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PLAINTIFF'S EXHIBIT CAPCO JEN 0004-517  INSTITUTE OF OCCUPATIONAL MEDICI ttg EVIDENCE FOR VARIATIONS IN THE PATHOGENIC EFFECTS OF THE DIFFERENT FORMS OF COMMERCIALLY USED ASBESTOSV A Review of the Literature by J.M.G, DAVIS Pathology Branch, Institute of Occupational Medicine, Roxburgh Place, EDINBURGH EH9 ?SU. (Tel. 031-667-5131) DECEMBER I98O 1. CAPCO JEN 0004.518 CONTENTS Page No. SUMMARY ... . . . .............................................. (iii) 1. INTRODUCTION .................................................................................. 1 2. EPIDEMIOLOGICAL EVIDENCE RELATING TO THE RISK OF ASBESTOS EXFOSURE IN HUM/iNS..................................... 3 V' 2.1 Evidence from exposure to one dust type .... 3 2.2 Evidence from exposure to more than one asbestos dust type ........... 4 3. ANALYSIS OF DUST LEVELS IN THE LUNGS OF HUMANS EXPOSED TO ASBESTOS ......................................................................... 6 4. EVIDENCE OF DIFFERENCES IN AS3EST0S PATHOGENICITY DERIVED FROM ANIMAL STUDIES ....................................................... 8 4.1 Injection studies ......... 8 4.2 Inhalation studies .........10 5- IN VITRO STUDIES USING DIFFERENT VARIETIES OF ASBESTOS.................................................................................................. 13 5.1 Tests with nucleated cells .......13 5-2 Tests involving the haemolysis of erythro-cytes . 1 15 6. CONCLUSIONS........................................................ 17 REFERENCES................................................................................................... 21 . 1> CAPCO JEN 0004-519 REPORT UO. TH/80/4 (iii) INSTITUTE OF OCCUPATIONAL MEDIC I H E EVIDENCE FOR VARIATIONS IN THE PATHOGENIC EFFECTS OF THE DIFFERENT FORMS OF COMMERCIALLY USED ASBESTOS A Review of the Literature by Davie C c. SUMMARY The main commercially used types of asbestos are chrysotile, amosite and crocidolite although relatively small amounts of anthophyllite and trenolite are also used by industry. Since the use of asbestos is subject to strict controls in most countries it is most important to know if there are differences in the potential harmfulness between the different types. Unfortunately, the available evidence is fragmentary and to some extent contradictory. Evidence from human epidemiological studies indicates that exposure to crocidolite asbestos results in a much greater likelihood of developing mesotheliomas than exposure to other asbestos types. However, it appears certain that both chrysotile and amosite can produce these tumours in humans although anthophyllite may not be able to do so. There is also some evidence to suggest that crocidolite exposure may be more likely to produce bronchial carcinomas than chrysotile. Extraction of asbestos dust from human lung tissue indicates that levels of amphibole asbestos are higher and chrysotile lower than would he expected from exposure data. However, two papers from France suggest that chrysotile predominates in the pleural tissues and in mesotheliomas. In vivo experimental studies mostly using rats have used the techniques of intrapleural or intraperitoneal injection of dust or inhalation to administer different varieties of asbestos. Almost all the injection studies showed that chrysotile was at least as carcinogenic as the amphibole dusts and usually more so. In one publication only, UICC crocidolite had produced more mesotheliomas than UICC chrysotile but a "superfine" sample of chrysotile had produced oven more. All inhalation studies where tumours developed have found chrysotile more effective in producing bronchial carcinc :`J than amphibole dusts and chrysotile also produced at least as many mesotheliomas. X '! jft r. ,1! i 1 CAPCO JEN 0004-520 (iv) With one exception all vitro studies using phagocytic cells have found chrysotile more cytotoxic than amphibole samples although one group of workers using non-phagocytic cells did find that amphibole samples killed a higher proportion of cells than chrysotile". Without exception a series of studies examining the haemolytic effects of asbestos have reported that while chrysotile is highly haemolytic, the amphiboles show very little effect. Possible reasons for the inconsistencies between results from humans and animal experiments are discussed. For the purposes of protection of individuals exposed to asbestos, epidemiological evidence must take priority o^fb that from animal in vitro experiments. However, it is important to reconcile the differences and further studies using all available techniques are required. 1 CAPCO JEN 0004521 1. INTRODUCTION Asbestos has been used sporadically by mankind for thousands of years a]though for much of the time it was little more than a curiosity. Industrial production was hardly attempted before the l8?0's and expanded slowly so that i't was only at the end of the 19th Century that the use of asbestos became widespread. As early as 1906 MONTAGU MURRAY in England discussed a case of pulmonary fibrosis in an asbestos worker but the recognition that this constituted a definite industrial disease was slow to develop. An account of Murray's case was not published and it was not until 1924 that COOKE reported a second known death from pulmonary fibrosis in an asbestos worker. By 1930, however, WOOD and GLOYNE were able to review 37 cases of "asbestosis". In 1935, LYNCH and SMITH reported a case of asbestosis with associated bronchial carcinoma and in the same year GLOYNE reported on two similar cases. A definite association between the two conditions was not immediately recognised, however, and as late as 1951 GLOYNE, while recording that many asbestos workers did develop bronchial carcinoma, was still uncertain whether or not this incidence was above that for the normal population. In 1955, however, DOLL reviewed all coroners' autopsies performed over a 20-year period on asbestos workers from a large factory and concluded that the incidence of bronchial carcinoma in this group was ten times higher than in the general population. Although a later paper by KNOX et al. (1965) indicated that excess bronchial carcinoma could be largely eliminated by good dust control, this hazard is now well accepted as a potential for all asbestos exposed groups. In i960, WAGNER et al. reported a third specific hazard of asbestos exposure. They had found that numbers of the normally extremely rare tumour, the mesotheliomaj were occurring in the area of Cape Province in South Africa where blue asbestos or crocidolite was mined. They had failed to find cases in areas where either chrysotile or amosite was mined and even in a second crocidolite