Document qmRZjy9XwVGNvZ1oaGL9jn0a5

EPIDEMIOLOGY RESOURCES, INC. PfenwL=D Pofi S'/\,\ /oMP-rtne (/ Vecs/ov PROJECTIONS OF ASBESTOS-RELATED DISEASE 1980-2009 FINAL REPORT August 2, 1982 By ALEXANDER M. WALKER, M.D., Dr.P.H. A ; 7770 P.O. Box 57, Chestnut Hill, Massachusetts 02167 (617) 734-9100 UCC 007726 TABLE OF CONTENTS Page List of Tables and Figures.................................................................................. ii Overview............................................................................................................... 1 Task 1: Determine the effective number of past asbestos workers.............. 3 Task 2: Project mesothelioma incidence............................ 16 Task 3: Project lung cancer incidence............................................................ 17 Task 4: Estimate asbestosis prevalence now and in the future.................... 21 Task 5: Estimate the amount of asbestos-related disease likely to occur in women.............................................................................................. 27 References.............................................................................................................. 28 l UCC 007727 k ; 7 77' Table LIST OF TABLES & FIGURES Page 1 Annual Age-Specific Mesothelioma Incidence for Males .............. 3 2 Proportion of Mesothelioma Cases with Asbestos Exposure History 5 3 Distribution (%) of 185 Canadian and 159 U.S. Male Case-Control Pairs According to the Probability of Occupational Asbestos Ex posure as Classified in Four Centers.............................................. 7 4 Relative Frequencies of Peritoneal and Pleural Mesothelioma In Heavily Asbestos-Exposed Groups ................................................ 8 5 Relative Frequencies of Peritoneal and Pleural Mesothelioma In Less Heavily Asbestos-Exposed Groups........................................ 9 6 Relative Frequencies of Peritoneal and Pleural Mesothelioma In General Populations and In Cases With No Identifiable Asbestos Exposure............................................................................................ 11 7 Numbers of Pleural and Peritoneal Mesotheliomas........................ 12 8 Year of Entry into the Asbestos-Exposed Workforce...................... 14 9 The Dissemination of Asbestos Exposure In Insulation Worker Equivalents Entering the U.S. Labor Force.................................. 15 10 Projected Numbers of New Mesothelioma Cases 1980-2009 in Men With Plausible Asbestos Exposure Using Two Models of In cidence .............................................................................................. 17 11 Incidence of Lung Cancer--Underlying Risk................................... 18 12 Selikoff Asbestos-Multiplier................................................................ 18 13 Risk Multipliers for Lung Cancer From Cohort Studies................ 19 14 Projected Numbers of New Lung Cancer Cases 1980-2009 in U.S. Men Plausibly Exposed to Asbestos (According to Exposure In tensity: Heavy Exposure and Light Exposure, Under Three As sumptions Regarding the Distribution of Light Exposures) .... 20 15 Lung Cancer: Percent Distribution of Year of First Exposure to Asbestos Products Alleged in Lawsuits (1975-1981) and Predicted by Model (1975-1979) ..................................................... 21 16 Projections of the Number of Prevalent Cases of Asbestosis in U.S. Males 1980-2009, based on the Incidence of Mesothelioma in Asbestotics........................................................................................... 23 17 X-Ray Changes in Asbestos Insulation Workers ............................... 23 18 Projections of the Number of Prevalent Cases of Asbestosis in U.S. Males 1980-2009, Based on the Equivalence of Asbestosis and Mesothelioma Rates........................................................................... 25 19 Projections of Asbestosis Lawsuits Assuming 9% of Prevalent Cases (Non-litigants) Bring Suit Each Year............................................. 26 Figure Ptge 1 Annual Incidence of Mesothelioma per 100,000 Workers by Years Elapsed Since First Exposure to Asbestos....................................... 2 Mesothelioma Mortality--Asbestosis Mortality................................. 24 24 a UCC 007728 A; 7772 PROJECTIONS OF ASBESTOS-RELATED DISEASE 1980-2009 Overview It is possible to estimate the amount of asbestos-related disease that will occur in the foreseeable future. One method of projection, together with its assumptions and limitations, will form the subject of this report. The method presented here is distinguished from other possible techniques in that it is tied to events currently being observed. Projections of future cases of mesothelioma and lung cancer depend on a number of steps, all of them starting with the number of cases of mesothelioma occurring in the United States. We begin with the cases of asbestos-related mesothelioma occurring in the late 1970's and infer the size of the asbestos-exposed populations which would be required to produce that number of cases. Using actuarial techniques and Johns-Manville (J-M) case data to provide some details of exposure timing, we then back-calculate to estimate the size of the original exposed work force from the 1930's on, whose remnants are now alive. Again using actuarial methods and drawing on known exposure-disease incidence curves, we then project the number of cases of mesothelioma and lung cancer which are likely to occur in the future in the exposed worker population. Since the clinical manifestations of mesothelioma vary according to the intensity of asbestos exposure, we can make a limited refinement of the procedure above by classifying the projected cases as deriving from relatively heavy or relatively light exposures. This is achieved by comparing the distribution of sites of mesothelioma in known relatively heavily exposed cohorts, such as insulation workers, in whom disease is peritoneal at least half the time, with that observed in the U.S. as a whole, in which peritoneal disease occurs only 10% of the time. Projection of the burden of asbestosis in the United States depends both on the rate of occurrence of new disease and on the prevalence of old disease, which may or may not yet have been medically diagnosed in any given individual. Accounting for prevalent, but, as yet, undiagnosed cases of old disease is necessary for asbestosis, but not for mesothelioma or lung cancer because the latter cancers are either detected or lead to death (usually both) within a period less than two years after clinical onset of disease. Asbestosis sufferers, on the other hand, may live for many years with diagnosable (but undiagnosed) disease, and represent a large pool of potential litigants who can "behave like" new cases at any time, simply by being made aware of the nature and probable origin of their disease. We have inferred the number of prevalent asbestosis cases in the late 1970's by two principal methods. In the first, we estimate what proportion of mesothelioma cases have diagnosable asbestosis, and we compare this figure to the rate at which people with asbestosis develop mesothelioma. Knowing the approximate number of mesothelioma cases with asbestosis and the rate at which mesothelioma occurs in asbestotics, we can calculate about how many asbestosis sufferers there must be in order to account for the observed number of mesothelioma cases occurring among them. In the second method, we have drawn on another, independent aspect of the asbestosis-mesothelioma relationship. In studies of groups occupationally exposed to asbestos, the death rates from mesothelioma and asbestosis have been found to be nearly identical. Thus, projections of mesothelioma deaths in persons exposed to asbestos can be expected to give a good estimate of the number of asbestosis deaths. Several studies have provided data on the mortality rate in asbestotics, and on what proportion of the mortality is due to asbestos. The number of asbestotics is then inferred from the number of asbestosis deaths and the mortality rates in persons with asbestosis. At this point the asbestosis projections depend on a scientific judgment which has to be made on the basis of almost no directly relevant data. The question is: do new cases of asbestosis continue to appear many years after the cessation of exposure or, after a certain lag period, does the occurrence of new cases stop? Put another way: does cleaning up the workplace diminsh the risk of those workers who have already been heavily exposed to asbestos but, as yet, have no disease? Preliminary J-M data I A :7773 UCC 007729 suggest that cleaning up the work environment does reduce the risk of those already exposed, although not immediately to zero. Asbestosis prevalence projections have been made on the assumption that new cases actually occur through 1984, and that from 1985 on, any apparent new cases represent new diagnoses of existing disease. Several other "quick and dirty" asbestosis projections methods are also available. These depend on drawing analogies between the United Kingdom and the United States, on use of relative mortality figures, and on the extrapolation of data from x-ray surveys of exposed workers. J-M data on women are too scanty to allow any direct estimation of the number of cases of asbestos-related disease on them. (Less than 5% of suits derive from women.) Estimating female disease has to be based on deriving approximate proportionality constants: based on the probable historical timing of female workers exposed to asbestos, the current 5% figure can be expected to decline to nearly zero over the next two decades. The tasks and subtasks which are involved in disease projection are as follows: 1. Determine the effective number of past asbestos workers. a. Determine the number of cases of mesothelioma in the U.S., 1975-1979. b. Calculate the fraction of mesothelioma cases with a documentable history of asbestos exposure and what fraction of the exposed are likely to have been heavily exposed. c. Estimate the timing of the exposure history for U.S. cases. d. Calculate the number of workers now alive and exposed at different times in the past which would be required to account for the current observed mesothelioma incidence. e. Using actuarial techniques, calculate the size of the originally exposed worker population which would yield the estimated numbers of currently living, previously exposed workers. f. For exposure in the more recent past (which would give rise to no current disease), estimate exposure which could give rise to future disease. i. Use survey data to estimate exposure histories. ii. Use information on changing workplace environments to adjust crude exposure estimates. iii. Adjust all original estimates of the number of exposed workers so that the total number of cases of mesothelioma being observed is consistent with total estimates of the exposed workforce (distant past plus recent past). 2. Project mesothelioma incidence. a. Actuarially adjust the size of the exposed population to account for future mortality and calculate the incidence of new cases in the reduced exposed populations. b. Examine sensitivity of projections to component assumptions. 3. Project lung cancer incidence. a. As above, adjust the size of the at-risk populations to account for future mortality. Calcu late the future incidence of lung cancer as a function of future age, future elapsed time from first exposure, and the future size of the population at risk. b. Compare projected and observed lung cancer figures. 4. Estimate asbestosis prevalence now and in the future. a. i. 1980-1984 prevalence using mesothelioma mortality in asbestotics. --How many cases of mesothelioma with asbestosis are occurring? --Mesothelioma incidence as in (la). --Proportion of mesothelioma with asbestosis. --Estimate frequency of occurrence of mesothelioma in asbestotics. ii. Prevalence after 1984. --Age the 1980-1984 prevalence group using actuarial techniques. 2 UCC 007730 b. 1980-1984 prevalence based on the equivalence of mesothelioma and asbestosis mortality, i. Derive expected number of asbestosis deaths from projected mesothelioma deaths. ii. Compare asbestosis deaths to death rates in asbestotics to derive an estimate of the number of asbestotics. c. "Quick and dirty" projections. i. U.K./U.S. equivalence. ii. Relative mortality data. iii. Extrapolation from x-ray surveys. d. Derive a general methodology for predicting lawsuits given propensity to sue and disease prevalence. 