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j Asbestosis: a study of dose-response relationships i in an asbestos textile factory G. BERRY1, J. C. GILSON1, S. HOLMES*, H. C. LEWINSOHN*"*, AND S. A. ROACH* From the lMRC Pneumoconiosis Unit, Uandough Hospital, Penarth, South Glamorgan, CPS IXW, *TBA IndustrialProducts Limited, Rochdale, Lancashire, OLI2 7EQ, and\lmpcriai Chemical Industries Limited, WUmslow, Cheshire, SK9 IQB abstract A group of 379 men who had worked at an asbestos textile factory for at least 10 years has been followed up. The prevalence of crepitations, `possible asbestosis', certified asbestosis, small opacities in the chest radiograph and values of lung function have been related to dust levels. The type ofasbestos processed was predominantly chrysotile although a substantial amount ofcrocidolite had also been used in the past. There was a higher prevalence of crepitations than had been observed previously at the same factory. The presence of crepitations is not a specific effect of asbestos exposure and `possible asbestosis', a combined judgement of two physicians on whether a man had developedsigns which might beattributable to early asbestosis, was preferred. Fifty per cent ofmen with a diagnosis of possible asbestosis were certified as suffering from asbestosis by the Pneumoconiosis Medical Panel within 3*5 yr. The most reliable data relate to men first employed after 1950; 6*6% of men in this group had possible asbestosis after an average length of follow-up of 16 yr and an average exposure to 5 fibre/cm* where the dust levels were determined by static area samplers. The forced expiratory volume and forced vital capacity declined significantly with exposure, after allowing for age and height, but there was no decline in the total lung capacity. The transfer factor also declined with exposure, but not to a statistically significant extent. The non-smokers and light smokers as a group had less crepitations, asbestosis and small opacities on the chest radiograph than heavier smokers with similar exposure. Combining dust concentrations to form the cumulative dose may not be completely satisfactory, and a family of measures was investigated which allows for elimination of dust from the lungs and includes the cumulative dose as a special case. Because the rate of elimination of dust from the lungs is unknown, and cannot be estimated from the data, this approach leads to a wide range of possible interpretations of the data; for example the con centration such that possible asbestosis occurs in no more than 1 % of men after 40 years' exposure could be as high as 1*1 fibres/cm* or may have to be as low as 0*3 fibres/cm*. This range is wide because the data relate to higher dust levels, and a shorter period of follow-up. Until data are avail able on groups exposed to lower levels it will not be possible to assess the effects of the current standard with any certainty. However, the results of this study show that it is important to continue to reduce dust levels to values as low as possible. In 1968 the British Occupational Hygiene Society (BOHS) published hygiene standards for chrysotile asbestos dust (British Occupational Hygiene Society, 1968). One of the features was that risk was related to accumulated exposure, that is the sum of con- `Present iddress: Raybestos Manhattan Corporate HQ, 100 Oakview Drive, Trumbull, Connecticut 06411, USA Received for publication 13 March 197S Accepted for publication 6 July 1978 centration x period of exposure to that concentra tion over the whole period of exposure. With an accumulated exposure of 100 fibre/years/cm* it was concluded that it was probable that the risk of con tracting asbestosis would be less than 1%, where asbestosis was defined as the earliest demonstrable effect on the lung attributable to asbestos and this effect was the presence of persistent basal rales. The recommendations were made with two main notes of caution. First, it was pointed out that few 98 A0236S Asbestosis: a study ofdose-response relationships in an asbestos textilefoamy 99 data were available and apart from the early study in the United States (DreessenetaL, 1938) the only relevant data came from an asbestos textile factory in England and concerned 290 men. 16 of whom had basal rales. Second, the conclusions could possibly have been biased because they did not indude men who had left the factory, some of whom may have had asbestosis. These two criticisms were repeated by Holmes (1973) and Berry (1973). Another criti cism was that dust measurements were not available before 1951. Earlier dust levels were taken as 1*5 times those in 1951 and thus underestimated the cumulative exposure ofworkers employed during those years. In this paper we give the results of a subsequent study at the asbestos textile factory considered previously (British Occupational Hygiene Society, 1968). In this work both the medical data and the information about exposures have been improved. Fust, the time over which observations have been made has been extended by 6*5 yr so that the number of man-years of observation is greater. Second, the system of medical surveillance has been mads more systematic and comprehensive by the regular use of lung function tests; in addition, technically improved chest radiography with independent multiple read ings using the ILO U/C 1971 classification (Inter national Labour Office, 1972) has been introduced. Third, ex-workers co-operated by returning to the factory for a medical examination and chest radio graph. Finally, personnel and departmental records provided details of all the jobs done by all the men. This additional study was undertaken for the purpose of reviewing the BOHS Hygiene Standard for cfarysotile (British Occupational Hygiene Society, 1968; 1973). In this paper we are concerned with presenting data and methods of analysis, but not with recommending standards. The first section of the paper gives details of the methods used in the study and also gives data on dust levels. The second section considers the relation ship of the medical findings to dust exposure. The third section explores different dose-response relationships and their effect on hygiene standards for asbestos. This involves discussion of the prob lems of mathematical modelling (Appendix). Methods THE CROUP STUDIED The earlier, 1968 study was of men who had worked at the asbestos textile factory for 10 years or more, with all their exposure after 1 January 1933, and who were still employed at the factory on 30 June 1966. In the present study the group is extended to include 89 men who had completed 10 years' service between 30 .June 1966 and 31 December 1972. Men who had left the factory after 30 June 1966 were included. There was one man for whom it was not possible to produce an unambiguous job history. In addition, 12 men had worked for several years (at least 7, average 17) in a subsidiary factory, where they were employed in the preliminary treatment of crude asbestos. Dust conditions at this factory are unknown for the period in question, but were probably markedly different from those in the main factory. Altar excluding these 13 men a total of 379 men remained. medical information For all the men the following were obtained from the records in the factory's medical department: (i) the most recent chest radiograph; (ii) the date of the most recent medical examination; the date on which basal crepitations (rales) that did not clear on coughing were first heard; and the date of the previous medical examination; (iii) the date on which the factory medical officer first suspected possible asbestosis and the date of the previous medical examination; (iv) the most recent measurement of forced expira tory volume (FEVj.o), forced vital capacity (FVC), functional residual capacity (FRO, total lung capacity (TLQ, residual volume (RV), transfer factor (TL) by the single breath technique, and pulmonary arterial pressure of carbon dioxide (PaCOt), together with height, weight, and smoking habits. Because tests of pulmonary function were not introduced until 1967, these data were available on only 311, or 82% of the men. All the men who had left after 30 June 1966 were invited to attend for a chest radiograph and medical examination. Sixty-eight out of 113 (60%) accepted this invitation. 