mining area in the Transvaal. Until this date there was no evidence that variations in hazard were associated with exposure to different asbestos types and as late as 1935 LANZA et^ al. in an early epidemiological study made the inaccurate generalisation that "the -.sbretos of commerce is chrysotile". The most disturbing aspect of WAGNER's report was the statement that some mesothelioma cases had received what appeared to be extremely low CAPCO JEN 0004.522 exposure to crocidolite. This and the subsequent finding of mesotheliomas in asbestos factory workers in Europe and the United States of America, some of whom have been exposed to crocidolite in addition to other dusts, gave rise to the suggestion that crocidolite exposure constituted an especially grave hazard. As a result of this, new British regulations by HM Factory Inspectorate in 1970 introduced a hygiene standard for crocidolite dust ten times .lower than that for other forms of asbestos. Some other countries including Sweden have singled out crocidolite as requiring especiallyT. careful handling and are currently considering the possibility of differential standards. Unfortunately, it has proved extremely difficult to obtain accurate human data on the relative harmful effects of the different asbestos types since as BECKLAKE pointed out in 19?6 "exposure to one fibre type only is rare (usually in mining) and most production workers have mixed exposure". Many epidemiological studies on groups of asbestos exposed workers have, however, been produced and while these report in detail on the level of asbestos health hazards, it is accepted that exposure to different types of asbestos has probably occurred. Studies of this type include those by SELIKOFF et_ al. (1965); HILL et al. (1966); HARRIES (1968) and (1976); ELKES and SIMPSON (1971) and NEWHOUSE et al. (1972); ENTERLINE et al. (1972). 1- CAPCO JEN 0004523 3. 2. EPIDEMIOLOGICAL EVIDENCE RELATING TO TliE RISK 0? ASBESTOS EXPOSURE JN HUMANS P.'i Evidence from oxnosure to one dust type For the most part the only asbestos workys to be exposed to a single dust type are miners and millers and epidemiological Gtudies of some of' these groups have provided a little information on the relative effects of ihe different asbestos types. In i960 WAGNER et al. published a report of 33 cases of pleural mesothelioma from South Africa. All but one of these were shown to have had some exposure to crocidolite asbestos. In 25 out of the 331 however, the exposure' to crocidolite had not been industrial, but the people involved had lived in the mining areas, in some cases for only a few years as children. It was concluded, therefore, that the latent period for mesothelioma induction by asbestos was long but that a low dose might be sufficient for carcinogenesis. McDONALD et al. in 1971 reported studies on a population of over 11,000 workers in the Quebec Asbestos Mining Industry where chrysotile is exclusively mined. The overall mortality of this group was lower than expected for the population of Quebec but in the highest dust exposure category comprising % of the cohort, the age standardised death rate was 2<# higher than in other groups. This increase was largely accounted for by an excess of bronchial carcinomas hut three mesotheliomas were also found. In 197** McDONALD jit al. enlarged the previous study to include a totaj of 28,000 men and confirmed their previous findings. Respiratory cancers appeared related to dust exposure but the overall excess of deaths from this cause was at most 50* more than expected. .Five nccoU.f" iomas were recorded, WEBSTER in 1973 updated the information on the occurrence of mesotheliomas in South Africa. It was reported that 158 out of 360 recorded cases had had definite exposure to asbestos but only 8 of these came from the mining areas where exposure to only one type of asbestos could be assumed. Of the 88 cases 8A had been exposed to crocidolite and four to amosite. In 1979 IRWIG et al. reported studies on 1,14!) men from the South African crocidolite runes x.i 5^8 who were involved in tre mining of amosite. It was claimed that pleural abnormalities visible on chest radiographs were significantly more frequent (at the 10,L level) among the amosite 1" thin cr.c.rg Iho.-ie who hod vorkc.! with crocidolite. There were B j; V fS 5 !?; CAPOO JEN 0004524. no other differences in recorded pathology between the two groups. In 1973 both AHLHAN ejt al. and KEURMAN e_t al. in separate publications reported on the incidence of disuse in Finnish anthophyllite workers. AHLHAN studied a population of 1,249 who had worked between 1936 and 1972 but only 170 of these had an exposure history of over 11 years. Among the whole group there were 105 cases of asbestosis. The population studied by MEURMAN ejt al. consisted of 1,04l individuals. Of 248 who were deceased, 21 had lung cancer compared to 13 expected but this difference was not statistically significant. Mo mesotheliomas were found. Apart from the mining industry a few studies do exist of groups of workers where it is claimed that exposure was to a single asbestos type. In 1972 SELIKOFF t al. examined the mortality experience of a group of 230 men employed in a factory that used only amosite. Total deaths were more than twice the number expected. There were 14 cases of "asbestosis and 25 cases of lung cancer where only two to three were expected. There were five deaths from mesothelioma, JONES et al. (1976) discussed the occurrence of mesotheliomas among women who had worked on gas-mask manufacture in Britain during World War II. No more than 1,600 had been involved, many for short periods of time, yet 26 mesotheliomas had been recorded. The asbestos type used in this gas-mask production had been only Australian crocidolite. A similar study was reported by t'cDONAl.D and McDCNALD in 1978. This involved Canadian gas-mask manufacturing during World War II. The same type of Australian crocidolite was used as in Britain. Out of 199 workers who had been traced, 56 had died by 1975* Of these, nine had a mesothelioma. 2.2 Evidence from exposure to more than one asbestos dust tyne Some studies on groups of people exposed to a mixture of asbestos types have attempted to distinguish between the harmful effects of each dust. Thus, ENTERLIHE and WEILL (1973); El.'TERLINE (1973) and WEILL et al. (1979) have reported on workers in the American asbestos cement industry. The final cohort size was 5*645 people with a 20-year . 