5. Estimate the amount of asbestos-related disease likely to occur in women. Task la: Determine the number of cases of mesothelioma in the United States, 1975-1979. The National Cancer Institute (NCI) has sponsored two major cancer incidence surveillance programs since 1969. The first, covering the period 1969-71, coordinated existing regional tumor registries and supported the establishment of new registries, permitting a direct assessment of cancer incidence for about 7% of the U.S. population; this was the Third National Cancer Survey (TNCS). In 1973, the NCI reconstituted the administrative structure of the TNCS to provide for an ongoing system of monitoring cancer incidence. This new program, named the Surveillance, Epidemiology and End Results program (SEER) has been in operation continuously since then. SEER reporting regions are Hawaii, Seattle, San Francisco-Oakland, New Mexico, New Orleans, Utah, Connecticut, Atlanta, Detroit, and Iowa. Collectively these represent about 10% of the population of the United States. In 1980, the NCI (Connelly 1980) released a detailed report of trends in mesothelioma incidence based on TNCS (1969-1971) and the first six years of SEER (1973-1978). The annual age-specific mesothe lioma incidence for males in SEER is given in Table 1 below, which also provides an estimate of the total number of men developing mesothelioma in the United States in 1977. The age-specific estimated counts were obtained by multiplying the SEER incidence rates times the Census Bureau's 1977 esti mates of the U.S. male population in the various age categories. TABLE 1 Annual Age-Specific Mesothelioma Incidence for Males Age Group 0-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 Incident Cases Per 100,000 Men Per Year 0 0.02 0.07 0.20 0.17 0.37 1.05 1.59 2.09 Implied U.S Total 1977 0 2.0 6.1 15.2 10.2 20.2 58.9 90.8 110.1 3 UCC 007731 A ; 777b Age Group 60-64 65-69 70-74 75-79 Incident Cases Per 100,000 Men Per Year 3.37 3.84 5.72 6.34 Implied U.S. Total 1977 147.6 143.6 148.5 100.7 853.9 The implied total of about 854 new cases of mesothelioma in U.S. men in 1977 is probably inaccurate for a number of reasons and should be adjusted accordingly: 1. Comparison of the TNCS (1969-1971) and SEER (1973-1978) age-standardized male incidence figures shows an overall rise from 0.51 to 0.88 cases per 100,000 men per year, approximately a 10% annual increase from the midpoint of the TNCS to the midpoint of the reported SEER years (1975 V2). To obtain a 1977 incidence figure, a further 15% inflation over the SEER incidence would be appropriate. (The 10% annual increase is virtually identical to the rate of increase in mesothelioma incidence predicted by the incidence model constructed for Task 2. That model predicts annual increases of 11.2% in 1970, declining steadily to 8.4% in 1975.) 2. Since the SEER regions contain proportionately more shipbuilding areas than the U.S. as a whole, the incidence rates are overstated to the extent that mesothelioma occurs more commonly in shipbuilding areas. SEER data suggest that this is indeed the case. The age-standardized white male rates for Seattle and San Francisco are 1.42 and 1.36 cases per 100,000 men annually, while those for Utah and Iowa are 0.82 and 0.54 cases per 100,000 per year. A reasonable estimate as to the overstatement of mesothelioma due to non-representative sampling of the U.S. in SEER overall would be 10-15%, with a best guess of about 12%. 3. Finally, the diagnosis of mesothelioma is by no means easy or clear cut. Selikoff (1980) maintains that a review of all medical evidence in the deaths of U.S. insulation workers from 1967 through 1976 indicates that of 175 mesothelioma deaths, only 104 (59%) had mesothelioma recorded on the death certificate. SEER diagnostic coding is generally felt to be of much higher quality than death certificate information, but since the SEER data are regional, they necessarily derive in part from smaller hospitals with less sophistication in diagnosis than is available in cancer referral centers. A reasonable estimate for the net underreporting in SEER is about 10%. Combining adjustments for time trends, non-representativeness, and underdiagnosis in the SEER data one arrives at a best guess for the number of mesothelioma cases occurring in U.S. men in 1977, not of 854, but of (853.9) (1.15)/(1.12)/(0.90) = 974 cases. The approximate number occurring in the 1975-1979 quinquennium would be 4870. Task lb. Calculate the fraction of mesothelioma cases which have a documented history of asbestos exposure, and estimate what fraction of the exposed are likely to have been heavily exposed. Not all mesothelioma occurs in men with a documentable asbestos exposure history. Assuming essentially no asbestos exposure in low incidence SEER regions, and that the entire difference in mesothelioma incidence is attributable to asbestos, the differences between the highest and lowest mesothelioma incidence would suggest that 38% of mesothelioma in the high risk areas might be "background" incidence. (The annual incidence per 100,000 white males ranges from 0.54 in Iowa to 1.42 in Seattle; 0.54/1.42 = 38%.) In low incidence areas, the fraction of disease attributable to background would be even higher. Inquiries undertaken among mesothelioma patients have yielded estimates of the percent with an asbestos exposure history running from 16% to 76%, depending principally on whether cases come from areas with heavy asbestos-using industries. Table 2 sum marizes the data from a number of sources. 4 A ; 7772 UCC 007732 TABLE 2 Proportion of Mesothelioma Cases with Asbestos Exposure History Reference Region; Subjects Source of Data Proportion of Cases with Asbestos Exposure (%) Peto, et ai, 1981 ............ Vianna, et ai, 1981........ Vianna, et al, 1981 ........ Tagnon, et ai, 1980 ... McDonald, et ai, 1973 . . Newhouse and Thompson 1965 .............................. Los Angeles 1974-1978; males New York State excluding NY City; males, 1973-1978 New York State high incidence counties 1968-1978 Coastal Virgina 1972-1978; white males All Canada (emphasis on Quebec) 1968-1970 Patients dying at The London Hospital 1964 and earlier Case or close relative interview Death certificate Occupational record Patient or first degree relative interview Patient or next of kin interview Relatives and friends interview Surviving relatives, medical records 69/101 69/91" 67/193 (68%) (76%) (35%) 24/31 (77%) 17/3Ib (55%) 43/56 (77%) 1l/69c (16%) 31/69d (45%) 40/76 (53%) 31/76b (41%) a Excludes those for whom interviewee was unsure of work history b Excludes indirect exposure (e.g. family member of an exposed person) c "Definite" or "probable" exposures d Includes "possible" exposure as well 5 UCC 007733 A ; 7 7 7? While much of the variation in Table 2 must result from real differences in the asbestos exposure histories of mesothelioma patients from different regions, there may also be a substantial variation depending on the group interpreting the exposure history. Table 3 (from McDonald and McDonald, 1980) illustrates this phenomenon. Three hundred and forty-four male cases of mesothelioma were paired with cases matched for age, sex, hospital, and year of death. The comparison cases had died with lung metastases from a nonpulmonary malignant tumor. Job histories were obtained from interview of relatives, coded and submitted to four asbestos research centers for interpretation. While there was general agreement on the proportion with "definite" and "unlikely" exposure to asbestos, there was much less concordance in the interpretation of ambiguous exposure histories. One center, the Environmental Sciences Laboratory of the Mount Sinai School of Medicine, was very much more likely than the others to interpret ambiguous histories as "probable" asbestos exposure. The consensus United States figures (from centers 2, 3 and 4) in Table 3, when averaged, yield an overall figure for the proportion of male mesothelioma cases with a definite or probable history of asbestos exposure of 54%. This number is in the middle of the range of Table 2, and will be used as a best estimate. The proportion with definite exposure appears to be about 20%, averaging the figures from all four centers in Table 3. A separate line of observation and inference indicates that the proportion of mesothelioma cases attributable to relatively heavy occupational exposure to asbestos is considerably less than the 54% with a definite or probable asbestos exposure history. This is based on the observation of the relative frequencies of involvement of the two major sites of appearance of mesothelioma, the pleura and the peritoneum. As indicated in Table 4, in heavily exposed industrial cohorts, the peritoneum probably accounts for about half of all cases. The most important exception to this pattern arose in a group with what (for an industrial cohort) is an atypical exposure pattern: 75% of the observation time in the group of Australian crocidolite miners reported on by Hobbs et al (1980) was in men with a total duration of exposure of less than 12 months. There were no peritoneal tumors documented among these men. In groups less heavily exposed, the peritoneum is less frequently involved, as indicated in Table 5. The least exposed groups are the general population series of incident mesothelioma cases, and those cases determined by direct inquiry to have had no identifiable asbestos exposure. In these groups, the proportion with peritoneal disease is on the order of 10%. See Table 6. From Tables 4-6, it appears that substantial occupational exposure results in mesotheliomas which are at least 50% peritoneal, and that moderate exposure may result in about 20% peritoneal mesothe liomas. If this is true, then only a small fraction of the total contemporary U.S. mesothelioma incidence (9-13% peritoneal) can be attributable to heavy occupational exposure; at most, about 26% of U.S. cases (the 13% peritoneal and an equal number of pleurals) can be attributable to heavy exposure. In fact, the true proportion of heavily exposed mesothelioma cases must be less than 26%, since peritoneal tumors do arise in persons with little or no known asbestos exposure (see Table 6). The 20% with "definite" exposure in Table 3 may provide a more realistic upper limit to the heavily exposed proportion of persons who develop mesothelioma. 6 UCC 007734 A -7 / TABLE 3 Distribution {%) of 185 Canadian and 159 U.S. Male Case-Control Pairs According to the Probability of Occupational Asbestos Exposure as Classified in Four Centers* Center* Canada (1960-72) 1 2 3 4 U.S.A. (1972) 1 2 3 4 Definite Cases Controls 11.9 1.1 11.9 1.1 i3.; 2.7 11.9 1.1 18.2 3.8 18.9 3.8 24.5 6.3 18.9 3.8 Probable Cases Controls 43.8 31.4 20.5 14.6 29.7 21.1 22.7 13.0 51.6 35.2 31.4 18.7 34.0 19.5 33.3 15.1 Possible Cases Controls 4.3 2.7 21.1 15.7 18.9 20.5 22.7 27.6 3.8 1.9 20.8 18.6 16.4 19.5 22.6 27.0 Asbestos Exposure Unlikely Cases Controls 40.0 64.9 46.5 68.6 37.8 55.7 42.7 58.4 26.4 59.1 28.9 58.9 25.1 54.1 25.2 54.1 Case-control difference ^or definite probable exposures 23.2 16.7 19.4 20.5 30.8 27.8 32.7 33.3 Centers: (1) Environmental Sciences Laboratory, Mount Sinai School of Medicine, New York (2) Gesondsheitsorganisatie TNO, den Haag, the Netherlands (3) Department of Epidemiology & Health, McGill University, Montreal, Canada (4) TUC Centenary Institute of Occupational Health, London School of Hygiene and Tropical Medicine, London, England 7 UCC 007735 A i 7773 TABLE 4 Relative Frequencies of Peritoneal and Pleural Mesothelioma in Heavily Asbestos-Exposed Groups Reference Source Population Selikoff 1980 ........ Newhouse 1981 . . . Newhouse 1981 . . . Finkelstein 1981. . McDonald & McDonald 1980 . Hobbs et al. 1980 . Elmes & Simpson 1976 . North American Insulation Workers 1/67-12/76 English Factory Workers 2 Years Exposure English Female Textile Workers Canadian Workers Receiving Asbestos Disability Benefits Insulation Workers, Asbestos Production and Manufacture US & Canada 1960-1972 Miners & Millers of Crocidolite W. Australia 1943-1966 Mesothelioma in UK 1/60-12/69 Classified from Medical Records as "Heavily Exposed to Asbestos" Peritoneal Pleural Mixed P-P Other 112 63 00 16 10 8 12 45 00 00 00 23 29 00 0 25 00 20 64 60 % Peritoneal or Mixed P-P 64% 62% 40% 44% 44% 0% 29% 8 UCC 007736 A : 7730 TABLE 5 Relative Frequencies of Peritoneal and Pleural Mesothelioma in Less Heavily Asbestos*Exposed Croups Reference Elmes Simpson 1976 Chovil, et al. 1981 McDonald & McDonald 1980 Source Population Peritoneal Pleural Mixed P-P Other Exposed, but not heavily 10 151 13 0 "Compensable" mesothelioma in Ontario, including exposure which was "relatively light, of short duration, in the distant past, or all of these" 9 23 00 Heating trades, shipyards, construction (excluding insulation workers), US and Canada 1960-1975 19 117 00 % Peritoneal or Mixed P-P 13% 28% 16% TABLE 6 Relative Frequencies of Peritoneal and Pleural Mesothelioma in General Populations and in Cases with No Identifiable Asbestos Exposure Reference Connelly 1980 Breslow 1982 Elmes & Simpson 1970 Baris, et al. 1979 McDonald & McDonald 1980 Source Population SEER 1973-1978 males TNCS 1969-1971 males U.S. Patients entering comprehensive cancer centers 1978-1980 No known exposure Peritoneal/Pleural/Mixed P-P/Other 43 369 0 55 9 83 0 0 36 234 0 0 7 52 4 0 Turkish villagers in a hyperendemic area ' No occupational exposure, US and Canadian cases 1962 1975 1 37 20 119 0 0 0 0 % Peritoneal or Mixed P-P 9% 10% 13% 11% 5% 24% UCC 007737 A ; 7781 Task lc: Estimate the timing of exposure in U.S. cases. Allegations in J-M mesothelioma case data provide information on the timing of asbestos exposure in those persons who develop mesothelioma. There are 278 J-M mesothelioma cases which give an analyzable asbestos exposure history: a plausible age at first exposure (between 15 and 54 years of age), and a year of first exposure between 1930 and 1954. (See Task If for an explanation of the 1954 cutoff.) By five-year age groups we have identified the alleged year of first exposure to asbestos. Applying the percent alleging first exposure at various years in J-M data to the age-specific estimates of asbestos-exposed mesothelioma incidence obtained (after adjustments) from SEER, one can esti mate how many cases of mesothelioma occurred among U.S. workers who were first exposed to asbestos at any given age and any given year in the past. This procedure is carried out separately for the 20% of U.S. cases of mesothelioma with presumed heavy exposure, and for the 34% with presumed identifiable light exposure, on the assumption that the relative frequencies of heavy and light exposures did not change greatly until the introduction of dust controls in the work place in the 1960's and the 1970's. Qualitative review of the J-M case data indicates that most current J-M cases are derived from the smaller, more heavily exposed portion of the work force (insulation workers, asbestos factory workers, etc.). Task Id: Calculate the number of workers now alive and exposed at different times in the past which would be required to account for the current observed mesothelioma incidence. How many exposed workers are there? This question can be answered by combining the esti mated counts of mesothelioma cases having exposure history with data on the incidence of mesothe lioma in exposed workers. Peto (Peto et al, 1982) analyzed Selikoff et al's (1980) data on the incidence of mesothelioma in insulation workers and found that incidence could be very closely described by the equation: I = 4.37 x I0"8 x t<3'2> x Pt where I is the number of cases of mesothelioma occurring per year, t is the elapsed time in years since first exposure to asbestos, and Pt is the size of the population of workers with first exposure t years previously. This incidence curve is graphed as a solid line on Figure 1 for a hypothetical population of 100,000 people. Having derived the above equation on the basis of SelikofTs data, Peto et al (1982) examined its generalizability by fitting similar equations, with the same exponent (3.2), to data obtained in a variety of settings. Table 7 provides, for five studies, the Peto estimate of the leading constant term in the above equation, the number of mesotheliomas observed and predicted at five-year intervals from first exposure, and the total number of cases observed. Observed incidence rates from the five studies are plotted on Figure 1, along with Peto's curve (with the constant term calculated from SelikofTs data). All show a sharp increase beginning 15 years from first exposure and continuing--so far as the data tell--indefinitely thereafter. 