Document QMkpRVgM4BBdmj2dVQE13BbpR

IT tx-f IKE 1.ANCET, MAKtlH 4, 1978 fllliUHU Occupational Health THE HYGIENE STANDARD FOR CHRYSOTILE ASBESTOS* Ji:uan Feto D-Jj-S.S Cancer Kpidetniology and Clinical Trials Unit, 9 Kcblc Hoad, Oxford Summary Previous studies, including the analysis on which the current 2 fibres/cm* hygiene standard is based, may have underestimated the risk of morbidity or mortality following exposure to low levels of asbestos dust. Accurate dose-response data at levels below 2 fibres/cm5 are unlikely to he available for the foreseeable future, and the biologically plausible assumption that excess cancer mortality is approximately proportional todust level should be provisional] y accepted. It may be reasonable, however, to postulate a safe threshold for mortality from asbestosis. If excess morta lity from asbestos-related disease is proportional to dust level for each cause, approximately 10% of male asbestos workers might, under certain assumptions, eventually die of asbestos-induced disease after SO years' exposure at 2 fibres/cmV Peritoneal mesothelioma is usually due to crocidolite (blue asbestos) or other amphiboles, but exposure to chrysolite (white asbestos) alone may lead to a substantial risk of pleural mesothelioma. These predic tions arc based on rather small numbers in a single fac tory, and further studies in other working environments arc required. Fibre counis based on optical microscopy are likely to be less relevant than total counts by elec tron microscopy, and excess mortality is virtually conlined to men first exposed more than 20 years ago, when lidlc or no accurate data on dust levels were collected. THE PRESENT STANDARD . Thu current hygiene standard of 2 fibres/cjtv' for chrysotilr asbestos dust was based on a study conducted in 1966 by the British Occupational Hygiene Society (B.O.H.S.).1 Currently employed asbestos textile workers who had been exposed for at least 10 years were examined, and the prcvalcnccf of crepitations (basal rtiles) was related to cumulative dust exposure Tlbre/cTn, years), A log-normal dose-response curve fit ted the data adequately and led to the prediction that the cumulative dose corresponding to a V'n lifelong risk of developing crepitations was approximately 100 librc/cm' years, or 2 fibres/cm3 for 50 years (Tig. I).3 Most men with cumulative exposures of less than 100 fibres/cm3 years had been employed for between 10 and 20 years at average dust levels of less than 10 fibres/cm3, and the absence of crepitations in this group was the basts for the prediction that the effect of 50 years' expo sure at 2 fibres/cm3 would be minimal. This prediction would be reasonable if crepitations Mtiivi'i) im u report prcv'nicil iiwhf AiUtmijv tiomiliiHn' mi AsK'sh'1' Ik'itltli Jiul S.-ilm ]-x.`fiiuvc- in I .nfitlnnnii |iijk* Hfc, 1`lhr firnutriuv vt upn r. ilit pniptirunfi r percmiu^ nl wurkrrs wuli ihr iipi ui |i pvMlciilur tilin'. 'Nils nimt hr tfislHiHimhfi) lrmn iur'jWruiv, whix'li j% itif ruir Ml jpfwurumT of new uncs in previously unullrilfti wii, unit is usiiulfic*prn%i*l Hi u ftrnjBvtiwB us pcrvcntimp per minum. (un early sign of the ellect of accumulated asbestos expo sure) rarely appear or progress after exposure has ceased. However, other assumptions consistent with these data could lead to a predicted risk an order of mag nitude higher than 1% following 50 years' exposure at 2 fibrcs/cm3. For example, suppose: (1) that pulmonary damage caused by inhaled asbestos dust is progressive, either because fibres remain in the lung or because the fibrosis they engender progresses after they have been eliminated; (2) that crepitations rarely appear less than ID years after first exposure; (3) that men are usually removed from employment when they develop crepita tions; and (4) that incidence (rate of appearance of new cases) is approximately proportional to cumulative expo sure after an initial lag of 10-15 years. The B.O.H.S. study comprised all men who had started work since 1933, had completed 10 years' service, and