Document X7Ov9K1j11ZgdYGzM8w7anvZB

RECENT RESULTS OF CARCINOGENICITY BIOASSAYS OF FIBRES AND OTHER Table 1. Test n PARTICULATE MATERIALS C. Maltoni & F. Minardi Institute of Oncology, Bologna, Italy Different types ot chrysotile (Canad anthophyllitefUK crystalline silica. . zeolites (13 miner;) types). Summary. Different types of natural, commercial and modified asbestos fibres were tested in a highly standardized manner by peritoneal injection into rats and mice in order to assess their carcinogenicity. Differences in mesotheliomatogenic effect were found between the various materials tested. Of particular interest is the finding that treatment of the fibres with phosphorus oxychloride and heating to 300C markedly reduces the carcinogenicity of chrysotile fibres. Introduction A systematic and integrated study involving long-term experimental bioassays on particulate materials was started in January 1981 at the Bologna Institute of Oncology and is still in progress. The study covers a variety of fibrous and non-fibrous, natural and man-made materials, present in the occupational and/or general environment. Some of the materials studied are of major industrial importance. Groups of 40-100 modified chrysotii rats and 900 mice lntraperitoneal(i.: (for most of the n detergent 4A zeol The animals are ki years from the b histopathologica! The study is aimed at: A summar -- identifying new potentially carcinogenic materials; Table 2. I -- assessing, in quantitative terms, the level of carcinogenic risk of a given In this pap } material, and comparing the risks represented by different materials (assess of natural, cor ment of the relative carcinogenic risk); (i.pe.) injectio -- helping to predict the target organs; The modif -- defining the role in carcinogenesis of the physical and chemical characteristics and from diffe of.the test compounds. This type of t -- determining the role of different biological and experimental factors affecting which might r the neoplastic response and, consequently, shedding some light on the In rats, th pathogenesis of the possible oncogenic effects; mesothelioma -- helping to reconstruct the natural history of the tumours which may be erionite (Tabl induced by the test compounds. The comp Information on test materials and animals and the experimental procedures is given in Table 1. In view of the aims of the study, the experimental conditions are strictly standardized. materials stuc some forms o; and mice, at examination. --46- plainTIFF'S EXHIBIT SA-544 JICITY IER .bestos fibres into rats and i the various of the fibres reduces the ntal bioassays on itute of Oncology t-fibrous, natural ral environment. c risk of a given materials (assess- ;al characteristics 1 factors affecting me light on the s which mav be tal procedures is al conditions are r * Carcinogenicity bioassavs offibres f 47 Table 1. Test materials, animals, method of treatment and experimental procedure Test materials Different types of natural, modified natural and man-made materials including: crocidolite (UICC), chrysotile (Canada, UICC), chrysotile (Rhodesia, UICC), chrysotile (California), amosite (UICC), anthophyllite (U ICC), commercial chrysotiles (3 samples), modified chrysotiles (4 types), asbestos-cement, crystalline silica, amorphous silica, alumina, wollastonite, talc (2 samples), kaolin, bentonite, natural zeolites (13 minerals), man-made zeolites (20 types), rock wool (4 samples), carbon fibres, synthetic fibres (2 types). Test animals Groups of 40-100 (20-50 males and 20-50 females), 6-8-week-old Sprague-Dawley rats. For erionite and modified chrysotiles, also groups of 40 (20 malessand 20 females) 8-week-old Swiss mice. A total of 10 760 rats and 900 mice ha%'e been tested. [ Method of treatment Intraperitoneal (i.pe.) (for all materials apart from carbon fibres), intrapleural (i.pl.) and subcutaneous (s.c.) (for most of the materials) injection, and ingestion (gavage) and intratracheal instillation (in the case of detergent 4A zeolite). \ Experimental procedure The animals are kept under observation (body weight and clinical controls) until they die naturally or until 2 years from the beginning of the experiments. All animals undergo complete autopsy and systematic histopathologica! examination. A summary of the experimental work so far completed or in progress is given in Table 2. ' In this paper the most recent results are presented of the bioassays of several types of natural, commercial and modified a|bestos, administered as a single intraperitoneal (i.pe.) injection, to rats and, in a few instances, to mice. The modified asbestos consisted of Canadian chrysotile of different fibre lengths and from different sources, treated with phosphorus oxychloride and heated at 300C. This type of treatment was used in order to bring about physicochemical changes which might reduce the carcinogenicity of the natural material. In rats, the peritoneum proved to be more responsive than the pleura to the mesotheiiomatogenic effect of asbestos; this is the opposite of what is observed with erionite (Table 3). ; The complete final results of the basic experiments on the effects of the asbestos materials studied in rats at a single dose of 25 mg, are available. Data on the effects of some forms of modified asbestos, as single administered doses of 10,5 or 1 mg, to rats and mice, and of 25 mg to mice, are preliminary and based solely on gross examination, since the experiments were started only 76 weeks ago. 48 Mahoni & Minardi Table 2. Summary of experimental work so far completed or in progress Materials Crocidolite (UICC) Chrysotile (Canada, UICC) Chrysotile (Rhodesia, UICC) Chrysotile (California) Amosite (UICC) Anthophyllite (UICC) Commercial chrysotiles (3 types)2 Modified chrysotiles (4 types)2 Asbestos-cement Crystalline silica Amorphous silica Alumina Wollastonitc Talc (2 samples) kaolin Bentonite Natural zeolites (13 minerals) Man-made A zeolites (2 types) Man-made X zeolite Man-made Z zeolite (17 types) Rock wool (4 samples) Carbon fibres^ Synthetic fibres (2 types) Water (controls) ' Injection i.pe. 4+ + + + + + + + + + + +* + + + + + + + + i.pl. + + + + + + + + + + + + + + + + s.c. + + + + + + + + + + + + + + + + Ingestion and intratracheal instillation + "Experiments still in progress ^Implantation. Table 3. Final results of tests on crocidolite, chrysotile (Canada) and sedimentary erionite" Material Peritoneal mesotheliomas . Tumour-bearing Average latency animals time (weeks) No. % Crocidolite _ Chrysotile (Canada) Sedimentary erionite Water (controls) 39 32 20 0 97.5 59.5 80.0 92.2 50.0 106.1 " Pleural mesotheliomas Tumour-bearing animals Average latency time (weeks) No. % 18 45.0 104.8 26 65.0 111.1 35 87.5 64.2 0- - "Sprague-Dawlcv rats (20 males and 20 females) were given a single intraperitoneal and intrapleural injection of the material (25 mg in I ml of water) and kept under observation for their full lifespan. Materials aru The asbesto York, USA) (n; (asbestos-cemei were injected ini mice. Groups o material and do The animals and examined f> m Inexperimer, full lifespan. In weeks, at which BT 2112 (Table Table 4. 1 asbestos-c Material Crocidolitc Chrysotile (< Chrysotilc (' Chrysotile (< Amosite (l"t Anthophylli Asbestos-ceWater (con; 2Sprague-I of the mate A complete sacrificed. A h: injection), bra. gonads, meseir organs and tise The strictly tative compart different expe: irogress Ingestion and intratracheal instillation + ) and sedimentary -liomas Average latency time (weeks) 104.8 111.I 64.2 meal and intrapleural aeir full lifespan. Carcinogenicity bioassays offibres 49 Materials and methods The asbestos materials, obtained from Mount Sinai School of Medicine (New York, USA) (natural asbestos), Associazione Cemento-Amianto (Balangero, Italy) (asbestos-cement) and CERAM-SNA (Canada) (commercial and modified asbestos), were injected into the peritoneal cavity of 8-week-old Sprague-Dawley rats and Swiss mice. Groups of 40 animals (20 males and 20 females) were used for each species, material and dose level. The animals were examined 3 times daily for general behaviour and were weighed and examined for gross changes every 2 weeks. m In experiment BT 2101 (Table 4), the animals were kept under observation for their full lifespan. In experiment BT 2106 (Table 5), the animals were kept for up to 104 weeks, at which time the survivors were sacrificed. Experiments BT 2111 (Table 6) and BT 2112 (Table 7) will also be terminated at 104 weeks. Table 4. Final results of tests on various types of natural asbestos and asbestos-cement (experiment BT 2101)a Material Crocidolite (UICC) Chrysotile (Canada, UICC) Chrysotile (Rhodesia, UICC) Chrysotile (California) Amosite (UICC) Anthophyllite (UICC) Asbestos-cement Water (controls) Peritoneal mesotheliomas Tumour-bearing animals Average latency time (weeks) No. % 39 97.5 59.5 32 80.0 92.2 33 82.5 89.7 29 72.5 85.3 36 90.0 66.7 35 82.5 73.3 21 52.5 99.7 0 flSprague-Dawley rats (20 males and 20 females) were given a single intraperitoneal injection of the material (25 mg in 1 mg of water) and kept under observation for their full lifespan. A complete autopsy is performed on all animals, whether dying naturally or sacrificed. A histopathological examination is carried out on the peritoneum (site of injection), brain, thymus, lungs, liver, spleen, kidneys, adrenals, stomach, uterus, gonads, mesenteric, mediastinal and subcutaneous lymph-nodes, and all pathological organs and tissues. The strictly standardized experimental conditions and procedures allow quanti tative comparisons between different groups in the same experiment and between different experiments. 50 Maltoni & Minardi Table 5. Final results of tests on various types of chrysotile and other non-asbestos fibres (experiment BT 2106) Material Code Type Treatment Chr 1 Chr 2 Chr 3 Chr 4 Chr 5 Chr 6 Chr 7 Chr 8 9 10 11 Paperbestos 5 - 100 M + 200 M* Paperbestos 5 - 100 M + 200 M* POClj + 300C Paperbestos 5 - 100 M + 200 M from asbestos-latex paper* Paperbestos 5 - 100 M + 200 M from asbestos-latex paper* POCI3 + 300C Short chrysotile 7 -- (by water fractionation of Paperbestos 5)* Short chrysotile 7 POClj + 300C (by water fractionation of Paperbestos 5)* Chrysotile (Canada, UICC) - Chrysotile (Canada, UICC) Rock-wool fibres POClj + 300C Kevlar fibres - Water (controls) - Peritoneal mesotheliomas Tumour-bearing animals No. % Average latency time (weeks) 33 82.5 78.3 17 42.5 88.6 17 42.5 87.5 15 37.5 94.7 29 72.5 76.4 3 7.5 97.6 30 75.0 76.1 20 50.0 90.0 3 7.5 79.8 0- - 0- - "Sprague-Dawley rats (20 males and 20 females) were given a single intraperitoneal injection of one material (25 mg in I ml of water) and kept under observation for 104 weeks. ^Supplied by IRDA. Table 6. Gross ft non-asbestos fib Material Code Type Chr 5 Short chr (by water of Papcrh Chr 6 Chr 7 Short cht (by water of Papcrh Chrysotile (Canada, Chr 8 Chrysotili (Canada. 9 Fiberfrax 10 Kevlar fil 11 Water (c< <ISprague-Dawley r.: (in 1 ml of water) a^Supplied by IRDA The bioassa performed in si. when the bioloj' ther non-asbestos iomas Average latency time ___ (weeks) 78.3 88.6 87.5 94.7 76.4 97.6 76.1 90.0 79.8 -------------------------- ,'ection of one material Carcinogenicity bioassays offibres 51 Table g. Gross findings after 76 weeks in tests on various types of chrysotiie and other non-asbestos fibres (experiment BT 2111)a Material Code Type Treatment Dose (mg) Peritoneal mesotheliomas Tumour-bearing animals No. % Average latency time (weeks) Chr 5 Short chrysotiie 7 (by water fractionation of Paperbestos 5)b 10 11 27.5 57.0 5 4 10.0 59.7 10 Chr 6 Chr 7 Short chrysotiie 7 (by water fractionation of Paperbestos 5)* Chrysotiie (Canada, U1CC) POClj + 300 C - Chr 8 Chrysotiie (Canada, UICC) POClj + 300 C 9 Fiberfrax _ 10 Kevlar fibres . 11 Water (controls) - 10 5 1 10 5 1 10 5 1 10 5 1 10 5 1 0 0-0"" 0 ** 14 35.0 61.6 11 27.5 60.3 0- - 3 7.5 61.0 1 2.5 67.0 1 2.5 64.0 5 12.5 65.2 0- - 0- - 0- 00- - '0 - - _ "Sprague-Dawley rats (20 males and 20 females) were given a single intraperitoneal injection ofthe material (in I ml of water) and kept under observation for 104 weeks. ^Supplied by IRDA. The bioassays of experiment BT 2106 (the first on modified asbestos) were performed in such a way that the nature of the materials tested was disclosed only when the biological data had already been obtained. 