10 UCC 007738 A ; 7702 1,400 \ FIGURE I Annual Incidence of Mesothelioma per 100,000 Workers By Years Elapsed Since First Exposure to Asbestos Annual Incidence of Mesothelioma per 100,000 Workers Years Elapsed Since First Exposure to Asbestos Legend: Peto incidence curve (Peto et al, 1982) ........ Breslow incidence curve (Breslow, 1982) Incidence rates reported by Peto et al (1982) for five studies (see Table 7): O Selikoff el al (1979) A Newhouse and Berry (1976) Peto (1980) Hobbs et al (1980) Seidman et al (1980) 11 A ; 7 7 S 3 UCC 007739 12927 98 1383 2026 TABLE 7 /^I ^ --- o -- oo -- M--oe (nN mN ^ 't i'OOn O O f"~ t"- <OOs*> o<N o o(N O(N <--N SO ^0 n o >< r- 2 <N f"- os rsi <N f"1 S = .5 >5 S - It 5 5.-5 -d J3 w a> o . o *T .e ^ g v o V >c tqt vO M fM ^ 't rcc r? a| W x j= a ^ M '*-' * *I ri n -n ^ 't M fe-i. (e0 fdlfi *E5 3h* u Jl 1 I jS i || S'* S^w ga a- *j '5 * *8 E a 5 *^a 2E g -IaI * as o Ofi .S ^a * sS-sa 'w' A 8 cn TM m o Cl>- ztS f' i/l IN (N M n Oi ---- m-- nCN ^t s f'l rO >0 ifi oo - S->* 0, Z LL S ^ <N O' fS fS ^ t fN -- t-- IN O M - O O fN I/) ^o -- -- -- -- m O n n oo - - n rJ VO -- -- -- <N r' 00 00 OOsC M-- OM--OCM-- -- O O pm^ s O - 't H O rr(N* r?> Q_ .>. cl&ZuS SaZillS E Z w (ft 2hmE os C` 1 w c -O4> I tO tfl O g o * - O *4c> cO cfl .u2Z."^x *4> _ g >% uo"s 't II ,> o 2 ^3 oo jy ^ `w T 2 x "(f sans ?> rn 3 0 0 0 fs3ig; Ii 8.7 a-= 8_ 2 >v o rM II OOO 2 ^ Os _: Sq o * TM ns .2 S-Ti --V 8 - otut rUa ^ (O ^ c E* JJ ?3 't S 8 E II J w " 3 z .s 5 g JL g 3 x 2fp J < Sj E . u 73 fl- 1/5 2618 * 30 or more years; 32.3 assumed in calculating expected no. 20 or more years; 22.5 assumed in calculating expected no.t 3174 M Y 3628 12 UCC 007740 A ; 7784 Although Peto's equation has the theoretically attractive property that its mathematical form is derivable from current theories of carcinogenesis, it is not the only possible mathematical description of the U.S. insulation worker mesothelioma incidence. Breslow (1982) has used the same data to esti mate the components of a second formula which incorporates an estimated latent period as well as the exponential and constant terms used in Peto's formula. The form of this equation was proposed originally by Newhouse and Berry (1976), and in a statistical sense it fits the observations more closely than does the Peto equation. Using the symbols as above, that incidence equation is: I = 1.37 X 10-5 x (t-15)'-,46x Pt. The better fit of this equation to SelikofTs data derives principally from the fact that it predicts no cases to occur in the first 15 years following first exposure; Peto's equation predicts a small number of cases. In fact, in SelikofTs data none were observed to occur. Breslow's function is plotted as a dashed curve on Figure 1. The two equations give very similar estimates. Throughout the ensuing analysis, Peto's equation has been used because it appears to provide estimates more consistent with the full range of reported values (as opposed to SelikofTs data alone). Nonetheless, projections carried out using the Peto equation have all been verified using the Breslow equation. Sources reporting to J-M's legal staff indicate that there may be some overstatement in SelikofTs data of the numbers of mesothelioma cases actually occurring. The overstatement certainly appears to be the case for asbestosis, and probably is negligible for lung cancer. For mesothelioma, we have provisionally adopted a correction factor of 0.8 in Peto's and Breslow's equations relating mesothe lioma incidence to asbestos exposure. This has the effect of expanding the size of the exposed popula tion required to account for currently observed mesothelioma cases. Given the number of cases which have occurred and knowing their alleged elapsed interval since first exposure, one can solve the equations above for Pt. We carried out this procedure for all five-year categories of age at diagnosis of mesothelioma in 1975-1979, and for all elapsed times since first exposure, giving a matrix of Pt's which corresponds to the distribution of asbestos workers alive in 1975-1979, which gave rise to mesothelioma, cross-tabulated by age and year of first exposure to asbestos. The size of the exposed population calculated in this step is an artificial figure corresponding to "insulation worker equivalents", that is, the number of asbestos workers as heavily exposed as the insulation workers studied by Selikoff who would be required to explain the current mesothelioma experience. As outlined in Task lb, it is likely that only some 37% of exposed mesothelioma cases (20% out of the 54%) actually arise in persons with heavy exposure. The remaining cases derive from larger populations with less intense exposure. For the purposes of mesothelioma incidence projections, there is no need to distinguish between the two situations. A population of 100,000 workers at one exposure level can be expected to give rise to the same number of cases as a population of 200,000 at half the exposure. Therefore the "worker-equivalent" has an interpretation which is independent of the actual distribution of intensities of exposure. For lung cancer, the distinction does make a difference; the larger population will have a larger "background" number of lung cancers to which the asbestosattributable cancers must be added. In either case, the impression of J-M's legal staff at present is that most lawsuits are coming from heavily exposed plaintiffs, indicating that the distinction may be rele vant for a person's propensity to sue. The cancer projections which follow (Tasks 2 and 3) therefore will be divided according to intensity of exposure. Task le: Using actuarial techniques, calculate the size of the originally exposed worker population which would yield the estimated numbers of currently living, previously exposed workers. Every group of workers now alive with first exposure at some time in the past corresponds to an originally exposed population, some members of which have died with the passage of time. We have used white male actuarial survival tables covering the years 1930-1979 to calculate the originally exposed population as follows: call the population alive in year y, of age a, with time t since first exposure, Py a t. Call the same population t years previously (when they were a-t years ld), Py_, a_, 0. If 13 UCC 007741 A :778b the actuarial probability for survival from age a-t to age a, starting in year y-t, is Sy_t.a-t.a, then: I*y--i.a--t.O t,a--t,a where Py-tia-i,o *s the number of workers entering the asbestos-exposed work force in year y-t at age a-t who would be required to produce in year y a surviving exposed population of size Pj,at. If that surviving exposed population has already been derived (Task Id) as one large enough to produce the estimated number of new exposed cases of mesothelioma of age a who report having been first exposed to asbestos t years previously, then Pj,_u_,,o is the size of the new workforce t years earlier which would be required to account for the current mesothelioma experience. A modification of the actuarial survival figures was necessary before carrying out the above calculations. As noted in Task lb, some 20/54 (37%) of the insulation worker equivalents estimated here derived from heavily exposed individuals. Selikoff has noted that insulation workers have a 37% higher overall mortality rate than the general population. As a result, a group consisting of 37% heavily exposed workers has approximately a (37%) x (37%) = 14% higher mortality rate than the general population. This correction factor has been introduced into all calculations of the survival of non-diseased, asbestos-exposed groups of insulation-worker equivalents. Task If: For exposure in the more recent past which would give rise to no current disease, estimate the quantity of exposure, since this could still give rise to future disease. The procedures of Task Id and le begin breaking down when first exposures less than 20 years prior to the 1975-1979 period are considered. Few cases of mesothelioma would have as yet arisen from this period, because of the delayed rise in the mesothelioma incidence curve; thus it is impossible to work backwards to the exposed population with any reliability. Instead, we have used the reported distribution of age at first entry into an asbestos-related industry from a survey of men aged 40 and above, conducted by Elrick and Lavidge. Although that survey does not allow us to calculate the absolute number of heavily exposed asbestos workers entering the workforce each year, it does allow us to calculate the relative number entering. Altogether, the Elrick and Lavidge survey identified 214 individuals who had worked in an asbestos-using industry, of whom 79 were aware of actual exposure to asbestos dust. The results of the survey were as shown in Table 8, from which it is apparent that the distribution of years of entry into asbestos-using industries is essentially identical for men who did recall and those who did not recall direct asbestos exposure. We have based our adjustments on the larger, statistically more stable numbers of all entrants into asbestos-using industries. TABLE 8 Year of Entry into the Asbestos-Exposed Workforce Vear Workers Who Recalled Asbestos Exposure Number % Cumulative % All Workers In Asbestos-Using Industries Number %_ Cumulative % Before 1930 1930-1934 1935-1939 1940-1944 1945-1949 1950-1954 1955-1959 1960-1964 1965-1969 1970-1974 1975-1979 5 6.3 1 1.3 6 7.6 17 21.5 14 17.7 5 6.3 10 12.7 9 11.4 7 8.9 I 1.3 4 5.1 6.3 7.6 15.2 36.7 54.4 60.8 73.4 84.8 93.7 94.9 100.0 16 7.5 9 4.2 19 8.9 45 21.0 29 13.6 19 8.9 29 13.6 21 9.8 14 6.5 5 2.3 8 3.7 7.5 11.7 20.6 41.6 55.1 64.0 77.6 87.4 93.9 96.3 100.0 The work force was calculated directly from the mesothelioma incidence data through 1954. From 1955 on, we assigned numbers proportional to the annual and special sample number for men in the survey reporting first entry into the asbestos workforce in each quinqennium. Adding the post-1955 workers generally resulted in a small increase in the predicted numbers of mesotheliomas for A ''7785 UCC 007742 1975-1979. Both pre- and post-1955 figures were then iteratively adjusted until: 1) the pre-1955 figures maintained the year of first exposure distribution implied by the J-M cases, 2) the post-1955 figures stood in the proportion to the pre-1955 that was dictated by the survey, and 3) the 1975-1979 mesothelioma predictions derived from the resulting distribution of exposed workers equalled the numbers actually thought to have occurred. From 1965 on, it is probable that exposed workers faced diminishing amounts of ambient asbestos fiber. We have accounted for this by recalculating the overall workforce size (as above) but with smaller fractions of the exposed workforce assigned to the post-1955 period. (In effect, this amounts to modeling the health effects of an unchanged number of workers exposed to less and less asbestos by assuming smaller and smaller numbers of workers exposed to essentially the same amount of asbestos.) Workforce discounts used to compensate for recent improvements in the workplace were: 1960-1964, 10%; 1965-1969, 50%; 1970-1974, 75%; and 1975-1979, 100%. Table 9 gives the number of insulation worker equivalents entering the workforce for each quin quennium 1930-1979, as estimated from J-M data directly, and with adjustment of the post-1955 figures to match the survey data in their calendar year distribution. Of particular interest is the general conformity of the worker distribution for earlier years (as inferred from J-M data. Table 9) to that actually observed in the Elrick and Lavidge survey. Table 9 also gives the number of insulation worker equivalents entering the workforce in each quinquennium from 1930 to 1979, according to intensity of exposure. For the heavily exposed group, one equivalent can be taken to equal (more or less) one worker. For the less heavily exposed group, there may be as many as five or ten actual workers making up each insulation worker equivalent. 1930-1934 1935-1939 1940-1944 1945-1949 1950-1954 1955-1959 1960-1964 1965-1969 1970-1974 TABLE 9 The Dissemination of Asbestos Exposure In Insulation Worker Equivalents Entering the IJ.S. Labor Force Heavily Exposed!I) Lightly Exposed(2) 2,700 13,800 55,900 35,400 38,100 34,900 22,700 8,600 1,400 3,700 18,100 74,900 49,900 59,400 49,300 32,100 12,200 2,100 TotaR3) 6,400 31,900 130,800 85,300 97,500 84,200 54,800 20,800 3,500 (1) In the heavily exposed, each insulation worker equivalent corresponds roughly to a single worker. (2) Many lightly exposed individuals are required to make up a single insulation worker equivalent (listed in the Table). (3) The total number of insulation worker equivalents, not the total of exposed workers. 