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I I I I I I I I I I I I I I I I I I A RETROSPECTIVE LUNG CANCER MORTALITY STUDY OF PEOPLE EXPOSED TO INSOLUBLE ARSENIC SALTS AND RADON Liu Yu-tang and Chui Jin Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Beijing, China Abstract The incidence of lung cancer for workers in four mines who had been exposed to insoluble arsenic was found to be 290/105. A dose-dependent decrease in the incidence was associated with a reduction in the concentration of insoluble arsenic in the air. The content of arsenic in the lung of subjects exposed to insoluble arsenic was 51.4, which was 17 times higher than the 3.0 [G µg/g(d)] found in control groups. Moreover, the content of arsenic was found to correspond with the number of years working in the mine and with the incidence of lung cancer. Metabolic studies of arsenopyrite showed that it is converted to products such as arsenous acid, arsenic acid, methyl arsenate and dimethyl arsenate, which are identical to those generated from AsZ03. Although these metabolic products are formed at a lower rate, they nonetheless show that arsenopyrite should be considered as a carcinogen. Potential carcinogens such as As, Cr, Ni, Be, and Cd were evaluated in lung specimens of miners with lung cancer and compared with values obtained in controls by logistic regression analysis. Only As was found to be significantly associated with lung cancer. The concentration of As in lung tissues correlated well with the amount found in the air of the mining environment. A retrospective/prospective interference epidemiologic investigation performed over a 40 year period showed that the risk of radon was overestimated. After regulatory measures were implemented in the mines to control for exposure to radon, the value of radon was found to be RR/WLM = 0.17%, which was 9 times lower than the values estimated in the past. Introduction As and Rn are carcinogens commonly existing in nature in extremely low concentrations. In metal mines, As and Rn usually coexist. The arsenate in the deposit is mainly composed of arsenopyrite (FeAsS), which is not considered to be a carcinogen because of its low solubility. Consequently, the etiologic agent for cancer in mines is often attributed to Rn or its daughters. Indeed, the concentration of Rn in many uranium and non-uranium mines is very high, and may be elevated to 4-5 times the recommended working levels (WL). Despite the high levels of radon, the incidence of lung cancer is not increased in these environments. China is a country rich in nonferrous metal mines. High concentrations of insoluble arsenic and radon and its daughters are often detected in the air of many mines. High incidence of lung cancer is seen among many miners. I

We have been interested in determining the relationship between insoluble arsenic and lung cancer, and the possible confounding role of radon, which coexists with As in ore deposits, in the occurrence of lung cancer. There are at least two significant considerations in our studies: First, if Rn is proved to have significant carcinogenicity, then large sums of money must be invested in order to give protection from Rn. On the other hand, if the carcinogenic action of Rn proved to be minimal, then only efforts to protect from As are needed, representing a saving of 90%. Second, an insight to these relationships may provide useful leads for the prevention of lung cancer. Our studies show that for effective protection from Rn, positive pressure ventilation should be adopted, whereas wet operation with adequate ventilation affords good protection from As. Results Part 1. Epidemiologic Investigations of the Role of Insoluble Arsenic in Inducing Lung Cancer A. Research on Lung Cancer in Miners in Realgar Mines AszS; is the main composition of the ore. The solubility is 0.00005 % at 18°C water temperature. Al. Concentration of As in the Mine Air (as As): Arsenic concentration was measured on three separate occasions and the following results were obtained: 1973, n=6, 0.004-0.577 mg/m', average 0.23 mg/m' 1981, n=14, 0.003-0.166 mg/m', average 0.06 mg/m' 1988, n=8, 0.028-1.442 mg/m', average 0.32 mg/m3 A2. Epidemiologic Investigations A regressive-prospective cohort study was conducted with follow-up from January of 1972 to 1989 (1,2). The total prospective person years was 6,942. The total post-statistics person years was 6,566, representing a 5.5% loss to follow-up. In addition, 61 died during the cohort period, and 289 retired or moved. A3. Results (1) Causes of death: of the 27 cancer deaths, 16 were lung cancers, accounting for 59.2% of the total cancer deaths and raising the possibility that As is a risk factor for lung cancer. (2) Incidence of lung cancer: of the 6,566 person years, 17 were diagnosed with lung cancer. Sixteen deaths eventually resulted from these cases and only 1 survived. The incidence of lung cancer was calculated to be 258.8/105. 2 I I I I I I I I i I I I I I I I I I I