13 (12%) refused or failed to attend, and the remaining 32 (28 %) did not reply. However, there were only 20 men still living who had not been seen in 1970 or more recently. None of these 20 men had been certified as suffering from asbestosis by the end of 1975. Ninety-three per cent of the men in the study had been medically examined or had a chest radiograph since 1969 or within three yean of death. The men working in scheduled occupations have periodic medical examination* by a Pneumoconiosis Medical Panel under the Prescribed Diseases Regulations of the National Insurance (Industrial Injuries) Act, 1946. In addition, some men applied to the Panel for certification as having asbestosis. We were allowed access to the records at the Pneumo coniosis Medical Panel for the men in the study and noted whether crepitations had been recorded at 100 G. Berry, J. C. Gilson, S. Holmes, H. C. Lewinsohn, tmd S. A. Roach the periodic examinations and which men had been possible asbestosis differed from that of the factory certified as having asbestosis, together with the date medical officer. There were 12 men, placed by the of certification and degree of disability. Information latter in the possible asbestosis group, but for whom on certification is complete up to 1975 on all men, none or only one reader had recorded a profusion of including those who had left the factory. small opacities of 1/0 or more, and there were 37 men The diagnosis of asbestosis is based upon the whom only the clinician had placed in this group, presence of physical signs of pulmonary fibrosis, for whom at least two readers recorded 1/0 or more. radiological appearance and lung function defects. The climaan and factory medical officer McVittie (1965) indicated that the Pneumoconiosis the complete medical files of these 49 men together Medical Boards diagnosed asbestosis in the presence and reached agreement on a diagnosis. Seven men of a history of adequate exposure, on the finding woe removed from the possible group and five of end-inspiratory basal tales, finger dubbing; were added to it. The most common reason for radiological abnormality and reduction of lung considering a case not to be possible asbestosis function such as transfer factor and vital capacity. was that it was thought more likely that the signs Adequate exposure plus two of the other relevant were attributable to other disease. This shows that criteria listed above is sufficient for diagnosis but the diagnosis of asbestosis cannot be made without the Board must be satisfied that the individual is considering all the clinical evidence, and sole disabled, before certifying asbestosis. reliance cannot be placed on any single feature It has been the practice of the factory medical used for diagnostic purposes. officer to examine all asbestos workers routinely every two years, and to advise them to change to DUST EXPOSURE less dusty jobs if he believes that they are developing Details of all the jobs performed by each man were symptoms or signs of early asbestosis. He bases his noted by an independent industrial hygienist (SAB.) suspicions on die finding ofbasal rales or crepitations, who visited the factory and examined the employ radiological changes of varying degree, a falling gas ment records. In all, 236 job descriptions were used. transfer factor, and restrictive changes in lung For each job description a dust level was calculated volume or ventilatory capacity. This condition is for each year by taking the average of the levels referred to as 'possible asbestosis' and is a diagnosis measured at the static dust sampling locations in based on signs insufficient to attract Disablement the area where the job was carried out. In all, 64 Benefit The company has supported this policy sampling locations had been used over the period by paying workers with possible asbestosis, who 1961-72. change jobs, a guaranteed basic wage plus an Fibre counts were not available for 1951-60, but ex gratia payment. thermal precipitator particle counts were available Workers were given chest radiographs every three for 1952 and I960. The fibre counts for 1951-55 yean from 1951 until 1967 and every year since then. were taken as those of 1961 multiplied by the ratio Lung function tests were introduced in May 1967 of the 1952 to the 1960 thermal precipitator measure and are carried out every two yean. ments. This ratio was dependent on job, ranging from The most recent radiographs were read in random 1*4 to 3-4 (British Occupational Hygiene Society, order, and without knowledge of the men's identities 1968). The counts for 1956-60 were taken to be or job histories, by four readen independently the same as 1961-65. There were no dust measure using the ILO/UC 1971 classification (International ments before 1950. For 1933-45 the concentrations Labour Office, 1972). The four readings of small were taken to be 1-5 times those in 1951 and for opacities were combined by scoring the categories 1946-50 as 1-25 times the 1951 values. These con 0/0, 0/1,.... 3/4 as 0, 1, .... 10 and taking the centrations, particularly for the early years, are average score. In most instances the profusion of probably underestimates of the actual concentrations irregular opacities exceeded that of rounded opaci (British Occupational Hygiene Society, 1968). ties, but whichever type gave the higher reading Some men were coded as doing more than one was that which was averaged; there were only five job at the same time; the dust level in these cases films in which the profusion of rounded opacities has been taken as the mean of the concentrations was the greater, and in all of these the average for the different jobs. When a man was away from profusion was 0/1 or less. the factory, or at the factory but working in a job The factory medical officer had originally diag away from the production area, it was assumed that nosed 60 cases of possible asbestosis. A clinician he was not exposed to asbestos. (JCC) reviewed the medical data for each man As an indication of the dust conditions within without knowing his occupational history, and noted the factory Table 1 gives the mean dust level and the where his opinion on the presence or absence of percentage of men in the study within the ranges J 1 I l Asbestosis: a study ofdose-response relationships in an asbestos textilefactory IOI Tabic 1 Dust exposure ofmen employed in certain years and 89 had one or more of them (Figure 1). Year 1936* 11*94*16" IMIf sr I9<1 1966 1973 Nw dun >win of mem nmwt to