were still employed in 1966. The proportion of men with crepi tations rose from zero at exposures below 100 fibre/cm' years to over 16% at 400 fibre/cm3 years. Under assumptions (1) to (4) the lack of cases in the lowers exposure groups might merely reflect a dday between first exposure and the appearance of crepitations, while the prevalence at 400 fibre/cm3 years would, if men were usuallv removed from employment within, say, 4 years of developing crepitations. Suggest that the annual risk of developing crepitations after a cumulative expo sure of about 400 fibrc/cm3 years might he Al7t per annum. (This figure depends on the average time from first detection of crepitations to early retirement, which has arbitrarily been taken to be 4 years. If employment normally continued for 8 years after the detection of cre pitations the predicted incidence corresponding to 400 fibre/cm3 years would be roughly halved.) If incidence is proportional to cumulative dose the incidence at 2 fibres/cm3 might thus rise from zero during the first 10-15 years to about 1*? per annum after 50 years, when the cumulative exposure would be 100 fibre/cm3 years. The risk of developing crepitations by retirement after 50 years' exposure at 2 fibrcs/cm3 would then he about 20r',', and some further cases would appear after retirement. This figure is not presented as a useful pre diction of the likely risk. It is intended only to illustrate the importance of the assumptions implicit in such extrapolation, particularly when prediction of the long term effects oflow exposure is based on initial response to relatively high exposure. worth siu the natur mortality tations excess ap; It sh'ii of devel'r (crilcri'x \ 4,, tHRESHO since* response of a Utri - applying < tciemift: - nndcrsu whether fr on thtxn linear d even wh larly for dcmic p could b: HT MORBIDITY AS A BASIS FOR A HYGIENE STANDARD The B.O.H.S. analysis is significant because it is the. basis of the current standard. However, the risk of'de veloping crepitations may not be an appropriate basis for a hygiene sumdurd. The sign itself is virtually asymptomatic and may not progress to severe breathless ness or entail a substantially increased risk of bronchial carcinoma or mesothelioma. In ihe absence of direct observation of the prognosis in afleeted workers a stan dard based on such early signs nitty thus be unreasons! hlv restrictive. Moreover, if datu On severe disability or death are sufficient to evnlun'e the significance of the sign they will also be sufficient to assess the serious ri*-: directly, so there may be little advantage in cotlsideriu the prevalence of such a sign in (ranting u hygiene slatdard. This is not to say that such early signs are tun "i 4,1971 On -fi mj.r pt)sure itj ulnianaryi ogrcuive,! causeihe? <ave bee#' te than c usually ' crcpita-c of new :>vc expo- B.O.H.S, 3fl since were still th crepi- fibn/cm' >* Under ie lower- beiween "is, while - if men "ay, 4 ve expo4'? per from t. Which ioyment ' * :e at 2 he first ) years, bre/em3 ifement then be Jr after fui pre:ustrate n such -e longisponse T)|K lancet, march 4,1978 v/i- ib studying. They contribute to un understanding of natural hisiury of the iliscuse process, ami increased ^,1. taliiy ina small proportion of workers with crcpilaljiuis can be delected and estimated before the overall excess approaches statistical signilicattce. li should also be pointed out that a 1*7. lifelong risk ofdeveloping such a mild condition may be too stringent a criterion. THRESHOLD AND t.tNltAH MODELS FOR CANCER INDUCTION Since the pragmatic implications of a non-linear doseresponsc model such as that in lig. I and the assumption of a threshold (absolutely safe level) are similar 1 shall apply the term "threshold" to both. The distinction is of scientific importance, but' in the absence of biological understanding epidemiological data cannot establish whether a safe exposure level exists. Crump et al. argued on theoretical grounds that legislators should assume linear' dose-response below the range of observation, even when the data suggest a quadratic model, particu larly for carcinogens,1 but for asbestos this is an aca demic point. The apparent threshold for crepitations could be an artefact for the reasons cited above, while Fig, t--Dose-response reliEuhip for prevalence of basal rAles to worker, la * cltrysodle asbestos factory (data from Derry1). Log-normal curve, Numbcrsofcases in italics. 