I I I I I I I I I I I I I I I I (3) Relative risk: post-statistics calculations showed RR=20.41, X2=15.49, P<0.01. (4) Standard mortality rate: the expected value was 0.3848, the observed value was 16. The standard mortality rate SMR was 41.58, P<0.01. The mortality of tumor in sites other than the lung was not significantly associated with As. A4. Research on Etiology It is well known that the incidence of lung cancer in smelters is associated with the presence of soluble arsenic. Because of the view that the arsenates (As2S3) in realgar mines does not dissolve, it is assumed not to accumulate in the body and accordingly presumed to have no association with lung cancer. Instead, Rn daughters have always been assumed to be the recognized agent for lung cancer. Measurement of Rn daughters in realgar mines, however, showed a value which was within the normal background level, making it unlikely that there existed a link between Rn daughter and the incidence of lung cancer among realgar miners. Accordingly, the concentrations of various carcinogenic agents in the mining air were measured; with inorganic carcinogens being quantified by ICP spectrography. In addition to showing the concentration of Rn to be within the normal background range, other suspected agents for lung cancer in humans, such as Cr, Ni, and possible carcinogens such as Be, Cd, were also found to be lower than the threshold value (Table 1). Table 1. The concentration of carcinogens in the mining air (mg/m') Measure Date N Carcinogens Minimum Maximum Average, 1988 8 As 0.0284 1.4422 0.3201 1988 8 Cr 0 0.0004 0.0003 1988 8 Ni (-) (-) 1988 8 Cd* 0.0002 0.0249 0.0047 1988 8 Be* 0 0.00001 0.00001 * Possible agents of human lung cancer. An attempt to examine the relationship between smoking and lung cancer yielded inconclusive results because of the few number of cases. Based on the number of cases that were actually collected, a non-significant association was found, with RR=3.007, Xz, - 1.54, P>0.05 IJ O , CO ~ -4 O W 1 3 V I

I B. Study of Lung Cancer in Tin Miners The main arsenate in the three tin mines (L. mine, M. mine, S. mine) is arsenopyrite whose solubility is 0.0005 % at the water temperature of 18oC. BI. The Average Concentration of As in the Air of Mines (as As) A total of 543 samples were used to assess As concentration. The average concentration of As in the air of mines was higher than 0.29 mg/m3 before 1950; 0.29 mg/m' in the 1950s; 0.022 mg/m3 in the 1960s; 0.015 mg/m' in the 1970s; and 0.010 mg/m' in the 1980s. These results showed that the concentration of As in the air of mines gradually decreased. B2. Epidemiologic Investigation Over one thousand cases of male subjects with lung cancer were analyzed in the tin mine study; 90% of these were exposed to insoluble arsenic before 1950. (1) Methods. Because of the limited database, a considerable amount of effort went into collecting cases and population controls as early as possible in order to obtain the CMR (crude mortality rate). In addition, a cohort of 751 persons who started working in the mines between 1960-1969 was established. Follow-up of the cohort continued until 1992. There was a 8.6% loss to follow-up. (2) Results. The CMR (crude mortality rate) was 290/105 in lung cancer cases in which exposure to As occurred before 1950s, as opposed to a CMR of 150/105 found in lung cancer workers who were exposed to As after 1950. In cases where exposure to As took place only in the beginning of the 1960s, the CMR was only 20/105. The gradual decrease of lung cancer mortality corresponded to the decrease of insoluble arsenic in the air in the mining environment and showed a dose-response relationship. B3. Etiologic Investigations (3-5) (1) The concentration of various carcinogens such as Cr, Ni, PAH, or possible carcinogens such as Be, Cd, in the mines were analyzed to further determine the cause of lung cancer. All had values below the threshold value, irrespective of whether the measurements were taken in the early or the late stage of the study. The only exception was the concentration of As (Table 2). I I I I I I I 1 I I I I I , N O Lp ~ ~ -4 tb 4- W s N CD ' , I