W(/7cm*) <2fjcm* Il-Sflon* >3/frm* 13*3 14*9 J3*2 40 * )0*f 3 0 0 2ft 100 96 96 19 3-3 2 J-J 6 3-6 23 40 35 22 3SSf3ti 1*9 32 63 3 One man was certified on post-mortem findings. In addition, out of 19 deceased non-certified cases, there were three where asbestos exposure was considered contributory to death, and who might have been certified if an application had been made. None of these four men had been suspected of suffering from asbestosis during life. Eight men who had been certified during life have since died. In three of these, asbestosis was not Thn m ae dun taaMiimmaa ia ilwn yoan aad tba Am Imls givca in conidawd id ba towr Itata. tFlbra cauas aoc mirii ia iban toon Itm anl recorded at post-mortem examination; however, histological material for two of these three cases was reviewed later, and there was evidence of slight asbestosis in both. less than 2 fibres (O/cm3, 2-5 f/cm3 and more than 5 f/cm3 for certain years, for those men in the study who were working in production areas on 21 Decem Table 2 summarises various aspects of exposure at the factory, and ages are given. For those with signs (crepitations, possible or certified asbestosis) ber of the year concerned. and the three men who could have been certified From 1933, most of the asbestos used in the at death, the cumulative exposures, years since first factory, amounting to many thousands of tonnes, exposure and ages have been calculated up to the has been chrysotiie. In addition, about 2500 tonnes first occurrence of the signs. This means that, within of croddolite have passed through all the textile exposure categories, the data cannot be interpreted processes. as prevalences; for example, for those first employed after 1950 although 4 (11 %) out of 36 with less than prevalence and incidence 50 f-yr/cm3 had signs, the other 161 men are known The results are quoted as either prevalences or to have reached 50 f-yr/cm3 without signs. The incidences. The prevalence is the proportion or prevalences can be calculated using life-table methods percentage of men with a defined condition at one and at 50 f-yr/cm3 the prevalence is 2%, not 11V,. point in time. The incidence is the rate of appearance Most of the signs were first observed after 30 June of conditions in previously unaffected men, and is 1966 and, for men first employed after 1950 and given as the proportion or percentage per annum. whose cumulative exposure was less than 100 f-yr/ cm3 in 1966, the incidence rates since then were Results I-6, 0-7 and 0-5% per annum for crepitations, possible asbestosis and certified asbestosis respect NUMBER of men with crepitations, ively. POSSIBLE ASBESTOSIS AND CERTIFIED ASBESTOSIS COMPARISON OF RECORDS OF CREPITATIONS Eighty-two men were recorded as having crepitations BY FACTORY MEDICAL OFFICER AND BY when last examined, 58 had possible asbestosis, and PNEUMOCONIOSIS MEDICAL PANEL (PMP) 34 were certified as having asbestosis. There was Ail except two of the men in the study had beat seen considerable overlap between these three conditions at some time by the PMP. The recording of crepita tions by the factory medical officer and by the PMP are summarised in Table 3. Although there was agreement on the proportion of men with crepitations, there were 58 men for whom the records of the factory medical officer and the PMP did not agree. Some of these discrepancies were attributable to the time of the examination; for example, seven of the men read as positive by the factory medical officer and negative by the PMP had been seen more recently by the former. Other discrepancies were probably caused by the transient Fig. 1 Number ofmen with combinations of conditions (crepitations, possible asbestosis and certified nature of the sign in some men and also, no doubt, by genuine observer differences. More detailed asbestosis) for whole group andfor those first employed analysis showed that there was a significant excess after 1950. (p < 0-01) of men with low exposures among those *02368 102 G. Berry, J. C. Gilson, S. Holmes, H. C. Lewiruohn, and S. A. Roach Table 2 Summary ofexposure atfactory Frpnagk foetan WWtot first wplijerf before 1931 Total miMMgMg rarmadutaar 1933-33 1934-40 1991-45 1944-50 1951-55 195440 1941-45 Muinka gsuual Him wghigit gvurapg conemratioa ((Tea1) <5 5-9-99 10-19*99 2040 Cumulative eacpoeiifv* (fyr/cm*) <50 50-99 100-149 ISO-199 330-249 250-549 Tima tinea tat employed at factory* (yr) <10 KM4 15-19 20-24 25-29 30-39 Agr* (yr) ' <40 40-4445-49 50-54 55-59 60-72 Total 11 50 21 93 -- -- 1 30 70 73 5 25 34 44 39 33 1 0 17 65 51 46 3 5 22 34 52 64 152 i 21 11 23 _ -- 0 9 24 27 .1 6 12 17 11 15 0 0 12 19 16 15 0 0 13 22 19 62 Workrrefirst emoloyod after 1930 Total Wuktttm -- atom anon 109 22 75 6 13 2 11 12 92 12 36 95 52 14 -- 9 74 >,,4 1 9 It 2 4 12 13 1 -- 1 16 13 36 0 25 3 31 4 35 4 33 11 37 6 197 30 For tinge wtth gippg, lhM in ralraliiwl up to U fim occumucu of tba lign*. Table 3 Number ofmen with crepitations recorded byfactory medical officer or by Pneumoconiosis Medical Panel Pmeomoconiotis Medical Panel Ym No Total Factory medical officer Yes Mo 31 27 31 268 82 295 Total 71 299 377 in whom crepitations were heard at the factory but were not heard by the PMP. RELATIONSHIP BETWEEN POSSIBLE ASBESTOSIS AND CERTIFICATION Except for the one man who was certified after death, and had not been seen in the factory medical department within the previous 10 years, all the certified cases were also in the possible category. An analysis, using life-table techniques, has been earned out on the interval between suspicion and certification. The results are given in Figure 2. which shows the cumulative percentage of certified cases plotted against tune since suspicion; 25% became certified within 15 months of suspicion and 50% within 3-5 yr. Of 19 men who were uncertified after five years' follow-up since first suspicion, only one was subsequently certified in. on average, a further two years' follow-up. radiological findings, lung function AND EXPOSURE The profusion of small opacities and bilateral pleural thickening have been related to cumulative dust exposure (Table 4). Again, these data cannot be AU236 Asbestosis: a study ofdose-response relationships in an asbestos textile factory 103 Table 5 Regression coefficients oflungfunction indices and exposure in menfirst employed after 1950 take FEVU. FVC TLC TL (y.medkmd' -- 0*121 0*019 - 0*106 00)5 -0*006 0-037 -- 0-066 0*046 *TIm pfdirfrf iha vn cilniliad from the wfmiri nliinhim UMd la Ita factory; Aar wlatiniBhiia an akataad oa an aoc rapmid to atawi aatf allow for w ( jt) tad haitht (ft. al>FEV,., . 