apparent from- this review, the communication between the chemical companies with regard to the risks of TCDD contamination has been much better. y^hc.ktfchringcr Company. FRG. already in 1957. informedits competitors about / a safer procedure for the prrvjlprrinn nf T r P .iA ir li w < yubsequently adopted by many of.them. However.: even; so,:m ajor accidents have occurred, e.g,, Coalli England,-in J968: and.Seveso.(Itaiy)in 1976.^In th e latter case a proportion of the ceiveral public-vTonhc first- time.;:became involuntarily exposed to the toxic'com pounds. * - V ' - !' 226 B. Holmsiedi ^"Thc author docs noi feel called upon to discuss technical details about synthesis but wants only to point out that "run away" exothermal reactions seem to have occurred' regardless of starting temperature and solvents used. In Seveso (Italy) there is no doubt whatsoever that the Swiss firm was fully aware of the potential risks in the manufacture ofTCP. Notwithstanding this, the process was carried out in a clearly risky manner, the most obvious evidence being that the safety valve opened out straight into the air. indicating gross negligence. At the time of the discharge the authorities were faced with the problem of obtaining quickly, information about the toxicity of different conceivable toxic sub- - stances discharged into-the surroundings. At the initial stage they were apparently re stricted to local libraries to obtain information that could servers a basis for action, this, of course, was a time consuming task. In retrospect: this is remarkable in as much as the Dept, of Dermatology of the University of Milan. Italy, in 1962. summarized five cases of chloracne occurring in workmen involved in the manufacture of trichloro- phcnol from ictrachlorobenzene (Hoffmann .and Mencghinu 1962). This was. an occupational exposure in 1959 at "Industrie Chimiche Melegnancsi Saronio"* in Milan. Through a former co-worker the author has found but that one of the exposed workers is still suffering from outbursts o f cftoracne 20 years later. ___ Authorities usually have some supervisory system to protect industrial labour.'and the population in general, from injury. Information'regarding the general labour protection at ICM ESA is extremely incomplete and information to the local people in volved may have been voluntarily or involuntarily neglected. The Italian law has articles regarding the obligation of firms to inform their employees about risks in their place of work. The number of the law is DPR (Decreto Presideme Reppublfca) 303. Art. 4. the date is March 19. 1956. - Under all circumstances one has to agree with Hans Paul Bosshardt from the Swiss Laboratory of Plant Protection, who in J973 wrote an article about dioxins, in the Neue Zrcher Zeitung, stating among other things:' "" r "In the future, to prevent damage, the technical production of chlorinated phenols and formulations will have to be improved so that polychlorinated-dibenzo-p-dioxins no longer occur. If this is not possiblethe use of these compounds will have to be drasti cally limited or totally forbidden. According to a new Swiss law-about poisonous substances* valid for about'one year, rules have been laid down which will allow a quick amelioration ofthese problems. Undoubtedly, the producers of chlorinated phenols, within a reasonable timelimit. wilt be willing to accept this and. without objection, institute changes in their production! It goes without saying ihm such problems do not have to be solved in Switzerland alone. Even in this instance an international collaboration is indispensable and. luck-ly. already partly realised. It behoves our country to be ahead of these questions and to suggest possible solutions of problems concerned with the prevention and decontamination of chemical environmental pollutants." Acim/KHcifyi-rtcnn. The Kicraturc on TCDD is already extremely lent thy. Therefore. Ibe author has not found'it reasonable in include reference* to everything included in this editorial since he ho* relied much ufv<no>rrt,>|i.inJer>ccanJ pefM*nal inter*iov*. In as for aj.lciU-ri. wre available. Ihev are yumed hch***.The author would like inespreis hit praiit^ie to the foHnwinp people who have contributed to tlw compilation - - ---- * ~ ~ ~ f u r_k.,u ^ -1."