15 UCC 007743 A 770-? / /u/ Task 2a: Adjust exposed population and calculate future incidence of mesothelioma. For every five year period in the future, we calculated the number of mesothelioma cases that would be expected to arise out of each group of workers we estimated to have entered the workforce at each age-of-entry in each calendar-quinquennium in the past. Using the notation of previous sections, call a the age in 1975-1979, and t the number of years elapsed since first exposure in year y. Call p the number of years into the future for which a projection is being made. Then the age at first exposure is (a--t), age in the projected future year is (a+p), and elapsed time from first exposure in the future is (t+p). The components of the projection equation (Peto et al, 1982) are: Ia+P, ,+p--The number of new cases of mesothelioma p years from 1975-1979 among persons then aged (a+p), with time elapsed since first exposure (t+p). Pa_t 0>y--The number of persons entering the asbestos workforce t years prior to 1975-1979, at age (a-p), in the year y. Sa_t a+p, y--Actuarial survival from age (a-t) in year y to age (a+p), taking into account recorded actuarial survival for calender years prior to 1979, and assuming age-specific mortalities after 1979 to be unchanged from their late 1970's values. K--A constant term derived from SelikofFs observation of insulation workers (Peto et al, 1981), 4.37xl0'8 for one-year incidence, 2.19 x 10--7 for five-year incidence, multiplied by a correction factor (0.8), for possible excess diagnosis in SelikofFs follow-up. The projection equation is: ^a+p, t+p -- Pa--t, 0, y ^ ^a -t, t+p, y X K X (t+p)8'8 The estimated populations of exposed workers presented at the end of Task 1 in Table 9 yield projections of mesothelioma incidence shown in the first column of Table 10 for the years 1980-2009, Use of Breslow's projection equation to derive the exposed population and the resultant mesothe lioma incidence leads to very similar projected counts, as seen in the second column of Table 10. Redefining K to equal 1.37 x 10'5 (multiplied again by 0.8), the Breslow projecting equation is: Ia+p,t+p = Pa--t,o,y X Sa_ti t+p, y X K X (t+p-15) I 846. 16 UCC 007744 A ; 7733 TABLE 10 Projected Numbers of New Mesothelioma Cases 1980-2009 in Men With Plausible Asbestos Exposure Histories Using Two Models of Incidence No Latency Period (Peto) Latency Period (Breslow) 1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2009 Total 1980-2009 3,200 3,500 3,600 3,400 2,900 2,100 18,700 3,400 3,900 4,200 4,000 3,500 2,500 21,500 Task 2b: Estimate the sensitivity of mesothelioma projections to the assumptions involved. Assumptions underlying the mesothelioma analysis fall into two categories, depending on whether they are reflected in the final mesothelioma projections in a linear or non-linear fashion. The linear factors affect the height of the projected curve, whereas the non-linear factors affect its shape. The linear factors are those of Task la (corrections of trend in incidence, non-representativeness of the SEER populations, general underdiagnosis of mesothelioma), and Task lb (fraction of mesothe lioma cases exposed to asbestos). While the net effect of uncertainties in these elements may be as much as 30% either way, it is crucial to bear in mind that the ultimate projections of mesothelioma lawsuits must be tied to the number of suits currently occurring in relation to the number of cases of disease occurring ("propensity to sue"), so that these variations in absolute incidence have no final effect on projections for numbers of lawsuits. Non-linear effects, because they affect the shape of the future mesothelioma curve, are highly relevant to projections of suits. The shape of the curve is relatively robust to large variations in the non-linear parameters. Assuming that the reported years of first exposure to asbestos in the J-M files were off by five years in either direction gives very distorted year of entry distributions (with peak employment coming before or after the war), and only shifts the incidence peak forward or backward five years, but does not change its broad, relatively flat character. Changing the age distribution of current mesothelioma cases (in the SEER data) by assigning 30% more cases to the 70 and over, or to the under-50 year old age groups shows similar five year shifts in the incidence peak. Assuming that the workplace was entirely cleaned up by 1965 slightly increases the short term projections for mesothelioma and decreased the long term ones, since the effect of recent exposures (or non-exposure) can be expected to be felt only many years in the future. Assigning all worker-equivalents the higher mortality of insulation workers leads to slightly faster decline in the pool of exposed workers, and a 5 10% drop in late (post year 2000) estimated mesothelioma incidence. Assuming that mortality of exposed workers is that of the general population leads to a 5% increase in late mesothelioma incidence. Task 3a: Adjust the size of the exposed population and calculate future incidence of lung cancer. The incidence of lung cancer among insulation workers has been reasonably well documented by Selikoff et al (1980) and others (Berry 1980, McDonald et al 1980, Henderson and Enterline 1979) to be the product of two terms: the "underlying risk" for lung cancer that would hold in the absence of asbestos exposure, and a multiplication factor resulting from exposure. The underlying 17 UCC 007745 k ; 7783 lung cancer risk is a sharply rising function of age. From the 1973-1978 National Cancer Institute report of the Surveillance, Epidemiology, and End Results program the underlying risk for white males is: TABLE 11 Incidence of Lung Cancer--Underlying Risk Age (years) New Cases of Lung Cancer Per 100,000 White Men Per Year 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 0.2 0.6 2.6 7.4 22.8 58.3 106.8 181.7 284.2 400.9 481.5 519.0 The asbestos-multiplier calculated by Selikoff et al varies not with age, but with elapsed time since first exposure. Values for the multiplier are: TABLE 12 Selikoff Asbestos-Multiplier Time Since First Exposure (years) 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 Multiplication Factor 2.55 3.40 3.48 5.00 6.08 5.68 4.93 3.89 Although the data which Selikoff has assembled on insulation workers represent the largest, statistically most reliable source of follow-up information, there have been a number of other studies of exposed cohorts. These are summarized on the following page (Table 13). Among all occupational groups, insulators are matched only by factory workers for their levels of lung cancer risks. Miners and, even more so, shipyard workers, have much lower risk multipliers, the former possibly because ambient fiber concentrations are lower in mining than in processing jobs, the latter almost certainly because the category "shipyard worker" includes many people with minimal exposure. 18 UCC 007746 j\: 7 7 ^ C TABLE 13 Risk Multipliers for Lung Cancer from Cohort Studies* Source Insulators Selikoff et ai (1980) Factory workers Henderson Sc Enterline (1979) Newhouse & Berry (1979) Peto et al (1977) Cement workers Weill et al (1979) Shipyard workers (except insulators) Kolonel et al (1980) Miners McDonald et al (1980) Nicholson et al (1979) Hobbs et al (1980) Minimum (years following ________ exposure)________ 0 10) 1.8 (O 2.42 2)(2) 1.25 (10-14) 0.77 (10-15) 1.1 (<10) 0.80 -- 2.10 (<1)(2> -- (0-9) Maximum (years following ________ exposure) 6.08 (30-34) 7.78 O) 5.38 (>2)<2> 1.71 (>20) 3.33 (30-35) 1.3 (>10) 2.65 (>20)(2) 4.19 (40-49) 2.46 (>15) (,) Time data not given separately from accummulated dust exposure (2) Time figures are for years of employment * In each study, if several exposure levels were given, the highest is reproduced here. The multipliers observed by Selikoff are unlikely to be purely the result of asbestos exposure. To the extent that the asbestos-exposed workers studied by Selikoff differed in their smoking habits from the general population, the multipliers include this effect as well. If part of the purpose of the projections was to estimate what fraction of cases in exposed workers were actually attributable to asbestos exposure, lack of smoking data from SelikofTs workers would represent a serious lack. In fact, the purpose of the projection is to decide how many cases of lung cancer occur in toto among exposed workers. For this purpose, it is sufficient to assume that the workers observed by Selikoff have approxi mately the same fraction of smokers as do asbestos workers in general. This appears to be a reasonable assumption, even for future projections. Although there has been a decrease in adult male smoking in the United States, the trend appears to include blue collar workers to a smaller extent than others (Surgeon General 1978). SelikofTs multipliers above describe the experience of a cohort of workers with lifetime exposure to asbestos, and may not correctly predict the future experience of workers, after occupational exposure to asbestos has been curtailed. Observations in chrysotile miners (Berry 1980; McDonald et ai 1980) and asbestos factory workers (Henderson and Enterline 1979) have lent strong support to the idea that relative risk for lung cancer (i.e., the multiplier) may be nearly linearly related to accumulated asbestos exposure over a fairly wide range. SelikofTs multipliers can be interpreted as reflecting a reasonably steady rise through working life, with a decline beginning around the time of retirement, that is, about the time of cessation of asbestos exposure. We have incorporated this phenomenon into the projection equations by constraining the lung cancer multipliers for each exposure cohort to decline from their 1975-1979 value at a rate of 10% per quinquennium. It should be noted that while this discounting of later multipliers fits the Selikoff data most closely, there is no a priori reason to expect a decline, and mathematical modeling of other, smaller bodies of data does not suggest a decline. While the values used represent our "best estimate" for projections, experts who disagreed would probably choose somewhat higher multipliers and consequently would project somewhat larger numbers of cases. 19 A : 779 1 UCC 007747 The projection equation has the following components: Ia+P,t+p--The number of new cases of lung cancer p years from 1975-1979 among persons then aged (a+p) years, with time elapsed since first exposure (t+p). Pa_t,0,y--The number of persons entering the asbestos workforce t years prior to 1975-1979, in year y at age (a--t). Sa-u+p,y--Actuarial survival from age (a-t) to age (a+p), beginning in year y. La+P--The underlying risk of lung cancer as determined from NCI tables for white males of age (a+p). Mt--Lung cancer risk multiplier for elapsed time since first exposure through 1975-1979, reduced by 10% for each subsequent quinquennium. The projecting equation is: fa+p,t+p -- Pa-t,o,y ^ +p,y ^ La+pX Mt. The projected incidence is calculated for each worker group entering the workforce at every age in every past year, and the projected number of cases occurring in every five-year period are summed. The projection procedure described above is, by itself, correct only for a heavily exposed worker cohort (such as insulation workers or factory workers). For a less heavily exposed cohort, such as shipyard workers, the projection predicts only the asbestos-attributable disease, plus the background lung cancers which would be found in a population whose size corresponds to the number of insulation worker equivalents. When the insulation worker equivalent exposures are spread out over a larger number of persons, more background disease needs to be recognized in order to project the total burden of lung cancer (both spontaneous and asbestos-attributable) in asbestos exposed persons. Table 14 presents projections of lung cancer for a worker population, which, on the average, is about one-half as intensely exposed to asbestos as insulation workers. Since our best estimate is that 37% of the "insula tion worker equivalents" are indeed heavily exposed, this implies that the remaining 63% of equivalents arif+ in workers whose exposure intensity is 2.6 times less than that of an insulation worker. TABLE 14 Projected Numbers of New Lung Cancer Cases 1980-2009 In U.S. Men Plausibly Exposed to Asbestos Year Numbers of New Cases 1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2009 17,800 13,600 10,200 7,000 4,300 2,220 Task 3b: Compare projected and observed lung cancer figures. Since no part of the model used to predict lung cancer incidence is based on data from lawsuits coming in to J-M, it is possible to test partially the validity of the projections by comparing details of the J-M litigation file against the model's projections. Table 15 displays the distribution of alleged year of first exposure to asbestos among the 349 J-M cases aged 40-79 who filed suit claiming lung cancer in the years 1975-1981, and who further gave a sufficiently detailed exposure history to allow them to be classified. The percent distributions are further cross-classified by the age at which suit was filed. In parallel are the age-specific distributions of years of first exposure to asbestos for the 22,248 male lung cancer cases for the period 1975-1979 predicted by the model developed in Tasks 1 through 3. Lung cancer is less well connected with asbestos exposure than is mesothelioma, both in the medical 20 A ; 7 7 9 2 UCC 007748 0 and in the legal communities, and so there may be an increased element of serendipity in bringing cases of disease to