485 for lung cancer and mesothelioma there is neither theor etical nor statistical evidence to suggest that the relation between dose and response is unythingother than linear. previous studies relating cumulative exposure and LUNG-CANCER MORTALITY The suggestion that the eventual proportional excess (relative risk minus one) of bronchial carcinoma is approximately proportional to cumulative asbestos expo sure* is supported by published work. Hntcrlinc's data1 suggest such a linear relationship, but he rather arbi trarily superimposed a normal distribution (lig. 2) and concluded: "Had larger numbers been available it might have been possible to identify more precisely a T.I..V, f threshold limit value) lor respiratory cancer in this type of population. `Hie available data suggest, however, that large increments in respiratory cancer appear at a cumu lative asbestos-dust exposure of somewhere between 100 and 200 mpcf-ycars." Similar data were reported by McDonald ct al.* These authors inferred that "excess mortality was virtually confined to men with exposure equivalent to at least 400 mpcf-years"and concluded that "considering alt facets of disease--death, roentgenogrnphic changes, pulmonary function changes, and respiratory symptoms--the 1% risk is reached by men in our third dust exposure category (100-200 mpcfycars)". However, a straight line appears to fit their data well (fig. 3), and the corresponding proportional excess of respiratory cancer at 150 mpcf-ycars--about 30'i--would alone constitute u lifelong risk greater than 1ignoring morbidity and asbeslosis mortality. A cohort briefly exposed to amosite at the beginning of the 1939-45 war has been followed up by Seidman et al.7 This study is particularly valuable for testing models of the likely long-term effects of asbestos expo sure, since the workers' cumulative doses (fibre/cm1 years or mpcf-ycars) have remained constant over more than 30 years, and the recorded duration of exposure, which was less than 2 years for most of the cohort, is probably closely proportional to cumulative dose. The relative risk for lung cancer rose tor about 20 years and U)T RD is the of" de- basis tually thlestnchial direct siantsoua ity or G" the is risk n Fig. 2--Relative risk (observed/enpected) Tor resplrnlury cancer In retired aebesias workers (data from Eniertlne et at.'). - -- ...------ Onpmil cumulative normal curve. NumiImt, ,,( deal hr in holies. il .100 tiiXI Cumuiativi! iJobo linpd ytw:l `mm Fig. 1---Agc-adjustcd respirelory-cancer mortality in chrysetile mine and milt workers (data from McDonald et al.*). Tile highest category [MX) nr more mpct'-yearO is pinned ai tout) uipcf.year*. Other categories arc pinned al iticir mid-range. Numbers ofdeath* hi iialies. T ihi'ii remained nearly const uni. Tile usKtimplion ih;n proportional excess risk is proportional In cumulative Jose may therefore be :t useful approximation iti retired workers or groups such as [he asbestos itortile workers described below whose exposure during recent years has been low compared with their earlier exposures, but a more sophisticated model is required to describe the slow initial rise. If the duration ofbricfexposure can be taken as a measure of tola) dose the results of this study appear to suggest that for respiratory cancer lower doses may be proportionately more dangerous, and Knox' in ferred that the cancer risk is proportionately higher at lower dust levels or shorter exposures. However, neither these data nor the studies he reviewed are described in enough detail to confirm such a pessimistic conclusion. Such apparent non-linearity could be due [o selective removal of workers who develop respiratory symptoms, saturation at very high exposures, underestimation of expected numbers, or random error in estimates of dose or duration ofexposure. A HYGIENE STANDARD BASED ON FlBREs/cM* The studies described in the preceding section support the suggestion that dose-response is likely ici be approxi mately linear for bronchial carcinoma, and the first iwn studies illustrate the common error of inferring that there is a safe threshold because mortality in the lowestexposure groups is not significantly inercased. They may be of little quantitative relevance in framing a standard based on fibres/em', however. The correspondence between fibres and particles is very variable,9 and the estimates of risk shown in figs. 2 and 3 differ by a factor of more than two, perhaps reflecting differences of par ticle size and type in different environments. Pleural mesothelioma should be analysed separately. Excess mortality is likely to be proportional to the amount of dust that penetrates the bronchus for bronchial car cinoma or reaches the pleura for pleural mesothelioma, but the relationship with airborne concentration is not known. Different types and sizes of fibre are.likely to be distributed and eliminated differently, h may be reason able. to relate excess mortality to estimated particle or fibre counts in a particular environment, but different working conditions may not affect the risk uniformly for each disease. OJ---------------- ---.-----,---------- --v--------------i----------- 1930 1940 1950 i960 1970 Fig. 4--Awrhgt dust tcvtls, weighted by tbe number of men nt each level, lit an asbestos textile factory, 1936-72. Cttoiu from l'etocl al.1'). MORTALITY IN ASBESTOS TEXTILE WORKERS The 679 men in the asbestos textile factory in which the U.O.H.S. study was conducted who entered sche duled areas after Jan. 1, 1933, and had worked for at least 10 years by Dec. 31, 1972, have been followed up to the end of 1974.,n The B.O.H.S. cohort is thus in cluded. together with men who retired or died before June 30, 1966, and those who completed 10 years' ser vice between June 30, 1966, and Dec. 31, 1972. Deaths from bronchial carcinoma, pleural mesothelioma, other respiratory diseases, and other causes arc compared with expected numbers based on national rates in table t. 'I his shows a substantial excess due to cancer and respir atory disease beyond 25 years after first exposure (35 observed; 15-7-4 expected}. Mortality due to other causes has been normal, except for the "healthy worker" effect between 10 and 15 years after first exposure (14 obser ved; 21.63 expected). These men were still employed ai the start of the period of observation and were therefore unlikely to be chronically sick during this first period. DUST EXPOSURE listimulcd average dusi level* over ihe period of the siudy are summarised in iig. A.10 The average (weighted by the number of men ut each level} teas approximately 13 fibres/'em1 up to 1950, falling to about 5 fibres/em1 by 1955, Individual exposure histories have nut yet been compiled for the whole group, but for diseases for which excess risk is approximately TABU: I MORTALITY IN 67*1 ASBESTOS TEXTILE WORKERS A ITER 10 OH MORE YlAtts' EKI'OSIIHE i Vc'iir'- 1 WipriilMHT '| Mini war- ' .MCMlllll'hlllllil ;1 krill* |V1 1 Ob*. imniiHr .. tllv, 1 Olhtr rrtpirutnry . .... disease Obs l....... 1 lap OiIkt All L'lH-I-M-'S-- . -- CIUI'.L'N (Hts lisp 'A- H\ l ".IT U y,i.i s u IMJ,| 1 >|KX 5 I V.l4 Ufk wm ; i I.-Ul _ -Jll .. n|v Mivta'ci I'll- 1 V|1 LWJH'l ll'll 0111*111 (LlllJUII u-lirsi* IJ.IJIWIS ij ui\\? 0 llljs l J? 1 Hjl'1 t i t-|JT ** ! 4?\ 5hi 1 At W*T * .Ml J . iMi'P Ji '1 Ih Vi 2 u : AVW54 r> 5-56 \ yi i; J'j-.K2S' \) i 2.1 22 2U7 231x Mr,< 3B5 It, .111 11? 