52 Maltoni & Minardi Table 7. Gross findings after 76 weeks in tests on various types of chrysotile (experiment BT 2112)^ Material Code Type Treatment Dose (mg) Chr 5 Chr 6 Chr 7 Chr 8 11 Short chrysotile 7 (by water fractionation of Paperbestos 5)* Short chrysotile 7 (by water fractionation of Paperbestos 5)b Chrysotile (Canada, UICC) Chrysotile (Canada, UICC) Water (controls) - 25 10 5 1 POClj + 300 C 25 10 5 1 - 25 10 5 1 POClj + 300 C 25 10 5 1 -0 Peritoneal mesotheliomas Tumour-bearing animals No. % Average latency time (weeks) 6 15.0 65.7 3 7.5 64.7 1 2.5 71.0 0 -- 0_ 0 -0 -0" 6 15.0 58.5 5 12.5 61.0 00" 3 7.5 70.0 1 2.5 56.0 0 -0- 0 -- "Swiss mice (20 males and 20 females) were given a single intraperitoneal injection of the material (in 1 ml of water) and kept under observation for 104 weeks. * Supplied by 1RDA. Results The results of the experiments are presented in Tables 4-7. The bioassays of different natural asbestos fibres and of asbestos-cement, at a dose of 25 mg, show that the mesotheliomatogenic effect (evaluated on the basis of the incidence and latency time of tumours) of the materials tested decreases (Table 4) in the order: (1) crocidolite; (2) amosite; (3) anthophyllite; (4) chrysotiles; (5) asbestos-cement. The chemic; markedly reduc `Paperbestos 5'. carcinogenic po `Paperbestos 5' results may be d The reductio Canada chrysoti preliminary inccmaterials are bei Conclusions The data rep may be used as a and, in the presc The findings at clarifying the technological ini for the asbestos i Acknowledge/ The study wa ENV/755/I) an< l'Amiante, Cana. pes of chrysotile 1 mesotheliomas tearing _____ % 15.0 7.5 2.5 * Average latency time (weeks) 65.7 64.7 71.0 - -. ---" 15.0 58.5 12.5 61.0 -" - 7.5 70.0 2.5 56.0 -~- -- I injection of the .-cement, at a dose n the basis of the reases (Table 4) in Carcinogenicity bioassays offibres 53 The chemical and heat treatment of asbestos fibres, tested at a dose of 25 mg, markedly reduces the carcinogenicity of 'short chrysotile 7' and to a lesser extent 'Paperbestos 5', while that of `UICC Canada chrysotile' is reduced still less. The carcinogenic potency of fibres from 'asbestos-latex-paper' is lower than that for `Paperbestos 5' and seems little affected by the chemical and heat treatment. These results may be due to the insulating effect of latex (Table 5). The reduction in carcinogenic potency of `short chrysotile 7' and also of `UICC Canada chrysotile'seems also to be confirmed at the present stage of the study by the preliminary incomplete results of experiments BT 2111 and BT 2112, in which the materials are being tested at various doses on rats and mice (Tables 6 and 7). Conclusions The data reported here seem to indicate that experimental long-term bioassays may be used as a tool for quantifying the carcinogenic potency of particulate materials and, in the present case, specifically of different types of asbestos. The findings presented may provide the basis for further analytical studies aimed at clarifying the possible mechanisms of asbestos carcinogenesis. They are also of technological interest; however, at present, it is difficult to predict their implications for the asbestos industry and, in general, for the manufacture and use of other fibres. Ackno wledgemen ts The study was supported in part by the EEC (Contracts Nos ENV/347/I-(S) and ENV/755/I) and in part by the Institut de Recherche et de Developpement sur l'Amiante, Canada ER ished in 1965 jn within the Vgency are at ularly on the the human ical research tive research Agency also 1 for cancer emination of mplete list is 0 September des Etudes et vool, basaltic -139). Repro- WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER Non-occupational Exposure to Mineral Fibres Edited by J. Bignon, J. Peto and R. Saracci IARC Scientific Publications No. 90 International Agency for Research on Cancer, Lyon, France 1989 Published by the International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France Publication No. EUR 12068 of the Commission of the European Communities, Scientific and Technical Communication Unit, Directorate-General Telecommunications, Information Industries and Innovation, Luxembourg International Agency for Research on Cancer, 1989 ECSC-EEC-EAEC, Brussels-Luxembourg, 1989 Distributed by Oxford University Press, Walton Street, Oxford 0X2 6DP, UK Distributed in the USA by Oxford University Press, New York All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the copyright holder. The authors alone are responsible for the views expressed in the signed articles in this publication. Neither the Commission of the European Communities nor any person acting on behalf of the Commission is responsible for the use which might be made of the following information. ISBN 92 832 1190 1 ISSN 0300-5085 Printed in the United Kingdom , Foreword .... j. INTRODUC . Mineral fibres i /. Bignon II. EXPERIM1 Mineral fibre of fibre type, J.M.G. Do Recent results materials C. Mahon Particulate-stai mechanisms M. C. Jaw Modification activity R.C. Bros- Mechanisms < macrophage rats inhalin. B. T. Mos> & J. Petru Brief inhalatii bronchiolarA.R. Broi Production othe. surface H. Pezera 1 :new .cured. always /ed. Drmally by the bscrip- olesale ilhelmBIEBER d 3 JENA t If I'OStZoitlllC.'S- lior Verlac .Iona, ,(-!{ I . ics Ministei rates ipilisrlli'II lili'i'J- - Verlade- lilt': IJxp. I'atlml. U2. 1U!i I ~v2 11!I871 \'EI! (i"ir-triv l-'ischei- VitIhst .Tfiia `i MJ-ilmnw-ln-' Instituc ftir I'lmveltliydicno an dor I'uiversitat Piissohloif. 13 - 4000 Diisseldorf; -1 Stadtisches kTaiikcnliaits. D-b'-'UH ilildesheim; M fur Expoiiniontolle Pathologic. .trediz/nischo Hoolischule Hannover, 1> - :$(]()() Hannover G1 ('iu-cinotreiiieity .studies on fibres, metal compounds, and some other dusts in rats lty !'. I'nTTli, 1". Zik.m1!. K.-.r. Ki-:ii-'i-njt11. K. IIi tii2i, II. Kttxsr3) and l\ Moiut3) .IrWr--- /or ' Orr> 'pumb ,/ : Prof. Dr. E. Purr, Meilizinischos fnstitnt fur L'mwolthysielU" an der , I'nivei-itac Diisseldorf. Aiif'm lloiinokamp ."ill. I)-4M(I(| Diisseldorf. J'.R.d. ; Kev words: rarcinogeiiiciry: ineral rotnpouuds; dust: mineral fibres: vitreous fibres: plastie fibres; * heavy metals: glass mierofibres: asbestos: attapulgite: eriouite: wollastonite: eadmium: nickel: 4 ferric oxides: corundum: tiranium dioxide: clirysotile; crocidolite; quartz: benzol a (pyrene: polyvinyl- I ehloiidi-: polyvinylpyridine-N-uxiile: wood dust: inhalation experiments: intratracheal instillation: imrapeiitoneal injection ! ; Sa in nmi'ii & About do dusts were examined on their carcinogenicity in rats mainly after intraperi- toneal injection and some after intratracheal instillation. Fn the i.p. test, very low (loses between O.Od and O.d lit" asbestos led to tumour incidences of about 20 to 80%. PolyvinvI- j. pyridino-X-oxide prolonged the tumour latency after injection of aetinolite. 00 mg atta- j. pnlgite from three sources with short fibre lengths were not shown to be carcinogenic but an %. attapulirite sample witli longer fibres had a moderate effect. Relatively thick rock and .Jx ceramic fibres (median - 1 /an) induced tumours, but slag and wollastonite fibres did ffx nut. probably because of their better solubility. Intratracheal instillations of glass micro- V'; fibres (20 O.o mg| led to lung tumours in ."> of 34: rats (0 in control). The carcinogenic :%X- potency of an inorganic fibre depends on its size and persistency, and possibly also on other if. properties, especially oil the surface. .'.'Jr Xickel powder, nickel oxide, nickel subsulfide and cadmium sulfide were all found to .if be carcinogenic in the two tests. Cadmium chloride and eadmium oxide could only be ,\ administered in very low doses because of their high acute toxicity. A high amount of magne- / tited-J Id mg i.tr.i led to an unexpected lung tumour incidence of <>!",,. The i.p. test in rats proved to he very sensitive for detecting the carcinogenic potency of "" non-aeuto toxic natural and man-made mineral dusts as well as metal compounds. This mean- that, if a high dose of one of these dusts does not induce tumours in tins test, no suspi- j cion of carcinogenic poteuev can he substantiated. ! ._ I / i`lI'utiiii'hiitl ' ! When in IP72 73 the fir-t experimental results on the tumour-inducing effect not only of ; a-be-tos but also of other fibrous dusts were published, the results strongly supported the I ..Id .hypothesis that tin- elongated shape of asbestos particles may be the cause of their i i-arcinogiMiicity (Xoiiinnxx litis: Li.xzi:\nr and Wkdi.er 11)4L: Staxtox and Wiuixcit j M'72: I'orr and l-'itilittitscti.-. IU72: W'm.xku et al. Dl73i. Moreover the question was raised i ..f a po--ilde carcinogenic effect of iioii-asbc'tos fibres in humans, especially of man-made { mineral libri-. because their production ha- ri-eit steadily since the fifties. As a consequence. ! pidcMiiolucic -tudic' <iii the iiian-made mineral fibre industry were carried out over the mist (im war-. The iV'iili- were reviewed recently by S.uiAcrt i liNtii and Uui.i. i lP8bi, They -uiipori the !,\ poi !ie-i- i h:>! maii-iuade mineral lihres - a- pre-ent ill the workplace atlim- . I'eilo in | o\ \. .........,n\i - on the iici a'ioii ol Ids i;nth birthday 12il * i -phei..... . early 'las; wool nick wool pntductiun - may have played a rule in tin* cau-auimi <if lum; cancer. I'p in umv. in inhalation experiments -ith very fine man-made mineral fibre.-; (glu--.; microfibres LOO and 104). tin statistically significant tiimnur rates have been defected il.i: HnrFKANT I98ii: (ioi.D.M'Kix 1984: Met oxxeu. et al. L984; Mrnr.ic et al. 198i>: Smith (-t al. I98i): WviiMcn et ;d. 1.0*s4ai. The strong carcinogen. crncidnlite. has similarly pro duced only a Imv inmntir rare in inhalation experiment--. Thorefnre. this rest model caniim lie enn.-idered as -ensitive for carcinogenic fibres. The positive results with ehrysntile were uli-erved after expo.-im* tu hisrher fibre concentration-' (Davis et al. 1978; Davis et al. liisii: Met'nxxKU. et al. 1984: Waoxer et al. 1984 al. Moreover it was demonstrated, that after it period of two years the number of ehrysntile fibres deposited in the rat lnm; can increase more than tenfold by splitting I Bei.i.mvxx etal. i98(i). However, this multiplication cannot happen with crocidnlitc and vitreous fibres. Most carcinogenicity .-todies with mineral fibre-- in laboratory animals were carried out by meaii- of intrapleural or intraperitoneal ad ministration. By these routes of application, a high number of fibres can become active in the serosal tissue which is obviously very susceptible to fibre-related carcinogenic stimu lation. This hitch sensitivity exists also in humans since the relation of him; carcinoma,< to mesotheliomas in asbestos workers amounts on average to about .'I to 1. althmuth after inhalation contact of fibres with the thoracic m- abdominal serosa .should be much more diffi cult than with the bronchial epithelium. The experimental results should lead to a Generally valid definition of carcinogenic libres. This aim is not yet reached. On the one hand there is a general consensus that lemttlt, diameter and bio-persistence represent the most important criteria for the carcinogenic potency of mineral fibres (Stanton etal. 1981: Waoxer 1080; D.vvrs 1 !)80: Purr Ifl87i. On the other hand, the relationship between the degree, of these three characteristics and the expected tumour incidence is not sufficiently known. There is a continuous transition from the non-carcinogenicity of fibres which are too short, too thick, or too soluble to tho maximum possible carcinogenic potency of fibres which have the "ideal51 size and are per sistent enough. However, it is an open question at which point the threshold is located be tween fibres which are too short, too thick or too short-lived in the tissue and fibres which are sufficiently Ions, thin and persistent regarding their carcinogenic potency for humans, l-'urthermore, for regulations, we need not only the distinction between carcinogenic and noil-carcinogenic fibres but also criteria for a grading of carcinogenic potency. For many years there has been the theory that the surface properties of fibres are tho decisive agents for the tumour induction (Bmxox and .I.veraxi) 1983: Bo.xxe.u' etal. 1980a. b: Crai.i.ev U)7I: Crai.i.ev and Lainuart L'JT.'I: Dcnnican 1984: Fisher etal. 1985: Lancer and Xoean 1985: Mo.ss.man L983). This theory is mainly based on the results of in rilrn testing where altered dust surfaces were seen to influence certain cytotoxic effects. But there are significant differences between a cytotoxic reaction in ritrn and tumour induction in rim, often, good parallels were found between results from carcinogenicity tests and some in ritm tests (Davis etal. 19851. Nevertheless, up to now in. ritrn tests have nol been able to provide reliable statements mi fibre carcinogenicity ( Waoxer et al. 19851. ' Recent re-ult-- after combined injection of a-'b.'st o anil tie* anti.