litigation. Nonetheless, there appears to be a fair correlation between the observed and predicted distribution of years of first exposure, particularly in the overall figures. Although the lawsuits tabulated do not represent the total number coming in to J-M (most do not have detailed asbestos exposure data), their distribution over age categories reflects a plausible pattern of litigious ness when compared to the projected distribution of lung cancers. The highest propensity to sue appears to be in the 40-49 year age group, with a gradual tailing off to age 69, and a precipitous drop thereafter. TABLE 15 Age at Diagnosis /Lawsuit Lung Cancer: Percent Distribution of Year of First Exposure to Asbestos Products Alleged in Lawsuits (1975-1981) and Predicted by Model (1975-1979) 1930-34 Total 1935-39 1940-44 1945-49 1950-54 1955-59 1960-64 1965-69 1970-74 % Count 40-49 L(l) 2.7 2.7 13.5 8.1 35.1 18.9 8.1 8.1 2.7 100.0 37 M(2) 0 0 0 19.7 30.2 29.2 15.5 4.6 0.7 100.0 698 50-59 L 1.6 9.0 30.3 23.0 18.0 9.0 5.7 2.5 0.8 100.0 122 M 0 2.7 20.3 19.5 20.7 23.0 11.5 2.1 0.1 100.0 3770 60-69 L 4.2 15.5 33.1 22.3 10.1 6.8 4.7 1.4 1.4 100.0 148 M 3.9 11.0 35.1 16.3 14.5 15.4 3.6 0 0 100.0 8313 70-79 L 7.1 16.7 33.3 14.3 7.1 7.1 7.1 7.1 0 100.0 42 M 0.8 10.4 56.0 20.3 12.4 0 0 0 0 100.0 9443 Total L 3.7 12.0 30.1 20.1 15.2 8.9 5.7 3.2 1.1 100.0 349 M 1.8 9.0 40.3 18.7 15.1 10.6 3.9 0.5 0.0 100.0 22,248 (1)L Lawsuits with anaiyzable exposure data registered at JM (2)M Model projections of total number of lung cancer cases arising in asbestos-exposed men in the United States. Task 4: Predict future asbestosis prevalence. Unlike persons with mesothelioma or lung cancer, persons with asbestosis are likely to live many years after the onset of their disease. Much or all of that time they may be unaware that their symptoms are due to asbestosis. From the point of view of medical and legal awareness of the disease, then, the key event in the progression of a case of asbestosis is not the date of onset, but rather the date of diagnosis. For predicting the rates of diagnosis (and hence suit) the key underlying figure to examine is the prevalence of potentially diagnosable cases in the general population. There are no direct measures of the prevalence of diagnosable asbestosis in the United States. There are, however, methods of arriving at educated guesses. One depends on the occurrence of mesothelioma in persons with asbestosis; another depends on an equivalence between asbestosis mortal ity rates and mesothelioma mortality rates. Task 4a: Predict asbestosis using mesothelioma mortality rates in asbestotics. Elmes and Simpson (1976) have reviewed the clinica^ pathologic and radiographic records of 327 cases of mesothelioma occurring in the United Kingdom between 1960 and 1969. They found that 70/247 cases with chest radiographs (28%) had clear radiographic evidence of concurrent asbestosis. This figure is not a biological constant; rather it probably reflects the particluar distribution of intensi ties and durations of exposure to asbestos which U.K. mesothelioma cases had undergone in the 1960's. If the general historical pattern of asbestos exposure in the United States is similar to that in the U.K., then one may estimate that about 28% of the cases of mesothelioma in the U.S. in the late 1970's, or about 273 cases annually, had concurrent diagnosable asbestosis. Put another way, of all the people with diagnosable asbestosis in the United States, about 273 developed mesothelioma each year. Three studies give rates of occurrence of mesothelioma in persons with asbestosis which are of the same order of magnitude. Berry (1981) provides the most extensive data: 25 cases of mesothelioma 21 A ; 7793 UCC 007749 occurred in 665 Englishmen with asbestosis certified for the purpose of disability insurance, followed for 4165 man-years of follow-up between 1952 and 1976. Thus, he found a rate of one case per 166 man-years. A total experience about three-fifths as large was reported by Edge (1979) who observed 7 cases of mesothelioma in 2637 man-years of observation in 429 men who had been identified by chest radiographs showing pleural plaques taken between 1964 and 1971 in an English shipyard community. His observed rate is one case per 377 man-years of observation. Least informative because of its small amount of observation is the report of Finkelstein et al (1981) who studied mortality among 172 workers receiving workman's compensation for asbestosis in Ontario between 1942 and 1979 followed for 733 man-years. There were three death certificate records of mesothelioma (one per 244 manyears) and six further cases identified by review of other records (total of one case per 81 man-years of observation). Totalling the experience recorded in the three studies, one obtains reports of 41 cases in 7535 man-years of observation, or one case in 184 man-years of observation. Exclusion of the six Finkelstein cases discovered only after record review would give an overall rate of one case of mesothe lioma per 215 man-years. We have chosen a figure of 1 per 200 man-years as a summary figure. As with the 28% figure for the fraction of mesothelioma cases with asbestosis, the one per 200 man-years estimate for mesothelioma in asbestosis should not be taken to be a biological constant. It too probably reflects the distribution of intensities and durations of exposure to asbestos holding rough ly over the three decades ending in 1975. If, however, we accept the rate of one case of mesothelioma per 200 asbestotics per year, and combine this with the expected number of mesothelioma-asbestosis cases derived before, i.e., 273, we arrive at an overall estimate of about 55,000 persons with diagnosable asbestosis in the United States in the late 1970's. Expressed algebraically, the line of reasoning above is as follows. Let I be the annual incidence of mesothelioma in asbestotics; let A be the number of asbestotics in the U.S.; let M be the annual number of new mesothelioma cases in the U.S.; and let P be the proportion of those with concurrent asbestosis, then A x I = M x P and A = M x P/I. Substituting known or estimated values: A = (974)(0.28)/( 1/200) A = 54,544 men with asbestosis. We have gone through the above calculation separately for each age group in order to derive projected prevalent numbers of asbestosis cases at every age in the period 1975-1979. At present it is not known for how long new cases of asbestosis will continue to develop among currently healthy workers previously exposed to asbestos, assuming that workplace contamination has been essentially eliminated since 1975, and greatly reduced prior to that. J-M's worker experience indicates that there has been a precipitous decline in new cases of asbestosis over the last decade (Chase 1981). This would argue in favor of not projecting the occurrence of new cases beyond 1985. As a best estimate then, we have based asbestosis prevalence projections on an assumption of continued new occurrence through the first half of this decade. Starting from the projected mesothelioma incidence in 1980-1984, we have projected asbestosis prevalence in each age group for 1980-1984 using the projection equation described above. For projections beyond 1984, we have aged the populations using modified 1977 white male actuarial survival figures. The modification is based on strong evidence of very much higher mortality rates in men with asbestosis than in the general population. Berry (1981) reports on 283 deaths in asbestotics with only 108.6 expected; Finkelstein et al (1981) report 66 deaths in asbestotics with only 16.6 expected. Together these give an overall mortality for asbestotics 2.79 times that which would otherwise be expected. Table 16 provides our projections of annual diagnosable asbestosis prevalence for each quinquennium through the year 2009. Of particular importance in interpreting Table 16 (and Table 18 in the following task) is that the prevalence figures are for clinically diagnosable (not necessarily diagnosed) asbestosis which would qualify for worker's compensation in the U.K. or Canada. This is inescapable, because the only 22 A ; 7794 UCC 007750 detailed survival figures available on men with asbestosis derive from these registered and monitored groups. Depending on the criteria used, very much more "asbestosis" can be diagnosed on the basis of minimal radiologic changes. Table 17 (Selikoff 1976) illustrates the problem. Chest x-rays of 1117 men were graded according to the degree of asbestosis, classified on a four point scale ranging from 0 (no disease) to 3 (severe asbestosis). The readings were cross-classified by time since first exposure to asbestosis. It is very unlikely that workers with SelikofTs minimal (grade 1) asbestosis would qualify for worker's compensation. If such workers were to be included in prevalence estimates, however, the projections of Tables 16 or 18 (Task 4b) would have to be roughly tripled. TABLE 16 Projections of the Number of Prevalent Cases of Asbestosis In U.S. Males 1980-2009 Based on the Incidence of Mesothelioma in Asbestotics Years Number of Men Alive With Asbestosis 1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2009 65,800 35,400 19,000 9,600 4,400 1,700 TABLE 17 Years Since of Exposure X-ray Changes in Asbestos Insulation Workers Percent Distribution by Asbestosis Grade No. 0 l 2 3 40 + 30-39 20-29 10-19 0-9 121 5.8 28.9 42.1 23.1 194 12.9 52.6 25.3 9.3 77 27.2 45.5 22.1 5.2 379 55.9 41.7 2.4 0.0 346 89.6 11.4 0.0 0.0 Task 4b: Estimate asbestosis prevalence using the equivalence between asbestosis and mesothelioma mortality. A second line of reasoning about asbestosis prevalence can lead to an independent estimate by which to gauge the results of the previous task. This is based on the near perfect identity of the time course and magnitude of asbestosis mortality and mesothelioma mortality in SelikofTs (1980) insula tion worker data, combined with independent estimates of mortality in men with asbestosis, SelikofTs (1980) observations of mortality from asbestosis and mesothelioma are summarized in Figure 2. It is of particular importance that the asbestosis mortality recorded by Selikoff is not simply an estimate of mortality in men with asbestosis, but rather specifically of mortality due to asbestosis. Berry (1981) found that 56 of 263 deaths (21.3%) in British men with asbestosis were actually attributed to asbestosis. Finkelstein et al (1981) found for the more inclusive category "non-malignant respiratory disease" 23 out of 61 deaths (37.7%) in Canadian men receiving workmen's compensation for asbestosis. This figure is consistent with Berry's, which is based on larger numbers and more specific reporting. Independent estimates of mortality rates among asbestosis sufferers place them at about 2.8 times the corresponding age-specific rates in the general population (see Task 4a). For any given age group, write the mesothelioma deaths among men exposed to asbestos as Ma, and the corresponding count of all deaths in men with asbestosis as Da. Then the Selikoff finding of an equality in the numbers of mesothelioma deaths and asbestosis deaths in insulation workers, combined with Berry's finding that 21.3% of all death is due to asbestosis, is Ma = 0,213 x Da. A ; 779b UCC 007751 FIGURE 2 Mesothelioma Mortality Death Rate Per 1000 Person-Years Number of Years Subsequent to Onset of Exposure Deaths per thousand person-years of experience of pleural, peritoneal, and total mesothe lioma among 17,800 asbestos insulation workers from 1967-1976, analyzed by duration from onset of employment in five-year periods. Ratios between observed and expected deaths cannot be computed since expected rates are not available for the general population. At least as of 45 years from onset, a decline in rates was not noted. This is consistent with the finding that cigarette smoking did not play a role in the risk of developing mesothelioma, in contrast to lung cancer. Asbestosis Mortality Number of Years Subsequent to Onset of Exposure Death rates of asbestosis among 17,800 asbestos insulation workers 1967-1976, analyzed in five-year periods of duration from onset of employment. Some decline is seen after 45 years from onset, possibly related to the added burden of smoking-induced lung disease superim posed upon asbestosis (at least in some cases) with selective survival of nonsmokers. 24 UCC 007752 ,7793 ft If the general death rate for men is G, and the number of asbestotics is A, then the total number of deaths in asbestotics is Da = 2.8 x G x A. A is the number of interest. Combining the above equations, A = Ma/(0.213 x 2.8 x G). Ma in available for every age and future year from the mesothelioma projections (Task 2) and G is estimable for each age group from current vital statistics data. SelikofFs data apply to insulation workers exposed to asbestos essentially all their working lives, and cannot, therefore, not be expected to give a reasonable estimate of asbestosis mortality far into the future, after the workplace has been largely cleared of significant asbestos exposure. (Mesothelioma mortality, by contrast, is affected almost entirely by age at first heavy exposure, and is not changed greatly by workplace clean-up, at least as far as concerns already exposed workers.) The problem is that discussed at the end of Task 4a: new asbestosis probably stops occurring (with some lag, perhaps 10 years) after the cessation of asbestos exposure. Thereafter mesothelioma/asbestosis relations observed previously (under conditions of extended exposure) became inapplicable to future projection. As in Task 4a, we have handled this problem by estimating prevalence based on continued new incidence through the 1980-1984 quinquennium, and have estimated subsequent prevalence by aging the 1980-1984 population as described in Task 4a. Table 18 gives the projected asbestosis prevalence figures for U.S. males 1980-2009, using this second projection procedure. TABLE 18 Projections of the Number of Prevalent Cases of Asbestosis in U.S. Males 1980-2009 Based on the Equivalence of Asbestosis and Mesothelioma Mortality Rates Years Number of Men Alive With Asbestosis 1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2009 64.000 45,300 31.000 19,700 11,400 5,700 Task 4c: Other methods of projecting asbestosis prevalence. There are several "quick and dirty" estimates of asbestosis prevalence which give estimates of the same order of magnitude as one another. 