2] 5S-.2iw1 <r A 5fl 121 I21.HI -|KVl47 42 2K in 1X1. ' * .nm^jiii'ili'iai'v. nh-.rm\l nmiusf v|UMt-*| Jui nu-s<iJirfiHi>i;p,l'irtinilkiJilvurvimjmi, jiiuI n'.ypwuHirydiM'ihV, 7.H-2A IIMW Mi4 IjjCCttS talrihutiihli rLd'tyciairtaliusi*ri* Ohs l-kp i/xccw. morijilitv n ill.'A. vxn1 1 `H u.rm (IPH.0(5r IlM*' n.tt h-44 ii. in 4i, 11-41 23. Vi II 14 proportion to overall i gnd IWl oi [jty limilur lotnparabli study. Mei id, w c' [ have expei | appears to ; after first i respirator* mesothriic by 31% ( this excess during tht ! it based oi 1 Mts that 1 yean beft fibrts/cm5 fibresAxn' Dual le nentbrsni 1961 ouv udes/ft' ' fibres/cnv obtained tneasurerr TABLE II MALE AS! Yen of first exposure 1933-J4 1935--39 1940-44 Total Men full fibm/cn . direct ot to fibres are base. | 1-3 time j cult to a j appear | between 1950.'* I between ' did nm . rial asst further I excess n i dominai I fibre prt 1 Mor: liomu t averup 6-57 c. I CrcDMh ncgligi levels i ^!> 41971 fUB LANCET, MARCH 4,1978 4H7 X in which 'cd schcd for at owed up thus in- J before ars' scr- ` . Deaths ' ia, other " red with i table i. * - ' effect 4 obser- loved at nerefore tod. . ' tie study by the 'res/cm1 dividual e whole ' dmuielv biiiahk CCS* rtalilv A- tNl in U U) 41 pfoiiontundl la dust level these urcrJ|;c levels cun be related j0 uverall escess mortality, us 100 men exposed m I ijbra/ciuJ ^id 100 at J librct/cm1 would show subsequent excess murliitity similar ui that of 200 men exposed to 2 tit)res/cmJ over u pjmpurable period. Such aggregatum is done implicitly in uuy Study. Measured levels vury considerably over time in each irc*> so even a group nominally exposed to 2 libres/cm1 will have nqwwnced it wide range of dust levels. The excess risk appears to be largely confined tu the period beyond 25 years after first exposure (table t), when the excess mortality Tram respiratory disease, including bronchial carcinoma and mesothelioma, exceeded the expected mortality from all causes by 31% (19-26/61-44). The average exposure which caused this excess can be roughly summarised by total employment during the 30 years following first exposure. Table it, which is based on the 138 men fullowed up Tor at least 30 years, sug gests that this exposure consisted on average of about 11 6 years before 1954 at an average dust level of about 13 fibrei/cm1 followed by 9-4 years at an average of about 5 fibres/cm*--a cumulative dose dose to 200 libre/cm1 years. Dust levels in fibres/cm3 were estimated in each area from membrane-filter measurements at fixed sampling points from 1961 onwards. Thermtd-prccipitator measurements in partides/ft1 taken between 1951 and I960 were converted to fibrea/cm1 using the observed ratio of parallel measurements obtained by the two methods in 1960 and 1961. Routine measurements were not made before 1951. Estimated levels in TABLE It--sxrosuas (TOTAL SERVICE IK SCHEDULED AREAS) IK MALE ASBESTOS TEXTILE WORKERS IN THE 30 VEARS FOLLOWING FIRST EXPOSURE* Year of fir exposure 1933-54 1935-39 1940-44 % distribution of Average exposure (yr) No. of men total to- exposure (yr) 15- 20- 25- up to 1953 ' (approx. 13 fibrw/cmJ) from 1954 (approx. 5 fibm/cm1) 6 17 0 67 17 104 25 19 19 37 48 23 19 31 27 14.1 120 10.5 7-7 9.3 10-0 Total 158 24 18 25 33 116 9-4 Men followed up fur In, Lhun 30 yeiin urc ..milled. ftbrea/cm1 in each ana of the factory arc therefore based on direct observation after 1961 and conversion from particles/ftJ to fibrcs/cm3 between 1951 and 1960. Estimates before 1951 are based on the assumption that levels in each area fell from 15 times the 1951 values between 1933 and 1950. It is diffi cult to assess the error in this factor. Excess mortality does not appear to have been much higher in men first employed between 1933 and 1950 than among those first employed after 1950,10 and in view of the technical continuity in many areas between 1933 and 1950 it was considered likely that dust levels did not fall substantially over this period. However, this cru cial assumption is open to dispute and cannot be proved umil further IbJIow-up bus provided 4 more accurate estimate of excess mortality in mure recent employees. Exposure was pre dominantly to chrysolite, although a small proportion of the fibre processed was erocidoliie at various times after 1933. since 1955. This