1' CAPCO JEN 0004525 5 fullow-up tirae. Exposure levels to either chrysotilc or crocidolite did not appear to differ between the dusts but the standardised mortality ratios from respiratory caiyer for the highest exposed groups were significantly higher for those who had had steady exposure to crocidolite and chrysotile than for those exposed to chrysotile alone. Rather surprisingly no mesotheliomas were found in this cohort although two. had occurred in men with less than a 20-yenr follo'w-up period. One of these had mixed exposure including crocidolite hut the other appeared to have been exposed only to chrysotilej,"'" l CAPCO JEN 0004-526  C C 6. J. ANALYSIS OF DUST LEVELS IN THE LUNGS OF HUMANS EXPOSED TO ASBESTOS A number of studies have been published which have involved the extraction, recognition and quantification of asbestos from human lungs and the relating of- dust content to pathology. Thus, POOLEY in 1973 examined the lungs from 120 European cases of mesothelioma. He found that 37 cases contained only amphibole, 27 contained only chrysotile and the rest contained a mixture. It was reported that all the chrysotile cases had low dust levels although some of those containing amphibole had quite a high dust content. No distinction was made between the amphibole types. *t SEBASTIEN ej; al. in 1977 examined a small series of 18 autopsy cases with varying recorded exposure. Most cases had been exposed to both amphibole and chrysotile but unless exposure had been recent, more amphibole than chrysotile was always found in the lung parenchyma. Chrysotile on the other hand was the most commonly found asbestos variety in pleural plaques. Most of this occurred as short ultimate fibrils. ' In 1976 KEIDERMAtlNS et al. examined the lungs of 17 people with asbestosis and some cases not occupationally exposed. Fibre levels were between 1.1 x 109 and 2.7 x 1010 for asbestosis cases and 4 x 107^ g and 9 x 10 for controls. Fibre recognition was attempted with varying success. Among the asbestotics, amphibole was positively identified in only three cases with fairly certain identification in a further six. In no case was chrysotile identified. LE BOUFFANT et al. also in 1976 loo'xed at the relative amounts of amphibole and chrysotile in lung and pleural tissues obtained from 200 cases either by surgical section or at autopsy. They reported that while amphibole fibres predominated in the lung parenchyma with the amphibole/chrysotile ratio being 2.9, chrysotile predominated in the tissues of the visceral pleura. Here the amphibole/chrysotile ratio was 0.3. In the parietal pleura or in mesothelioma tissue no amphibole was found but quite large levels of chrysotile fibrils occurred almost all of which were less than 5 microns in length. 1 CAPCO JEN 0004-527 7, In e study on the types of asbestos fibre forming the central cores of asbestos bodies, CHURG and V/AHNGCK (1979) found that all of the 123 bodies examined from 21 patients contained amphibole. The reason why most workers have found relatively more amphibole fibres than chrysotile in human lung specimens in spite of the fact that chrysotile makes up the bulk of industrial asbestos usage was probably indicated by JAURAND e_t al. in 1976. This group produced evidence for the chemical dissolution of chrysotile in the lung tissue V" and rather surprisingly found that this was most marked in the fibre core of asbestos bodies. 1. CAPCO JEN 0004528 b. EVIDENCE ON DIFFERENCES IN ASBESTOS PATHOGENICITY DERIVED FROM ANIMAL STUDIES *.1 Injection studies Following his report of an association with blue asbestos exposure and mesotheliomas in humans, WAGNER (1962) showed that similar tumours could be produced by the intrapleural injection of asbestos dust in experimental aninnls. However, when the results of a very large study involving the injection of amosite, chrysotile and crocidolite into rats was published (WAGNER and BERRY, 1969) it was found that chrysotile produced slightly more tumours than crocidolite with only amosite showing significantly lower figures. In this study groups of approximately 100 SPF rats and a similar number of standard rats were injected with the three main asbestos types at a dose level of 20 mg. Tumour levels for the SPF and standard rats injected with chrysotile were respectively 63# and 69# while corresponding figures for crocidolite were 5^# and 68# and amosite 39# and 31#. In similar studies (WAGNER et el., 1970) the effects of varying doses of asbestos were also examined. In this case groups of 12 SPF rats were injected with doses of 0.5, 1, 2, b and 8 mgs of either chrysotile or crocidolite. Averaged over the doses, 36# and 19# of rats developed mesotheliomas from chrysotile and crocidolite respectively. The induction period was 100 days lower for chrysotile than crocidolite. In a later paper (WAGNER et al., 1973) it was confirmed that crocidolite dust specially prepared from bulk samples received from Cape Province in South Africa was in general no more carcinogenic than most samples of chrysotile. A sample of specially prepared "superfine" chrysotile was, however, the most carcinogenic dust tested. This paper did include a direct comparison between the standard UICC reference samples of amosite, anthophyllite, chrysotile and crocidolite. Thirty-two rats were injected with each sample and the mesothelioma induction rates were as follows: amosite 38%, anthophyllite 25#, Canadian chrysotile 31#, Rhodesian chrysotile 23# and crocidolite 59#* The authors treated all the data relating to the .animals in the different groups by n complex method of statistical analysis which they claimed gave clearer results. This produced a "carcinogenicity factor" for the different dusts of: amosite 0.66, anthophyllite .0.3(3, Canadian chrysotile 0.50, Rhodesian chrysotile O.bb and crocidolite 1.15 This publication CAPCO JEN 0004529 9. remains the only one in which amosite has ever produced more tumours than chrysotile. These results of WAGNER ej^ al. were ntfT confirmed by STANTON and WRENCH in 1972. These workers implanted a number of samples of mineral fibre including UICC amosite, chrysotile 'A' and crocidolite into groups of 30 rats. These groups developed 6C$ and 6l$ of mesotheliomas .; r.pcctively. In a recent study'(BOSTON et al. (in press)) intraperitoneal injection was used to compare the carcinogenic effects of a number of asbestos samples. This site proved more sensitive than the pleural cavity and the dose used (25 mgs) produced tumours in almost 10C$ of animals. However, there were significant differences between the tumour induction periods for chrysotile ar.d amosite samples. Crocidolite vias not used in this study. The dust samples were injected into groups of rots and for four chrysotile samples the main tumour induction period was 312, 375, *<00 and ,i31^ days respectively. For two amosite samples (ho corresponding figures were 505 end 566 days. A number of other workers