-ilic-ific effective sub -lance polyviiiylpyridinc-X-oxide indicate that the surface properties of asbestos fibre- might not only be important for its cytotoxicity in rilrn but also for its carcinogenicity i I'nrr et al. 19X51. Since the carcinogenic potency of fibre- i- eompo-ed of. at h-a.-t. their length, diameter and durability, and a- the -peetrum of fibre dim-m-ioii- in a -ingle -ample i< wide ranging', it i- verv difficult to explain a particular tumour rale u.-ing only one -peeifie parameter. WiUi tln-e difficultie- alway- in mind, we are going to describe a number of result- which mav add -ome piece- to the puzzle. The experiments were carried out over tin* la-t 15 year- and onlv ...... of them have already been published, although not with all the detail- now de-elibed. i:;tl I-:.;.. I'.rhoi. 32 !9"7 ; A further quo-' carcinogenic sub-t genie, nnn-caroim carcinogenicity all additional carcime. because up to now reports on nickel on and 8cii u.i.er In oxide have been k a review of the <q two substances amium is also su--p. cadmium sulfide, induced lung tuum To widen the ha titanium dioxide. I Mnlrrinlr <nul Mi h ]. Laboratory a In most of (lie farm 8. Ivanova.- i 13 Sprague-Dawle the animals were Buntonbaeh. Soldi male rats grow mo(no. 7) male rut.- u- The animals u. proved in the late Wuorden XLi and The weight of average age of tie average age of the i. Substance- i Some of the dn agencies and u-ed mineral wools, were the animal experio by M'dimeiitation. median value- in ' Bki.i.m\xn and IHannover. F. I!.f. 1'uiversilai Dii.--emedizin der Fni\e weltehemie lllld ' were de-eribed bv . 1 rli/nillh . I'.liji. I >r. Sentxv * mei !, I ir. 3ii im.. . le/l /(((/()' . I `It `I It it kouior Boiir. I-.I-' a- mainly de-irbeen u-ed in anoi1 ;r i mil.1 in tin1 *;!u-atinn mineral fibre- i^lavi ' have been defected 'f 1.1. i`t 111. I ilSli; ,s\[| |-|[ ii<`. Inis simifarlv jn-.,hi- test model <*;inji >i wiili chrv-oiilc were :il. I!I7S: Divis et ;il. at demonstrated. 1 liar <1 in tlia rat Inn" can 'Vr. this miilti|)licatiiui 1 v 'todies with mineral I ur intraperitonral ad>- can become active in i'll carcinogenic -rimiti "f Inn" carcinoma,- fu i tu I, although after thl he much niirre diffi- mitiun of carcinogenic ! consensus that, length, m for tlin carcinogenic wrs ISIHH: Butt HI87|. tree characteristics and a continuous transition it. or too soluble to the `deal" size and art* perilircshold is located he- ti--tte and fibres which ic potency for humans. I ween carcinogenic and > potency. pertii's of fibres are the I in'll: BoN'XK.vr etal. \s 1084; Fisiikr etal. nlv based on the results "i tain cytotoxic effects. II m rifr/j and tumour 1- from carcinogenicity |i 10 now in film test' aenicity ( W.viixr.K et al. i-ilientie effective <llh........... . ashestos fibre' for its carcinogenicity ". !heir length. dianieter -ample is wide ranging, -peciiic parameter. Willi "l rc'ult- which may ter llie ht't !."> year' "t with all the detail- A further ipiestion emieerns the relation of the carcinogenic effect of fibres to chemically careinoirenie >tt I is tat ices in the applied test systems. For comparison, a number of carcino genic, linn-carcinogenic and questionable carcinogenic substattees were tested on their carcinogenicity after intraperitoneal injection and intratracheal instillation. In this context, additional carcinogenicity studies with smite nickel anti eadmium eompmmds are desirable beeanse up to now there is tm consensus on their carcinogenic potential. Of course., numerous reports 011 nickel carcinogenesis have lieen published in various reviews! f.VRC IlJ7(i; Raitiii:i, and Sett u.t.f.R Mini: Sr\in:i(.\r\x LltSl; SrxnutiM\\ l`if>4). Nickel powder and nickel oxide have lieen known to lie chemical carcinogens for a Ions time. But recently, following a review of the epidemiologic and experimental results, it was proposed to classify these two substances as non-eareinogenie for humans and animals (I.oxustai-t etal. IUS4i. Cad mium is also suspected to be carcinogenic in the relevant compounds eadmium oxide and cadmium sulfide, since inhalation of relatively low ruuccutrutinns of eadmium chloride induced him; tumours in rats (Taki:x\ka et al. Mis.'li. To widen the basis of comparison, further dusts were included in the study e.g. corundum, titanium dioxide, ferric oxides, polyvinylchloride, and wood dust. Mulri'iiiU mul Mfthhil< 1. Laboratory animals and animal keeping In most of the experiments female Wisfar rats (Wistar-WT KiBleggj from the breeding farm S. Ivanovas (ICiBlegg, Alliriitt. F.B.t;.i were used and only in experiments no. It) and 12 Spraguo-Da-wlev SIV of) rats from the same breeding farm. Before each experiment the animals were randomly allocated to plastic cages on wood granule bedding ("T-grol)", Biintenbaeli. Solingcn. F. R.G.I. and numbered mostly 8 10 to a cage tit. the start. As male rats "row much bigger than female rats and need more, space, in only one experiment (no. 7) male rats were also used. The animals were maintained tinder emiveutiimal conditions and these could he im proved in the late 70ies. A standard pelleted laboratory diet (BM1I-TM. Fa. Hope-Farms Wnerden. NL| and water were given nil Ubilum. The weight of the animals was determined before the start of the experiment and the average age of the groups was calculated according to tables of the breeding farm. The average age of the animals is given for each experiment in the tables of results. 2. Substances used Some of the dusts or chemicals administered were bought from manufacturers or their agencies and used in the condition delivered. -Watty materials, especially the man-made mineral wools, were delivered front manufacturers or agencies or other person.' and prepared for the animal experiments by cutting and milling. Sometimes the milled dust was fractionated hv 'cdimentatioii. Thi- work and the measurement of the fibre -izes t mentioned onlv as median values in tallies I and .'li was performed in several laboratories, espceiallv by l>r. IIKt.i.Max.\ and Mr. Mrm.i-: t Fraunhofer Institut fiir Toxikologie mid Aerosoll'orseliung. Hannover. I\ K.tl.i. Mr. I`"nti;m,.tnts 1 .Medizinisches Institut fiir I'mwcltlivgiene an dcr I'nivor.-itat Miisseldorf. F.li.tl.i. Mr. Biiina.'fKiti.Kn iln-rititt fiir Arbeit'- mid Suzialineilizin der I'niveisitat (iicl.len. F. B.H.i. and Mr. Sitrxy (l-'ramiliufer Institut fiir I'mweltelieniie mid (lktoxiko|ogie. Selitnalleiiberg-i Jraf-'chaft. K.R.H.i. The Nt'C samplewere de.-i-rilied by Rt:.\n w.t. 11!t7(li and Ti.miiri:!.i. i I !i7d 1. A'-tifitilr. r.lt.C. Origin; A dialia- quarry near Selimallenherg. F. R.H. 1`reparatioii; Mr. Scrux v > method -cc Sern.w et al. I'.|7'.|ai. .Mea-iinmiein `if fibre -izes; Mr. Bki.i.m 1 if. Menu.. A'tinnl'l-. fni'uini,,, 1. Origin .lukiiowir. a -mall rock wu~ -oitaim-d from the .Mini-nilien,<mitor i> 1111 it. K.li.ti. I'reparation: Mr. l-'i:i:,j>j;i< it-. The nincr<.'iopiea)!y fibroii- -tnu-tiir" wa- mainly dc-tro\.d hv milling in mi agate hall mill. A part ..1 thi- -ample had aireadv ..... . tt-ed in another experiment il'urr et al. i!<7ii . ;r Kxn. I'athol. ;|g. pis;,|;;| Aitlltiiiilnjllilr. / !('<'. -- Origin: Finland. AHniiul<jH<\ Om-.-re--. - Origin: Torrejon de Kubio Cacercs, Spain. Preparation of a verv line fraction (reference Xu. 821) by JI. PjIzkrat (Universite P. of M. Curie, Paris, Franco). Mea-uremeni of I'ibn* -izes: KiimaspitRaicR ot al. (I!)87i. AiUijiiibjitr. Cfdrtiia. -- Origin: Georgia. U.S.A. Delivered under the name "Pharmasnrb colloidal" from riicniic-.Minoralien KG, Bremen. F.R.G.. and a product, of Engelhard Mine ral.-Cliemicah Corporation. Edison. X. J.. U.S.A. Measurement of fibre sizes: Kcidri.slociu.KK ct al. ( 19871. Altmiuhjdc, r.i'hfija. -- Origin: Lebrija, Spain. Delivered with the label "Pulvo fabrica" from Tolsa S.A.. Madrid. Spain. According to the analysis of ROmasiMCRciCR ct al. (198?) the .-ample was identified as attapulgite with hiirh probability. It was used in the condition obtained. Measurement of fibre sizes: Kui>i-:r.si>i-:u<;i:R et al. (L987). J/m//uh//7o. .1fnrwnirun. ~ Origin: Mormoiron. h'rance. The sample used was the drug "ga-tropulgite" which contains 88attapulgite and is produced by Beaufour, Dretix, Franc". The fibre sizes measured came from a sample ``Gastropulgite 50"' which is produced under licence of Beaufour by Sehwabe. Karlsruhe, F.R.U. Measurement of fibre sizes: RoinascKKOKit et al. (1987). Ilmnll mud. - Producer: Griinzwcig Hartmann und Glasfaser AG. I.tulwigshafcn. F.R.G. Preparation: Dr. Sentvv (method see Spcuvv et al. 1979bi. Measurement of fibre Mzes: Dr. Bki.i.m\nx.Dr. Mrui.i:. I!en:<i('tjp!iei'ii<`. - Delivered from Fluka AG. Xou-LTin, F.R.G. Code-Xo. 12780. Purity 97".,. Itruritr, MylOHj,. - This mineral is the granular form of magnesium hydroxide (fibrous form: see nemalitei. Preparation: Dr. Fniuimtcits (Friwirichs 1974). ('ndiniuin rldnridi' fiiK'l.,.- If2()). -- Delivered from Merck, Darmstadt, F.R.G. Purity 99"u. ('adhiivin. ((.rid?. -- Delivered from Merck, Darmstadt, F.R.G. Purity not indicated. ('(idlin'aw. aulfidc. - Delivered from Aldrieh-t'hemic GmblL<Co. KG. Bteinheim, F.R.G. Purity 99.999",,. ('a'dinic iriiid. F!ln`rfriij\ -- Producer: Carborundum. Diisseldorf. F.R.G. Delivered from Ifocker Werke GmbH <$: t.'o. KG. Weil, F.R.G. Preparation: Dr. Spcrvy(method see Smt.vv et al. 1979bi. Measurement of fibre sizes: Dr. But.t.M.tx.y Dr. Muuu:. Crfiimh- mud. .l/.l.V. - Producer: Manville Corporation. Denver Co.. U.S.A. Delivered from Dossier. Hamblin:. F.R.G. Preparation: Dr. Smt.vv. Measurement of fibre sizes: Dr. Bi:u,Mtv.v Dr. Mrui.i-.. ('In iixidilc. Ciilidrin. Origin: California. U.S.A. The material was prepared for the produc tion of asbestos paper. The sample u.-ed was obtained from Dr. Routine. Asbest-lnstitut, Xeul.i. F.R.G. Measurement of fibre sizes: Mrui.i-: et al. 1980. r/mg.-o/i/c. I'li'i' A. - Origin: Zimbabwe (formerly Rhodesiai. Measurement of fibre sizes: Fitinnnji u- 11978). (7(,osii/<7". rirr .1. IlCI-h.ulal. The standard .-ample wa- boiled in J X IIC1 Cor 8 h. The magnesium content probably wa- leached alnio.-r completely. The Ins.- of weight amoiint- ,,,[ tu The fibre- were shortened and partially .-plit up. f'/o-o-oM". I'lrr .1. mHli'il. The standard .-ample wa-' dry milled in an agate ball mill for 4h. Mea-uremeiit of fibre size-: FniKnnicu.- (|97Ri. A part of this .-ample wa> used in larger do-T- in other experiments t Pur r et al. 1972, I970i. I'li'i' II. - origin: Canada. Measurement of particle ~izo~; TiMiiniti.t. (Ift701. i It lias to lie umlerlined Dial tin- iv-ult- of men-urcincut of I lie t wi-ted ehry-otile fibre.- are rather doubtful. Exteii-ivo treatment uitli ultra-ound homogenize- the .-u-pioisjun and change- the fibre number by -plitting o| Die bundle-. t '/o-usi.to'e. rirr uiillid. The -inndurd .-ample wa- dry milled in an agate ball mill tor h. Mea-oreim-nt .! fibre -iz"-: Dr. Bkii.mwv Dr. Mrui.i:. 