1. Berry (198,1) reports that 133 workers were certified annually by U.K. pneumoconiosis panels in 1973-1976 and that the median survival of the least disabled certified workers was 15 years. This gives a maximum steady-state prevalence of 15 x 133 = 2000 workers in the U.K. with certified pneumoconiosis (essentially all asbestosis). The U.S. is'about four times the size of the U.K. Histori cal exposure patterns being equal, this implies the existence of about 8,000 asbestotic workers or former workers in the U.S. Apart from the looseness of the analogy between the U.K. and the U.S., this projection suffers from its dependence on the number of workers actually certified in the U.K. This is a lower limit to the number actually ill. 2. Burnham (1982) cites an unpublished estimate of the National Center for Health Statistics (NCHS) that there were 427,000 (range 248,000 to 606,000) pneumoconiosis sufferers in the U.S. in 1980. He also points out that the Mortality Statistics Branch of the NCHS noted 1422 deaths ascribed to pneumoconiosis in the U.S., of which 72 were ascribed specifically to asbestos. Applying the death proportionality to the pneumoconiosis prevalence gives an estimate of (72/1422)(427,000) = 21,000 asbestotics (range 12,000 to 30,000). The pneumoconiosis prevalence figure, however, was based on a 25 A : 7797 UCC 007753 questionnaire only and is therefore likely to be an underestimate, and the reporting of asbestosis on death certificates is notoriously low, 3. The prevalence of x-ray changes in workers listed in Table 17 can be multiplied by our estimates of the size of the heavily exposed work force (Table 9), to obtain estimates of asbestosis prevalence ranging from about 18,000 to 150,000 depending on whether radiologic grade 1, 2, or 3 is used as the minimal criterion for a diagnosis of asbestosis. Although the correlation between x-ray changes and symptomatology is imperfect, the low end of this projection (18,000 grade 3 cases) would certainly represent symptomatic individuals in every case. The upper end of the projection (150,000) would include many people with few or no symptoms, whose asbestosis would be detectable by physical or radiologic examination only. Task 4d: Derive a general methodology for predicting lawsuits as a function of asbestosis prevalence. Although it is not the purpose of the present work to derive estimates of a person's propensity to bring suit given that he has disease, the difference between asbestosis and the cancers insofar as diagnosability and survival times are concerned calls for some comment. Mesothelioma and lung cancer come to diagnosis fairly rapidly and reliably, and as a result the propensity to sue can be related directly to disease incidence in order to derive an expected number of lawsuits. Asbestosis is not diagnosed nearly as reliably or as quickly, so that the pathway leading from prevalent disease to a lawsuit involves two probabilistic steps: diagnosis and decision to sue. Men with asbestosis live for decades, and so may be diagnosed for the first time and sue years after the onset of diagnosable disease. Perhaps the best way to interpret overall propensity to sue for an asbestotic man is to calculate an annual probability of suing. The pool of prevalent, asbestotic men who are potential litigants can then be thought of as being diminished with the passage of time through two effects: first, through their own mortality, and second, through their bringing suit, thus removing themselves from the pool of potential litigants by becoming active litigants. Over years, then, a constant propensity to sue acts on a dimin ishing pool of potential litigants to produce a declining annual number of lawsuits. By way of illustra tion, Table 19 gives the expected number of lawsuits by quinquennium, assuming asbestosis prevalence pools as listed in Tables 16 and 18, with cases appearing (and being removed from the pools of potential litigants) at a rate corresponding to suits from 9% of all potential litigants appearing each year. TABLE 19 Projections of Asbestosis Lawsuits Assuming 9% of Prevalent Cases (Non-Litigants) Bring Suit Each Year Years Method Of Projecting Asbestosis Meso Incidence in Asbestotics Meso-Asbestosis Mortality Equivalence 1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2009 24,800 8,300 2,800 900 200 100 24,100 10,600 4,500 1,800 700 200 The 9% figure was chosen for Table 19 so as to yield current lawsuit rates for the present quin quennium. Bear in mind that the rapid decline of lawsuits in Table 19 is the product of two factors, which hold true only for workers with symptomatic asbestosis. The first is the high mortality rate in these men, discussed in Task 4a; the second is the finite (though large) size of the pool of potential litigants. From Table 17 it should be apparent that the number of workers with minimal disease 26 A : 7703 UCC 007754 (Grade I) is very much larger than the number of seriously affected workers. If in fact a large number of lawsuits derive from the relatively well, exposed population, neither of the conditions on which Table 19 is predicated would hold: mortality in the minimally diseased is not much elevated, and the number of minimally diseased persons is so large that current litigation rates will not result in any meaningful depletion of the pool of potential litigants. Limited J-M data suggest that, in fact, lawsuits from asbestotics do not decline as rapidly after last exposure as one would anticipate from Table 19. In effect, Table 19 represents minimal projection. If only a fraction of current cases are coming from symptomatic cases, then the symptomatic pool is being depleted more slowly than projected in Table 19. Symptomatic cases will come in over a longer period, and the remaining, minimally diseased cases will continue to flow in at a rate (determined by socio-legal factors) which is unlikely to be bounded by purely medical or epidemiological factors such as population mortality rates or depletion of a pool of injured workers. Taking all of these factors into consideration, a reasonable central projection of the number of lawsuits seen from 1982 on is likely to be about 45,000, with a reasonably firm lower bound of 30,000 and a very indefinite upper bound on the order of 120,000. Task 5: Estimate the amount of asbestos-related disease occurring in women. Approximately 5% of the lawsuits being filed with J-M derive from women. This number is consistent with an estimate from a variety of sources of about 10% of the asbestos-exposed World War II workforce being female, with a diminished fraction after the war. Exposed female workers still alive can be expected to have an age-at-first-exposure distribution which is even more concentrated in the war years than that of men. The consequence of this is that asbestos-related disease will have reached its peak in women earlier than in men, and is probably past that point already. The number of female cases in J-M is too small to make a direct test of this hypothesis. Probably the most reasonable projection of female cases would involve accepting the current 5% figure and projecting the proportion of female cases to taper off gradually to a negligible number by the year 2000. 27 UCC 007755 * 17703 References Baris, YI, Artvinli, M and Sahin, AA. (1979) Environmental mesothelioma in Turkey. Annals New York Academy of Sciences 339:423-432. Berry, G. (1981) Mortality of workers certified by pneumoconiosis medical panels as having asbestosis. British Journal of Medicine 55:130-137. Breslow, N. (1982) Unpublished review of NCI data. Burnham, CE. (1982) Unpublished letter to Norman Breslow, June 2, 1982. Chase, G. (1981) Preliminary results from a morbidity study of domestic J-M asbestos-using locations. Johns-Manville Corporation internal document, July 30, 1981. Chovil, AC, McCracken, WJ, Dowd, EC, et al. (1981) Occupational cancer: experience in Ontario. Canadian Medical Association Journal 725:1237-1241. Connelly, RR. (1980) Mesothelioma incidence in the United States. Presented at the Workshop on Opportunities for Research and Education in Asbestos-Related Disease, Bethesda, MD, June 17, 1980. Edge, JR. (1979) Incidence of bronchial carcinoma in shipyard workers with pleural plaques. Annals New York Academy of Science 350:289-294. Elmes, PC and Simpson, MJC. (1976) The clinical aspects of mesothelioma. Quarterly Journal of Medicine AXK:427-449. Finkelstein, M, Kusiak, R, and Suranyi, G. (1981) Mortality among workers receiving compensa tion for asbestosis in Ontario. Canadian Medical Association Journal 725:259-262. Henderson, VL and Enterline, P. (1979) Asbestos exposure: Factors associated with excess cancer and respiratory disease mortality. Annals New York Academy of Sciences 330:117-126. Hobbs, MST, Woodward, S, Murphy B, et al. (1980) The incidence of pneumoconiosis, mesothe lioma and other respiratory cancer in men engaged in mining and milling crocidolite in Western Australia. In: Biological Effects of Mineral Fibres, J. C. Wagner (ed.), vol. 2, Lyon IARC, pp. 615 625. Hughes, J. and Weill, H. (1980) Lung cancer risk associated with manufacture of asbestoscement products. In: Biological Effects of Mineral Fibres, J. C. Wagner (ed.), IARC Scientific Publication No. 30, IARC, Lyon. Kolonel, LN, Hirohata, T, Chappell, BV, et al. (1980) Cancer mortality in a cohort of naval shipyard workers in Hawaii: Early findings. Journal of the National Cancer Institute 64:739-743. McDonald, AD and McDonald, JC. (1973) Epidemiologic surveillance of mesothelioma in Canada. Canadian Medical Association Journal 709:359-362. McDonald, AD and McDonald, JC. (1980) Malignant mesothelioma in North America. Cancer 46:1650-1656. McDonald, JC, Liddell, FDK, Gibbs, GW, et al (1980) Dust exposure and mortality in chrysotile mining, 1910-1975. British Journal of Industrial Medicine 37:11-24. Newhouse, M. (1981) Epidemiology of asbestos-related tumors. Seminars in Oncology 3:250 257. Newhouse, ML and Berry, G. (1976) Predictions of mortality from mesothelial tumors in asbestos factory workers. British Journal of Industrial Medicine 33:147-151. Newhouse, ML and Berry, G. (1979) Patterns of mortality in asbestos factory workers in London. Annals New York Academy of Sciences 330:53-60. Newhouse, ML and Thompson, H. (1965) Mesothelioma of the pleura and peritoneum following exposure to asbestos in the London area. British Journal of Industrial Medicine 22:261-269. 28 h : 7 3 0 ,,C UCC 007756 J Peto, J, Doll, R, Howard, SV, et al. (1977) A mortality study among workers in an English asbestos factory. British Journal of Industrial Medicine 34:169-173. Peto, J, Henderson, BE and Pike, MC. (1981) Trends in mesothelioma incidence in the United States and the forecast epidemic due to asbestos exposure during World War II. In: Quantification of Occupational Cancer, R. Peto and M. Schneiderman (eds.), Banbury Report 9, Cold Spring Harbor Laboratory, pp. 51-69. Peto, J, Seidman, H and Selikoff IJ. (1982) Mesothelioma mortality in asbestos workers: Implica tions for models of carcinogenesis and risk assessment. British Journal of Cancer 44. Selikoflf, IJ, Hammond, EC and Seidman, H. (1980) Latency of asbestos disease among insultation workers in the United States and Canada. Cancer 46:2736-2740. Surgeon General (1978) Smoking and Health. U S. Dept, of Health Education and Welfare. Tagnon, I, Blot, WJ, Stroube, RB, et al. (1980) Mesothelioma associated with the shipbuilding industry in coastal Virginia. Cancer Research 40:3875-3879. Vianna, NJ, Maslowsky, J, Roberts, S, et al. (April 1981) Malignant mesothelioma: Epidemio logic patterns in New York State. New York State Journal of Medicine pp. 735-738. 29 UCC 007757 A ;7801 51k08Z! V Scientist says chemical make-up not to Marne u o -- 11kR* u" S- "S .1 -5 ** e.ft t o u VJ u lI CJ 1 "T 2 Cc W5 T? to3-S 2 3 -- CJ rt ^ uUl * -- a.~j '-o -- a p< f3 (S o u e? V3 Sa C C9*- /> CJ un p--4 10 -- -- *2 IS - 2 zI O w " -S " r; s m y *& = -s tx , 2 * - - r? S -Q , a 5w _ i, "3 y i --c oRc c ~ ^ ^ .*.*-. o ^ -R '*J n c? -- A Cp Ltft *- ua -1*` " > : rs ^ >t _ ; 1 S E i ** -Q U *= o St v: c ^ o> tj k_ ^ u. ss s-2 I -w Mo i-- U= s: 9 ^ k.c- X yU VS tfi * V) ^ -- t- O Vi ~ *r\ - = o = _ "3 H - pC c <9 '35 3>es ^= 53 `i 2b IIk^ e=S5&^"?3 = ^a - i = -S S 5 go' 9 -S S s \ Z O ^ z " g jS h : c .3 c 1 A J3 . . U TH cw . r * * "_ 3^ ^n ^ T5 S3 .2 <S= i-/S; d- **5 j*3 2 .__ wV). ^g yC -- iCk;J. ~ t= --1 T> *ts n i. 2 -, S <J <w H.-- JUs ^ Lc ^ W C- _U u ^ 3 -- lw CJ k P> CJu l-> -- e -* v> s o^ e ri- C ^ s J=o a b> :"= s = C"S | 2 TS = iC ; i a .kyi ,,- ^5 -ocR ^ <0 V c5 u -A ^ .5 o *o gab IB ' : =. w w cfl yi V '^5 i & ^- tMftfi *oOw --s5 o i> _ T3 -5 j w rc* C c;. .S2 >i =rc u -?i'3^5=^cu.= "' s- 5y nSz w ^ S ao_ -Jxuilt-oo?; ^_ -."3tfO ^ TS *" _? --o ra E * Ic? c- jC ,,rp-- 5- = " -u > S * -" TM s ,^. F c S -S Mw u -- re *5 *" - S ,J1 c t *o J5 s-a | y- 3 Vfil - .i: 5 w cn U 3n ccc o 5< V Q *- ^ ^ w c 2n g J ^ 3 r: * u - s o= n ~ `3* u ^ o S CS & UJ --n UCC 007758 Kelti c . res : Rarr.-izzini. B. cjitoied 1 n ref. 3 -I mlinj. G . `Cerrwrt eczema and ehr.'mu;.n ailurg}-. The.-K. Univ. c: Scrgea. Suwol of Medicine. 1970 C,. ran. C. D.. J. oceitp. Med., 1900, 2. 15 - Fregert. $, &. Gruvberger, B-, Berul'sderm.. !9?2. 20. 23S i\j;uii, M. \V.. Brit. J. Derm.. 1972, 36. 