2-13*- 0*039 + IMS: FVC - t-M* - 0-032* - 3*34; TLC - 7*24 A - 0*<X21 a - 3*43 ;Tt - }2-0* - 0*20 a - 17-0. Fig. 2 Time between suspicion and certification of interpreted, as prevalences within the separate exposure categories because some of those subjects with radiological abnormalities wen suspected to have asbestosis and were therefore transferred to less dusty conditions. The lung function measurements have been ex pressed as percentages of predicted values allowing forageandheight(seefootnote toTable5).Theanalysis was restricted to Caucasians first employed after 1950 (141 men) and the mean lung function values within exposure categories are shown in Figure 3. Table 5 shows the regression coefficients on cumulat ive exposure. FEVi.o and FVC were significantly related to exposure but there was no evidence of a relationship for TLC; the relationship for TL could have arisen by chance but cannot be considered to be unimportant. THE INFLUENCE OF SMOKING Information regarding smoking habits was available for all except three of the men. The associations between the most recent smoking habits and crepita tions, possible and certified asbestosis, and small opacities, are shown in Table 6. The cumulative exposure was similar for each smoking category, as also was the time since first exposure to asbestos. For men first exposed after 1950 there are dear indications that non-smokers and light smokers are less likely to have any of the conditions. However Table 4 Radiologicalfindings and exposure Cmnhnw txpomrw (f-rrtcmT) Totmi Pnfimom ofsmall opacities* on no m Pint conformant before 1931 <23 23-49 50-74 75-99 100424 125-149 150-174 175-199 200-224 225-249 >250 Total Ftnl employment altar 1950 <25 25-49 50-74 75-99 100-124 123-149 >130 Total 2 2 9 15 8 29 20 25 22 16 34 1(2 5 31 59 37 26 22 17 197 1 1 2 3 4 7 7 4 3 4 6 42 1 10 9 14 2 6 4 46 00 00 2r 30 00 44 44 1 0 5v 30 10 2 35 10 00 20 J3 11 50 30 22 18 6 1/2 or more 0 0 0 ) (1/2. 1/2. 1/2) 1 (3/3) 1 (1/2) 0 1 (3/2) i am 1 (1/2. 1/2) 3 (1/2.2/1.2/1.2/2.2/2) 14 0 1 (1/2) 1 (1/2) i am 1 (2/1) i am 0 5 BUanrml piowml 0 0 2 4 0 1 2 3 1 4 19 1 2 2 3 0 I 0 9 'Avctub of 4 reader*; if tbe average i> halfway between two adjacent categories the reailim was rounded downward! (there were 27 such caeca between 0/0 and 0/1). tAt least 2 of tba 4 r--dm recording bilateral pleural thickening. AU237C J04 G. Berry, /, C. Gilson, S. Holmes, H. C. Lewinsohn, and S. A. Roach the non-smokers were on average younger the smokos, aged 55 yean compared with 58 yean for those first employed before 1951, and 47 yean compared with 52 yean for those fint employed after 1950. The data are shown in age groups in Table 7. After taking account of age, there were significantly fewer signs in non-smoken and light smoken than in heavier and ex-smokers, for men fint exposed after 1950: for crepitations, p < 0-01; for possible and certified asbestosis, p < 0*1 and for small opacities P < 04)5. Dose response relationships Fig. 3 The relationship between indices oflung function and cumulative exposure to asbestos,for men first employedafter 1950. The dose-response relationships considered in this section are those between the prevalence or incidence of one of the three signs (crepitations, possible, or certified asbestosis) and a measure of dust exposure. The mathematical forms of dose-response relation ships and a discussion of methods for combining the Table 6 The association between smoking andsifits ofasbestosis Empieptmmt gnmp amitmokiag habit Mamaammlmtha iufiyprtfucmrn*) Humbert ofmam Totai Crepitation Enodwatbtioatit First employed before 1951 Nmnaotat 1-4 dpittf/dir 5-14 apnOM/diy 15+ a'tMOM/dar Hi-dookm First employed after 1950 Never smoked 1-4 dwctn/dor ^14 dpwna/diy 134* agamem/day Ea-emokevs 197 22 109 7 its 62 197 62 192 28 79 42 91 13 19 48 4 68 tl - 24 4 3 22 20 7 0 0 tl 11 4 3 j IS 18 6 0 0 6 4 3 ProfiMioo I/O or non. Table 7 The association between smoking, age andsigns ofasbestosis Employment group aad tmakiag habit 4rt|m Humbert ofmam Totol Crepitation Ptuobsessibtloetit Certified atbewtoait 2 I 7 9 5 0 0 j s 2 Certified Small mdinbglrmi opoeitlet* 4 2 18 22 13 2 0 11 11 4 oSmpmdaicaoilitloiegsi*eal FirHstaemmtpslmoyoekdedbeafaodre11-9^5d1 pncta par day {r-53434* 11 18 7 6 2 0 6 Debar smokers aad a-emoken (r-554J+ 37 11s 7 42 5 34 2 19 6 47 Fin* employed aAar 1950 r-44 26 0 0 0 1 Never smokad aad 1-4 dinettes per day^ 45-54 17 0 0 0 0 12 0 0 0 1 --44 32 0 0 0 1 StOLber smokers sad e*emokcrs 4 45-54 ji 8 5 4 10 l 55+ 18 8 6 15 Profusion 1/0 or sore. &02371 Asbestosis: a study ofdose-response relationships in an asbestos textile factory 105 dust levels experienced at different times into mea 6% in 1966). This is attributable both to the longer sures of exposure are given in the Appendix. follow-up and to a difference between observers; If the factory medical 'officer suspected that a man the factory medical officer changed in 1967. Third, had asbestosis, then be would recommend transfer the 1966 data were taken entirely from men still to a less dusty job. Such a modification to a man's working at the factory whereas in the present study exposure based on medical signs is of relevance to this selective effect, although still present, has been the methods used to relate these signs to dust ex reduced by including men who left the factory posure; an unbiased analysis can be made only between studies. As an indication of the difference by using the times at which men with positive signs this makes, if the analysis had been carried out only first reached this stage. The observed dose-response on those still employed at the end of 1972, then the relationship is obtained using life-table methods. prevalence of crepitations would have been 17% (42/241) instead of 22%. This selective leaving ap RELATIONSHIP OP SIONS TO CUMULATIVE peared not to be caused by crepitations as such, DUST EXPOSURE but may have followed certification which was The simplest measure of exposure is the integrated correlated with crepitations; 29 out of 34 workers dust concentration over the period of exposure. with certified asbestosis were not employed at the This measure, which is the one used previously factory at the end of 1972. (British Occupational Hygiene Society, 1968), gives equal weight to a given concentration without DATE OF FIRST EMPLOYMENT taking into account when the exposure occurred. Dust conditions in the factory were measured only The data are first presented in terms of this measure from 1951 onwards. The above analysis depends on of dust exposure, and for all the men in the study. assumptions of the dust conditions in the period The dose-response relationship (British Occupa 1933-50, but an analysis restricted to men first tional Hygiene Society, 1968) was based on the employed from 1951 onwards does noL In addition, assumption that the distribution of exposure at such an analysis largely eliminates the bias caused which a sign first occurred was log-normal. A similar by the exclusion of those who left the factory before approach has been followed, except that the logit 1966. Forthis reason, the analyses have been repeated transformation has been used instead of the probit for the group of men starting at the factory after transformation, and the relationship fitted to the 1950 (Figure 1). Figure 4 shows the observed and signs (crepitations, possible asbestosis, and certified fitted relationships between the three signs and asbestosis). cumulative dose for men first employed after 1950. In the 1968 analysis, it was estimated that 1% The exposures giving 1 % prevalences were 37, 46, of those exposed would have crepitations after a and 63 f-yr/cm3 for crepitations, possible asbestosis dose of 112 f-yr/cm3 with 90% confidence limits of and certified asbestosis respectively; again, these 51 and 153 f-yr/cm3. In the present analysis the figures are given as illustrations only. response at a given dose is higher, and a prevalence of 1 % is estimated at 43 f-yr/cm3 (90% confidence LIMITATIONS OF CUMULATIVE EXPOSURE limits, 34 and 52). For possible and certified asbestosis Relating the prevalence of disease to the dust the 1% prevalences are estimated at 55 and 72 concentrations weighted by duration of exposure f-yr/cm3 