182 Kvp. I`;iT. eg K'-T 0 ('ornndum. - Ti werke. Offenbac* Cl'nridoliti`. Sniil greater). Prepar.sizes: Mrui.i-: et .- EriomU'. (Iri'ijnn. Medical Researci of the material u sizes: Dr. Riim.i Ei'iiiiuti'. I urL'i 'i from Dr. Baiii.-. fibre sizes: Dr. I! \-Fi`ri`(c iij'idr lull of rapes. Kstima of I: .`>0.(100. y-Fi'lvic ij.i'iih' hi, Measurement of y-Ferrit' o.i'idi' l< Estimation of tie (Hiiss film's. tin. sample was sup Penartli. Wale(Wao.vkr et al. (Units fillres. F< &. Voss, 11 n in bit mill for 20 min as 100. Pen men (Hass flbri's. Ini in 1974 (no fun emission by E. I At.VVN etill. I9R< Corporation bo scissors the w(charge 21 and were also used (Hass fI'brt's. 11' ed in 20 ml I. lure. After |u (pore diamete! ease, the re-id and the parti" meiit with IP 1.7 and 0.8 .. urement of lib (lllISS I! Ill'I'S. I` from Lehimn for :'.0 min. M- (!lass fill/',,*. with 1.4 X I'1 t The re-i-ta:tiolied ail"'. <- nitration of a verv rit*. Paris, I-'ram-f t. .aim' "Pharmasorb if Kngelhard Miimuv 'i/,os: Kiimas- I ''Pnh'o fabriea" iti.itR ct al. CP's"i '4 in tlic condition 1'i`d was rlto drug Pmaufour, Dreux. ` which is produced 'nt of fibre size-: \<i. Ludwigehafou. i' it re me n t of fibre -Xo. 12780. Purity hydroxide (fibnni-' V. I!.(I. Purity W.,. t indicated. . Sti'inlii'itn, l-Ml.tf. `.ti. Di'livi'iTii from nii'tliod see .SiTHN y S.A. I lelivercd from 'ire .-iz.es: I )r. I'oil for tin; produet\. Asbest-Iu.-iitut. .i-urement <>f fibre :!i I X 11( I lor y It. - <>f wiirlit amount - . an agate liall mill <- -amp|o wa.~ u-.-o A'Ttti. i It li:i- t'. o.a'-' ratlu-r dotiltllul. i i haiigc- t In' Ii<11* !; attain liall loT Ciifiniihiiii. Tim alitiniiiium oxide dust was delivered from Maschinen- nnd Selileifmittelwerke. Offenbach. K. K.ti. I'fw-iihiUU'. Smilli Afric". origin: South Afrii-a (like CICC cmeidnlite but fibre lengths <rre;tteri. Preparation: l)r. Itiixn\i.i,, .lohanne-hurg. South Afrii-a. Measurement of fibre -ize-: .Mnti.K ct al. IDSii. Frimule. brci/o/t. Origin: Oregon. I'.S.A. Tim du.-t .-ample was supplied by Dr. Wai.xkr, Medical Ke.-ettreli < oitueil Pneumocoiiio-is I nit. I'enartb. Wales. C. K.. as representative of the material used by him itt hi- experiment-' < Wii.wku et al. |i85i. .Measurement of fibre -izes: Dr. Kfi(n:i..--I'lvit< mihVoi/nYc. Tmi,i'ii. Origin: Karain. Turkey. A small rock of the fibrous material was sent from Dr. Haris. Ankara to Dr. Sitrxy and prepared by Dr. Smixv. Measurement of fibre sizes; Dr. Bki.i.m\.xx Dr. Mrirt.i:. x-Fn'iir oxide lt//dr/ili'. - The extremely short fibrous material was obtained from a producer of tapes. estimation of the fibre -izcs according to tt microphotograph with a magnification of IDUO. y-Fi'n-ir u.riili> hi/ilniti f I). - The fibrous material was obtained from a producer of tapes. Measurement of fibre sizes; Dr. Mrtn.i-:. y-Ferr'u; oxide lii/druti' (i). -- The fibrous material was obtained from a producer of tapes, estimation of the fibre, sizes according to a microphotograph with a magnification of 1:50,01)0. dn** fibre*. 100 Fen. - Producer: Manville Corporation. Denver, Co., I'.S.A. The dust sample was supplied by Mr. Skidmore, Medical Research Council Pneumoconiosis I'nit, I'enarth. Whiles. C. K., as representative of the material used in his animal experiments ( Warner ct al. 1084a). Measurement of fibre sizes; Dr. Set'RXv. (1laits fibre*. IOO.L&W - Producer: Manville Corporation. Delivered from Lehmann et Voss. Hamburg, I--.K.(l. After cutting with scissors, the fibres were ground in a knife mill for 20 min. It is not known whether this sample has the same chemical composition as 100 Pen mentioned above. Measurement of fibre sizes: Dr. rfpfRXY. da** filin's, 104'1074. Producer: Manville Corporation. Delivered from Lehmann A" Voss in 1074 (no further data). The chemical composition was analyzed with proton induced X-ray emission by IT Bomhici.k \ und Dr. P.-W. Richter, I'niversity of Marburg(published in Beu.maxn etal. ISlSiii: this analysis yielded about the. same composition as reported bv Manville Corporation for the glass fibre Tcmpstrau B' Class electrical Alkalifree. After cutting with -cissors the wool was ground in distilled water in an agate mill for I h (charge I) or 2 h (charge 2l and then dried ai 80 C. Measurement of fibre sizes: Dr. Spcrxy. These samples were also used in other experiments (Pott et al. 15)80. L5)84a. L!)84b). (Ross fibre*. 104 107/, lJl'l- or XnO If-treated. --- 500 mg of the fibres (see above) were incubat ed in 20 ml 1.4 X MCI or 1.4 X XaOII for 2 or 24 h in a magnetic stirrer at room tempera ture. After 10 min centrifuging at 1.200 -,g they were filtered through Xucleopore filters ipore diameter 0.1 /tmi. The sediment was washed twice with 20 ml distilled water in each case, the residue filtered and the fibres dried at 80C for Idli. The centrifuged particles ami the panicles on the filter were then weighed. The loss in weight 2 and 24 h after treat ment with 11 Cl amounted to 25 and .'id",, respectively, after treatment with XaOII to 1.7 and 0.8"n. and after treatment with di-tilled water to !.7",, i Pott et al. 15)84ai. Meas urement of fibre sizes: Dr. Sitrxy. Chi** fibre*. 104 47b. - Producer: Manville Corporation. Type: Tempstran 475. Delivered Irnm Lehmann A Vo-s. After miring with -oi--ors. the wool was ground in a knife mill for 7>(l min. Measurement of fibre -ize--: Mrui.i: et al. P.mi. (llti.-< fibre*. IO1 47o. 11li-livuled. -- The libres mentioned before were treated fur 24 h with 1.4 X IIC1 a.- described for gla-,- fibre- Pi4 P'74. Tim los- in weight amounted to 0.5- ... The ro-i-ianee of Tenm-i ran 475 i- much larger I linn that of the glass fibre:- 104 15>74 meut ioimd above i. Bxp. Pathol. 32 (l!l>-71 5 Lid dins filin'.-'. I tui, Producer: Mauville Corporation. Delivered I'nmi Schleicher mid Sell fill. Dus-cl. Preparation and measurement of lilire sizes: Dr. Friedrichs. The material wa- al-o u-!({ fur other -rudies ( Pott and Friedrichs IH72: Pott et al. liiTtti. Chi-- HS-- The (endlessI textile fihre wa.- delivered from Gewetex. Diisseldurf, F.R.G. Preparation and measurement of fihre -ize.-: Dr. Friedrichs. The variation in fibre diameter-- was in a limited range: I0",, II.II ion. W)"., < 4.2/tm. Length: (i//m. !KI",, < 7)0//m i l-'iii1 fITSi. (Hu.-.' filmi/riil--. />' o iiml i. - These (endles-i textile fibre- were obtained from Klbckncr & Schott. Dortmund. F.R.G. Preparation and measurement of fibre sizes: Dr. Friedrichs. In tlie.-e -ample- the diameter variations were in a limited ralitre: FS.7: I0",, < 4.Sm, (it)",, C b.-'l ant: K.- 7: Id'1,, <" (i.S//m. `.*(1 ",(S.I //m. Length Fs .7: I< 24//m, Pd"., < SO/tin: Ks 7: !()",,< 23//m. P0",,< 102//m ( Friedrichs l!t7Si. G'/a-s A'/ro/in/or/. - Pieees id' glass milled to a fine dust. Preparation: Dr. Friedrichs. Ki'i-lm't Trademark for tint nude fibresi. - Prodneer: 1C. I. dn Pont de Xentonr.- and Coinpitny. Xewark. Delaware. F.S.A. It wa- not possible to make a suspension with separated fibre- from the flaky material. The suspension of sample (11 for experiment ID was prepared by ultrasonie treatment only, l-'nr sample (2t used in experiment lb tin attempt was made to tret finer fibres and better suspension by drvimr. milling and ultrasonie treatment. This difficult preparation was carried out by Dr. SerR.w. However, the suspension injected wa> not homogeneous like that of mineral fibres. Miii{iii`lih'. Delivered under the name "Ferroso Ferric Oxide" from Research Organic Inorganic Chemical Corporation. Bell vide. X..I.. I'.S.A. and obtained front Dr. OiserikTrster. I'nivrrsity of Rochester. X. V. The particles are very small and cannot be measured by light microscopy. A'ewo/f/e, MgOH,. - This mineral is the fibrous form of magnesium hydroxide. It was obtain ed from the .Mineralienkontor. Bonn. F.R.O. ( Impurity with chrysotile possible.) Prepara tion and measurement of fibre sizes: Dr. Friedrichs ( Friedrichs ID7Si. A/(/,'(>/ lu-iih' fSiOj. -- Delivered from Aldrich-Chemie (Imbll et Co. IvG. Steinheim. F.R.Ci. Purity SUUtfl",,. A"tcM /inirilcr. -- Delivered from Inco .Metals Company. Missisauga. Ontario. Canada to Dr. Mfiii.i;. Purity not indicated. A`irl.fl *iili.<ul[iih` (A7'rs'.,|. -- Delivered from Inco Metals Company. Missisauga. Ontario. Canada. Purity not indicated. /'obf/<ro///em\ The fibrous dust was obtained ready milled by Rhodia AG. Freiburg im Breisgau. F.R.G. Measurement of fibre sizes: Dr. Bei.i.maxx Dr. Mciilk. I'lihji-iiiijlrhhiridr. -- Produced by Chemisehe Werke Hills. Marl. F.R.G. Particle sizes !K)",, 2.7)//m. Measurement: Dr. Bei.i.maxx Dr. Mciii.e. l-l'nliiiiiiijliiiii'iiliiit-S-nriili' 1HYS'dj. - Produced by Bayer AG. Wuppertal. F.R.G. as a 2".. -olution probably in distilled water (Charge V :ibt)4| for silicosis research in the sixties. (//mil: Df//2. - origin: Dbrentrup. F.R.G. The "Ground Product Xo. 12" (in short: Dt)12i with a -ize di-tribution of<7 (i0//m wa.- delivered from Dbrentrup Sand- und Tonwerke (imbll m1 Dbrentrup. A b//m size fraction was prepared from this material by centrifugal separation inttir (Roiiock P.i73i. The fine du-t wa.- obtained from Steinkohlenbergbauvei''in. F.--en. F.R.Ci. Thi- quartz -pecimen has often been used by German institutes in volved in -ilico-i- re-earch. I!ml. mini >m a. ~ Produced iu Sweden. Prepared for animal inhalation -tudie.- at the Medical Research Council Pneumocotiio-i- I'nit. Penarth. Wale-. 1. Iv. (Wm;.xi:k et al. I'.is-Ti. A -ample wa- obtained from Mr. Skidmore. One part was u.-ed in it- delivered form, another was fractionated hv Dr. Sr<'Kxv t<i obtain a sample with finer fibre- 1 metImd Srvnxy et al. 1070b*. Mea-urenieur oi fibre -ize-: Dr. Sernxv. 134 Exp. Pathol. 321 l'.e-T 1 3 tiUnj coo/. HU. incut of fibre 4/ filntj iriml. YA. ment of fibre -D, 77/oo/d/o tlltiini. form i- anata-. Yoll-illlif it'll. .-/ (faliforiiia. F.S. \ II Illlllstlillifr, wa- obtained p-. by Dr. Scriixy. II 1niil tinsi. Iniii Olsberg. F.R.G. 1 I). Method o| . The du-t- am I min. The ii instillation- un/h mostly 2 ml per young rat.- in e\ only it very -ni;n weekly. The Id ; tively thick gla-tomia in nembic Polvvinylpvr (table.'5l. Three 0.4'',,i. Two of ' jected four time group.- in expertperitoiienlly fit. and Hi month-. 4. Method ol The animalexperiment-, tie mortem examin Part- of tuiiioi!' histologieid exa wholly fixed in (listed in rablethroiigh i-ii 1111 ib rat.- lo-t during Hl-SIlli.- Table I li-ieal te-t. All r:c counted a- tun: experimenr- tl' Tlie-e three to-o me time- i w . malignant fin tumourela--iti"ii .1- a admini-i'-roo : hleichcr mill Schiill. ricks. The material . IStTCi. < icwetcx. Diis.-eldnri. -. Tile variation in 'in. Length; in"., lined from Klbckuor Dr. i:i*iu< us. .8 b: HI ; 4.>vtm. -b: Id",, 24'm. > I > I ir. Fiui:i>nicu-. Xcmour- and ('uin- u-ion with separated lent l.'i was prepared n attempt was made mic treatment. This -u.-pen.-iou injected in Research Organic ,ed front l)r. OiikrI eanimt lie measured ssixide. It was obtaiii> possible.) Prepara'-I. 11. Steiuhcim. !'.R.<I. 1 iiuarin. Canada to Mi-si.-auga. (intariu. Jlindia At!. Freiburg u i.i:. '.li.C. ('article sizes Vuppertal. F. 11.0. as -earch in the sixties. 12" (in short: D<,U2i sand- und Tonwerke aterial by centrifugal Steinkohlenbergbaurnian in-iitute- ill ation -indie.- al the . K. i W \i.xi;r ei ai. in ii- delivered ioriu, :luer fibre- inei> -d Slmj triml. UII. -- I'rnduced by Rheinstahl. (ielsenkirehen. F.R.tL Preparation and measure ment uf: filire <ize-: Dr. I'rikiiricus ( I-'ritcmticus IU78|. Shj until. /,[. - I'rmltieed by Ximmermaiin. Sprockhbvel 2. F. R.tb Preparation and measure ment uf filire 'ize-: Dr. I-'rikdkiciis (l-'xtti:iirichs: ID781. Tihitiiinii tlliuttlr. - Delivered From Degussa. I'`raiikl'urt. F. R.(I. signed P2b. The crystal form i- anata-'. I 'ttlrif it if /-/(. Si. [{,!, uhtained fro in Dr. R.\\m:. Fniversity of California. Davis. California. F.S.A. WJIti-ltuulr. - Origin: India. A dust -ample with relatively large particles signed D-L wa.- obtained from (isthoff-l'etrasch Ivti. Hamburg. F.R.tL Preparation of a fine fraction by Dr. Secnxv. Measurement of fibre sizes: Dr. Ri-:llm.\.xx Dr. Mrui.i:. ]\'nt,il tlitxt. ht'i'rh. - Signed "Rucheiimehl (IroBoOC". Delivered from "hriider schulte". (Il.