t I I I I I I I I I I I I I I I Table 2. Concentration of carcinogens/possible carcinogens measured at different periods of the investigation Carcinogen 1950 1960 Time 1970 1980 Cr mg/m' 0.010 0.008 0.003 0.001 Ni mg/m3 0.008 0.006 <0.001 <0.001 Be* mg/m' 0.003 <0.001 <0.001 <0.001 Cd* mg/m' 0.005 <0.001 <0.001 <0.001 PAH µg/m' 0.025 *Possible carcinogens (human lung cancer) (2) Metabolism of insoluble arsenic. The inorganic arsenic in ore mines is mainly composed of FeAsS, known as arsenopyrite, which is formed from FeAs03.2HZ0 by oxidation. This compound, as mentioned above, has extremely low solubility and was not considered a carcinogen for a long time. The biological properties of arsenopyrite have not been investigated before 1981. Our work in 1981 demonstrated for the first time that arsenopyrite can be dissolved and metabolized by rats. The metabolic products, namely, arsenous acid, arsenic acid, methyl arsenate and dimethyl arsenate, are the same as those formed from carcinogenic AsZOs. Compared to the soluble AszO3, however, arsenopyrite is metabolized at a much slower rate. Nonetheless, these results show that, despite its low solubility, inorganic As may act as a carcinogenic agent for lung cancer in miners. (3) Measurement of As contents in lung specimens. To further elucidate the involvement of arsenopyrite in the development of lung cancer, the target dose of As, which referred to the concentration of the putative causative agent actually found in the affected organ, was determined. The following results were obtained. The content of As in the lungs of 42 miners who were exposed to insoluble arsenic and developed lung cancer was 51.4 G µg/g (d). The content of As in the lungs of 3 miners exposed to insoluble arsenic without developing lung cancer was 6.2 G µg/g (d). The content of As in the lungs of 38 subjects with non-lung disease was 3.0 G µg/g (d). These results showed that the content of As in the lungs of As-exposed miners was 17 times higher than that of the control group. The amount of As accumulated corresponded with the number of years working in the mine and showed a dose-response relationship with the morbidity rate. tV O ~ V 00 W 3 ' -5_ V . <O !

I In summary, although the insoluble arsenic is slowly dissolved and metabolized in the body, it is able to be accumulated over an extended period of time and therefore would be able to exert an effect in diseases, e.g., lung cancer, with a characteristic long incubation period. (4) Confounding factor analysis: In order to ascertain whether other carcinogens or possible carcinogens coexist with As in the target organ and, as a result, exert risks that are based on multi-factor interactions, a logistic regression analysis was performed. Methods and conditions. A total of 21 male miners with lung cancer, who had worked in the mines for between 6-42 years, were matched with 21 controls, i.e., subjects who had cancers in locations other than the lung. The variables consist of the generally recognized carcinogens such as As, Cr, Ni and possible carcinogens such as Be and Cd. They were represented by X1, X2, up to X5. A status of 0 was assigned to controls, while a status of 1 was assigned to the cases. EPIPAC software was used in calculation. The multifactor logistic regression analysis showed that, among the 3 carcinogens and 2 possible carcinogens considered, only As entered the model and reached statistical significance (Table 3). Table 3. Logistic Model variable BET EXP S.E.. BET/S.E. P As Xl 0.81678 0.01851 0.21725 3.7595 0.000170 Cr X2 0.11251 0.10113 0.87614 0.12841 0.897820 Ni X3 -0.29078 0.97134 0.10933 0.26597 0.790263 Be X4 0.15943 0.11728 0.27023 0.58998 0.555202 Cd X5 -0.66154 0.93558 0.58775 1.1255 0.260357 (5) Smoking and lung cancer. Of the 751 subjects that constituted the cohort, 85 % were smokers. Through a 29 year follow-up study, the incidence of lung cancer was only 20/105 and was well within the normal range. A note of emphasis was that miners usually smoked through a bamboo pipe and thus only breathed in smoke that had been water-filtered. Part 2. Epidemiologic Investigations of Rn daughters Rn daughters have long been considered a lung cancer inducing agent. A cumulative dose of 100 WLM of Rn daughters is often taken as a level which is correlated with an abnormally high incidence of lung cancer in China. The risk of Rn has also been estimated by using an ERR 0.015%/WLM, as recommended by BEIA IV (1988). -6- N O tb ~ N tp W ~ tb 0 I I 1 I I I I I I I I I I I