respectively. These figures are given as to them is unsatisfactory because this ignores the illustrations only, and not as suggested standards; probability of developing disease after exposure has other points have to be taken into account in setting ended. This disadvantage may be overcome by standards. using a measure of exposure which weights the dust There are three reasons for the differences in the concentration at any moment by the time that has dose-response relationships for crepitations between elapsed since exposure (Jahr, 1974). Such a measure 1966 and 1972. First, the dust exposures are now attaches more importance to exposure a long time known more accurately and, in particular, it is ago than to more recent exposure, and continues known that some men spent part of their rime in less to increase after exposure has ended. When applied dusty jobs than the job category defined in 1966. The to men first exposed after 1950 it gives quite different effect of this extra information is that the average interpretations from those of Figure 4; for example, cumulative dose up to 1966 is now estimated as 1 % crepitations occurred at a dose of 163 f-yr*/cm3 about two-thirds of what it previously was thought which represents the dose accumulated by the end to be. Thus the figure of 112 f-yr/cm3 originally of 50 years' uniform exposure to a concentration calculated represents about 75 f-yr/cm3. Second, of 0-13 f/cm3. (Using the unweighted cumulative crepitations were recorded more frequently than exposure, the same risk occurred at the dose from previously (82/379 - 22% compared with 16/290 * 50 years' exposure to 0-74 f/cm3). For possible A02372 I l J' iI i J i I I t i mbbimi 106 G. Berry, J. C. Gilson, S. Holmes, H. C. Lewinsohn, and S. A. Roach Fig. 4 The relationships between the percentage developing the conditions, crepitations, possible asbestosis and certified asbesrosis, and cumulative exposure to asbestos,for menfirst employedafter 1950. The observed relationships were obtained by Ufe table methods. and certified asbestosis the 1 % prevalences corre first exposure; using this time as a measure of spond to 50 years' exposure to 0*19 and 0-37 f/cm* dose gives just as satisfactory a fit to the data as respectively. using cumulative dose and its generalisations; Thus, the choice of a suitable measure of exposure however, talcing account of the dust level is more is highly critical, and it is not known what measure appropriate biologically. is most appropriate. If, over a long period, dust is eliminated from the lungs at a rate proportional ALTERNATIVE DOSE-RESPONSE MODEL to the amount present, and disease is caused by The dose-response model used has a reasonable cumulative dose weighted by residence time of each biological basis, but other models may be appro contribution, then a family of exposure measures is priate. An alternative is that the incidence rate produced. This family is indexed by the rate of of diagnosis of an adverse effect is proportional exponential elimination, or half-life time, and, as to the amount of dust in the lungs (see Appendix). extreme cases, contains the cumulative dose (half The analyses have been repeated with this model, time zero) and the cumulative dose weighted by which was satisfactory for the case with a five-year time since exposure (half-time infinity). Further lag provided that the half-life was at least five yean. details are given in the Appendix. This family ofcurves has been fitted to crepitations IMPLICATIONS FOR MODERN CONDITIONS and possible asbestosis for a number of half-life The disease pattern observed in this study has times for men first employed after 1950. It was occurred as a result of higher dust levels than those impossible to estimate precisely the half-life time which occur now (Table 1). It is interesting to giving the best fit to the data, and any value in predict the likely disease pattern with current stand excess of three years was considered to be adequate. ards and the concentrations estimated to result Failure to estimate the half-life time reliably is not in a given percentage of men with disease. This surprising, because the critical data would be has been done for continuous lengths of exposure observations on men who had left the factory many of 30, 40 or 50 years. The percentage of men esti years previously. mated to have reached the possible asbestosis Another way in which the exposure measure may category by the end of a period of exposure to be inappropriate is that a given dose is assumed to If/cm? has been calculated and, in addition, the be effective immediately. The measure can be concentration necessary to limit this percentage amended to accommodate a lag period for the to 1 % has been estimated. These calculations have development of an observed effect by assuming been based on the parameter estimates from the that, however severe the exposure, disuse is not post-1950 group for both models for a range of observed until some minimum time has elapsed since values of the half-life time of dust elimination the start of exposure. There are insufficient data to (Table 8). estimate this lag period and the model was fitted Varying the half-life time of dust elimination incorporating a lag of five years. has a marked effect. For example, after 40 years' Cumulative dose is correlated with years since exposure to 2f/cmJ, and using the logit dose-response A 02373 %i ) 1 i i Asbestosis: a study of dose-response relationships in an asbestos textile factory 107 Table 8 Estimatedprevalence ofpossible asbestosis after uniform exposure to 2flat? and estimatedconcentration giving a prevalence ofl */, Holf-Uft ofUmimtiom ofAm from Enimettd rniotemo Ufrl/ltm* Ueetkeftneoemeiyri JO 40 50 EsAmtod co"C*MT*tio*(J}cM*)-l prrmUmet Loofth of npiwrt Q) JO 40 so Lofit modot (ao tec) 0 nimnterin dna 5 10 25 2 4 7 I-S ii 0-9 ts o-s4 7 it 1*0 0-7 0*5 59 0-S 0*4 o-s4 u I* 0*4 0*4 0-J 7 14 24 0-3 0-2 Logit model (S-rmr leg) 0 cinmilitnw doer 5 10 25 so ao dimaauioA Aiwrath* node! (5*)w tec) 0 5 z1s0 cd m to ilimiMrite to4 4 9 1*0 6*7 0*5 0 14 0*4 0-3 0-2 12 17 0-3 0-2 0-1 t 14 21 0-2 0*1 0*1 9 14 24 0-2 0*1 0*1 toT 12 0-2 0-2 0*1 . I 12 17 0-3 0-2 0*1 * 1 14 21 0-2 0-1 0*1 9 17 24 0-2 0*1 0*1 relationship with no hay period, the prevalence counts between 1951 and 1960. Second, the selective varies from 4% with cumulative dose to 14% with effect of men leaving the factory for health reasons cumulative dose weighted by time since exposure was largely eliminated. (Table 8). Incorporating a five-year lag into the There are errors in both the response and dose model changes this range to 6-16%. and using the in the dam analysed. Evidence of uncertainty in alternative model makes very little difference. response is provided by the differences in the Hence, the method of accumulating exposures to recording of crepitations by the factory medical dust over a period of time to produce a single officer and the Pneumoconiosis Medical Panel. Even measure ofexposure is critical, mainly because of the when the medical findings, are not in dispute it does unknown rate of dust elimination. not follow that exposure to asbestos is necessarily It is impossible with the data in the present study the cause. Crepitations may be caused by bronchitis, to discriminate in a statistical sense between any and pulmonary fibrosis may be detected on the chest of the possibilities listed in Table 8, except that