including PEACOCK and PEACOCK (1968); REEVES et al. (1971); POTT and FRIEDRICHS (1972); POTT et al., (1976) and WIRTH (1975) have undertaken intrapleural or intraperitoneal injection studies using different varieties of asbestos and other minerals. Mot ;C1 of these studies were designed specifically to compare the carcinogenic effects of asbestos samples alone and those that did use more than one asbestos type produced results that were insufficiently clear-cut to make definite comparisons. in 1975 adopted a new ay.r.roech by examining the short-term effects of asbestos on lymph nodes following intraperitoneal injection into groups of 12 rats. Three dose levels were used, 5, 10 and 15 mgs. Five animals v;ere examined from each group after three months and seven after six months. It was found that crocidolite produced a greater increase in lymph node weight than chrysotile. Mean lymph node weights from animals treated with chrysotile and crocidolite respectively were at the different dose levels, 2*1, 29 and 26 mgs, and 3^, 53 and 53 mgs for 1- 'i.--'i:irt-`iinl lyirnh nodes "no ;2, i2 39 mgs and 55, 53 and 62 mgs for the cranial mesenteric lymph nodes. CAPCO JEN 0004530 10, As far as the effects of different varieties of asbestos on lung tissue are concerned, KL0STERK0TTER (1968) used intratracheal injection to administer long and short fibre samples of chrysotile, crocidolite or amosite to rats. Groups of 25 rats were used with each asbestos type and the dose was 30 mgs of dust. In all cases the short fibre samples produced almost no fibrosis while the long fibre samples did stimulate the production of fibrous tissue. No figures for levels of fibrosis were given but it was reported that "long asbestos fibres were strongly fibrogenic in the following order of magnitude: chrysotile, amosite, crocidolite.. h.Z Inhalation studies Inhalation studies in animals represent the most natural approach to the study of asbestos related disease and a number of publications have reported experiments involving different varieties of asbestos,used in order to determine relative levels of fibrogenicity and carcinogenicity. Thus, HOLT et nl. in 1?65 reported studies in which guinea pigs were given a short but heavy exposure of either amosite, anthophyllite, chrysotile or crocidolite. The dose levels of each dust were not accurately recorded and animals were followed up for only a few months. Widespread pulmonary fibrosis was reported ar.d no quantitative differences in reaction were noticed between the different dust types. REEVES et^ al. in 1971 and 1971* treated by inhalation five different animal species with either chrysotile, crocidolite or amosite. The sizes of the various animal groups varied'from 20 rabbits, to 30 mice and guinea pigs or 70 gerbils ar.d rats. Dust exposure was at a level of approximately 5 mg/m3 of air but it was admitted that the hammer milling process used in dust generation resulted in much destruction of asbestos fibres and less than of dust particles had an aspect ratio of more than 3:1. All species produced pulmonary fibrosis with some asbestos types. Although no methods of quantification were reported it was stated that crocidolite and amosite tended to produce more fibrous tissue than chrysotile. Only rats produced any tumours in these studies. There were two bronchial carcinomas and one pleural mesothelioma following chrysotile inhalation, one bronchial carcinoma and two pleural mesotheliomas following amosite inhalation and four bronchial carcinomas but no mesotheliomas after treatment with crocidolite. 1 CAPCO JEN 0004531 11 In 1963 V/AGNER had reported an inhalation study which had attempted to' compare the pathogenic effects of chrysotile, crocidolite and nroosite on guinea pigs and vervet monkeys. However, while the chrysotile and amosite dust samples were relatively pure, the crocidolite sample contained less than 1QS5 asbestos and the results were not, therefore, comparable. In 197f, however, -WAGNER et al. published the results of a large inhalation experiment in which rats had been treated with the UICC standard reference samples of either amosite, anthophyllite, chrysotile or crocidolite. Dose levels were approximately 10 mg/m3 of air and a number of different dose periods were--yvsed. Groups of approximately 50 animals were exposed for either one day or three months and groups of approximately 25 animals for either six months, 12 months or 24 months. There were significant differences between the levels of pulmonary fibrosis caused by the different asbestos types (P < O.Ol). Amosite gave the least fibrosis and anthophyllite and Canadian chrysotile the most. Crocidolite and Rhodesian chrysotile were intermediate. The overall numbers of malignant pulmonary tumours were: Rhodesian chrysotile 30, Canadian chrysotile 17, crocidolite 16, anthophyllite 16 and amosite 11. The number of pleural mesotheliomas produced were: Rhodesian chrysotile 0, Canadian chrysotile 4, crocidolite 4, anthophyllite 2 and amosite 1. In most of the experimental studies involving asbestos inhalation there has been relatively poor characterisation of the dust cloud in terms of fibre sice and shape. In 1978, however, DAVIS jet al. published a report of a study m which the UICC standard reference samples of amosite, chrysotile and crocidolite have been compared at equivalent dust mass or equivalent fibre number in the dust clouds. Groups of 48 rats were used. These results indicated that chrysotile was more fibrogenic and carcinogenic than the other asbestos types. For animals examined 17 months after the end of dusting, the equal mass (10 mg/nv') chrysotile cloud had produced more than double the pulmonary fibrosis of any other treatment (P < 0.001). The differences between the other four asbestos clouds were less dramatic but there appeared to be a definite gradation with the lower (2 mg/m3) chrysotile cloud having produced more interstitial fibrosis than any of the nnphiboles (P < 0.01). At the same time amosite appeared to have produced more damage than crocidolite but the differences were not significant. All malignant lung tumours found in this study 1. CAPCO JEN 0004-532 12. occurred in animals treated with chrysotile, eight and two in the high and low dose groups respectively. This finding was significant (P < 0.001). I C CAPCO JEN 0004533 13. 