-berg. F.R.tL Commercially used for bread baking. Particle sizes about 10 -100/rm. d. Met hod of administration The dusts were dispersed in 0.8",, XaLI solution with ultrasound, most of them for about I min. The intraperitonea.l injections were given without anaesthesia, the intratracheal instillations under CO., anaesthesia. The animals received 0.3 ml per i.tr. instillation and mostly 2 ml per i.p. injection. Only 0.8 or 1 ml was injected intraperitoneally in the very voting rtits in experiments 7. LI. 13. and in those croups of experiment If) which received only a very small amount of asbestos. If more than one i.p. injection was given, it was done weekly. The 10 to 20 i.tr. instillations were also applied weekly. The large amounts of rela tively thick glass filaments in experiments 4 and 5 were inoculated in 4 ml saline by laparotomia in nembutal anaesthesia. Polyviuylpyridine-X-nxide (PVXO) was applied in experiments 13 (table I) and lb (tabled). Three groups received actinolite i.p. suspended in I ml PVXO-solution (2",, or 0.4",,i. Two of these groups were not further treated: one group was additionally i.p. in jected lour times with I ml 2",, PVXO-solution 4. 8, 12. and 10 months later. The other group- in experiment 13. labelled "PVXO separately", received L ml PVXO solution intra peritoneally five times: one day before the i.p. injection of asbestos and after 4. 8. 12. and 10 months, 4. Method of examination The animals died spontaneously or were killed when in a bad health condition. In some experiments, the surviving animals were sacrificed about 2.b years after treatment. Post mortem examination was made of the abdominal cavity of rats injected intraperitoneally. Part.- of tumours or organs with suspected tumour tissue were fixed in formalin (0",,i for histological examination. In the intratracheal experiments the lungs and tracheas were wholly fixed in formalin for histological tumour evaluation. The number of rats examined (listed in tables I -4i includes all autopsied rats and does not include those animals lost through cannibalism or during anaesthesia. The percentage of dead rats does not comprise rat.- lo-t during anaesthesia but it does include those lost through cannibalism. /iY.~- <(//. Table 1 list- ill chronological order the results of 13 experiments using the intraperitoncal test. All rat.- with sarcoma, mesothelioma or carcinoma of the abdominal cavity were counrcd as tumour-bearing rats. The most frcipient diagnoses were sarcomas as in previous experiments (Porr et al. 137(1: Smi-:ri:R et al. I873i; only a lew carcinomas were found. Tlic-c three tumour-type- could not always be differentiated with certainty histologically: -ometime- two rumour-type- occurred together. Since b K)",, of the control group showed malignant tumours of the uterus, part of them with meta.-ta-ses. rats with malignant uterine tumour- were not counted a- tumour-bearing rats. Thu- it i- possible that a tumour wacla-'ified a- a -poutaneou- uterine tumour even though ir wa- induced by the -ub-tance adiiiiiii-tcrcd and occurred accidentally alongside with a malignant neoplasm of the uterus. K.\p. I'atliol. :(2 dti.'-Ti13b ii; = 5 JS r ~ i -fl 7! - := m 71 71 -- 71 71 71 = '=5 = 5 = z = ~s T .ib lr l. Ivi-m iIn .illn m ii.ip riiin u r;il iiijr r tiu ii of various fibrous iiiul "la n u h ir <!um = 77 77 77 : - A A f. -r 77= 7. H 'r C- =: S~54 ?i 7i 5 r> ?i 5;?i f, _ 7 ?i 71 7i tititititl inti -- Er -- ~r ~r ^ = 5, 2. = -, 71 7. t ,-t = 71 = c J=Z*c .E '--s == ;j i- i- 77 ^ ,,33 *"-- :--_ tS-I. t71 J i: i.M i EE 1 1 i:ji Kvp. I'atlwl. B2< r.i'Ti ! 2 7.x = == --- - 7= = = = = Jr Jr Jr - -- _ ~" * ?_ ? = Jr Jr Jr Jr E = m'| z.------r. .1 ^ = -_'2 r :==.- t. 5. =i. ii. Si;- .< -- -/. -r. / -- < r. Ij = =.< -- = i! 11115 ti3 = - 7. 7. | ^ 0 S i! B "^ ^ H 7 7. i~ ~ 5 " 2 7 7 -- (- E >1 -7 7.; rx52sir;=;cr t z r r---- I >"2 i .5 =-=.= E-i-i .;2 s.-=f-s= J-'-- 11---3 =z -- < < -_ " X. ---_ /. *3 x r. .7 :' 7j*1s' *^Vi -= i- I- ?7 - - hi if T. 7" 7" 2 'A A 3. / / -ll ill --z---- --/f /~f---/t /Jf7_,----z llilr-s|>;iii ii'iliiic il 11\ in i. in nm nlli I.'I ~ 7. ~ -- ~m A -- -- r l- ~! -- {- ~ -- U " ?J zz y -- li -i -- -- 2 B15 B f 0 5 s ~^ "'"= - u~ r~i-2-~^-j ^ j ^1;-.2 S '5 #." 'z2 y u ;= " .7 :7 < ~ - x 71 __ _ r. v. i- i; i~ 3 "? _ ' -r TJ7l 1~7 Sr -------0 7--1--Tl71C --~ /X. --- i--- i7-i :X7 .771 --T --r. IT ^ .7 3 3 i' i--- -- rl- ?Ii- - 7--i --I- ?l-i ..j7|= kkzkkk 71 .7 x -- <7 .7 t- 7 l- |7 3 3 T :: l- (------- 77 C l--------c 71 .7 ,7 X k c - -1- r " i-7 lO '-- 37 i"7 :~ '^7X/.r---- X x -t 7 r. i ZZ ^ : KS25i: = 3^ 17- 71 -' 7 77 J5 3 -. ! ! -i = - ji j= == == : . - . ?, 7, _ r 2 - j- 7171 ---- 77r7 71 55 i-- > >S Z ---- I1IT'--- _ j = r: .= = -: xH- =r;; 3 dr i; j^;. J"rJ: ! 3r j; I =`-i i i= = c s =; s t,7 i7 >7 >7 i7 O 3 -3 3 ~ 3 'Tt I-- I- -* I - -' _' J 1> U J _j. -j. . Jr Jr =r ^ - ="=='is. 5. X 77 --737: 7 7.717. ry ;= x xx77.7-- r. -.7.77 71 -- 1:||.l : - : J. ^ ^-=f Iil'-I- = = s :.C!= r= _ i d rs f,. _ s'- !I Tt-t-^l = i ; :' ?7' /t r r r 1. = _ = J7 -Tl -3 -" -- -- L 7 = ;* // // JrX- .=-' ." .---r .7. = = ' -7 ,, :K---- = !?-.- = = mu = K\|i. I'atlml. S2 1 l!'"7i.! V.Yt Z JZ -- /. -- S'xi : : .-2 s ?: f- T '=9.7. ;D7 ;vf .77 E~.'eT-. = S E liist `i E :- ! = 5^;S 5 S9. 9. -. 2A . : ' = -=:' 2;=3:.t;= ^E^Tl'E = 5 r- z - 5. ~~ ^ S ^ !c S S s Is -r ~ y: ci Z =7 E5 E: 5r. \%'zL | ._ 2 =^ = === x; = - 5 -4 2,-= H-' ''' ?. _ E 2. = -t ?t ct - rT ?4 = S-54 -r q r: r: t-.i-n c r: s ^ .5 E " v > s ~ -T "P =rr -r -r -r-- 'i . ~ -5 E i: - = -i'if = u;:2-2 J 7i7i35^| I_r ^ -- Ij; 1^ 1 - ::J?,r,2:5 rt /: /. ~. :r. -t - r: ?t----------m 71 - ~ = = - 71 7; :7 -= = r. = T A- -- _i- ^ ~ 7~---f .2 ? 2 : I || ~*i ~~ s- s- xs r r. 5/?. .f7_mr =r =- E~-zZ/.E'=Z/-=.'j--AZz: _E-*--E_*z-~~=_ -- 1 54 T a: 2:- z 2'ZH X- --= -2 = l- s"5. U -J 5 5=; - 5S> = = | = == --5 . C i i7 - = r- - - A r- - - = - A--------. . r. ....' . { ! ! - -z =t ---J--- --- -E---J--:-E-- -~ --- -z -Z -Z E--l =- - =.= ._ = = =:; = = ^ - -- -- i .= i i IT? =.= = =s; Z.Z.i:z z S-= I = -;=;= :a < 12: r Z r != 5 i:;-' Km.. IVI...,, :ti. 1 !''T 1:: or 21)4 rattuilloiirs ill flic ;i 1 carcinoma 1. In wore round (K >;r occurred occasion tauoous and wit. those fisfiiri'd arc ; The ry|iical isome cases, a lice ina-l- -li.iwed .ml' orisiiiatcd I'rmn i' turn minus. In m. cavity so that tl inctii'tascs .1 itcu ' The interval I averatre survival '. and the dose and had the .shortest I rats were injeetc. very |.iu<r |a(rnr\ solution: 1 he I'iM deuce of 4S",! wa lntra|)eritone:. reactions with 10 alterations aura in experimental it'i'o later in the texi dearer of adhesi.. peritoneal inject 1 in iioii-auaesthet; always he avoide jecti'.u of small a corundum or Ion side- of the nine! I'nlv in cert a happens with ca1 some of the a 11 i 11 do-.- experiment^ jeetion of aroalci of I'll- peritonei! spit.- 1.1 this, t he cr.ieidolite or er I.") io tahle III. 11 mei-r- ol .') and 7 illdtleina effeel . I'ihrosi' ranIron the 'tipert a- v,e|| a' hv e nodule' of one * mat..'. Die and- \- le.eut'oio- ee.|,'li-pec- 1 ni- 1.' in 1 In- je -a& -- "in : n| 204 rat- injected iutraperitoneally with saline alone. 7> ( i!..7)i had malignant t it in nuf' in the abdominal cavity other than uterine t iinninrs (3 sarcomas. I mesothelioma. I carcinoma i. In .'114 rat.- in jected with titanium dioxide nr corundum. I.r> neoplasms ft",,) were ftiittid sarcomas. (i mesothelioma'. I carcinmuai. Several other tumour-tvpos that occurred occasionally in Imtli the control and the test "'roups were also considered as spon- tanooii' and were not included in the percentage of the tumour-bearing animals. Among tho'C tigured are adenoma.'. angiomas. I'iliroimt'. myoma', malignant lymphomas and others. The typical tumour' cau'ed by I'ihre.' were accompanied by hemorrhagic ascites. In ,'Oine ca'i". a hemorrhagic ascites was round hut no tumour. .Macroscopically. a few ani mal' 'Iiowed only a -ingle tumour, yiiiite often there were several neoplasms that mostlv originated fro in the upper abdominal serosa, especially from the omentum majus and omen tum minus, hi many ca.'e.-. the primary tumour had .'proud diffusely within the abdominal eavitv 'o that the visceral and parietal peritoneum was covered with numerous minute meta-ta'C' often numbering more than a hundred. The interval between injection and death of the first tumour-bearing animal and the average -urvival time of the tumour-bearing animals depended on the type of dust applied, and the dose and the age of the rats at the beginning of the experiment. The 7th experiment had the shortest latency period of 17 week'. In this experiment, .`l-week-old female and nude rat' were injected iutraperitoneally with the relatively high dose of 10 mg "lass fibres. A very lonsr latency period was observed after the injection of d.S 111" actinolite in I'VXOsolution: the first tumour-bearing animal died after Of) weeks. Nevertheless, a tumour inci dence of 4S",, wn' still reached. Intraperitoneal injection of liitrli dose' of non-carciungrnic dusts can lead to inflammatory reaction.' with more or less distinct adhesions of abdominal organs. The decree of these alterations attain depended 011 the type of dust, the dose and the ago of the rats. For the experimental "roups shown in tallied, a quantification is given which will be explained later in the text. Supplementary to table I. only a few important findings concerning the degree of adhesion in some experimental groups should be mentioned. After correct intrapcritoiiea! injection of Xa('l-.'olution no irritant or inflammatory reaction occurs. Hut ill noii-anaesthetized rats, a puncture of the intestines with the injection needle cannot always be avoided and may subsequently lead to adhesive inflammation. Kven after in jection of small amounts, non-soluble dusts with a specific colour, such as titanium dioxide, corundum or ferric oxide, can be -een deposited oil the peritoneum and especiallv on both side- of the omentum majus. 1 iiilv in certain ca-os does the degree af adhesion increase with the tumour rate. This happens with carcinogenic fibres in a medium range of doses. After injection of high doses some of the animals died from the adhesion' before a tumour could develop. In the lowdo-o experiments ties' than I mg per rat with a weight of more than l.'ibgi or after the in jection of greater amounts of very short fibre', many animals showed such minor change' of the peritoneum that they could hardly lie detected macroscopically or not at all. In spite nt this, the tumour incidences after injection of 11.27) mg to (),7> nig actinolite. cliry-otile. crocidolite or orionite were between 7>() and 'Ul',,, (experiment Hi in table I. experiment 1.7 ii tabledi. On the other hand, the injection of relatively thick glass filament'with dialuei<!*' o| .`i and 7/<m led to clearly vi-ible adhesion' of the abdominal org.in-. while a tumour inducing effect could nor lie proved (experiment 2i. i-ibro'i' caused bv quartz (experiment 2- -ignificaurly differed in it- macro'eopie view frm:. the 'iiperfieiallv spreading filiro-i' rau-ed by natural and man-made mineral fibrea v..-(I a- iiy metal compound' lexperimeiit 14c Alter the injection of quartz, numeroiiiiioi d'- oi one to 'overal millimetre' in diameter could lie -een, e'pecially in the omentum maiit-. The abdominal organ' u-uallv did not grow together. mentioned in the chapter "'ub'iauce- used", it wa- not possible to produce a homngci ei.ii' ' i'peu'ioii ot Kevlar fibres. Theretore. ihe-o tibre- were more likely .........-cur it: t-iii 1 :i- in the peritoneal eavitv than were the oilier du-t' (experiment' Id and |7n. K'-.p. I'arlio!. 42.!!i 1 I dll t in In tho-c groups wlii-rt1 llu` ~i!rvi\";iI timu* wa- not shortened by flic toxicity nr tnm*iurinduciug cl'l'cct of 1 In- given 'iibslaneo. 20",, nf the animals (lied >t() tn 100 weeks from the 'lari nf the experiment: .Ad", 'urvived lietween 100 tu 120 weeks and 20",, up tn alnmt I-Jo week'. As far a.' 