radiograph in the absence of exposure to asbestos; those based on cumulative dose may be relatively for example, Weiss (1969) reported its presence unsatisfactory. in 0-6% of non-smokers and 2-2% of smokers. One reason for the wide range of values in Table 8 The prevalence of crepitations and radiological is that only six men had average exposures of less changes in the absence of asbestos exposure in the than 2 f/em*, but all of the figures in the Table are area where the factory is situated could be established below this value. Another reason is that the maxi- only by examining a control group; this was not num follow-up in the data is only 23 years, but done in the present study. The dust concentrations longer exposures are considered. Therefore the used were obtained from static sampling sites and. figures in Table 8 are all predictions derived from therefore, took no account of the work-style of extrapolations, and illustrate the difficulties of individual men. This may be the reason why the drawing any firm conclusions on the safety of dose-response relationship fitted the data just as well present standards from, data relating to the with time since first exposure as with the various dustier conditions which existed until recently. measures of cumulative dose. The effect of errors in response and dose, even if it were valid to regard Dlscnsshm them as purely random, would be to give lower dust levels associated with low prevalences of signs By restricting the main analysis to men first em than would have been the case if it had been possible ployed after 1930, two important sources of bias to collect the data without error. Thus, for example, have been reduced. First, estimated dust concentra the dust concentrations given in Table 8 would have tions for earlier years were not used, although, it to be increased before being applied to a situation was necessary to use the thermal precipitator in which the dust was measured by personal samplers. 2 3 7.\ 108 G. Berry, J. C. Gilson, S. Holmes, H.C. Lewinsohn, and S. A. Roach Most of the men in the study had been employed dues to the most appropriate value of the half-life elsewhere before starting work at the factory; only time of dust elimination. If elimination were slow. 40% started before age 30. Of the 13 men in the then cases of asbestosis would be first diagnosed post-1950 group who had possible asbestosis, five and certified in men who left the industry many had worked in the cotton industry. One of these yean earlier; if this were not the cam, then the use had been a stripper and grinder for 20 years and was of cumulative dose would be reasonably valid. It is considered to have readied the possible asbestosis known that an excess incidence of lung cancer and category within eight years of first employment at mesothelioma occurs in men many years after the the factory studied, the only sign within 10 years end of exposure (Newhouse, 1973) but information (Table 2). Another man who was certified as suffer is lacking on the diagnosis of asbestosis in former ing from asbestosis after 12 years in the factory asbestos workers. had previously been a chemical worker for 20 yean; There are several reasons why the might asbestosis was not confirmedat death. It seems likely, be inappropriate. First, if the diagnostic procedures therefore, that some of the signs observed in this were not uniform over the period 1961-73, then study were at least partly attributable to previous some of the recorded new cases could be attributable employment in other dusty occupations. to a change in diagnostic criteria rather than to true the association between smoking and signs of clinical changes. The factory medical officer was asbestosis (Table 6) is in agreement with Weiss (1971) replaced during this period and, in addition, lung who found pulmonary fibrosis in the chest radio function testing was introduced at about the graph in 40% of smokers and 24% of non-smokers time. Second, the assumption that the amount of among workers exposed to chrysotile asbestos. dust deposited in the lungs is a fixed proportion ofthe The data have been analysed in terms of a family airborne concentration would not be valid if there of exposure measures, an inherent feature of which had been changes in the particle size in the airborne is that there is the equivalent of an exponential dust cloud during the period 1951-72. In view of the decline in the amount of active material. This could changes in dust levels over this period, a change in arise as a result of both elimination of dust and a the size distribution would not be surprising; how reduction in activity of the dust remaining. Beattie ever we have no relevant data. and Knox (1961) determined the mineral content A dose-response relationship between morbidity after death in lungs of workers from the factory, and asbestos exposure has berm considered in two and found no evidence of a decline in the first eight other studies. McDonald et at. (1974) studied years after exposure had stopped. However, they several facets of disease, death, radiological changes, took no account of changes in dust level; those who pulmonary function changes and respiratory symp had survived for a period after leaving the factory toms and related these to the cumulative exposure were, on average, probably first exposed about measured as millions of particles per cubic foot 15 years earlier than those who died while still times years (mpef-yr). They concluded that there employed, and 70% of the men in the study had was a 1% risk of acquiring clinically significant been employed before 1932. There is evidence that disease for an exposure between 100 and 200 mpef-yr. trace metals are leached from chrysotile asbestos Some of their observations were based on a complete in mo (Morgan et at., 1971; Morgan et al., 1973). cohort but others only on current employees. Weill This leaching, and other changes within the lungs, et al. (1975) considered lung function measurements may reduce the hazard of the remaining material. and irregular small opacities on the chest radiographs The range of measures was introduced because it and found little evidence of a dose-response relation was felt that the simplest measure, that of cumulative ship below 100 mpef-yr. Using the results of simul exposure, might not be completely satisfactory taneous sampling with the impinger and fibre because of its inability to allow for the possibility counting method they equated this dose with of development of disease after exposure has ended. 