I I I I I I I I I I I I I I I I I I Different concentrations of Rn daughters have been found in many mines, including uranium and non-uranium mines. Although many other carcinogens such as As, Cr, Ni, are also found in the same locations as Rn, emphasis has always been placed on Rn daughters. In our tin mine study, high concentration of Rn daughters and insoluble arsenate were both present. Thus to reduce the risk of exposure to these agents, reasonable, economic and effective preventive measures must be taken. Because As and Rn exert their harmful effects in different ways, different preventive measures are needed. To effectively discharge Rn in the mine, positive pressure high wind speed is needed, whereas protection from As is adequately achieved with wet operation and negative pressure low wind speed ventilation. From the economic point of view, energy consumption associated with Rn discharge is 90% higher compared to methods designed to minimize exposure to As. A. Regressive, Prospective Interference Epidemiologic Study The study is designed to test the relationship that may exist between changes in concentration of As and Rn in mine air and the incidence of lung diseases. Another objective is to study the separate role of these two agents in the etiology of lung cancer. The approach involved first surveying the carcinogenic capacity of Rn by epidemiologic methods, followed by estimation of the associated risk using a cumulative dosage method. The results of the 40 year regressive/prospective interference epidemiological study (regression for 25 years and prospection for 15 years) showed that the concentration of carcinogens and the dust in the mine air began to decrease in the middle of the 50s after wet operation began to be adopted to prevent pneumoconiosis. In the 60s, the wet operation became fully adopted; resulting in As being reduced from 0.29 mg/m' in the 50s to 0.015 mg/m' in the 70s. The radon daughters, being a naturally decaying product, were not expected to be affected by changes in the production mode to dry versus wet operation. Their concentration remained high (3.1 WLM L. mine) from the 50s to the middle of the 70s, during which period the incidence of lung cancer decreased from 150/105 in the 50s to 20/105 in the late 80s. Hence there is no epidemiologic evidence to support the existence of a link between the incidence of lung cancer and the concentration of Rn daughters. B. Radiation Accumulative Dose of Rn Daughters and Lung Cancer The relationship between Rn daughters as a causal agent of lung cancer is based on the radiation accumulative dose received by the workers. The method for calculating the cumulative dose of Rn daughters is amply illustrated in the literature. As mentioned above, the dose of Rn to induce lung cancer is suggested to be 100 WLM in China. Whether such a dose is supported by epidemiologic findings is unclear. Thus, in addition to examining the connection between Rn daughters and lung cancer, another objective of our study is to find out whether the alleged harmful accumulative dose of Rn matches with data provided by epidemiologic -7- I