'iirvival time' are eimeerned it Ini.' tn lie borne in mind that the naiural pnint . i death iva- ni'feu nut awaited fur when the animal' were in a Imd condition. Must I the experiment' were terminated alter alum! twu-and-a-half years. In 'nine groups mure than 20 uf the rat' were 'till alive after that period. Since the animals were nut kept under SI'F-conditioiis. the 'iirvival time''are affected to a greater ur lesser extent by inl'eetiuii'. Furthermore. it ha- tu he emi'idered that the Spraguc-liawley rat which wa- ii'cd in experiments 10 and 12 hits a lower life expectancy than the Wistar rat. Table 2 shows the tumour rates and survival times after intraperitnneal injection of Mime nickel and cadmium compounds. The duse< injecred were chosen after examining the acute toxicity: they appeared to he the maximum tolerable amounts. Moderate to 'troinr adhesions of the abdominal organs were oh'crved in all trrotips. Table .`I shows the preliminary results of a still uncompleted intraperitoneal experiment 2* months from outset. AltItomrlt at this point many rats in several groups were .-still alive, the tumour rates already give interesting information on certain questions. For each group in this experiment not only the tumour incidence is given but also the degree of adhesions of the abdominal organs. To make a better survey and to quantify the adhesions, the great variety which was visible macroscopically had to be summarized and simplified. We classi fied the adhesions into the following grades: Crude 0: Xo adhesions of abdominal organs. Crude I: Only punctual or very narrow adhesions up to about 10 mm2. They are mostly found between the omentum majtts and the liver or intestines. Sometimes the omentum is not extended normally, but slightly shrunken. This is probably due to a minimal local fibrosis. Crude d: Adhesions over small areas between 10 and 100 mm2. They mostly affect, the omen tum and liver, the liver and diaphragm or the spleen anil stomach, and less often the intesti nes. There are extensive adhesions between the omentum and stomach. The mesentcrium may also be slightly deformed. Crude:): Adhesions of more than I cm2. All abdominal organs are clearly distinguishable and. except for the omentum, only slightly deformed. Crude 4: Adhesions over large areas with severe deformation of more than one abdominal organ. Crude o: The adhesions and deformation of the organs are too strong to ,allow their separation in the section. tirades 4 and A did not occur in experiment IA (table 2l. They have been observed in rats after injection of A0 mg or more of asbestos or other corresponding fibres {Fort' et al. lOTiit. Similarly strong adhe-ions also occurred after injection of 10 mg glass fibres into ;i-week-old rats- (experiment 7i. The adhesions of the abdominal organs develop within the first weeks after intraperitoneal injection of the dust-'. If in the. later course of the experiment a tumour spread'' in the abdomen, thi- growth also frequently leads to adhesions. Thus the original degree of adhesion cannot be judged correctly. The degree of adhesion after in traperitoneal injection of I mg of ehrysotile has therefore been put info ( i: in this group sit!of the rat- showed tumours. Table 4 show- the re-ults after intratracheal in-tillation of crocidolite and glass fibres, beu/.otaipyrene and -onto metal compound''. A' in the i.p. tc-t with metal compounds, the doses applied were cho'on alter examining the acute toxicity (loss in weight, mortality). The diflercnco in the acute toxicity of cadmium oxide and cadmium Mill'ide wa- not a- high .I- after i.p. injection, 'mr it ran be e-rimated in tin1 relation of I to 2d. I 40 < toxicity iir >um<ur- i I fl(l week- l`ruiii I lu ll rl 2D ll11 t< ;t11-.ul miu<1 that lIn- miluriil . Iniil t'diirlitinn. Mu-t III -nine u'l*"ll11~ li''i|'i` iiimal- witi- nut k..,,i --or extent liy iiii-i-- rat which wii- il'-d rat. M-ritiiiii-al In............... . -'<'11 sift it i-x;i 111 in iiiir nonnl.Mudi-rati- in peritoneal i-sin-riiit-nt .r--uii-- were .'till alive. - inn,'. I'nr cadi iii'iiii ji decree ill' adhc-imi-idhe-ious. the irri-ai ~Ini|ilifii'd. We cla--i- - in-. They are mi~tl v -ictimes the omentum hu- tn a minimal local o.-rly affect the omeuI less often the intentiich. The mesonteriimi Icarly distintfuishable " than one abdominal allow their separation ave been observed in limr fibres (Pott et al. ') mtf <fI ass fibres into ti- develo)) within the ir-e of the experiment I' to adhesions. Thus -if adhesion after inutn t i: in thi' croup ; -lire and <flsi.-- fibre-. Mi metal compound-. - hi weight. mortalitv 11fitic was not a- Inch .') i ^ i x II ?i tf ~ -- 22 i I Ii I 7= K\p. I'athol. :!2 i lUsT i:! 141 ] 42 K\|>. I'atlml.i '> Iv.jp. I'atlml. .`{2 lii.-'T-:: 14'! Ili.-Ciiffinll Tlir (l[i.-i< wliicli were examined for their carcinogenicity can lie divided into (> groups: (h a'I ie>t os. (2 i other natural mineral filires. (.'ll man-made mineral fibres. (41 plastic fibres, (`it metal compound-; and (tit other granular dust.'. The results will be discussed in the given order. However, because of the Isirire number of dusts applied, the wide explanations of their biological activities and the numeroii' connection.' to other studies can only be discll'.'od briellv. /. ,I'/'/os The experiments with asbestos have produced findings on the following points: dose respon.'e-relation.'hips in very low dose ranges, significance of length and durability of fibres lor their carcinogenic potency and effects of the prolonged latency period for tumour induc tion by PVXO. Ivven d.O.'i mg actimdjte or chrysotile ('ICC B had a clear carcinogenic effect after i.p. injection (experiment I fit. This is the maximum amount of airborne chrysotile which is per mitted in I m;i at the workplace in the F. K.<!. (TR IC-- Technische Richtkonzentration == tech nical guiding eoncentrationt. Certainly, the dose response-relationship found with the i.p. test cannot lie extrapolated to the lung of humans: however, the results confirm in prin ciple the hypothesis that there is no threshold for the carcinogenicity of asbestos down to an extremely low dose range. After i.p. injection of 0.05 mg actiuolite or chrysotile. no adhesions were observed (microscopically. A histologically detectable fibrosis should there fore lie extremely small. Lt is not common to call such a small, (microscopically undetectable fibrosis a scar. If such minor tissue alterations cause a tumour to develop with a relatively high probability, many other dusts should also have led to tumour development while they in fact only induced macroscopically detectable adhesions and fibrosis but no tumours. These ob.'orvations contradict Kuseii.xicr's hypothesis (li)80l. According to this a scar is always (lie necessary morphologic base for the tumour development caused by asbestos. Should a fundamental difference exist between a minor fibrosis induced by asbestos and the fibrosis induced by nun-carcinogenic dusts and how could this be substantiated? Already Davis (IW-ll stated that ``the correct diagnosi.' of early asbestosis remains one of the greatest [problems for pathologist.'". Ihu.Tiix et al. (1!IH4| also found tumour.' after i.p. injection of very small amounts of chrv.'Otile and crocidolite. But mostly much higher (loses wen1 applied in serosal tests, e.g. 40 mg ( Wet al. Id7:i: Wauxkr et al. Id84ai or 40 mg (Ktaxtox etal. L077. liiSlj or up to 100 mg (Pott etal. 1072. 1070: Sciikckk etal. L073). The strong fibrosis which is caused by large amounts of asbestos has encouraged Kcscuxkr (IOHOi to revive the scar hypothesis developed about 50 year.' ago (Lixzuacii and Wedi.kr l(J4L). At that time, it appeared a plausible explanation I'm' case.' of lung carcinoma that were accompanied by ,'ovorc asbestos induced fibrosis. Large amount' of fibres shorten tin1 tumour latency up to a certain degree, (in the other hand by causing 'even' fibrosis they also shorten the animal or human lifts--ptm and thereby reduce the tumour incidence (mt taide I. experiment 71. It is remarkable that no tumour.' were observed after i.p. injection of 50 mg ground chry'otile Tin' B with very 'hurt fibres (50".. 7 ().5(l/<mi (experiment xi. However, in ihi' experiment, the average survival time of the rats was greatly reduced by an infection: iicvci l11cl**". in another group tumour' were found in 07"., of the animals after injection of actiuolite. In earlier si udii-'. Mill mg of milh-d ehrv'otih I'lCC A had induced tumours in 40 .ir.'l- ' .of the rat' i l'o it et al. 1072. 107im. At that time it had already been discussed whether tin- lew remaining 'li'otigly carcinogenic long fibre' or the preponderance of 'lightly carci nogenic short fibres are rc'pou'ible lor the oll'ert. We 'till have no clear answer to this. In mg of the -amo sample did not lead to tumour' in experiment <i. In experiment !'!. a Californian ehrv'ol ile i ('alidrin w,0' ii'od. which had mo previously '..I: U"'"Oil in animal li-'t-. The iutraperitoueal injection oi n.5 mg did not -how a clear carcinogenic cifecr. I'erhap- the ( aliioi'.iia:i cl.ry-.o.iie i- h-- durable than Hie two fil l I .'4 i: .n. I' .'I."! :!2 t'O'Ti :i chrysotile sampt chrysotile. We must tin persist in the lo formation into ; which have Pm prototype for fib of these fibres ;. damage: all aid The half-life of a instillation ( Bki silie acid which . flUTSi in his rein et al. (IdSI i Ion' of the acid treat creased durahilit sium plays an in The inhibiioi k<">ti:r and Bitm its the developn time in two exp. with a 2I'VX lead to inhibit!" on the surface o under cxpcrinic! substance lead' ' the first year of i j igenie potency . up in the body. ,2. S'iilaful nil'/"- The carcinogi where this filir..et al. |d7Ki. The and intrapleiira also caused nicwitli similar file of 2K rats ( W and in cxpcrinic result' corresp. no explanation experiment of U We could <"! do'Cs of the 'aim luineralogieallv Attapulgile had no careiiiog in relation I" to hemolytic a.-ti. cytotoxic and . The only elearlv bigger appeared durii.. 1 oiniiaring : ided into ) groups: (41 pla.-tic fibre.-. -cU.-M'd in tlu* given i'll' explanation- of e- ciiu only In- ili'-- ! i\vi11tC point.-: ilo.-o durability of film-.? d for liimour iuduc- -nic effect alter i.p. .-y-otile which is periii/.i-iitratioii -- leclidp found with tin: ill- confirm in priny of asbestos down ill- or chrvsotile. no ilimsis should tltcre pically undetectable Sup with arelatively i-lopmcnt while they il no tumours. These iii- a sear is always 11v asbestos. Should. --los and the fibrosis ' i-il ? Already Have- "in- of the greate-t -v -mall amounts of in serosal tests, e.sr. .\ et al. 1977. lilKl i -mr fibrosis which i-'it to revive the sear fli. At that time, it -re accompanied by -Hour latency up to a -liorten the animal i. experiment. 7i. A - n of ."it) mg grim ml - lit *i. However, in o-t-d by an infi-etioii: .al- after injection of flood tumour-- in 4** -il di-eu.-.-ed whether ii.ro oi -lightly oarri- `ar an-wor to tin-. -.-oi uni pivv iou-1-. 'Al M- t ~h"\v a I-!--:- nan Ho- two l b elirvsofile samples. Jlnm-t et al. (1980) also did not find tumours after inhalation of Calidria eh ry.-utile. We must turn to the cell biologists for an answer to the question how long fibres must persist in the bronchial wall or in the serosal tissue to alter the cells sufficiently for trans formation into tumour cells without the further presence of fibres. Former chrvsotile fibres which have lost their magnesium content through acid treatment can be regarded as a prototype for fibres with very low durability in riv<>. Within one week. i.p. injection of 25 mg of tlie.