5. IN VITRO STUDIES USING DIFFERENT VARIETIES OF ASBESTOS In vitro studies have been used as an alternative approach to animal experiments for the comparison of t)}biological effects of different ' asbestos types. These studies produce results much more quickly and cheaply and it is hoped that eventually sufficient data will be available from comparisons between the two systems to be certain whether or not in_ vitro work can predict with accuracy the fibrogenic and carcinogenic potential of dusts. This stage has not yet been reached but data from a considerable number of studies is available. Most workers have used phagocytic cells maintained in. culture but some non-phagocytic cell lines hove been used os well as red blood cells. 5-1 Tests with nucleated cells In 1968 PARAZZI at al. treated guinea pig peritoneal macrophages with both chrysotile and crocidolite. The crocidolite was a standard sample from South Africa but the chrysotile came from Balangero in Italy. This is the only occasion that this type of chrysotile has been used in experimental studies. Dose levels were AOO fig of dust to 1 x 10^ cells. Toxicity was estimated by a fluorochromatic staining technique and by the production of lactic acid. The tests were run for a maximum of seven hours at the end of which all cells treated with crocidolite had lost their fluorochromasia but only 63 of cells treated with chrysotile. Similarly, all lactic acid production had ceased in cells treated with crocidolite within one hour of dusting. With chrysotile, production continued for almost all of the seven hours. In 1973 ALLISON using mouse peritoneal macrophages reported that chrysotile was much more cytotoxic than crocidolite or amosite. Dose levels were 100 pg/l x 10^ cells and after **8 hours the percentages of viable cells were I8/0 (chrysotile), 62* (crocidolite) and 735 (amosite). It was suggested that with chrysotile in the absence of serum there was an immediate toxic effect when the dust particles came into contact with cells but that this was delayed by several hours if the cells were grown in a medium containing serum. dusts. No such effect was seen with amphibole Similar results were obtcined using hamster macrophages by BEY and CAPCO JEN 0004.534. 14 IIARINGTON (1971) and MILLER and HARINGTON (1972). This group used dose levels of between 36 and 144 pg of dust/l x 10^ cells. With amosite and crocidolite the various dust dose6 produced little variation and at 72 hours the numbgj^of surviving cells expressed as a percentage of the undusted control figure was approximately 7C$ for all amo3ite cultures and 50 for crocidolite. Chrysotile was more cytotoxic and a dose effect was observed. The percentage of surviving cells at ?2 hours was 6C$ for a dose level' of 36 pg of dust, 35$ for 72 pg and C$ for 144 pg. T1 R0B0CK and KL0STERK0TTER (1971) and (1973) treated guinea pig macrophages with the different .UICC asbestos types and estimated the ability of the treated cells to reduce triphenyltetrazolium chloride (TTC). The dose level was 1.2 mg of dust to 8 x 10^ cells. The results, which were expressed as a percentage of the very cytotoxic effect of DQ12 quartz were as follows: chrysotile 'A* 6l$, anthophyllite 6*$, amosite 4C$, crocidolite 32$ and chrysotile *B' 3C$. Both WADE in 1976 and WRIGHT t al. in 1980 adopted a slightly different approach. In these studies the macrophage-like cell line P388D1 (DAlvE and POTTER, 1957) was used to improve reproducibility between experiments. Both workers reported that chrysotile samples were more cytotoxic than amphibole. WADE used chrysotile and amosite at dose levels of 10, 50 and 100 pg of dust for an initial cell concentration of 4 x 10^. After 72 hours the percentage viability was 95*3$, 61.1# and 46$ for the amosite doses and 45$, 5-7$ and 0.9$ for chrysotile. WRIGHT tested a series of chrysotile and amphibole samples at dose levels of 10 and 50 pg/5 x 10^ cells. After 48 hours the percentage viability ranged between 8.4$ and 25-8$ for the various chrysotile samples, between 52.4$ and 6C$ for amosite samples and was 96.4$ for UICC crocidolite. NEUGUT et al. (1978) used CHO cells, an epitheloid line derived from Chinese hamster ovary and K22 cells, an epithelial cell line derived from rat liver. In this case the results were given as growth curves rather than percentage viability at a fixed time point. It was found, however, that for both cell lines a 10 pg dose of chrysotile was more cytotoxic than either amosite or crocidolite. . 1 CAPCO JEN 0004-535 Similar results have been obtained in 1968 by SCI1LIPK0TER using a number of asbestos type and L cells which are a fibroblastic cell line. Results had also been expressed as growth curves and a dose level of 2,* mgs/l x 10 was used. The asbestos types in descending order of cytotoxicity were chrysotile, amosite, crocidolite and anthophyllite. CHAMBERLAIN and BROWN (1978) tested the effects of a series of dusts including UICC asbestos samples on two non-phagocytic cell lines. These were the V79-4 line originally obtained from Chinese hamster lung and the A5**9 line which appears to have tha(-characteristics of type II alveolar epithelial cells. While quartz dust had little effect on these cells all the asbestos varieties were cytotoxic. In these experiments amosite was the most cytotoxic followed by crocidolite, UICC chrysotile 'B', anthophyllite and "superfine" chrysotile. It was suggested that while this test system gave little information on the fibrogenicity of a dust it might give a better idea of carcinogenic potential. It was pointed out, however, that in animal experiments the "superfine" variety of chrysotile had proved more carcinogenic than any other asbestos type. 5-2 Tests involving the haemolysis of erythrocytes The following workers have tested the ability of asbestos dust samples to haemolyse erythrocytes. In 1967 KacNAB and HARINGTON tested a 2% suspension of sheep erythrocytes with a number of dusts including the main asbestos types. Incubation was for a period of 50 min at 370. While chrysotile caused 7haemolysis in this time amosite, anthophyllite and crocidolite asbestos lysed erythrocytes only after prolonged' incubation. In 1968 SCHLIPKOTER examined the ability of different asbestos types to lyse human red cells in different buffers at a variety of pH values. Results were expressed as the amount of asbestos by weight needed to produce JOSS haemolysis. While the amount of chrysotile was very low, the figures for anthophyllite, emosite and crocidolite were at least in order of magnitude greater. Also in 1978 VAILLE and COUCHARD tested the haemolytic effect of three samples of chrysotile and three amphibole varieties. While chrysotile CAPCO JEN 0004.536 .16 samples produced between 92 and 26#, chrysotile 9# and amosite haemolysis, anthophyllite produced Very similar results were obtained in 1970 by SCIiNITZER and PUNDSACK. These workers also tested the haemolytic effects of a number of asbestos samples on a 2# suspension of sheep red cells. After two hours' incubation, all of a series of chrysotile samples had caused marked, haemolysis, usually over 99#. No fig&res were given for the results of tests using naturally occurring UICC samples of amosite, crocidolite, anthophyllite .and tremolite but it was stated that "none of the samples of amphibole asbestos minerals was substantially active". WRIGHT _e_t al. in 19PO reported a study of the same type in which the haemolytic activity of a number of chrysotile samples ranged from 44# to 89#. The corresponding figure for UICC amosite was 2.