I investigations. Accordingly, mines with plentiful exposure to Rn daughters were selected for our study. Rn concentrations, people groups, patients with lung cancer, coexisting exposing factors were analyzed. Individuals who began to work in the mine in the 60s were included in the cohort. Observations were continued until 1992. B1. Radiation Accumulative Dose of Rn Daughters Since the installation of a ventilation system in the mines in 1976, the concentration of Rn daughters has been steadily declining: the concentration before 1976 averaged 3.1 WLM; the cumulative total averaged 5.4 WL from 1977 to 1985 (9 year period); the cumulative total averaged 2.7 WL from 1986 to 1991 (6 year period). B2. The Accumulative Calculation Result The year of 1965 was taken as the median of years of exposure to Rn. With that as a reference, the accumulative dose was calculated stepwisely. After 27 years, the radiation accumulative dose of Rn daughters received by each member in the cohort averaged 619.6 WLM. However, the incidence of lung cancer was only 20/105. B3. The Risk Assessment Even with an accumulative exposure dose of 619 WLM for a total of 27 years, the incidence of lung cancer was still within the normal range. Another group of workers in the same mine began to be exposed to Rn in the 50s and had a total exposure of 42 years. Their accumulative dose of Rn averaged 1120 WLM. According to information released by NIH in June, 1994 (7), the incidence was 43.4/105 after adjustment SMR 1.72, p<0.01. Suppose the accumulative exposure dose is 900 WLM, SMR 1.36, P>0.05. The RR carried out by BEIA IV (1988) is 1.5% WLM. Because the incidence of lung cancer ranges under the normal level under the accumulative dose 900 WLM, the former RR should be raised 9 times, that 1.5/9.0=0.17% WLM. In the new data released by NIH recently the RR claimed by BEIA IV (1988) has been altered greatly. Processing the data from China, ERR is changed into 0.5 % WLM (7). The result is a very close approximation to ours in 1990 (5). Summary 1. This paper investigates the incidence of lung cancer among miners in 4 mines who were exposed to insoluble arsenic. Long term exposure to high concentrations of As was associated with a high incidence of lung cancer. -8- I I I I I I I I I ' I I I I

I I I 2. I 3. I I 4. I 5. I 6. I I I I I I I I A 40 year interference epidemiologic investigation shows that the incidence of lung cancer in tin miners decreased in parallel with a reduction in the concentration of insoluble arsenic in the production environment, showing a causality between them. The so-called insoluble arsenate "arsenopyrite" is dissolved and metabolized in the body. Its metabolic products, i.e., arsenous acid, arsenic acid, methyl arsenate and dimethyl arsenate, are identical to those derived from the generally recognized carcinogen Asz03. Thus the arsenopyrite is proved to be a carcinogen. The incidence of lung cancer in miners showed a progressive yearly decrease, against a background in which the concentration of Rn daughters remained essentially unchanged. Even when the radiation accumulative exposure dose of Rn daughters averages 619.6 WLM, the incidence of lung cancer is only 20/103. A 40 year follow-up studies of a cohort demonstrates the carcinogenic role of Rn was over- estimated in the past. In determining the cause of lung cancer in miners who were simultaneously exposed to multiple factors including Rn, the RR of Rn daughters was calculated to be RR=0.17 % WLM, which was 9 times lower than the past estimation. ' 9- N O i -I tb W o0 I W

I REFERENCES 1. Lu, Y.T. et al. An epidemiological studies on occupational cancer. J. Hygiene Research 1980 9(4):10. 2. Lu, Y.T. et al. An epidemiological investigation on occupational cancer in workers exposed to arsenic. Chinese J. of Industrial Hygiene and Occupational Disease 1986 4(4):200 3. Lu, Y.T. etal. Chemical etiology research on lung cancer in Yjnxi miners. J. Hygiene Research 1980 9(4):15. 4. Lu, Y.T. et al. On a etiology of lung cancer in Yunxi miners. Chinese J. Industrial Hygiene and Occupational Disease 1987 5(1):20. 5. Lu, Y.T. et al. Etiological research on lung cancer excess occurrence in Yunxi miners. The selected papers of the symposium on occupational safety and Health in Asia-Pacific Region: 101. October 7, 1991, Beijing. 6. Lu, Y.T.; Chen Z. and Wang A.D. Metabolic study of insoluble arsenic. J. H iene Research 1981 10 (4):50. 7. Lubin, J.H. eta l. Radon and lung cancer risk. US Department of Health and Human Services. Public Health Service National Institute of Health NIH Publication No. 94-3644. - 10- I I I I I ! I I I I 1 I I I I I I I