-a-.f alto pre!)** relied onthe so-cllcd Kamedo report n Scveio ndthis. perfiifiS. require* an exKmcdo if Swedish prfaniration of catasuophy medicine. It consists of a number of ,-rf->,\c."ed cieniitu in viribuitiefdj. the number of which can be increased ad hoc by suitable experts. P t .--"rose of Kamedo ij primarily to pain experience on how to handle medical catastrophies.'To thi*ef* ;tc:. *>h.' .1.-, accident happen* expert*-can be immediately and promptly sent to the area where it ha* oc curred. Decision* are made by only a few people, mostly a chairman and secretary or the organization. The c:v!.'.x are expedited without it being necessary to po throuph various channels. Passports, xisas and rr.onrj are available at the airport. A report is submitted later. In the case of the Scvcso catasuophy the S" fd:*h mis*ion`i rcpon is dated 1976 not long after the incident and hat also been translated into Gern r r,, , " he author would al*o point out that in addition to (he literature given below, he ha* also relied upon the ;*o v':Tic:aI chronologies, completed in 1978. ofthe 1CMESA accident, provided by the Region of I_o,T.r;rcy. Iialx. References A2cr.s. E .\f _ Irish. D. D.. Spencer. H. C~ Rowe. V. K.:The response ofrabbit skin to compounds re- . prrtcJ to have caused acneform dermatitis. Industrial Medicine, Industrial Hygiene Section 2, 1--4 t : ( E a r l i e s t publication of rabbit car method for monitoring chforacncl * S.. Cohen. E. M_ Kncip.'T. J- Lambert. J. I_ Zwcig. G.ieds.): Chemical analysis of the envi- ronr-.fnt'jthd other modem techniques. Chapter of J, R. Plimmer: Tlie significance ixf pesticide .vr.i.iiinani. Progress in Analytical Chemistry. x-oL 5. Plenum Press 197.1 (Where Cux-allant i'Ha:.-.ed information about TCDD) BaaJer. E. \V,, Bauer. H. J.: Industrial intoxication due lo pemachlorophenoL ImJ. Mud.'Surg. 20. liO -N O (19511 -r Bauer. H.. Schult. K. H Spiegelberg. U.: Occupational intoxications in the manufacture of chkiro- compounds. Arch. GrwrrbcpaihoL. Gewerbehyg.. I8..538--555 (196II 5- ilCughman. R. W.: Tctrachlorodibento-P-dioxins in the environment. High resolution mas* spec- uometry at the picogramm leveL.Thesis presented by Roben. W.. Baughman to theDept- of ---^Chemistry. Harvard University. Cambridge. Massachusetts. December.. 1974 (An extremely com- - f^ c mimeographed account of TCDD and other chlorinated compounds) -- 6. Berlin. A_ BjirttillA2"Vr,der-Venne.- M. Thr:'Proceeding*-ufiln tjtpm mm ing on ihCjproWems ** raised by TCDD pollution. pT179. Milan. Italy. 30 Sept. and. I O ct.-1976- . 7. BirIburg. Wallen. M - Brodktn. R_ Applebanm. L L : Industrially acquired .porphyria. Arch. De/maioL 89. 795-797 (1964) ...... 8. Bvsstardt. H, P.: Dioxine --crmtSckiechc Gifte in unserer Unrwch (Entstehung. Eigenschaften und -- eri-Uten von polychlorienca Dtbcnzo^J-dioxinenX Neue Zrcher Zeitung. Forschung und Technik. -** Montap. 2. 12. 1973- Minagausgabc Nn. 70--33 (Dr. Bosshrdt's 'warning to the Swiss industry. /Translation by the author) 9. 5uler. H.