200 f-yr/cm*. Their observations were based on Crepitations appeared to develop in five men while current employees only, and for some, exposure they were not exposed, but in two of these the change had started only shortly before the study. could have beat caused by observer differences. The results of the present study are disappointing The changes in the other three men could have been in that it is not possible to draw any definite con attributable to the transient nature of the sign or to clusions on the effects of the present 2f/cm* standard. reasons other than asbestos exposure. Comparison of the present results with those given Because so few of the men have been retired for earlier (British Occupational Hygiene Society, 1968; even five years, we are unable to discriminate Berry, 1973) shows that there is a higher prevalence between the different dose-response relationships. of crepitations at any dose than was observed Data of this type from other sources would provide previously. However, in view of the doubt that A 0 237S Asbestosis: a study of dose-response relationships in an asbestos textile factory 109 cumulative dose is an adequate measure of exposure, the prevalence of crepitations which would occur in those employed for a lifetime under the present standard can be predicted only within wide limits. Crepitations are not specific to asbestos exposure nor would their presence be considered as significant disease, defined as disability or shortening of life. Possible asbestosis is a better indicator but may not be either specific or significant disease; however it correlates well with certification (Figure 2). In the group first employed after 1950 the average cumulat ive exposure was 84 f-yr/cm*, the average follow-up since first exposure was 16 years, and the prevalence of possible asbestosis was 6-6%. In view of these findings there is no room for complacency about the 2f/anJ standard and efforts should be continued to reduce asbestos dust to as low a level as possible. At this stage it is impossible to state definitely that the standard is inadequate, because its introduction is so recent, and it is essential to follow up groups exposed to low levels in order to improve the data necessary for the formulation of better standards. We are grateful to Dra P. G. Harries and V. H. Springett who read the chest radiographs (the other two readers were JCG and HCL); to Dr A. N. Dempsey of the Manchester Pneumoconiosis Medical Panel for allowing us access to data; to Dr P. G Flmca who suggested making allowance for exponential elimination of dust from the lungs; to Dr J. C. Morris who provided extra information; to Mr J. Peto who suggested the alternative doseresponse model; to Dr J. G Wagner who examined post-mortem material, and to all those who helped and encouraged us to carry out the study. dustry. Public Health Bulletin (Washington), No. 241. US Government Printing Office: Washington. Holmes, S. (1973). Environmental data in industry. In Biological Effects of Asbestos, pp. 135-137. Edited by P. Bogovski. 3. G Gfison. V. Timbrell, and 3. G Wagner. International Agency for Research on Cancer, Scientific Publication No. 8. IARC: Lyon. International Labour Office (1972). ILO VIC International Classification of Radiographs ofthe Pneumoconioses, 1971. Occupational Safety and Health Series No. 22 (revised). ILO: Geneva. Jahr, 3. (1974). Dose^esponsa basis for setting a quartz threshold Emit value. A new simple formula for t-y the `lifetime dose* of quartz. Archives of Environmental Health. 29, 338-340. McDonald, J. C, Beckiake. M. RvGibbs. G. W,, McDonald. A. D.. and Rossiter, G E. (1974). The health of chrysotile asbestos mine and mill workers in Quebec. Arddres of Environmental Health, It, 61-68. McVitrie, 3. G (1965). Asbestosis in Great Britain. Annals of the New York Academy of Sciences, 132, 128-138. Morgan. A^ Holmes, A-, and Gold, G (1971). Studies of tbs solubility of constituents of chrysotile asbestos in tiro using radioactive tracer techniques. Environmental Research, 4, 558-570. Morgan. /L. Lally, A. E-, and Holmes. A. (1973V Some observations on the distribution oftrace metals in chrysotile asbestos. Annals ofOccupational Hygiene, 16, 231-240. Newfaouse, M. L. (1973). Asbestos in the work piece end the community. Annals ofOccupational Hygiene, 16. 97-107. Weill, IL. Ziilund, M. M., Waggenspaek. G. and Rossiter, G E. (1975). Lung function consequences of dust exposure in asbestos cement manufacturing plants. Archives of Environmental Health, 30, 88-97. Weiss, W. (1969). Cigarette smoking and diffuse pulmonary fibrosis. American Review of Respiratory Diseases, 99, 67-72. Weiss, W. (1971). Cigarette smoking, asbestos and pulmonary fibrosis. American Review of Respiratory Diseases, 104, 223-227. Beattie, J., and Knox. J. (1961). Studies of mineral content and particle size distribution in the 1unes of asbestos textile workers. In Inhaled Particles and Vapours, pp. 419-433. Edited by C N. Davies. Pergamoa Press: Oxford. Berry, G. (1973). Hygiene standards--theory and application. In Biological Effects of Asbestos, pp. 145-149. Edited by P. Bogovski. 3. C Gilson. V. Timbrell. and i. G Wagner. International Agency for Research on Cancer. Scientific Publication No. S. IARC: Lyon. British Occupational Hygiene Society (1968). Hygiene sundards for cbrysotile asbestos dust. Annals of Occupa tional Hygiene, 11,47-49. British Occupational Hygiene Society (1973). Review of the hygiene standard for chrysotile asbestos dust. Annals of Occupational Hygiene, 16; 7. British Thoracic and Tuberculosis Association (1975). Opportunist mycobacterial pulmonary infection and occupation'll dust exposure: an investigation in England and Wales. Tubercle, 56. 295-310. Dreessen, W. C,, DaltavaUe, 3. M., Edwards, T. I., Miller. 3. W., Sayers, R. R., Easom, H. F.. and Trice, M. F. (1938). A study of asbestosis in the asbestos textile in Appendix MEASURES OF EXPOSURE In this appendix, certain forms of dose-response relationships are discussed. First, it is necessary to define the dose, that is, to derive a measure of exposure in the situation in which exposure takes place over a period of years with different concentra tions. The simplest and most commonly used measure of exposure is the cumulative dose, which gives equal weight to the concentrations of airborne dust experienced in each year of exposure. Thus, for example, suppose a man started work in the factory at time zero and was exposed to a concentration of ci up to time n; this was followed by concennation ci from time h to tt; cj from tt to fa; and finally c* up to time /*, the time the exposure is to be 4 0237 r. I I I i 4 I Asbestosis: a study of dose-response relationships in an asbestos textile factory Ill with a threshold, Le. P zero for all values of D below some non-zero threshold. The first dose-response relationship is defined by: ln{J7(l -/*)} a + bln(Z This is similar to that used previously (British Occupational Hygiene Society, 1968), which was based on the assumption that the distribution of dose at which a sign first occurred is log-normal. The relationship now being used differs only in that a logit transformation has been applied to P instead of a probit transformation. As the logit and probit transformations are approximately equivalent, this modification makes negligible differences to the fitted relationships, and has been used to simplify the calculations. An alternative way of looking at the response is to consider the incidence rate of new cases. 