^5 while the other amosite samples and crocidolite were less than 1%. CAPCO JEN 0004537 c 17. 6. CONCLUSIONS Human epidemiological data show that crocidolite has been the form of asbestos most liable to cause mesothelioma and perhaps bronchial carcinoma as well. Animal experimental studies suggest that chrysotile is more fibrogenic and produces more bronchial carcinomas following inhalation than the amphibole varieties. Whether administered by injection or inhalation, chrysotile appears to produce at'least as many mesotheliomas in experimental animals as crocidolite and more than amosite or anthophyllite. In vitro studies also suggest that chrysotile is more cytotoxic and haemolytic than ampbiboles in almost all cell systems examined. At present there is no definite explanation for ^ these inconsistencies but a number of possibilities deserve consideration. (i) It could be that rats, the most frequently used experimental animal, react differently to the various asbestos types than humans especially in relation to tumour production. However, rats are used routinely in toxicology to screen substances for carcinogenic potential and do show the same three general toxic effects of asbestos as humans, viz. fibrosis, bronchial carcinoma and mesothelioma. A better animal model is unlikely to be found. (ii) It is possible that for all species tumour induction requires'a g- large fraction of the lifespan. Chrysotile could veil be the most V an' chemically unstable and the most likely to dissolve in lung fluids. Chrysotile may be able to survive in rat lungs long enough to exert its full carcinogenic potential but be removed from human lungs over a period of many years. Amphibole fibres may remain in human lung sufficiently long and in sufficient numbers to provoke mesothelioma. (iii) While in most experimental studies the dust dose was accurately known, at least by mass and more recently by fibre number and length, the levels of industrial exposure more than 30 years ago are not known with any certainty. In the experimental situation crocidolite asbestos is certainly the easiest of the asbestos types with which to generate a dense cloud. Chrysotile requires much more severe mechanical treatment to generate a cloud and the fibres tend to flocculate and produce visible l;-i i] fj CAPCO JEN 0004.538 18, but non-respirable masses. It may be therefore that workers exposed to crocidolite in the past received doses far in excess of those applicable in chrysotile usage. There is some evidence to support this idea in the work of GIBBS afitPDU TOIT (1973) who reported on the levels of dust in crocidolite, amosite and chrysotile mines and mills from South Africa and Canada. These findings unfortunately were' produced either by konimeter or thermal precipitator and represent both fibres and particles but it is obvious that in the past the crocidolite operation in the North West Cape was far dustier than work Y' with amosite or chrysotile. WEILL (1979) found no evidence for increased dustiness of crocidolite operations in an American asbestos cement factory compared to processes where chrysotile only was used. However, in this case also the midget impinger was used for dust estimation and dust was expressed as particles per cubic foot of air rather than as fibres. (iv) Another major possibility that could explain the difference between human experience and experimental studies is that the exact particle size and shape is the important factor in disease rather than fibre chemistry. It is possible that experimentalists working with crocidolite and other amphiboles were in fact using materials with different characteristics to that found in industry. This is especially likely in the case of the gas-mask workers studied by JONES et al. (1976) who were exposed to Australian crocidolite which was little used in industry and has never been used in experimental studies. TIMBRELL (1973) suggested that the lack of mesotheliomas in the Transvaal crocidolite mining areas could be explained because the crocidolite from this area had thicker fibres than found in North West Cape Province. It was assumed that the thin fibres penetrated more easily to the pleura. Following the work of STANTON et al. (1972) and (1977) it is now generally accepted that the most carcinogenic fibre size is a length in excess of 10 microns and a diameter of less than one micron. Experimental studies have, however, indicated that all mineral fibres in this size range may be equally carcinogenic. Some evidence for the importance of fibre size arises from the work of WAGNER & BERRY. In 1969 when they reported injection studies showing chrysotile more carcinogenic than crocidolite, the published electron microscope 1* " . CAPCO JEN 0004-539 19. ' photographs of the dust samples used showed that the laboratory processed crocidolite contained fewer long thin fibres than the chrysotile. In 1973, however, UICC crocidolite was used containing many more long fibres. In this the crocidolite produced more mesotheliomas than UICC chrysotile. Only the artificially separated "superfine" chrysotile appeared more dangerous. However, both the inhalation studies of WAGNER jit al. (1971*) .and DAVIS et_ al. (1978). used UICC crocidolite. In the former study it appeared no more dangerous than UICC chrysotile and in the latter it appeared much less dangerous. ' From the point of view of protection of the workforce, reliable epidemiological evidence must take priority over that obtained from animal experiments. There is very strong evidence that exposure to crocidolite in the past has had a far greater potential to cause mesothelioma than has exposure to chrysotile or amosite and crocidolite should be used by industry with considerable caution if at all. From the biological point of view, however, it is most important to determine why experimental studies have not shown an increased level of hazard with crocidolite. Until these differences have been fully explained the hazards involved in the use of the different asbestos types will not be completely understood. It is essential that further work should be carried out to identify the factors responsible for carcinogenicity. This is particularly important because, for new types of asbestos products, human epidemiological evidence cannot be available for many years and animal studies represent the only possible way of obtaining advanced warning of increased hazard. Further examination of the characteristics of dust clouds produced in the asbestos industry in all phases of production and use and the relation ships between these characteristics and epidemiological, animal and cell toxicity data is required to elucidate these problems. 