155 n TeclimcaJ report on admixtures for concrete'. London: The C\m- Societv Meucaiiii-a, C. L., personal communication 5 Burrows, D. & Carnap. C, D., Tr3tn. Sr. John's Ho*?.De.v;. Sue.. 1965, 51, 2T '' Mencghini. C. L., Rantcccio, F. &. Riboldi, A.. Beruftdttrrr , ;96\ II, 131 ` 10 Miescher, G., Amrein, H. P. & Ledcr, M., Dermatologies, 1^:5. no, 266 11 Wahlhcrg, J.. Berufsderm.. 1969. 17. JS4 Samitz, M. H.. Gross, is. 5c Katz. S.. J. irr'. Dorm., iv"'2- 53, 5 1J Cronirt. personal communication '* Frcgett, S.. personal communicaiion 1S Fregcrt. S., Gruvberger, B. &. Hcijcr. A.. BcruJsJerm.. 1-rO. 13, 254 . ; j 1 i i t 1 i -i Peter C Elmes That part of the human lung where oxygen passes through into the blood stream in exchange for carbon dioxide is made up of liny chambers called alveoli. These are lined by a laser of cells so thin that it took the electron microscope to prove that they actually existed. To preserve these ceils from drying and breaking, a layer of moisture lies between them and the air in the lung, moisture whose surface tension is reduced by a surfactant to prevent the alveoli from emptying completely when you breathe out. This delicate arrangement is protected from damage from dust by the extremely efficient filtration, moistening and warming system provided by the nose, the trachea and bronchial tubes. Coarse particles of du>t are removed by the hairs at the entrance to the nose. Front thereon down the airways are lined by cells coated with a layer of watery jelly known as mucus. This mucus layer is kept moving by cilia. tiny hairs which wave in a coordinated manner so as to propel the mucus both front the lung and the nose into the back of the throat where it is swallowed. As ;ur is drawn into the lungs it passes down tubes which branch repeatedly into smaller and smaller tubes. At each branching the airflow is thrown into a vortex which spins out the heavier dust particles until they touch the mucus lining in the tubes and become caught. The dust panicles caught ^y th; mucus are cleared from the tubes of the normal lung within in minutes of A 7 9 7 ^inhalation and end up in the stomach. Size and shape of dust particles The system of filtration is so efficient th.n only a small range of panicles reach that part of the 'ung where gas exchange occurs. If deposited there particles can do harm. The vortex clearance of the particles from the air stream is proportional to the sedimentation rate of the particles in moist air. For approximately round particles anything larger than 5win is filtered off. Particles between 5 and bourn tend to be retained in the alveolar part of the iimg because they land beyond the mucus escalator. Particles below i'-baa tend to Professor Elmes cf Queen's University. Beirast delivered tvs caper at a meeting of the Road & Building Viarenals Group of the SCI in London on 23 November *972. .. . remain suspended in air and be breathed out again without doing any harm. Elongated particles such as vegetable and mineral (asbestos) fibres sediment in air at a rate proportional to their transverse diameter. This means that fibres at 100 am or more long could get down into the lung provided they were thin enough. Furthermore, a long particle may get caught at one of the places where the tubes divide and be driven through the wall into the underlaying tissue when the person breathes out. Fortunately .most vegetable fibres (cotion and so on) and woo! or hair are too coarse to get very far down the airway, Almost all commercial glass fibre is also too coarse. The molecular structure of asb;,to-> is such that it readily splits lengthways into very fine fibres. Chrysotile. the most 'widely used commercial asbesto> readily breaks up into bundles of fibres only 200-300A in diameter, amosste and crocidolite easily form fibres in the 600 t I2C0.A range. Bundles of this thickness, and from 1 to say IcOvm in length, would be retained in the lung provided they were straight. In practice dust particles of amositc and crocidolite are straight and a large proportion of inhaled parades of this size range are retained in the lung. Because they are curved the fine fibres of chrysotile are more readily caught by the filter system and are less likely to be forced through the bronchial walls into the tissue, (t is probab!.* for this reason that chrysotile dust is less likely to cause i.mg damage than similar dust derived from amosite or crocidolite. !n general, the size of the dust particle generated by any process depends on the speed of impact. Hand-dr: , en tools produce very little respirable dust but high-speed drills, crushers, saws, and so on produce a high proportion of fine dust which, unless it is accompanied by larger particle'., is invisible to the naked eye. In time dust particles tend to aggregate with each other and especially with particles of moisture to form larger particles which are removed 'ny the respiratory filter. Therefore dust is moat dangerous a. vc to the point at which it is formed. Chemical nature of dust A dust particle, irrespective of its chemical nature, will create a disturbance when it lands on th; lining of 'five airway and therefore most people cough and wheeze when, they UCC 007759 -1art inrj-.'.r.'i e.ven inert dust. The p` articles which wcet throug"h 're filter to be retained in the alveolar or gas exchange part the lane cause no immediate disturbance. If they are ue't. like the iron particles retained by an arc welder, they wii be packed away in special cells in the lung and remain there for the rest of the individual's life. Silica dust is not inert and as long as it remains in the lung it dissolves to give an ae.d which destroys cells while the lung tries to imprison the particles in a scar. The process of cell death and scar : :"nation makes the lung stiff so that it become* more and tare difficult to use because of the work required getting t.te air in and out. Although all asbestos minerals are silicates they do not chase like pure silica particles. They cause damage to the --ng apparently because of their needle-like shape rather than because of the release of a toxic chemical. Asbestos fibres become coated with brown material and may be .den dried in the lung 30 or more years after they were Mauled. From the occupational health point of view. _sbestos differs from silica in two important ways. Firstly, "articles of respirable size may be released from prepared -sbestos by simple handling, high-speed impacts are not necessary. Secondly, although chemically inert, a heavy load dust panicles continues to damage the lung for many .-ears after exposure has ceased. History of asbestos usage Asbestos was used by prehistoric man in Finland to reinforce c.ay cooking pots, and by the Greeks and Romans to make :.ks for altar lamps and shrouds for emperors. Its special rroperries were not fully appreciated until the middle of the 'eteenth century when fireproof insulation became essential the manufacture of ships and locomotive*;, anyw here where ugh pressure steam was generated from a furnace and boiler, Jld mines in Northern Italy and Finland were enlarged and '.ben large deposit* in eastern Canada, South Africa and *:~eriu were discovered. Very large quantities of cheap fibre became available by the end of the first world war. Lntil h:a: time asbestos cloth quilts and boiler compound (a r.-.'.iure of magnesia and fibrous asbestos! were the main end product, both being used for insulation. Between the wars and following the second war. the `.rength. durability and cheapness of the material was acrreciated increasingly. Asbestos is now mainly u*ed to -'.-engthen cement products such as corrugated roofing and '..rfueing boards, pipes and heat-resistant cladding of the nee! framework of buildings. This consumes oxer 90 per cent ' the world production of asbestos. Ret:'Arcement of "'..Stic tile* and so on and pure-insulation .''mes ue\t. and tuer. sere 'mail quantities in certain special filters and other -jo. The main technical problem at the present time is aether asbestos is really essential in the asbestos cement "redacts or whether a cheap safe substitute can be found. Occupational hazards of asbestos -- 5 c estosi 3 A i 7973 Because of its chemically inert nature, manufacturers and . rkers handled asbestos like wool without fi..:r of the . ".sequences until 1930. Cases of lung damage in asbestos orkers had been reported by doctors from !9t!0 onwards. .'ere usually attributed to a modified form of tuber- ,-lo'i>. It -'as not until a survey of asbestos factory workers carried out by the factory inspectorate that it was refused that many workers were dying of .erg fibrosis '-.thin 15 years of first exposure.1 Death was due to a pro gressive replacement of the lung by scar tissue resuiting from its destruction by very large numbers of asbestos fibres perhaps a million fibres in every' millilitre of lung. Regulations were introduced in the asbestos textile aad parts of the asbestos cement factories to control the dust levels. As a result asbestosis among factory workers entering the industry since 1933 has almost disappeared. Studies with chrysotile dust indicate that if the dust level is kept beiow 2 fibres per millilitre of air, less than I per cent of w orkers develop asbestosis before they retire after 50 years' work. This is a cumulative limit of 100 fibre years,, ml, and appears to hold good irrespective of the age at which the worker is first exposed-2 Similar standards have been applied to the use of amosite and crocidolite but are probably not satisfactory r reasons which w ill appear later. This standard of less than 2 fibres per millilitre in the breathing zone of workers in asbestos factories has been achieved in most factories in Britain, it was not applied to the handling of asbestos in the user indus tries such as shipbuilding, civil engineering and the manufac ture of cars and so on. The incidence of new cases of asbestosis among asbestos factory workers began to fall soon after the introduction of the new regulations in 1933. By the early 1950s it was already apparent that the only serious new cases were derived from the diminishing population of workers who had been employed before 1933. However, new cases of asbestosis were being reported from insulation workers n factories and shipyards and by the middle 1960s these cases exceeded the cases arising from the asbestos factories and the total number of case* certified each year continued aye. The new regulations, if applied to all tiic user industr:;; should sec a change for the better in the number of case* of a*bcsto*is certified in the next few year*. Lung cancer Lung cancer, especially in men who smoke, has become increasingly common during the fast 30-4t) years so that the first few reports of cancer in asbestos workers were regarded a* chance occurrence*. However, the Medical Inspector of Factories in his report for 1947 noted that P per cent . men dying after certification for asbestosis had luug cancer* a* well.3 This was beyond the realm* of chance and pro* oked an investigation in one particular factory population1, whim confirmed an increased ri*k of lung cancer in workers v:;h asbestosis. However, thi*. and a f..llow-up study published m l9fV suggested that the risk was only serious in Lcto'y workers who had been exposed before the introduction o' the 1933 regulation*. There remained Lite problem of men being exposed to asbestos in the user industries. By !A-y Buchanan had shown* that over 5U per cent of men certified as suffering from asbestosis in Britain died with lung cancer and this proportion may now be about 70 per cent. Report* from America indicate that this lung cancer risk may only affect cigarette smokers and that asbestos does not came serious increase in lung cancer in non-smokers.7 If it prove* possible to apply the current dust regulations to the con struction industry then the risk of lung cancer may be avoided, but men who have already been exposed to large amounts f ' dust are likely to develon their lung cancer at about the age jf 55 or 60 if they continue to smoke irrespective of the.* future du*t exposure. The withdrawal of men from ' because on X-ray or other medical testing they show evidence of heavy dust exposure dee* not reduce the risk of can-er far as we know. UCC 007760 ' - ' - n i-i f* !r*r* Fi U U M p\r ! 