1, instead of the prevalence, P. The incidence and prevalence are related by: '-S/a-* It can be shown easily that the logit dose-response relationship may be written as l mbPA/D where A is the amount ofdust in the lungs as defined earlier. If, instead of assuming that the distribution of dose at occurrence of a sign is approximately log normal, it is assumed that the incidence of cases is proportional to the amount of dust in the lungs, then an alternative dose-response relationship is obtained: /- cA which may also be written in the form: In (1 - P) - - cD Both the above relationships have equated the prevalence or incidence of a sign at time r with the dose evaluated up to time r. This is equivalent to assuming that the effect of dust deposited in the lungs may be immediate. This may be unrealistic and. instead, it could be assumed that there is a lag period of length * for the development of an observed effect after the dose responsible has been attained The dose-response relationship then has theform^(r) -- f (D(t -- )). FITTINO THE DOSE-RESPONSB RELATIONSHIPS For a sign, such as crepitations, a man is known either to have reached time h without crepitations or to have developed crepitations at some time between fi and it, where rt is the time of the latest medical examination at which crepitations were not recorded and rt is the first medical examination at which they were recorded. The log-likelihood of the observations, L, may be written: L .Tin{I - P(h)} + la (P(h) - P(n)} where the first summation is over men without the sign, and the second summation is over men with the sign. Substituting for P using the dose-response relations. L is dependent on the parameters a, b,T,w or c. T, w. An attempt was made to estimate these parameters by the method of maximum likelihood, proceeding as follows. For the logit model with no lag period Lev-0, and for a fixed value of T, the parameters a and b, or c, were estimated iteratively by the Newton Raphson method. This was repeated over a grid of values of 7*. from zero to infinity, in order to find the maximum likelihood estimate of T. For crepitations the loglikelihood increased as T increased from zero but, for T greater than 10 years, L was almost constant, showing a variation of only 0-25 in the range 10 to infinity. The 95% confidence interval for T was obtained as the interval in which L was within 1-92 of its maximum, half of the 95% critical value for a S* test, with one degree of freedom. This confidence interval was from three years to infinity, so that it was impossible to estimate T with any precision. The alternative model was fitted in a similar manner but gave a worse fit than the logit model. This was to be expected, as the alternative model contains one less parameter than the logit model, but if the alternative model is considered as satisfactory as the logit model only if the log-likelihood of the former is within 2-0 of the latter, then the alternative model was not satisfactory. The whole process was repeated with a lag period of five years. It was still not possible to estimate Twith any precision, and its 95 % confidence intetval was from two years to infinity. The alterna tive model gave as satisfactory a fit as the logit model, provided that T was at least five years. Finally, the same procedure was applied to the sign of possible asbestosis. A similar pattern of results was obtained except that, because there were fewer cases, the confidence intervals for T were even wider than were those for crepitations. It was not possible to attempt to estimate the lag *0237? 1 110 G. Berry, J. C. Gilson, S. Holmes, H. C. Lewinsohn, and S. A. Roach evaluated. In this example some of the concentra tions could be zero to cope with a break in exposure, d or es * 0, or with retirement, c* " 0. Then the cumulative dose is given by: but is assumed to be proportional to the concentra tion. Then the amount of dust in the lungs at time is, apart from a constant of proportionality, A(v) given by: cumulative dose -- cifi + c*(ft -- ti) + ea(ft -- ft) + edU -- ft) r.AM c(u) <-> du This is how the cumulative dose would be evaluated in practice, but to simplify a more general approach it may also be written as an integral. Suppose exposure started at time zero and is to be evaluated up to time t, and that the concentration at time u is c() for 0 < u < r, again du) would be zero during breaks in exposure or after retirement. Then If it is supposed that each component of dust which was deposited in the lungs contributes to the dose for the time it remains in the lungs then the dose D{t) evaluated at time t is given by: fXr) J* <4(v)dr Jcumulative dose -- du) du -- J J* du) ('-*1 du dr This measure attaches no more importance to exposure a long time ago than to recent exposure, -- j" du) J" e~A dv du and does not alter after exposure has ended. Both of these properties are unrealistic for a disease, such as asbestosis, which is dependent more on early exposure than on recent exposure and which may 1 Jf du) {1 -- e~* w-*1} du A develop after exposure has ended. The simplest way of allowing for both of these points was given by Jafar (1974) who suggested that each component of exposure should be weighted by the time which has elapsed since the exposure occurred. Thus, cumulative dose weighted by time since exposure is given by This is the generalised measure which, except for infinite A, has the properties that, first, it gives more weight to exposure a long time ago than to recent exposure and, second, it continues to increase after exposure has ended. If A tends to infinity then D tends to zero, but in such a way that AD tends to cumulative dose. Thus, in effect the cumulative J (r -- u) du) da dose may be considered as a special case of the generalised dose when elimination of dust from the lungs takes place very quickly. If A tends to zero, then D tends to the cumulative dose weighted and, in practice, evaluated by summing contributions by time since exposure which, therefore, is also a 1 of the form cd.it - ft) {t-i (ft + ft)} over each period ofexposure to a fixed concentration. special case of the generalised measure when there I is no elimination of dust from the lungs. B To summarise, the generalised measure consists B ofa family ofdose measures with each member ofthe B family defined by the parameter A, or. in an equiva- B The weighting factor could be regarded as the lent manner, by the half-life time T. The full family fl time that the dust has been in the lungs if elimination is obtained by allowing T to vary from zero to has not taken place. Looking at the measure in this infinity. The approach followed here is akin to that way, and postulating that elimination does occur, of the British Thoracic and Tuberculosis Association leads to a generalisation. (1975). Suppose that, over the long term, dust is eliminated from the lungs at a rate proportional to the amount DOSE-RESPONSE RELATIONSHIPS in the lungs, and the constant of proportionality is A; If P is the prevalence of a sign at dose D, then a in other words, in the absence of further exposure the dose-response relationship is defined by a functional amount of dust in the lungs declines exponentially relationship between P and D, that is, P -- f(D). at rate A and will be reduced to one half of its level All the relationships considered are such that P is in time T In2/A, the half-life time. The actual zero when D is zero, and as D increases above zero amount of dust deposited in the lungs is unknown. then so also does P\ this excludes relationship A 0 2 3 78 112 G. Berry, J. C. Gilson, S. Holmes, H. C. Lewinsohn, and S. A. Road period by maximum likelihood because of the sudden changes in the concentrations when a man changed jobs. This meant that L was not differenti able with respect to w and prevented the application of maximum likelihood theory. However a graphical comparison of the observed and fined dose-response relationship suggested that there were insufScien data to discriminate between the model without : lag period and one with a lag period of five yean The lag period cannot be much more than five year as there was one case of possible asbestosis only 7-25 yr after first exposure.