1 CAPCO JEN 0004.540 :C C c .21 REFERENCES AIILMAN K, PARTANEN TJ, RINTALA E, WIIKERI M (1973) Anthophyllite mining and milling as a cause of asbestosis. In: Bogovski P, Timbrell V, Gilson JC, Wagner JC.'^cis. Biological effects of asbestos. Lyon: International Agency for Research on Cancer: 165 - 168. (IARC Scientific Publication No. 8). 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McDonald jc, eecklake mr, gibbs gw, mcdcnald ad, rossiter ce (197*1) The health of chrysotile asbestos mine and mill workers of Quebec. Archives of Environmental Health; 28: 6l - 68. MacNAB G, HARINGTON JS (1967) Haemolytic activity of asbestos and other mineral dusts. Nature, London; 21*t: 522 - 525. HEURMAN LO, KIV1LU0T0 R, HAKAMA H (1973) Mortality and morbidity of employees of anthophyllitc asbestos mines in Finland. In: Bogovski P, Timbrell V, Gilson JC, Wagner JC, eds. Biological effects of asbestos. Lyon: International' Agency for Research on Cancer: 199 - 202. (IAKC Scientific Publication No. 8). MILLER K, HARINGTON JS (1972) Some biochemical effects of asbestos on macrophages. British Journal of Experimental Pathology; 53: 397 - *105. NEUGIIT AX, EI5EHBSRG D., SILVERSTE1N K, PDI.KRABEK P, WEINSTEIN IB (1978) Effects of asbestos on epitheloid cell lines. Environmental Research; 17: 256 - 265. HEWHOUSE ML, BERRY G, WAGNER JC, TUROK ME (1972) A study of the mortality of female asbestos workers. British Journal of Industrial Medicine; 29: 13** - 1*t1. PARAZZI E, PERNIS B, SECCHI GC, VIGLTANI EC (1968) Studies on the in vitro cytotoxicity of asbestos dusts. Medicina del Lavoro; 59: 561 - 576. PEACOCK PR, PEACOCK AJF (1968) Attempts to assess the carcinogenicity of different types of asbestos. In: Biologische Wirkungen des Asbestes. Internationale Konferer.z. 1963, Berlin: Deutsche Zentralinstitut fur Arbeitsmedizin: 227 - 255* POOLEY FD (1973) Mesothelioma in relation to exposure. In: Bogovski P, Timbrell V, Gilson JC, Wagner JC, eds. Biological effects of asbestos. Lyon: International Agency for Research on Cancer: 222 - 225. (IARC Scientific Publication No. 8). FCTT F, FRIEDRICHS K!l (1972) Turooren der Ratte nach i.p. Injc-ktion faserformiger Staube. Naturwissenschaften; 59: 318. 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SCI1LIPK0TER HW (1968) Tierexperimente und in vitro Untercuchungen mit Asbeststaub. In: Biologische Wirkungen des Asbestes. Internationale Konferenz 1968, Berlin: Deutsche Zentralinstitut fur Arbeitsmedizin: 67 - 74. SCHNITZER PJ, PUNDSACK FL (1970) Research; 3: 1 - 13. Asbestos hemolysis. Environmental SE3ASTIEN P, FOKDll'.ARE A, BIGNON J, MONCHAUX G, DE3B0RDERS J, BCNMAUD G (1977) Topographical distribution of asbestos fibres in human lung in relation to occupational and non-occupational exposure. In: Walton WH, ed. Inhaled Particles IV. Oxford: Pergamon Press: 435 - 446. SELIKOFF IJ, CHURG J, HAMMOND EC (1965) The occurrence of asbestosis among insulation workers in the United States. Annals of the New York Academy of Sciences; 132: 139 - 155. SELIKOFF IJ, HAMMOND EC, CHURG J (1972) Carcinogenicity of amosite asbestos. Archives of Environmental Health;' 25: 183 - 186. STANTON MF, WRENCH C (1972) Mechanisms of mesothelioma induction with asbestos and fibrous glass. Journal of.the National Cancer Institute; 48: 797 - 821. STANTON 11F, LAYARD K, TEGERIS A, MILLER E, MAY M, KENT E (1977) Carcinogenicity of fibrous glass: pleural response in the rat in relation to fiber dimension. Journal of the National Cancer Institute; 58: 5^7 - 603. t TIM3RELL V (1973) Physical factors as etiological mechanisms. In: Bogovski P, Timbrell V, Gilson JC, Wagner JC, eds. Biological 11 effects of asbestos. Lyon: International Agency for Research on CDncer: 295 - 303. (IARC Scientific Publication No. 8). CAPCO JEN 0004545 VAILLE C, SOUCHARD M (1978) Action hemolytique de l'amiante. pharmaceutiq'ues francaises; 36: 23 - 32. Annales WADE MJ, LIPKIN LB, TUCKER RW, FffSflK AL (1976) Asbestos cytotoxicity in a long term macrophage like cell culture. Nature, London; 264: 444 - 446. WACiNER JC (1962) Experimental production of mesothelial tumours of the pleura by implantation of dust in laboratory animals. Nature, London; 196" 180 - 181. y-'- WAGNER JC (1963) Asbestosis in experimental animals. of Industrial Medicine; 20: 1 - 12. British Journal WAGNER JC, BERRY G (1969) Mesotheliomas in rats following inoculation with asbestos. British Journal of Cancer; 23: 5^7 - 581. WAGNER JC, BERRY G, SKIDMORE JW, TIMBREI.L V (1974) The effects of the inhalation of asbestos in rats. British Journal of Cancer; 29: 252 - 269. WAGNER JC, BERRY G, TIM3REI.L V (1970) Mesothelioma in rats following the intra-pleural inoculation of asbestos. In: Shapiro HA, ed. Pneumoconiosis. Proceedings of the International Conference, Johannesburg. Cape Town: Oxford University Press: 216 - 219. WAGNER JC, BERRY G, TIMBRELL V (1973) Mesothelioma in rats after inoculation with asbestos and other materials. British Journal of Cancer; 28: 173 - 185. WAGNER JC, SLEGGS CA, 11ARCHAND P (i960) Diffuse pleural mesothelioma and asbestos exposure in North Western Cape Province. British Journal of Industrial Medicine; 1?: 260 - 271. WEBSTER I (1973) Malignancy in relation to crocidolite and amosite. In: Bogovski P, Timbrell V, Gilson JC, Wagner JC, eds. Biological effects of asbestos. Lyon: International Agency for Research on Cancer: 195 - 198. (IARC Scientific Publication No. 8). WEILL 11, HUGHES J, WAGGENSl'/.CK C (1979) Influence of dose and fiber type on respiratory malignancy risk in asbestos cement manufacturing. American Review of Respiratory Disease; 120: 345 - 354. CAPCO JEN 0004.546 WEIXER M (1979) Wirkunf? von Ar.best und Asbest-Quartz Gemischen ira Intraperitonealtest an Ratten. International Archives of Occupational and Environmental Health; Jt2: 169 - 1&3- WIRTH T (1975) Die Wirkunj; von Asbestzement, UICC Asbestproben und Quartz im Peritoneum der Maus. Pathologia et Microbiologia; if2: 15 - 28. WOOD WB, GLOYNE SR (1930) Pulmonary asbestosis. Lancet;' i: M5 - ^48. WRIGHT A, GOKHLEY IP, COLLINGS P, DAVIS JUG (1980) The cytotoxicity of asbestos and other fibrous dusts. In: Brown'RC, Gormley IP, Chamberlain M, Davies R, eds. The in vitro Effects of Mineral Dusts. London, Academic Press: Z'y - 31. CAPCO JEN 0004547 /XOL/JUkD JL (Limited by Guarantee) 68 GLOUCESTER PLACE, LONDON WiH 3HL MEMORANDUM TO: Member Associations FROM: Director General AIA/8/PAC 28 January 1982 Subiect2__Summary_gf_Hain_Features_ofj=Warning_Labels Enclosed is a copy of our schedule "Summary of Main Features of Warning Labels" which incorporates all amendments notified up to 15 January 1982. V CAPCO JEN 0004548 AIA Inform ation Memorandum No 4/81 A IA /8 /PAC 15th (January 1982 ASBESTOS INTERNATIONAL ASSOCIATION -- Summary o f Main Features o f Warning Labels UJ o5 4 os w < 03) oH P >a oQ 1o11 ^VO os z CL. 