5* v4 i X - 1 . *i Jdssathfjiioma In the late 19505 a number of cases of a rare cancer of the lining of the chest wall occurred in South Africa, a number fa: in excess of any prev iously reported. These patients had asbestos dust in their lungs and had at some time or other lived near (but not necessarily worked in) the blue asbestos (crocidolite) mines in the North West Cape province. Fifteen such cases of mesothelioma had already been reported from Belfast and subsequent studies there, in London, in other shipyard cities and in New York have confirmed the relationship between this tumour and asbestos exposure. The worrying aspects of this work have been the slight degree of exposure to the dust (3-6 months handling asbestos liner pads tor gas masks u7//i local exhaust ventilation) and the very long latent period between exposure and the develop ment of the tumours. The average age of death from this tumour in Belfast is about 60 years and the mean interval between first exposure to asbestos and the development of the tumour is 43 years.9 Much work has been done on this tumour during the last 15 years. It now seems likely that* crocidolite is responsible for the majority of cases but that amosite may be responsible for some. It is possible that chrysotiie does not produce this tumour at levels of exposure which have existed up to the present time, although it can cause the tumour in experi mental animals. It seems wise not to allow any exposure to crocidolite dust in any industry and to restrict amosite to essential uses. But restrictions applied at the present time are not likely to affect the rising incidence of tins tumour for many years to come. There muM be many thousands of individuals who have already received their dose of dust and who will develop this tumour when they reach tire age of 60 (give or take 1.5 years either way ). Sl ipping I'uriiter exposure to dust and stopping smoking are both unlikely to influence the outcome. The tumour may be present for weeks or months before the patient is aware of it. It usually starts in the chest but can start in the abdomen. The patient is usual'y stiil in good general health when he first consults hi> doctor because of a ci.il ache or heaviness in one side of ins chest, ('nnrodactive cough and breathlessness soon follow. M this stage the patient is sent to hospital and investigations reveal the presence of fluid (which may contain blood) or scarring around one lung. It can be difficult to-establish the diagnosis for certain without an operation and even then the diagnosis may remain doubtful. There is no satisfactory treatment and patients usually die about a year to eighteen tn<*mhs after the onset of symptoms. Increasing breathlessness k the man dillieuity and tins can sometimes be relieved by the periodic with drawal of fluid from the chest. Towards tl'.e end live patients may develop difficulty in swallowing and lose weight rapidly. Pain often becomes severe and is difrlcy.lt to control with drugs. This may persuade doctors to try various forms of treatment including operations which are of little value. In some cases these patients may survive for aui to three years alter the onset of pain and one can but admit e the fortitude with which many cope with this situation. From being a rare disease this kind .1 cancer is now occurring at a rale of 100 to 150 new ca e- cacti .ear and this incidence is likely to continue to rive. Ai7974 Specific industrial risks . The general description or the ha.ta.-d' \ he.. :t. l icit may result from expox'urg'to iubestO'ia a'ar r.Y.e a addii.ic-u t ,o interpret in relation to specific occupations or industries. The studies`which led to the regulation of the dust concentrations in asbestos factories were only done on textile workers. For the next 20 years attention was focused on these workers and men doing similar work in asbestos cement factories. Even in these sitaations dust analysis was not done regularly .aid it i> difficult to estimate the cumulative dust exposure of older men who have been in the industry since boyhood. In most user industries, especially those like construction w ar.-, which moves from site to site, information on dust level? dees not exist. Changing materials, changing techniques .rid to..- .ise of high-speed tools ail alter dust conditions so that the prediction of the heaith hazard in a working population from the iceords of past exposure is impossible. The only way to deter::.me the hazard is to study the health of the workers. No -eiev .mi study has yet been made in the construction industry. S-eh studies are urgently needed and a study done on insulation workers in Belfast illustrates the way in which studies can be carried out. The conventional way of investigating an industrial health hazard is to examine a representative sample of working men and see whether they show any signs of disease w hen com- I pared with a sample of the general population. This kind of survey is effective in revealing disease which develops relatively early in a man's working career provided he is able to remain at work after the disease has become apparent. It was effective in demonstrating the presence of axke-tosis j in textile workers in 19301 only because conditions were j very bad. In Belfast 5U insulation workers were 'elected and 1 compared with 50 men from the municipals transport department who were matching them for age. height and [ smoking habits. There was no difference between '.be two groups of men. either from the point of view of their general heaith. or as a result of X-rays and detailed tests m their lungs. Both groups contained some older men m.j heavy j smoker-, who had shortness of breath, a cough and the other features associated with chronic bronchiii'.1" j This preliminary study was followed by a the-mush j examination of all the insulation worker;, in N nhern j Ireland who were willing to spend half xt day wth us. 93 Per cent of the men came and they appeared nvmuti for their age. \s in 'he first 'ample the older men t-ended to have the symptoms of bronchitis and the X-ray' showed .: high proportion of abnormalities in these older men. In a very fevv it was possible to >ny for certain that they w ere '.iffertng from asbestosis, but-even in these it was hard to --keii'er their asbestosis was causing them as much trouble e.s their chronic sronchitis. There were no -.-uses of lung ...ueer or mesothelioma picked up in this survey of men at w-. rk.`- The third part of the investigation consisted of genre over > the records of the trades union branch to '.hie'' these , insulation workers belong and the records of tc.e eon- tractors who employ them to find out who we.' doing irsuki- tion work in 1940.u One sinister piece of inf'-mation : which came from the union was that there were no :r. illation workers drawing their old age pension from their eontriautory pension scheme. It was possible to identify !6e men .a work. ; in 1940 and Mrs Simpson had the te.sk ,.f finding o-.u wiuit < had happened to them. If they had died we then ". end out hot!) from the Registrar Genera* and the h.-spita! re.^rd- the cause of death. Wherever possible this diagno-l- con firmed by re-examination of preserved '.Issues removed at '..per,.:ioris or post-mortem. This was necessary oe.v. >e in the -early part of the period i !94<>-55i most pathoi. .1 were ` UCC 007761 Fig 1 ...j * a - I ^ - H .* r r\d' 3 ' c- I-1 '. ,,:i eir ; ?. s*G i-3 fait. 4. Fig 2 -i'j in.-." vorke.> ' -40 n P-:- ' - cv>' mm ( f.vi> >v P unlikely to differentiate between a mesothelioma .md .1 !::ny: cancer. The experience of these men was compared with the Registrar General's analysis of eau-es of death in Northern Ireland for men of the same age as our insulation workers o\cr the same period (1940-66). The results of this complex investigation are shown in three graphs. In the fi-st (Fig I) Lite survival is compared with the survival of equivalent men m the general population of both Northern Ireland as 1 whole and more specifically of Belfast where these figmes were available. The lines start to diverge in 1950 and by lO'-fi only fir men survived of the 168 when. about !<!(i -homd have survived. There had been 35 more deaths than exnected. In the second and third graphs (F:gs 2 and 3> the number of men dying m each, five-year :-er!od r- co'-pared with the number expected. In Fig 2 deaths due to all kinds of cancer are shown. In Fig 3 deaths from lung cancer and mes.uu are shown together. Both graphs show that from 1951) otv-vards the number of men dying from cancer, in pc-ticaiar cancer of the lung and pleura, are many drr.es '-he number expected. This investigation revealed an obviously unaccept able occupational hazard which was net even hinted at by the results of studies on men still at work. The reason for different results from the two meihcds of study is the delay between exposure and the development of these to cancers (25 to 30 years for the lung cancer and perhaps 4.) yearn for (he mesotheliomas') so that the iiir.ess m..y not develop until after the man has left the industry. I:i any case a man does wot continue to work for -'`..c.-o oft.T a cancer has re. -hed the stage at which it wou.J be revealed by X-ray or mi.ucai examination. Fig 3 UCC 007762 s. i 34 j preo. Der.rs cv.-j t-r-;-:c -t. - 8 ,# 't ., Sels^r.ion of groups for study It would be a monumental task to set up this sort of investigatioa for all construction workers who handle asbestos at some time during their working lives. However, there is a ; method of finding out which workers are likeiv to be at ' hazard. The mesothelioma is a rare tumour and in Britain about SO per cent of cases are thought to be due to exposure to asbestos at work. Therefore if an investigation is made of the work history of all people dying of mesothelioma then it is possible to show what occupations arc responsible and consequently need further investigation. In Belfast the cases can be divided iuto two main categories, those working most of their lives in the shipyards and those who were mainly employed elsewhere. Of 62 cases recently investigated, the occupations are as shown in Tables 1 and 2. In Table 1 it is seen that the shipyard has given rise to 45 out of the 62 cases, but that only 10 of these occurred in insulation workers. The majority of the shipyard cases arose in men whose exposure was an incidental result of the work mainly because of working in confined spaces near men handling insulation material. It is understandable that pipe and engine fitters should be exposed especially during repair work because their concern is with equipment normally covered by insula tion. But platers and so on and electricians were less expected and the extent and circumstances of their past and present exposure manifestly needs investigation. Outside the ship yard there were 17 cases and of obvious concern to the construction industry are the eight cases arising in builder's labourers, joiners, sawyers and limber workers. In the latter group, retrospective questioning did not reveal the source of avbestos. This was a relatively small study in one city heavily biassed by the presence of a large shipyard. To be of real value this kind of investigation should be carried out on a nationwide basis. It has the major disadvantage of revealing the con sequences of working conditions many years before. But it is the only method of pinpointing hazardous occupations with respect to asbestos at the present time. Once identified the extent of the hazard requires detailed investigation along the lines used in the Belfast insulation study. This work takes time and awareness of the possible risk should be the reason for the introduction of preventive measures rather than waiting for the results of detailed studies. Table j Mesotheliomas in shipyard workers in Belfast - 45 of a group of 62 cases InbLuanors; Full-time Transient Other occupations (helpers and labourers included): Plumbers, pipefitters and boiler makers Engine titters Platers, riveters and welders Electricians Other s}10 17 4 4 3 _ Table 2 Mesotheliomas in non-shipyard workers in Belfast - 17 of a group of 62 cases Known exposure: Heating engineers and boilermen Builders' labourers and joiners Dockers No known exposure: Linen workers (women) Sawyers and timber workers Baker Postman . 2 6 .1 2 2 1 I References I Merewether, E. R. A. & Price. C. W., 'Report on the effects of asbestos dust on the lungs and dust suppression in the asbestos industry', 1930, London: HUSO 'Hygiene vtandards for chrysotile asbestos dust', British Occupation Hygiene Society. 1963. Pi.`r-.'Lrnn>, Press * ' Merewether, E. R. A Annual report of the Chief Inspector ol Eac- tones for the vear 1947. 1949. p79, London: HUSO 4 R,, Brit. .1. htd. Ated.. 1 o5. 12, 31 " Knox. J. F., Holmes, S.. Doll, R. & Hill, !: D., ibkt, i960, 25, 243 * Buchanan. \V. \V,, Aim. V.Y. Atad. Sci . 1965, 132. i. 507 ' Hammond. E. C. & Seiikotf. I. J,, 'Relation of cigarette smoking to risk of death of asbestos associated disease among insulation workers in the United States'. Meeting of a Working Group to review the Biological Effects of Asbestos. Lyon. 2-5 October 1972, in press 8 Wagner, J. C., Sieges, C. A. & Xlarchand, P.. Brit. J. ind. Med., 1960, 17.26 ' Elnes, P, C.. Journo! !r. Co!!.. P/nsic. Stir., 1972, 1. 117 10 Wallace, W. F. M. & Lanai-.ids'. J. H M.. Bdt. J. but. U.-.t,, 1971, 28. 21 l ' II Elmes. P. C. & Simpson. M J. C. ibid. 197!. 23. 226 1; Lanelands. J. H. M , Wallace. W. F. M. & Simpson. \1. J. C.. ibid, 1971. 23. 217 j | j I i | ; : ' j ! A i 7 9 7*0-------------------------------- Galalin emulsions in the formation of microcapsules Sir. - Dr A. Courts in his lecture on 'Gelatin emulsions in the formation of mierocap'ules' before the SCI Food Sym posium in March 1972 and reprinted m Cicmistry and Industry1 states that tile most profitable application for micro capsule technology is to be found in the carbonless copy paper manufacture. ,W'e are convinced that the.readers .of Chemistry ami Industry will find Dr Court's lecture extremely valuable because it presents a la:r picture of the present know ledge on gelatin based micro encapsulation technique. There are, however, some errors which \\e would like to correct. Dr Courts states 'The capsules are coated onto the underside of a sheet of paper and this is then contacted, with a surface coat of attapulgus clay on the following sheet. When the capsules are broken by the pressure from a typewriter key, or a pen, the dye is released and reacts with the day surface, vvhich induces oxidation leaving a blue coloured print. One dye is oxidised immediately and the second dye provides the more lasting effect'. In actual fact2-3 the primary mark on breaking the capsules is brought about by the immediate ring opening of crystal \ ,olet lactone in . contact vytth the day UCC 007763 surface. NO other chemical reaction is involved and a blue image of limited light stability is produced. The lasting bluegreen image occurs slowly through the decomposition of benzoyl leuco methylene blue in a complex mechanism' involving oxidation as well as the action of light. Yours faithfully H. R. Ballister The Clay tort Aniline Company Ltd PO Box 2 Clayton Manchester Mil 4AP References 1 Cour.s, A,, Chew. A Htd.. 1473. cgf 2 Abraham E. N,. Chen,, dt- Ik./.. 14-2. 1512 3 'Recent advances in the progress of applied chimi-iU-y'. vol Ml, 197!, p;)4 i3 vol XVII. 1972, p 135 4 Ports. H. A.. Wood. A. H. ik CTaok, C. C.. J. cppl. Cr.etn. Bio-techno!.. I9'2, 22. 651 Letters to the editor.continued an pipe !0i0