imcrpreiaiimi ts supported by an earlier study. J're-1933 workers, who were exposed to very high levels before 1933 and comparatively low levels subsequently, showed a similar luck of progression beyond 20 yeurs for high bronchial carcinoma und nvboiinsh itmrmMty.11 If the eventual proportional increase in mortality due to bronchial cnrcinuinn is approximately linearly related lo cumulative exposure mid the risk is doubled at 200 flbrc/end years, a level of I librc/em* Miithi* after 50 years' exposure, increase mortality due tu this cause by 25% after retirement, corresponding 10 a lifelong riskf of bronchial carcinoma attributable to asbestos uf about 3'if in smokers,4 The risk in non-smokers is probably very smull. Asbestos and eigureitc smoking appear tit enhance each other's dlcct* in causing bronchial carcinoma,13 bat mortality due tu ibis cause is so low in asbestos workers who have never .smoked that the risk due u> asbestos Clillkil be estimated with any confidence from published work. A MORE GENERAL LINEAR MODEL tOK UUONCM1AL CARCINOMA This analysis is based on the assumption that the relative risk for bronchial carcinoma is increased in proportion to cumulative dose. As this is not precisely true a less restrictive assumption may be preferable. Bronchial carcinoma accounts for an approximately constant proportion of male deaths in England and Wales '12rV at age 50-54, lulling to M>\ at age 70-74), and various studies suggest that the relative risk for this cause does not fall with the pussage of time after exposure iu asbestos has been substantially reduced or ceased. T he observed excess mortality due to bronchial carcinoma us a pro* portion of total expected mortality beyond 25 years (7-43/6L44, or 12%) is therefore a reasonable estimate of the lifelong attributable risk in this cohort. It would follow, under Any model which predicts that the increase in risk is approxi mately proportional to dust level, that a similar period of expo sure ai a reduced dust level would produce a proportionately lower risk. Thus a group that had on average been exposed tr> 1*3 ftbrcs/cm3 rather than 13 fibres/cm* for about 12 years fol lowed by 0*5 fibres/cm1 rulher than 5 tibrcs/cm3 for about l> years would probably have a lifelong auribuiublc excess risk due tu bronchial carcinoma of ahum 1-2%. The conclusion that about 20 years' exposure at about l llbre/em1 is liketv m cause bronchia] carcinoma in roughly l man in UN) thus fol lows from any tincur model, but a more specific assumption is required to predict theelfect of 5t> years' exposure. PMWRAI. MESOTHELIOMA As only 5 eases of pleural mesothelioma have occurred in this group, any model-lining or extrapolation must be very speculative. Then: 5 eases ore tabulated by man-years of obser vation in table t, which suggests that incidence rises sharpy wills increasing time since first exposure. A formal residence time model with Linear dose response for cancer incidence is given by the equation: Incidence at time T after first exposure i [ (j T-l \k cttl.Jl URONCIIIAL CARCINOMA Mortality due to lung euncers other than pleural mesothe lioma in this cohort has been approximately twice the national average beyond 25 years after first exposure < 14 observed; iS-57 expected). There is an evidence (hut the relative risk in* ^ creases beyond 25 years, which perhaps reflects the relatively negligible incrcuse in cumulative dose in recent years. Dust levels in this asbestos textile factory have been much reduced where cit * ts the dust level at time 1. The value k 1 lit* ilie incidence rates in tuble t well and corresponds closely to Newhouse and Berry's finding that incidence rose as ,t `>i after heavy mixed exposure to chrysolite and craciLloliic had ccuncd,u,M Applying the observed rates in table t, the predicted fllwaSiS. fuf 5vhK4 I lie {XClttt ribk |KniS|K lKwWl H'hfOiWUI CllUllltl I'C s||l|V iiurmnl tn r nsfc .r tiiiimlitiiva' pri^.ilfiki- ,il . |>.jriKiiJ.n .mi'. I lit- a^ins pn.uv MiiUsiu' ^ ih,- |w.ntm-ii.iii ^liit tn-ill orihiMlb >111' ! ilii` .liM'itw .is. .1 rr*nli il il>-ir W]nsiili' I Ins *s ift-sirily.l thnsiip.liiNii .is On- 'In,Cm: n%V* T w u ii& ium IKK prevalence alter 50 years' exposure m 1 (ibre/cm1 correspondin): io this model is I ti'.i The L-iirrt`S[x)Httiii)i lifelong attributable risk to a man exposed in 1 librc/cin1 Irani ape 15 to t>5 is approximately 2'',. Ii must lie emphasised ihai this eslimme is necessarily titirdiaide. Ii is based on only 5 cases, and 2' nl' ilicse eere in men employed in an area where rase asbestos was bandied who should perhaps be excluded I'rum ilie ctdeulaiinn, almost liulv. ill): I lie predicted risk. mtn:t [>m non-occupationai. uxposuHt: MutigituM diseases such as mesothelioma or branchial curcinoma for which the incidence rises as the third or higher power or time since first exposure to u carcinogen cannot be uiidcrsitn>d without such formal analysis. I:nr example, there hatl up to the end of 1*175 been 10 cases of pleural nicsnthcliomu aiming approximately 20 000 men first employed it) this factory after 103.1. To express this us n risk of (l-05'r is mean ingless. The lifelong risk tn a man employed continuously since 151.31 may exceed I0'i. On the other hand, the suggestion that brief exposure is extremely dangerous is equally misleading. I'rolintinary results of a study including the entire past and present workforce support the suggested model, and only 1 cusc is known ui have occurred in approximately 15 OCX) men exposed for less than 2 years since 1933, Isolated case-reports with a history of minimal exposure must be viewed against some hundreds of thousands of men and women with slight occupational exposure aiul several millions with casual nonoceupationul exposure. A recent study confirming that the risk of mesothelioma is dose-related suggests that only very high dust levels produce an appreciable risk after brier exposure.15 minimal CKoanoi.m. exposure in chrvsotiu: WORKERS It has been argued that pleural mesothelioma is due to crccidolite even when it occurs in workers whose exposure has been largely to chrysolite with minimal exposure to other fibres, lividence from three sources appears to contradict this inter pretation: (l) 9 cases1 have occured in Canadian chrysotilc miners and millers with no exposure to crocido]He;i'2i the in cidence in our study hie- been comparable in thut in Ncwhnusc amt Derry's" cohort of workers with heavy crocidolite exposura. 't heir daia show a clear dnsc-response for both severity ami duration ol exposure. Although average exposures were longer in our cohort, total exposure to crueidnliie was so niuel) lower that the risk of mesothelioma should have liecn far less than that observed in the factory we studied if crocidolite were the sole cause ol mesothelioma: i3- workers exposed to crucidohie show a eomparahle incidence of peritoneal and pleural mesothelioma. l:or exit tuple, 22 of the 45 mesotheliomas reported by Newhoirsc ami Kerry1* were peritonea! in origin, bone of the 34 that have occurred in workers in the factory we studied t including women and pre-1933 employees) or the 9 eases in Canadian miners and millers were peritoneal. An obvious explanation lor this difference is that chrysotilc causes only pleural mesothelioma, whereas crocidulite causes both pleural and peritoneal tumours. AXitiisrosi* 'Hie lifelong risk of death Irani asbcsiosis following exposure to t or 2 lihres/enr* cannot be predicted with any ctmlidcnee. 'llicre are oo grounds for assuming linear dose-response for such a generalised progressive disease, and although a quuliiulive dose-response has been demonslratcd ui very high expo sure levels" there' may well he a safe or virtually safe thresh- '.AvtunilliJ' (bat k ? aihl I link jmCjUr?I.** Hi VfHP. ulltf lint L'JlfHrtHfi' bjlJulA'Iilp IP ft vrur\ n> |.( lUvis-cu#' mill *t-4 vcwv ui S librrVcip' 'mfok 41 i* `i |Wf IdtlO (n l rfmiilli, liihh k. t.