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PC *H C J3 44 H > P C P TJ U- 44 *H 44 C O C 44 o 43 > H <UO<v-/ a C o z >* TJ TJ C E Oa >* p 02 CJ T*H3 /--v P P h nr 44 rH 4T 04 44 p o to H p 44 m 3C H P -U_iI ij . c TJ rH r --i Advisory Council o f the AIA CAPCO JEN 0004.549 Voluntary I n i t i a l l y asbastoa By ei fib re s then a /c 1981 producte. On bags o f fib r a from Mabe mines by end o f 1981. Others in near fu tu re . US V-- < O r*. os <c to o sg o lu mj u^ os z a. a CJ \ >>- os os o < to f-- _j -> Z3(A Z3 a-w _J X aa > cj X os OS LlJ a 2: u. s z to H-t z ^ o <f _J CJ w < z OS oo Q Q < 44 H LI 44 44 U c 0 a. O 0 0 H 44 a. 0 E? a 3 *0 *4 ao ua. ocl 0 M a. o J c <D (4 X 4COJO 0) 44 a) 3 CO OS <.a X >* u >* (4 CO a J 44 cc 33 H i-4 O >- O >* 44 c e 44 8 0. ^ ao X 4i a rH X3 fH < >> L* 44 e 3 rH O > rH o 44 ^ 44 I C . . ~ O J3 CM U CO > CN ^ hhj 01 44 a c 0 *^-t*o3 hc 4- fr4 O *H 4- CL H U < CL 44 1 * rH JC O JH O 4J OH u x --- d 44 ^ >-- u n 03 o JC C44 C *H Li -J ao. o o c w ~ *4 a a. a. U u >uH a XU o *H 44 i-t c K3 Cc* 3 3 3 3 0. H h*ohjj e O O 030 > CJ CM > X O D 3 C -H OO H O 44 4- -o c u E 4e1 O 4-3 a 3 os *u 3 TJ *0 C a 3 m N U --I 43 (4 rH 3 O *-4 XO H* U a 1 44 0 >s 3 H M *0 44 W 0 O tf. CJ 3 O 44 u O O 0Xc O 44 *o l lh a H -o 44 O 0 03 C JZ c X3 C X3 a u a. o c *0 x *0 a. to 44 *a 44 < 44 a 03 O 44 c C c H > *H C 0 Li H J3 0 44 U -O O 03 CE c c0 O O a X3 c 4-> 0 O Z 3 O XS 44 H 44 os 0 O U X) f-t 0 U 03 JZ -Q 1 2 q.k\ (n cj rH X) *0 rH rH 3 0O sz c H * CJ O OS rH li. H O 0 4- 44 SZ u 44 44 X Li 0 O CL 44 X 44 US >. 03*0 Q. CCD. 33 C 03 Lt *0 3 CJ U 0NU UU *0 > C1t- 43 LL LL c 4O4 JC 4o4 44 44 x (0 44 o 44 -H 44 H X*H fl) O X JQ 43 < < < 3-H to z 1-4 o OS o. 3= K\ o CJ o o LJ LJ CO O > CT < c I. ^H wC o 3 o *u 3 44 44 >u n o XI n 03 w- rs 03 C 44 *cH D3*oH 4C4 44 -4CH4 4O34 Oc L 434 4l4 O 43 CJ Q C` o > >E < * L n 44 CJ o 3 x o c 44 XJ c *H *u0 N rH C O* 3 o c X OS H C *H 44 H X XS X C 44 44 44 44 Q f-t 44 44 c a u a (*a <0X3 x to a < CJ HON < _J ^ >- >- >- >- Yes Contains a3bB8to8, Obaerve Safety Rules. Avoid breathing duat. >OS JC (4 3 ME o c 0 c >* c E CAPCO JEN 0004.550 >ece S' S' g. *H JJ X <0 (4 C<T (D a. o 0 M G> a. o u0 0 a. o 44 ucd 0 a. o H 4-> (0 n CD a. o f-- UQi Q UJ VO o c_> w or z a. o CJ (4 X 3: a or s. >>- QT or o < CO zH- _r)l ^in ZD Q- OO s> cj >u% 0 x c 3 H O >* 73 0 X u- a o3 TD 23 uO lA Q. >> (4 0 44 C 3 H O >- 0 CC oa 1 > o <sc: os or ui HZ Co o 2: 0 b_ ZD -H z in 4 z ^ CH (00 4*HJ a <r Ex -J cn c o >% c I z cc oo 00 tA CTX 3 CC 03 Q *-( H 0 o 0 OH <c CD > 0 44 0 0U x0 X 0 5 or >> (4 o 0 H Xu o 0 H x Li 0 44 33 C CL E O CL 3 EH Oa CJ CJ > >* * 0 JO X 0C 0 C X 0 0 *H OH J0J 4OJ XP cHn X C 0o C U .0 0 O.UJ 3 OX X (4 0 0 C X X 0 *H 00 H CHT33 P0 *<-H .OH . OQ X X Lt S 0 0 CL 4J H *-4 (4 X <*- c o o> o 0 0 *H > J J lMA JO Z0 L* 0 ft f4 X X e <2 >^T3 0 0 *-H rH C c o 0o*c0 o 0 0 t4 0 0 0^ T3T3 05 aO o o a. 0 S&nJ0x 04J 3 0c (4 O 0 ^ 0 *H X H O E Ot 0 3 3CH CM O C X C CO Li 0 O0\Z OH4J 1)44 CD Z 1--< O or CD ^ ^ PA 0 CD O -J O H ` O 5 0 0 0 U-. O u X 0 O X u- 00 X3 0 0 *U c 00 C OlX OOC X X CX 0 XXX 3 C 0 X (4 OX0 X XC0 0 X O Ll c < CJ X X JZ 0 0 44 0 O I HH X 003 0 00U 0 X on JZ x 0 COX oh mo X 0 <*- XX E 0 X000 M O *0 *U O CD C X 0 0X Lt O 0 cn 0 O c0> HOP O cx 0 (4 0 0 0 0 OX 1--^X0 >s 44 r-i 0X 3 *0 TJ O X 0 44 O 0 0 44 3 3,'0 O 3 0*H X L< m0 o c0 0 JHC Ol 0 0C0 c c EX 3 O X O S X0 44 44 X 0 3 C O O >* 0 CJ O CJ >(4 <0 0 O CD ^ 0 0 00 zO CM 0 Oo o 0 X w >- >- >- >- 0 0 c- o *0 O X c (4 >or *c0 0 o uH XC Ll H 0 c O XX 0X 3 44 harm CAPCO JEN 0004-551 Operating Export markets. on agreed fo r Home & 90S o f a ll prod- luicat t3 V o lu n ta ry g. CO Pi 02 CL O in a HcOx- UZ02J ^ OQUU'O'-' 02 z a. o cj A Ol c (D A 00 j3 C <L S*H CJ as 3 4J X) AGO HOP <aa s>->oz 02 O Z<Hc 3i>nJiA =3 a-w Az oo S> CJ Z 02 az uj o 2: U- 33 z in -< z * o <f -J 0 c zo o02 o Q c u o CO 3 CL O CJ CD J= OA I 4-> A O CD 3C Pi * CL n*D 4- SO U - o CD A O* CD A C CT S 8 * A H C *H A O P< XX TJ CO A C Po CL A A C AMP Oo C Aa H CL A OH A 4- ea c E O A M A CD A CD OA O A CO A C A A CD CD CD CD 3 A A 0) A A T3 A C A Ah- A3 O A 3= > CD CO C*4 C Ao OA A cxi CO au> 4A 0)0 CA A CL O Pi cA OA A3 OX A "O X aus a o o as Pi A Q. Pi CAA A * Ol A 00 CD 3 O 0. A3 E A OA CD CD OT CT 3 3 CA X3 O T3 A A Pi C O A A Pi H o cn a <o> AAc C *0 A A A a T3 C E3 E* A al *4 . Pi a. tA a a. 0.-3 u * a o _ A Pt O A A00X Ac A (4 A e * ce * P4 3 A X A E Pi A XX * A cn 3: "3O Ol OPQ<. ACC APi t A0 A4JZ AC Ao UO AO Pi A4A AaPci AX CJ* *0 0 Ol A4- AC TAO XcX EO AO X X Pi Pi O AA C3 CL o * O CJ XX Pi ,, A XX CA jz a P A A 3 A * 3C**AOl o PI SS M c > CO X A C AO Pi Pi A < . = AA COC OA A A A -X O C A A. A Pi O 3 A 0 I3 1 ^ Pi jc a a OA AA C A CJ Pt XX 3 XX 0 X3 * A *0 O CO* A CXI A 01 u. cO 4. C AO A A CPA A A O JAZ A 3o A C CL 3 A A c T3 3 A Pi A PI o A rt 02 a * CJ M 3: = A A Observe the safety ru le s . dust can damage h e a lth . Warning: breathing aaba8toa Take care w ith a3be8toa. o 02 OO C3 O <H CoO3 C*4 < A'-' CXI EC O AA C Pi A C O ?A >Of C XX O z XX A c A- A CO u XX N CAPCO JEN 0004552 Lted Kingdom Yea Yes EKONHE YAN STOF AF ST0V UJ X z UJ o OM 1-- z Ul ui X CO X X o (4 o X 1=3 *4 UJ o X J-- UJ z H < x - uj 2 H- bC UJ 1-4 < ui to < X >- Oi Xow h- b- < Ul t=3 W aa oz . t=s x C I-- ac co *H H Cu 03 H a o CD (R <C u Si B 03 x o *0 03 o C03 e > u m i 6 oo 0) 3 in c c H *D {4 O 3= s in i Q U. UJ Ul X UJ X X QX s t-c uini O CO CJ m in CO -1 X rj X *-< UJ Xo > CO uj in 03 < JHO ouo ->*-:> > UJ > *- X UJ O a hx in UJ UJ >9H 8C Ul in uj Q *-- UJ Lu X - XX UJ ^ to uc in -J X> TSH O u. to u- czo HH .*9 QCzOzOC < Ki uzj f*4 UJ UJ UJ * Q UJ o--4 UzJ o X -J X <C 0.0 UJ Xc M UJ hh in >> CO CJ KUJM XX < J-H s H- ui Z CD u <c > uo in ui x in in ton u-Jj Q in uj x t Oof z >> UI ui czo u--j icno fu--. o X < in X Z h-i UJ O HX O < xH- UCDJ z tn uj < u<c U< SCO DX od o in Xo X< UJ I-- >- in a in UhI* za UI M X -J X zz UJ CO o UJ < > Ul CJ X< Xui X UinJ uj : z< in in o- CJ -J CD Ul UJ O JO uo co 5o >-< j-- in in, Z*- oH-' ' <m I-- UJ Z CD* Ul UuJ. >x i<n tn ui u tn uj _i z O I-- H < J-- co uj in POLYERE EINZUATMEN POUSSIERE CAPCO JEN 0004-553