-e fibres led to the death of most animals, possibly because of an observed kidney damage: all animals given fi mg survived and did not develop tumours (experiment 1). The half-life of acid-treated chrvsotile fibres in rat lungs was only 2 days after intratracheal instillation (Bnr.utA.vv et al. 198(5|. Such magnesium-free fibres only consist of amorphous silic acid which easily disintegrates in the body: this has already been recognized by Beger a!i:W i in his remarkable study, although he disposed of only simple instruments. Moxcii.vrx et al. (1981) found a reduced carcinogenic effect of chrvsotile. dependent of the intensity of the acid treatment. The authors did nut interpret this effect as a consequence of a de creased durability but concluded that, in connection with fibre surface properties, magne sium plays an important role in tumour induction. The inhibitory effect of PVXO on experimental silicosis was first described by Sciilii-KiiTKit and BjuirKirAgs (LIKiOi. Tests were performed to establish whether PVXO also inhib its the development of asbestosis and tumours induced by asbestos. The tumour induction time in two experiments was significantly prolonged when actinnlite was injected together with a 2",j PVXO-snlutinn (experiments 13 and lb). A separate injection of PVXO did not lead to inhibition. It has to be clarified whether PVXO neutralizes a carcinogenic agent on the .-urface of actinolite fibres by adsorption, or whether some side effect, present only under experimental conditions, prolongs the tumour development. Maybe the polymeric substance leads to the formation of fibre aggregates in the abdominal cavity, so that during the first year of the experiment the fibres are not distributed normally in the tissue.The tumourigenic potency of chrvsotile was not affected by PVXO, possibly because the fibres split up in the body, as demonstrated by Bei.lmann et al. (1980). 2. Xatnrnl mineral fibn^ nlltar Ilian asbasto.i The carcinogenic effect of erionitc was first described in inhabitants of a region in Turkey, where this fibrous zeolite occurs naturally and was formerly used for house building (Baris et al. 1978). These fibres not only induced tumours after intraperitoueal injection in mice and intrapleural injection in rats (SrzfKi 1982. Wagner etal. 1985;. After inhalation, they al.-o caused mesotheliomas in 27 out of 28 rats, while inhalation exposure to eroeidolite with similar fibre size distribution led to a tumour (squamous cell carcinoma) in only 1 of 28 rats ( Wagner etal. 198b). In experiments LO and LI. Turkish erionitc was injected and in experiment 13 an erionitc sample from Oregon, which Hr. Wagner had also used. The re-ult- correspond to what can be expected from the dose and fibre size. So far. there i.no explanation for the unique mesothelioma-inducing effect produced in the inhalation experiment of Wagner et al. (10851. We could confirm the carcinogenic cffecl of nemalite (experiments 3 and <ii using several do-os of the same material described earlier (Port et al. 197li|. (Iraitular magnesium hydroxide, mineralogieally signed brucite. did not induce any tumours (experiment 3i. Attapulgite ( palygorscitei from four source.- was examined. Three samplesie.xperimeut 9i had no carcinogenic effect, the fourth with longer fibres (experiment 13) had moderate effect in relation to the applied do.-e. II \rvkv et al. (1984) found in rltrn ,-trong cytotoxicity and lu-niolvtic activitv in a .-ample from Ooorgia. I'.S.A. Therefore, different mechanisms ol evt-iti-xir and carcinogenic effect- can lie a.--umed. The onlv wolla-tonite simple examined had a median diameter of l.l uni and thi- wa~ i-ii-arlv bigger than the otlu-r natural fibre-. Inspire the high dn-c of |t)() mg. no tumoura-.iiieared during the lir-t two year- of the experiment. Titer-- wen- no -even- adhe.-ion- either, i "iiipamig tin- re-ult with rook and ceramic fibre.- of a .-imilar .-iz<- which are di-eu.-.-ed later Kxp. Pathol. :!' 11U-Ti:: 14b mi. the effort of tlio tinted wullastuuite fibres is much smaller or even zero, i'robablv wollastonite lias a low durability in mv>: taken 30 mg of the fibres tested in the animal experiment, 10",, dissolved after 24 h in 0.9 0 ,, buffered saline (/ill 7.41 at 37 C. The lack of carcinogenicity of 10(1 imr fibrous gypsum after i.[). injection has also been explained by its high solubility (Pott and Frikiikiciis 1972). J. .1 fitn-nlfldn int/tf'i'fil fiht'CS Since 1972. glass nticroi'ihre-" with median diameters of <0.3/nu have been well known to lie carcinogenic after intrapleural and intraperitoneal administration. They are. produced in various chemical compositions. These differences could be important for thei carcinogenic potency as well as their sizes. The treatment of sample 104'47b with acid did not reduce the tumour rate obtained by 2 mg. On the contrary, it even seems to have in creased it (experiment 13i. This increase might be accidental. But in comparison with other results, it seems more likely that the tumour rate for unrreated fibres is too low. The reac tion to H Cl-treated K-glass fibres type 194 L974 was quite different. The fibres lost 33u(, of their weight by the 24 h iiri-treatmeut. This loss mainly involved aluminium oxide and calcium oxide, each of which makes up L0 --20% of 12-glass (Bi-:i,r,>r.vxx et al. 1.9801. The carcinogenicity of these fibres was strongly reduced and. in comparison with the control group, not statistically significantly increased (experiments 10 and Hi. Also, the half-lift' in the lung was dearly shortened (Bur.r.si.v.xx et al. 1980). It was surprising that after 2 h of IK'i-treatment the weight loss already amounted to 27>"'), while the decrease in carcino genicity was much less significant. After treatment of glass fibres 104.1974 with XaOlT. there was only an initial prolonga tion of the tumour latency. A general inhibition could not lie detected. The administration of glass filaments with diameters of about 3. 5 and 7/zm did not lead to increased tumour rates (experiments 2. 4. o|. Because of their thickness, the actual number of fibres was small despite the great mass, and fibre-induced tumours were therefore unlikely to occur. An increased tumour rate could only have been expected if the glass filaments 1283 (experiment hi were at least as effective as ceramic or basalt fibres (table 3). As stated earlier ( Pott et al. L980). Sprague-Hawley rats may be more sensitive to the carcinogenic effect of glass fibres in the i.p. test than Wistar rats, but the difference does not appear to lie significant. We prefer Wistar rats for the i.p. test, because they are thinner than Sprague-llawley rats: therefore it is easier to diagnose ascites or abdominal tumours in the animals when they are still alive. The intratracheal ill-filiation of 20 (l.j in; glass niicrofibres 104 477) induced lung tumours in .7 of 34 rats (table 4i. This 10 "0 tumour incidence is not very high but statistically significant, especially with regard to the zero-tumour-rate of mm-dusted Wistar rats which also was found in other long term experiments (Ifmxiucit ot al. 198(1 a. b: Muin.r: et al. 198(Ji. The result confirm- earlier ones obtained after instillation of 8 I mg glass fibres 104 1974 in Syrian golden ham-ters (Pott et al. 19841)1. En that experiment two samples with different lengths were administered (they were also used in experiments 7 and IOi. (if 130 animals instilled with the longer fibres, .3 hamsters with lung carcinoma,- and 37 with mesotheliumas were found: the shorter fibres induced 0 lung carcinomas and 2b iiicsolheliomas in L38 hamster-. The high mesothelioma rate can be explained by the high amount if fibre- which reached the pleura immediately after instillation. PICO croeidolite which contain- relatively .-Imrr libr"- induced lung carcinoma- jn ;i and mesotheliomas in x of 142 ham-lev-. l'!:e tumour latoiuv \va- rather long: m-arlv all 1 iimour-bearing animals -arrived lor a period >(' l1- mouili- alter ilie fir-t iu-tillation: aboiil 7)0",, lived for longer (hail two year-. The morphological a-pc.-v- of the induced me-otheliomas were i|e-i-riin-d bv tfoui: ei al. i P.M-. In a -imilar xperii'.e n' .- 'uyi\ et al. i p.cs.'u. ham-ter-- received t!0 i mg of glas- miri'oiiuro- whii h re-ulr.'d in -tr-ngcr inflammation and a -Imrr survival time. Tim experimoiil ha- !;; :ii.i-lo-d alr-ady after -0 weeps without showing an inerea.-ed tumour rat" HO i:.o. I'.:0:o. 42 i.-7 ; either with gla-the negative re.-i While the vci isolating wools fr tities. Their med fibres from the . the injected fihr> than witli microi with a diameter 3) has 300 time- in experiment I glass fibres 104 4 The interpreisince on re-exami measured 0.18/k again too -mall (00 or 104. Xcvertllcle.--. compares (lie no per animal doc.(experiments 12 samples (experino verification and 1 all four rock and age of very long one adenoma, an and tumour-' in 1! Finally. the m also be mentions tumour rate com: to be regarded li the very low can compound. 111 an 1970). Recent i.mt 1984: Atuki -. later, again rai-e /. /Ve.-7fC I't A tumour iud is much higher fibre-. We mu-t ' able rc-iilt- -Inm O. ,1/c/o/ CO/,1 [Hilt. The iuirapcrexamine the eur to lie more liia'i toxic than iih'lo which could on!' period- (exper'c I tier illjeel witli ioMe o'..i 1,.... a ud o'...... "i|er loi'l.l >.'  rii zero. I'mbitlily wullain the animal experiment, lie hiek of carcinogenicity ied liy it.' high mlnhilitv ''I..'!//1M have liei-ii well dmini-.fratiun. They are !il be impiirtant fur rhei |e 104 47.j with acid did even seems to have iun comparison with other re-: i< tiiu lew. The reacnt. The fibres ici-r 33% dveil aluminium oxide i.mvxx et al. I!ISlji. The .arismi with the emirrul d lit. Alsu, the half-life -urprising that after 2 h the decrease in earcino- iiily an initial prolongaied. .'i and 7/znt did not lead cuess. the actual number - were therefore unlikely r the glass filaments KS3 , table 3). v be more sensitive to rats, but the difference >. rest, because they are - ascites or abdominal 104 47.") induced lung rv hitrli but statistically isted Wistar rats which I'-irstia. b: Afrtri.i-: et al. "f * I mif glass fibre-) < peri incut' two --amplexpcriments 7 and 1 tl>. nm' carcinoma- and .'id irciimmas and 2U mc-oicd by the liiirh amount Tire crocidolite which helioma- in 8 of I 44 nine: animal- -urvivcd -d tor loner than tw.i ' de-i-ribc,l bv AT im:: d 2'i ' mi' a gla-'> a! tllll". Tile lief- .:.crca-cd rumour rat- either with glass fibre- or with crocidolite, I'lic -hurt life-span of the animals can explain the negative result,-. While the very fine class microfibres are only produced in small amounts, the common isolating wools from -hit', class, rock or aluminium silicate (ceramic) are used in grear quan tities. Their median diameter is several times as wide as that of microfibres. The thinner fibres from the wools were enriched for the animal experiments: the median diameter of the injected fibre-- wa.- between d.9 and 2.t>/<m. Therefore one needs a. much larger mass than with microfibres to achieve the same number of fibres. For example, a cylindric fibre with a diameter of l.-qaiii and a length of 14//m t - median of the slag wool Zl in experiment :>i Ims 30(1 times the mas-- of a fibre with U. 13/<m X 3.2,urn t median of glass fibres 104 475 in experiment l.'ii. Consequently. a zero effect of the slag wool sample in comparison with glass fibres 104 47b cannot lie proven with the given dose. The interpretation of the results on .-lag wool (I'utt et al. 15<S4ai also has to be revised, since on re-examination of the fibre sizes a median diameter of l.3m instead of the earlier measured d. |8m was found. Thus, the number of fibres quoted in the experiment was again too .-mall to anticipate a carcinogenic effect in comparison with glass miemfihres 100 or 104. Xeverthele.-s. -lag wool seems to be le.