-l ' I 111- MhAk-li Jii In* |ii\|rlM'if . bill li'l ('Ms ci. .p: [iiiri^ksc n I*- irn k'v.Mii ulii ttii f inuk itiV rksy riMif'Jih it*- *u*. iln*- mnili'1 |iri'Jn,1'.. in (-*<> 'I Ill'M' IlKluf-i *tt Uiintls prufNirlinniiJ |m vuPlIL's iM 1 hi-lwvirti 2(1 ;tkuf Mlyc;ir,i,Ui>dfci;l4>'A. 2(kycu(b(Wdu.HtrN5.r thi: i.AHcn; march 4,1 V7r tHe i./ old. There were 17 dentils (*M7 cxpeetedl due in nun mitligiinnl respiratory disease over 25 years .tiller lirxi exposure in-our study, including 5 attributed to ushesinsis. If it IS assumed ilitii incidence is prnporliuiiul In ciiimihnivedusc, l lie currcs|mnilitig lile-long iillribiiinblc risk tiller 51) years' exposure ul l libre/em* would exceed I'i,4 bill lifts mndcl it presented for luck of another rttlhcr than because it is particu larly plausible biologically, f urther data on curly pulmonary signs may indicate whether u threshold exists, but even if the incidence of crepitations is linearly related to dust level the prognosis in affected workers may be related to the tcverily of preceding exposure. DISCUSSION There have been too few deaths in our study to esti mate the risks or evaluate the suggested models adequa tely for each asbestos-related disease, but the overall excess is substantial. There were 80 deaths (61-44 expected) more than 25 years after first exposure, in cluding 14 (6-57 expected) due to bronchial carcinoma, 17 (9-17 expected) due to non-malignam respiratory dis ease, and 4 due to pleural mesothelioma. The excess for asbestos-related disease thus exceeds the overall expected number by about 30%, The implications of these figures arc perhaps obscured by the necessarily complex statisti cal models presented for each separate cause. Ifdose-res ponse were linear for all causes (i.e., the risk of death due to asbestos exposure were proportional to dust-level for any given period of exposure) it would follow that about 20 years' exposure at about 1 fibre/cm9 would in crease total mortality by about 3% 25 years after first exposure. The trend in the right-hand column of table i suggests that this proportional excess is likely to persist with the further passage of time, so such exposure might be expected to lead to fatal asbestos-induced disease in about 3%, of men. The assumption of dose-linearity is dubious for asbeslosis mortality, but both epidemiologi cal findings and contemporary knowledge of carcino genesis suggest that excess mortality from bronchial car cinoma and pleural mesothelioma is likely to be proportional to dust level. These predictions might be grossly inaccurate. Indi vidual cases have not been investigated in detail, and previous employment in dusty working environments may have ctmtributcd in the excess mortality in this cohort, limplovmem histories arc now being re-exa mined, but the estimates of pre-war asbestos exposure are not reliable, and the assumption thut there is no safe threshold cannot he confirmed without long-term pro spective observation of workers exposed to low levels. The recent l.A.K.C monograph on asbestos,1' which provides a comprehensive reference source and summary nf recent work, concludes that "at present, it is not pot, sihle lo assess whether there is u level of exposure in hitmans below which an increased risk of cancer would not occur." There arc lints three alternatives: 1. 'lit conclude that tin- economic consequences of mure re strictive legislation are not justified unless a further 15 or more years' observation ol' workers exposed to low levels or purr dirysmile shows the ctirrenl siandiml to he dangerous, 2. To husc a decision on These analyses. Ignoring sampling error, nor results suggest that ala nil 5 III') nf men exposed lor 5(1 years lo ehrysniih- asbestos conceit I rulii ms Ilf I- ' tibies/em* arc likely to die nf asbestos-induced disease, t'lllil' ible * foci* which fore*** 3.1 prime. plates duct' to OSS' lures factor lion dies 1 emph; on the geode other TI liom; the > from whit' ccntt bebt to di distr plot ik>m worl appi I som lun) site; - othi the) . P<m' lily live I Pro* vari! tier j.r 2.1 \ u * A itirtlw nnr%mlifJniftui iieiTirrnl m wmiiim i (tab ftatfiiHmum wta> IihJ rrr vmmty hetn lutfut-'kifuliM-.