CANCER MORTALITY PATTERNS IN THE LEAD INDUSTRY W. Clark Cooper Tabershawl Cooper Associates, Inc. Berkeley, California 94704
The data to be presented in this report were obtained during a study of the mortality of 7,032 men who had been employed for at least one year in either a lead production facility or a lead battery plant during the years 1947 through 1970. The findings have been presented in considerably more detail elsewhere; 1v the emphasis in this report will be upon deaths attributed to malignant neoplasms. Several points should be emphasized with respect to the occupational exposures of the individuals who were studied. First, actual exposures to lead and other substances could not be quantitatively described for most of the individuals whose mortality patterns were studied. However, information that was obtained on urinary and blood lead concentrations in the same plants indicates that a great many had absorbed lead considerably in excess of currently acceptable standards. Second, the population studied, particularly those in lead production facilities, was potentially exposed to many substances other than lead, including arsenic, cadmium, and sulfur dioxide. Therefore, although many of them had high lead exposures, one is not warranted in attributing all effects to lead alone. METHODS
The cohort studied was derived from microfilmed personnel records of six smelters and ten battery plants, which had been selected from 84 plants that had responded affirmatively to a preliminary questionnaire. Participating plants were selected on the basis of size, geographic distribution, the adequacy of records, and the length of time they had been in operation. No attempt was made to get either a representative sample or a random sample. From a total of 24,494 individuals who had been employed by the 16 plants during the period 1946 through 1970, 7,032 met criteria for inclusion in the mortality study, i.e., they were male, had been employed for one year or more, and had complete data on hire date and birth date. Follow-up of these individuals was pursued through company employment records and the usual techniques for tracing individuals. Death certificates were requested for all known deaths, and these were coded by the rules of the Seventh (1955) Revision of the International Classification of Diseases, Injuries and Causes of Death. Proportionate mortality for twelve selected causes was compared with the distribution for United States male deaths in 1959. Standardized mortality ratios (SMR’s) were calculated for a 35-cause list (plus some causal groups related to infectious diseases and to renal disease). Data on urinary and blood-lead concentrations were available from six battery plants, which had contributed 89% of the study population, and from four lead-producing plants, which had contributed 80% of the smelter workers in the study. 250
Cooper: Mortality Patterns in the Lead Industry
25 1
RESULTS Follow-up to determine vital status was successful for 96% of the study population, i.e., 98% of smelter workers and 95% of battery plant workers. The 1,356 deaths during the 23-year period 1947-1970 were the basis for mortality analyses. Death certificates were obtained for 1,267, or 93% of the known deaths. FicuRe 1 summarizes the establishment of the study population and the subsequent follow-up.
Women ca. 950 q1 y r ca. 16,000 Missing data ca. 350 Alive 5,387(77%)
Certificate received 1,267
Dead 1,356(19%)
V i t a l status
No c e r t i f i c a t e 89(73)
FIGURE1. Summary of the study population and follow-up, 1947-1970. Of the 289 unknown, 193 were from two smaller plants, where there was no Social Security follow-up. Of the 89 with no certificate, 70 were from one plant in Pennsylvania. (By permission of the publisher of J. Occup. Med.2)
Indicators of Probable Exposure The population studied included more than 3,000 men who had been working on January 1, 1946, and exposures extended back to 1920 or earlier for some individuals. No quantitative data on lead absorption existed for the period before 1948, and for most plants it began later. TABLE 1 summarizes the employment history of the 7,032 men in the study, based on date of termination or December 3 1, 1970, whichever came first. This indicates a high percentage who had worked for 20 or more years.
Annals New York Academy of Sciences
252
TABLE1 DISTRIBUTION BY NUMBEROF YEARS EMPLOYED FOR SMELTER AND BA~TERYPLANTWORKERS Percentage of population with more than indicated number of years Smelters Battery Plants
Years Employed * Over 5
54.0 39.6 3 1.7 24.0 15.3 9.4 4.7
10 15 20 25 30 35
* As of date of termination or Dec.
69.9 53.0 41.1 35.2 29.3 19.2 10.0
31, 1970, whichever came first.