-,- dangerous than rock or ceramic wool--. If one compares the median sizes described in the experiments, the number of injected fibres per animal does not differ too much. Hock wool, basalt wool and the two ceramic wools (experiments 12 and lot show a dear carcinogenic effect in contrast to the two slag wool samples (experiment 31. For it. final interpretation we have to wait for the results of a planned verification and re-evaluation of the data on fibre sizes. In any ease, it is remarkable that all four rock and ceramic wool samples induced tumours. Perhaps the relatively high percent age of very long fibres (>20/<mi caused this unexpected effect. Davis et al. (I!!84| found one adenoma and three carcinomas in 48 Wistar rats after inhalation of ceramic fibres and tumours in the abdominal cavity in 3 of 32 rats after i.p. injection of 2b mg of the fibres. Finally, the very short ferric oxide hydrate fibres used in the production of tapes should also be mentioned. The fibre tested in experiment 9 shows a statistically significant increased tumour rate compared to other groups. But in view of the high injected dose the effect has to be regarded as very small. Furthermore, it is not certain whether the effect was caused by the very low carcinogenicity of the very -hurt fibres or by a chemical effect of the ferric compound. In an earlier i.p. te-t on 2 ferric oxides, im tumours were detected (Pin-rot al. 1971)1. Recent evaluation of ferric oxides gave no evidence for their carcinogenicity (lluxscni.kr 1984: SthKixokk 1984). but the findings on magnetiteitable 4i. which will lie discu--ed later, again rai-e rhi- que-thm. /. I'lttgUc |7/'I''S A tumour inducing effect has not been found so far. Hut the interlacing of plastic fibres is much higher and their capacity for Mi.-pcii.-ion.- in water much .-mailer than (hat of mineral fibre-. We mii-r therefore make allowance for rlifferenl condition.- m rim. and these favour able re.-ult- -hoiibl be judged with caution. 1. Mrtill rniii litiilltd' The inrraperitoiieal experiment with nickel and cadmium compounds wa- dc.-igucd to examine the carcinogenic effect of maximum tolerable do-e-. Cadmium oxide wa- found to lie more than a Hid time- as acutely toxic a-- cadmium -ulfide. Nickel oxide wa- much ;e-- toxic than nickel powder and nickel -ub-ulfide. With the exception of cadmium oxide. which could "UK lie given in very low do-e--. high tat.... . rale- wen- found with -horl laleucv period- (experiment 14. table 2'. Therclore one can -till expect increa-ed tumour rateafter injection m do-e- 2d * bd rime- lower than tin- ..ne- applied here. Running -tmii"vith lower d'..... will gi\" more definite re-ub- "U Co- rei.-itiie carcinogenic potemv-- o' i oe-o and ..tuor eirke! eooitioiiud-. Tiiev will mane :ei--itih- a cun.pe.ri-un with the rank'ng riicl" toiiud dv > x,n.t:\iw iP.'-A- alter ! -high- i.m. adiuiui-trati-m o| !4 teg nieiv- n K a. Pat hot. :)2 nickel compound- Ki Fischer ruts. Cadmium sulfide also induced local sarcomas in rats after i.m. and -.c. injection (IC.y/axtzis and Haxih'ry 19<>(>|. All three nickel-containiiur dusts caused lung tumours after intratracheal instillation ('tallied), fn relation to the tlu.-e, nickel sub-mlfide had the strongest effect, nickel powder a -liichtly smaller one while nickel oxide vni< clearly tin1 least effective. Since cadmium sulfide has a considerably lower acute toxicity than cadmium chloride and cadmium oxide it could he dosed much higher and. depending on the dose level, led to lime' tumour-; (table 4i. The highest dose of 10 nut cadmium in cadmium sulfide caused early death of 'ome, animals. The tumour rate therefore appears to he too low. Also, after inhalation, cadmium sulfide seems to induce lum; tumours in rats (Ou)t<n-:s and Gl.wur t'.ikiii but not in hamsters and mice (llt-nxiucit ct al. LUSOci. .Most surprisimt wa-' the hitch lum; tumour rate of <>9"j after In intratracheal instillations of l"i mg each of very fine granular magnetite. This raises the question of whether an un specific reaction of the rat lum; to the large surface of the particles led to the tumours. This possibility is discussed for the inhalation of liitrli concentrations of TiU., (Li-;t-: et al. 1985). Ihit in contrast to other ferric oxides, maynetite could also have a ehemicallv carcinogenic effect. (i. OiluT ijriundnr <lustx A' non-carcinogonic control dusts we took corundum (experiments (>, 9|, titanium di oxide (experiments 9, 10. 11. It!, to), glass powder (experiments 2. fti and volcanic ash (ex periment 12). The tumour rates were between 0 and about 10%. Besides the above-mentioned metal compounds quartz was the only non-Fibrous mineral dust which had a low tumour inducing effect after i.p. injection of a higher dose (40 mg. experiment "2). l[of,i,.\xn etal. (1'iHiii found lung tumours in rats after inhalation of quartz dust. (Froth etal. (1980) after intratracheal instillation, and Waoxbr and Burry (1909) aftei intrapleural administra tion. I'olyvinvlchloride (PVC) was injected in a very high dose(o 100 mg), but the preliminary result (experiment 15) shows no clear carcinogenic effect. Since, the density of PVC is low, the animals received a high dust volume. Tn addition to a chemical carcinogenic effect, foreign body-induced tumours could be expected from the high mass which was deposited in clumps (Opckxiikimbr et al. 1948: Bra.xo 1980). The low tumour rate found after i.p. injection of high masses of granular dusts indicates that the. carcinogenicity of fibres cannot lie explained by a simple foreign body effect. Beech and oak dusts are known to induce carcinoma-; in the nose in humans, tn experi ment I") we tried to assess whether the i.p. test is sensitive for the unknown carcinogenic agent. The preliminary results (table 3t do not reveal an existing sensitivitv. ('ttin bl-on//.-' The length and durability of fibre-, are of great significance for their carcinogenic potency. It -hoiild be r-e-examinod how far this also applies to the diameter because the effect of relatively thick rock and ceramic fibre.-was unexpectedly strong. Further possible explanafioii.- could be surface properties or an especially strong carcinogenicity of verv long fibres i .29/ruu. which have been quite numerous in the samples used. A second measurement ol --vend of tlui used fibre samples is nece--ary for a better evaluation of the relation be tween fibre dimension- and carcinogenic effect. The available data of the fibre size distribu tion- a-e not comparable in all ea<e- because mea-urement-- wen' carried out at different time- u-ing different m -thods and by different working group-. Tile imraperitoiie d f-t in rat- i- ea-y fea-ible and is proved to be verv sen-dive for de lecting the carcinogenic effect o! durable natural and man-made mineral fibre- as well a.inet.-d compound- with low actin' toxicity. Tiii- mean- that, if a high dose of one of tlie-e du~t- doe- not induce tumour- in thi- t"-t. im -it-picion of carcinogenic poteiicv worth mentioning can lie -idi-iantiaied. .Maybe the pre-cut example.- are too few to In- certain 1.4-8 Ji.xp. l-'atlio:. :!2 )!i-7.:t that this is true i step would be t. negative result.a carcinogenic p inhalation of tinfcrablc to (lie h advantages and 1984l. The inlial risk of yielding I with crocidolitei pounds hut it inhalation by dm. While these influ the difference in point needs furl I /iV/i'riU/eCs- I!Minis, V. I., Sw I'lCl.i. A.: An . Karain i'rgfip liivi.-Kii. I'. ,f.: f'li. Dhu.m\.xn', I!.. made iniiK-i:it Fibres in tinpress). Ihnxox. J., .f u i holes. Kuviioi. lior/rox. |{. |< asbestos on on ferciire Kite:. 2. Intermit. I.. ISoXXKU'. I... Si I. Active sitc- Mm.aiiii. ('.. eliaraetei istii lies. I9SC,; 41 Hawn. K. <;.: I F.. Wixx. 1). \ eille. Praegel vol. 12i. Cmr.i.i.v. I.. ,T.: , to exposure '. -- I.uxuuir. W atri ilmtcd i<. Ihvi-. ,f. M. t;.. of fibre- in j'5 i, -- The palholoL -- - Bot.rox. It. f. parisons oi t f,In: Iti-.i k. K. lleillelheitf l'r -- Antii-ox, .r. vats ii-ie.g ; exp. I'arh. K' Doll. K.: (iverv I'ill VII oil 00-1!1 Itf.vxn.' v. .f.. : I9.--4: 7>7; Ki i.-iiX. V.-.f.. to tilllo i- g' pyi.-u.. < -- il 'arcuma.' in rats -tracheal in~tilhu!< u ifi-Ct, llickcl poWlItT i c;ulmimu chloride j i lie (lose level, led uiuill 'iilfide cau.'-ed tun low. Also, after ..DlliK'i illlfl (il.A'KJi - radical in.'tillatioii.s i of whether an mi le the tumours. This l.j 1 Ll-IK et ill. ISIK.JI. Mill-ill I \- ean-illogeuic. - ii. !I|. litaniiiiii diud videanic ash (ex lie above-mentioned . had a low tumour ' 2i. ILdi.i.axd et ill. rUOTII et ill. (19891 apb-ural administra- , hut the preliminary u.'ity of l'\T is low. carcinogenic effect, which was deposited rale found after i.p. eiiy of fibres cannot humans. In experiiknowu carcinoirenic vii v. in-mugeme potem-v. M-eailse the effect of er possible explana- of very long fibre--coiid mea.'iirenieiit of the relation lic fibre 'ize di'tribuieil out at ditfereiit "I V 'Oll'illve f.,r deo-.i! libri- a- W"! a 1".......f oiu- of i ii...... .-nii- p-Ueuev wort Si . lew to lie i-i-rtaiu that this i> true for every negative result, but this seems to be hittlily probable. An important ,'tep would be to establish a simple test meilmd that exclude' with a high probability false negative results for a certain group of 'ub.'tiinces. It is more difficult to deduce whether a carcinogenic potency resulting from the i.p. test in principle applies also to the lung after inhalation of the duets, and whether the observed order of carcinogenic potency is also trans ferable to the lima'. A- discusM-d in detail, there exist substantial differences with clear advantages and disadvantages lor each between the inhalation test and the i.p. test (Pott Iiis'41. The inhalation test simulates realistic exposure conditions but is open to the great ri'lc of yielding false negative results ie.g. some negative or weak positive inhalation studies with crocidulitei. The i.p. test has a high sensitivity ot carcinogenic fibres and metal com pounds but it cannot simulate the selection of particles which occurs physiologically after inhalation by deposition in different parts of the airways and by the clearance mechanisms. While these influences can be estimated more or less precisely, it is more difficult to measure the difference in the carcinogenic response of the bronchial epithelium and the serosa. This point needs further research. /I'c/'crc/o-es |>Minis, V. 1.. Smiin. A. A., O/.umii. AT., Knnsi:. 1.. (l/.ex, li.. Koi.uax, U., Ai.tixoiis, Af., (Iokti:1-kli. A.: An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain-Crgfip in Anatolia. Thorax 1978: 33: 181--192. )!i-.i;i:i.\ I'. J.: ['her die AsbcstosiskiSrpcrchon. Virchows Arch. 1933: 290: 280 --35:!, Rm.i.maxx, I!., Mi'iiu-:. II., Pott, I-'., Kiixio. 11., KloIH-kl. II., Sccit.w, K.: Persistence of man made mineral fibres i xrxrxn-'l and asbestos in rat lungs. Intermit. Symposium Man-Made Mineral fibres in the Working Kiivironmenf. (let. 28- 39, 198(1 in Copenhagen. Ann. On-up. Jlyg. iin press). limxox. .T.. .T.u'uvmi. M. C.: ISiologicalTo rilrn and in n'ro responses of ehrysotile veisus ampliiboles. linviron. Health Perspecr. 1983: 51: 73 -89. liourox, K. li.. Ihvis. .f. ,\f. (1.. Mii.li-o, 1!.. lfox ilusox, K-, Wiuoirr, A.: Tile effect of dose of asbestos on mesothelioma production in the laboratory rat. VLfh Internal. Pneumoconiosis Confeicure 1983. VI. Intermit. Pneiimokoniose-lvimfereiiz 1983. lioehum, 29--23. .Sept. 1983, vol. 2. Intermit. 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Pathol. 82. 17 VEB Oustav Fisi-b- Department of Fii Clinic of Internal A The periinusi By II. David. I. With 7 figures .Ithlnva [or I'nri'' Electron Microseop 1040 Ivey words: amvspace; Kupffei ret atrophy, hepatoeyi .8'n iiiniiirn The close nun the perisinusoid;0 results with the tiou of amyloid, the endoplasmic moved into the \ identical with lip the vascular probably played (rowing arm the vascular poll spacing between H) and 14m to tioll of orgaiieile- , / iili'nauri/t/ii Findings olu.. .suggest absence amyloid deposit was thought t" to hypoxia. In e-. SeiKo t1070'. ID (llhiiii. and Ski in fibrils, betwrfilling up the I d rily derived Irm may be found b lar material idissolved. Amv Xo informa' in the pa-t m- cells, mi the "!- 41 iced by benzyl lies on nephro- fer, D. Scholz and ubin in partially 73 liolipid secretion le rabbit Short communi- 81 89 Irugs: V. Factors and liver tissues 95 f drugs: VI. In excretion and acmature and adult 99 !CH. tase and .dpppe^fe^-'' .ralazine id 'Swiss1 '' IJL9 -X'iutrb'sogH^i'' " .testine of the-rat. .................................. 123 . 80. 87, 88. 93. 118. 127 EXPTAX 32(3) 129-192 (1987) PERIMENTAL PATHOLOGY Founded by F; Bolck, Jena by:. , . , !<:X- ' .i, , -, W JiHQ (!,v;yr-^r u.-ZWierter, Jeha '": - `' ' ``9 0-8190$ `r TO VEBbl^AVHSeHERyERLAG JENA Volume 32 198? ISSN 0232-1513 . Exp. Pathol. Jena 32(1987)3 pp. 129-192 No. 3