*R_: Polychlorinated dibenzo-p-dioxias and dibcnxofuraiu: formation, occurrence and ~ analysis of environmentally. hazardous compounds. Dissertation. Dcpc of Organic Chemistry' * L'rJxcrsity of Uroei. Sweden, and Swiss Federal Research Station. WaedenswiL Switzerland, pp. I--" '* 11978) (A good summary* of modern analytical techniques for chlorinated compounds) . C iuareni. F.:, Letter (two pages) to HoimoeduDept. of Toxicology. Karolinsla Insu Stockholm. . Sweden. 13. 6. 1977 l:_0*tibcnL F.: Letter (one page) to Holmnedt. Dept, of Toxicology. Karolinxka ln_ Stockholm. Syeden_..0 . I. (978 , , * . a .. -- C stierem. F,, Cax*al)aro. A - GaHL G. (eds.): Dkrxvt-toxicolocicxl and chemical expectx. p. 222. New Vork. London: Spectrum Publications. -- Inc. 19"78 Summaries by many, author*s) Daiderup. L. M.: Safety measures for taking down buildings cdmartiinctcd with toxic material II. T, Sw . Gcneesk. 52. 6 1 6 -6 2 5 ( 1974) 228 B. Helmstedt 15. Eko' Chemical Co.: Summary of safe handling of 2.3,6.S-ieirnchltvodib<nio-p-diniin (TCDDlin the l;:Nir:iii*ry t*f Dow Chemical Co.. Biochemical Research Laboratory. MidlanJ. Michigan. l*SA. 10. 2. l`/7t) (reissued 1978) 16. Dugois. P.. Mirechil. J.. Colomh. L.: Chloracne caused by 2.4.5-trichIorophcno!. Arch-Mai. Prof. 19. 626-627 (1958) 17. Evemo ICM ESA: Chronology issued by the Reeione Lombardia. Giunti Regionale over :hc period 10. 7. 1976 lo 31. 7. 1976 (1978) IS. Evemo fCMESA: Cronistori 1976. Final version Regione Lombardi*. Giunta Regionale. At- sossoraio ilia Saniti. Via Pontaccio. 10. Milano. 1978 19. Firestone. D.: The 2 J .7.8-lctrachJorodibenro-para-dioxin problem: A review. In Chlorinated phenoxy acids and (heir dioxins: Mode of action. Health risks and environmental effects. EcoL Bull. . (Stockh.) 27 (1977) (In press. 1980) ' 20. Forth. W.: 2.3.T.8-lctrachlorodibcnzo- L4*dioxtn (TCDD). The Seveso incident. Dtsch. XmcM. 44. 2617-2628 (1977) 21. Goldmann. P. J.: Schwerste akute Chlorakne durch Trichlorphenol-Zersetzunpsprodukic. Ar- heitsmed. Sozialmed. Arbcilshyg. 7, 12-18 (1972) 22. Goldmann. P. J.: Schwerste akute Chlorakne, eine Masscnimoxikation durch 2^.6.7-Tctrachkw- dibenzodioxin. Hautarzt 24. 149--152 (1973) 23. Hay. A. V,'. M.: Tetrachk>rodibcnzo-p-dioxrn release ai Sevcso. Disasters I. 289--308 (1977) 24. Hofmann. H.-T.: Neuere- Erfahrungen mit hochioxischcji CMorkohlenwisscrstoffeTi. Naunyn- Schmiedebergs Arch. Expi 'PathoL Phinh4]poL 132, 228--230 (1957) 25. Hofman. M. F_ MenegWnLC. La:A'proposiio ddle folBcolofl da idrocarburi dorososttluuo(acneck>- __nc*l G. Ital, Perm: 103. 427-4 5 0 (1962T ' - '< 26. Honynek. J_ (Grvat>dan):-Lenerifo HoInut&L DepL of Toxicology. Karofmska Insu 5iocthohn. Sweden, regarding -TCDD analytical method. 9. 5. 1977 27. Huff. J. E~ W usom. J. S.: Chlorinated dibaizodioxins and dibenzofurans. Environ. Health Perspect 5. 283-t3I2 (1973)-(Review-which Regglani took-with him to Sevesa Italy) 2X. (ARC: (International Agency for Research on Cancer); IARC monograph* cmthe evaluation ofcar cinogenic risk of chemicals'to4man. VoL IS. Some fumigants, the'herbicides 2.4-D and 2.4.5-T. chlorinated dibenzodioxins and miscenaneous industrial chemicals. World Health Organization. Lyon. France. 197.7 ' ^ ~A` v . " 2V. IARC: IARC internal technical report No.*7Sf00t (DraflL Coordination of epidemiological studies on the long-term hazards of chlorinated dibcnzodioxins/chtorinaLed diobenzofurant. World Health Organization. Lyon. France;'1978 ' 30. IARC: Joint NIEHS/IARC' Working Group Report. Long-term hazards of polychlorinated <5- benzodiozins and polychlorinated dibenzofurans. International Agency for Research on Cancer. Lyon. France.' 19^8 :"i" ' : "7 " 3 1. Jirisek. l _ Kalensky; J Kubec. K.: Acnechlorina and/xvpAmfo cutanea tarda during the manufac ture of herbicides. CesL'DermaibL`48. 306--3 17 (1973) 32. Jtrsek. 1 Kalcnsky. J ,, P a z d e f t j v i. J - UikaL EAcne chlorinaporphyria cutanea tar da and other manifestations general imoa*citk>n during the manufacture of herbicides. 11. CcsL DermatoL 49, I4 5 -!5 7 (I,9v7 4 r ;- ;. ,_ ___ 33. Jirisek. I-- Kalcnsky. J,, Kubeck- K_ Pazderovi. J_ LukaL E-i Chlorakne.porphxtia cuianca tarda ' und andere Intoxikationen durch Herbizid.-Hautarzt 27. 328--333 (1976) - ' >4. Kamcdo: Rapport XXXIV -- FOA 5. Katanrofmedicinska studier i Norditalien. FSrsvirets Forskningjanstali. Huvudivcfdninp 5 KAMEDO. -104 S3 Stockholm. SO ( 1977) 35. Kimbrough. R. D. et il.: Epidemiology and pathology of a TCDD poisoning episode. Arch. Environ. Health 63. "7 f 1977) 36. Kimmic. J..Schulz. K. H..'Occupational acne (so-called chloracneIdue to chlorinated aromatic cyclic cihen. Dermatolofica 115..540--5-16 M9<?1 37. Kimmig, J.. Schulz. X. H.: Chlorieng aromatische zyklische ther als Ursache der sogenannten , , Chkwakrte. Nalur*-iitcnschaftcn'44.-$ i7--338 (1957) (The important summary hj Schulz of the prt*pcrtK> of TCDD) ? ' _ ., 37a. Krau-v *t L,, Itratao. H^'K-thmr.rnischrr Beitrag ru >g. Chkvaknccrkrankungen au th-rn Jahre Iw54*3.V Arheitxmcdirin iw'aalmcitirin PrJxeimtmexli/in (3. I Prolegomena to Socto 229 G.:Chloracrv:f:o.mhc accidental production of tcirachlorodibcnzodioxinrBrJ. Ind. Med. JO, " 6 - 3 8 3 I T975) (Detailed dcicription of the Coalite accident) 59. JU iztotit. C,: 1CMESA. Milina. *1976 (Translation by the author) CO. Mc.'dsnn. M. S_ VVcsiir.g. A. H.. Constable. J. D.: Background material relevant to presentations at , the N 70 ar.n jal meeting of the AAAS. American Association for the Advancement oi Science.! Ier* Svic; Assessment Commission. 92nd Congress. 2nd Session. US Congressional Record. MS. .S5227-S5235 tl972) (TCDD in 'spent orange") J I. Meselson. M. S.. Westing. A. H., Constable. J. D,, Cook. R. E.: Preliminary report of Herbicide As- setfmeni Commiiiion of the Americin Association for the Advancement of Science. USA Con- crcisional Record. Proccedinps and debates of the 92nd Congress. Second Session. 118. part 6. pp. .?f06--SSI5 (March 2--9. 1972 (TCDD in "apenl orange") 2. Meselson. M.. O'Keefe. P. \V,, Baughman. R.: The evaluation of possible health hazard* from TCDD Li the environment. In: Presentation for Symposium on the Use of Herbicides in Forestry. Arlington. - Virginia. |v7S (in press. 1980) TCDD in "apenl oranpe" Milnes. M. H.: Formation of 2.3.7.8-lctrachlorodibcnzodioxin by thermal decomposin'! of Milium 2.-..<*trichlorophenaie. Nature 232. 395--396 (1971) .Mivra. H.. Omen. A-Shfbuc. M.: The effect of chlorophenols on the excretion of porphyrin*. in urine. Jpn. J. lr.d. Health 16. 575-577 (1974) -5- N'acei. K,: Document *-iih questions from K. NageL A in Provinciate Staten van Noord Holland, dated Haarlem. II. 1. 1972 -tfa.'Ncirrick. T. J- LamparstL L. I_Stehl. R. H.: Synthesis and identification of the 22 Tctrachloro- 'dibe.iao-p-dioetn isomers by high performance liquid chromatography and gas chromatography. *" .Analytical Chemistry S t. 2273--2281 (19791 Ncuher.'2T2 fGivsudan): Letter to Prof. Bo Holmstedt. Dept, of Toxicology. Karolinska Inst... .Stockhoim. from Dr. Ncuner. Civaudan Fcrschungsgcsdltchaft AG. regarding dctcrminaiKui ttf 2.5.7.S-teirichloro-dibe:uo-p-dioxin (TCDD). State of the an at Givaudan Research hy July. 1976 iLeitcr dated IS. 7. 19761 - 7. Pazderova.J- Lukas. _ Nemcov*. M_ Spacilova. M-Jirasck. L- Kalensky. J-John. J- Jarasck. A_ * Piekov*. J.: Chrome poisoning by chlorinated hydrocarbons formed in the production of 2.4.5* trichioropbenoxyactute. Prac. Lek. 26, 332--339 ((9741 -'S; 'Poland. A. P_ Smith. D_ Metier. G_ Fossick. P.: A health survey of workers in a 2.4-D and 2,4J-T / pl*m.*Arch- Environ. Health 22, 316--327 (1971) ^-.R appe. C-: Decontamination of produas formed during the industrial preparation ok2.4_S-iri _ >chWoph<nitL Proceedings of Workshop on TCDD. Milano. Pvbt-AncharofT. Specimen Publications -Inc.. Hotli^oodLlNrV:"H423--{kP~7) ----- - --- - - - - ----------------- TO. Rappc. C.: Introduction. Proceedings of Workshop on TCDD. MSano. PubL AncharoffSpcarum PuKications Inc, Honisnood. N.Y., 11423 (1977) 5L Reggiani. G.: Toxic effects ofTCDD in man. Presented by Dr. G. Reggiani at the NATO-Workshop *w Ecotoxicology. Guildford. England (July--August. 1977) Reggiani. G.: Lcner to Prof. Bo HoimaedL DcpcofToxicoloty. Ksroiinsfca Inst-Siockltolm. 21.2. 1 ivTT 5-V- Reggiani. G.: Letter to Prof. Bo Holmslcdt. Dept. ofToucotogy, Karolinska Inst- Suv:kholm. 3. J 0. -.1577* S.'Reggiani. G.: The estimation of the TCDD toxic potential in the Eght of the S o t ' accident. Paper - ' presented at the 20th Congress of the European Society of Toxicology. Berlin (West). 25.-28. 6. J. I9'PI 55. Reggiani. G.: Letter to Prof. Bo Holmstedt. Dept. ofToxicoloty. Karolinska Inst- Stockholm. 6. 3. . : (97B .Sa/idermann. \V_ Stockmann. H_ Casten. R.: Pyrohrsu of pentachlorophcnoL Cheni. tier. 90. ` 690-692 (19571 ** *7, Sandcrmanr.. W.: Letter to Prof. Bo Holmstedt. DepcofToxicoloty. Karolinska Inst- Susckholm. V. . L2. l g70 tPersona) information about the first synthesis of TCDD) 58. Sehw'ctx. B. A. et al.: Toxicology of chlorinated dibenxodioxins. Environ. Heahh Perspect. (Exp. Is... tuci J. 67 <1973) 5". Suikind. R. R.: A m ie*- of occupational exposures to dibenzo-p-dioxins. Procm.-ufon to a Con- -..ercr.cc on dihcnzodicvin*. dihenzofuran. 18. II. 1976. Rougcmont. NC. 1976 - 230 B. Holmsicdt t*0. Teiceina. K. A,, Bikbulatova, L. 1.: Affliction of the follicular apparatus of the skin in workrri ccupied in ilie pmduciion of butyl ether of 2.4.5-trichlt'ruphcmuyacciic aciJ. W>in. Perm.Ut*l. Vcncrol. 44. 35-39 (1970) 61. Tbiess. A. M_ Goldmann. P.: Follow-up-Repon ber das Trichlorophcnol-Dioxin-Unfallceicheheft in der BASF AG vom 15. November 1955. lv lh Medichem Congress. Haifa. September 1976 (Follow-up study of exposure in 1953) 62. Tbiess, A. M.. Frentad-Bcymc. R.: Monality study of persons exposed to dioxin after an accident which occurred in the BASF on 13.11. 1953. Vih International Medichem Congress. San Francisco. 5th to 9th September 1977 (Fo!k'-up study of workers exposed in 1953) 63. Vahrenhrtlu F.: Sevcso -- eine beispiellose Umwcltkaiastrophe? Umweh 1. 59. 60. 62. W .. (1977) 64. WaldovoceL G,, (-Pres. ofGtviudan): Letter to M. UfTiciale Sanitario di Seveso e di Meda. ICMF.SA Spa. Via Privata ICMESA. Meda. Milano, dated 23. 7. 1976 65. Wiilsft. J.: Sevcso: The questions persist where.dmsin created a wasteland. Science 197. IOM- ItViT (1977) 66. Vtts. J. G - Moore. J. ATMZinltl. J. G.: EiTccu of 2.3.7.8-ictrachkvodibenjo*p-dioxin on the immune system of laboratory animals. Environ. Health Perxpect. (Exp. Issue) 5. M9--162 ( l u73) 67. Young. A. L_ CalcagnL i. A.. Thatken. C. E_ Tremblay. J. W.; The toxicology, environmental fate. and human risk of herbicide orange and its associated dioxin. Report OEHL TR*78-92. USAF Occupational and Environmental Health Laboratory. Aerospace Medical Division (AFSCL Brooks Air Force Base. Texas 782 35 (197?) (Criiicafrepon of many previous episodes particularly with regard to "agent orange")_____ _4 6S. Zack.J. A.Susktnd. R. R.: The mortality experfetce of workers exposed to tctrachlorodihcfirodKnin in a trichlorophcnol process accidcnL J. Occup. Med. (in press. 1980) 69. Zelikov. A. Kh- Danilov. L N.: Occupational dermatoses (aches) in workers engaged in production of 2.4J-trichlorophcnol. Sov. Med. 7. 145-146 (1974) Received January 14. I960