Data on urinary or blood-lead concentrations were obtained from nine of the 15 plants that had routine monitoring programs as of 1970 (TABLE2). Many workers had no levels recorded because their entire work experience had been before their individual plant began monitoring. PbU levels were available for less than 10% of deceased workers; PbB values were available for less than 2%. Study of the urine and blood lead concentration did, however, provide valuable indirect information regarding the relatively high levels of lead absorption by a substantial portion of the workers in the plants under study. TABLE 3 summarizes the numbers of men whose mean PbU values over a working lifet h e exceeded certain indicated values. TABLE 4 summarizes similar information on blood-lead concentrations. Proportionate mortality, i.e., the relative proportion of the 1,267 certified deaths which fell into each of 12 major categories when compared with male deaths in 1959, is shown in TABLE5. There were slight excesses for some types of cardiovascular renal disease and for certain malignancies. Since such a proportional mortality table does not take into account the age of the population at risk, it is regarded as only a suggestive indicator. The total mortality of the 7,032 individuals as summarized in TABLE 6 was approximately the same as that of the general population, 1,356 deaths having occurred where 1,348 were expected, giving a standardized mortality ratio (SMR) for all causes of 101. The SMR for smelter workers was 107, that for TABLE2 SUMMARY OF URINARY LEADAND BLOODLEADDETERMINATIONS
PbU PbB
Number of Analyses
Number of Men
Analyses/man (average)
97,002 16,152
2,274 1,860
43 9
Percentage of total (7032) 32% 26%
Cooper: Mortality Patterns in the Lead Industry
25 3
TABLE 3 NUMBEROF WORKERS WITH TEN OR MORE PBU DETERMINATIONS OR EXCEEDED INDICATED CONCENTRATIONS WHOSEMEANVALUESEQUALED (!a/L) (UNCORRECTED)
Type of Plant
Numbers of Workers with over 10 determinations
2150
2200
2250
2 300 pg/liter
Smelters Battery plants
497 1,053
289 249
164 59
70 17
27 7
Total
1,550
538
223
87
34
Number with mean values
TABLE 4 OF WORKERS WHOSEMEANPBB VALUESOVERA WORKINGLIFETIME NUMBER EQUALED OR EXCEEDED THE INDICATED CONCENTRATIONS Number with mean values Type of Plant
No. of Workers
2 40
270
280
2 100 wglloog
Smelters Battery plants
534 1316
457 976
138 350
83 105
25 52
1850
1433
488
188
77
Totals
TABLE 5 IN
PERCENTAGES OF 1267 CERTIFIED DEATHS SMELTERAND BATTERY-PLANT WORKERS,DUE TO SELECTEDCAUSES, WITH PERCENTAGES AMONG US. MALES FOR 1959 COMPARED (PROPORTIONATE MORTALITY) Cause of Death
Major cardiovascular-renal Vascular lesions of CNS Hypertensive heart disease Other hypertensive disease Chronic and unspecified nephritis Malignant neoplasms Respiratory tract Urinary organs Cirrhosis of liver Suicide Motor vehicle accidents Other
U.S. Males
53.9
Smelter Workers 45.7
9.7 3.2 0.7 0.7 14.6
57.3 7.4 3.1 2.2 2.2
21.3 3.4 0.9
1.3 1.5 3.0 25.7
Battery-Plant Workers 7.1 3.1 1.4 1.5 19.7
6.8 1.5 0.6 4.0
4.6 23.8
6.5 0.5 2.8 1.7 1.9 16.6
Annals New York Academy of Sciences
254
TABLE6 EXPECTEDAND OBSERVED DEATHSBY CAUSE JAN. 1, 1947-DEC. 31, 1970 FOR LEADSMELTER AND BATTERY-PLANT WORKERS Cause of Death Tuberculosis, all forms Bacterial and viral diseases plus influenza and pneumonia Malignant neoplasms Major cardiovascular renal disease Violent deaths All other certified causes Total for certified causes All causes including uncertified Number of workers Person-years
* Correction of
+5.55%
Obs.
Smelters Exp. SMR*
Battery Plants Obs. Exp. SMR t
4.55
23
5
14.84
37
8 8.17 69 54.95 151 165.29 59 40.52 36 46.15 324 319.64 342 319.64 2352 33482
103 133 96 154 82 107
23 186 540 62 127 943 1014
26.82 180.34 575.21 89.63 141.45 1028.37 1028.37 4680 69828
92 111 101 74 97 99
1
applied for 18 missing death certificates.
t Correction of +7.52% applied for 71 missing death certificates.
battery plant workers 99. The SMR for all malignant neoplasms was 133 for smelter workers and 111 for battery plant workers. This group of deaths was studied in more detail, based upon anatomical site, as shown in TABLE 7. Tumors arising in the digestive organs and in the respiratory system were slightly elevated in both groups, the excess being close to significance at the 5% level. No other sites showed appreciable deviations from expected numbers. In attempts to demonstrate relationships between TABLE7 EXPECTED AND OBSERVED DEATHSFOR MALIGNANT NEOPLASMS JAN. 1, 1947-DEC. 31, 1970 LEADSMELTER AND BATTERY-PLANT WORKERS Smelters Battery-Plant Obs. Exp. SMR * Obs. Exp. SMR t
Cause of Death All Malignant Neoplasms (140-205)
Buccal cavity and pharynx (140-148) Digestive organs, peritoneum (150-159) Respiratory system ( 160-1 64) Genital organs (170-179) Urinary organs (180-181) Leukemia (204) Lymphosarcoma, lymphatic and hematopoietic (200-203, 205) Other sites
* Correction of
+5.55%
69 54.95
133
186 180.34
111
0 25 22 4 5 2
1.89 17.63 15.76 4.15 2.95 2.40
150 148 101 179 88
6 6.02 70 61.48 61 49.51 8 18.57 5 10.33 6 7.30
107 123 132 46 52 88
3 8
3.46 6.71
92 126
7 23
9.74 17.39
17 142
applied for 18 missing death certificates.
t Correction of +7.52% applied for 71 missing death certificates.
Cooper: Mortality Patterns in the Lead Industry
255
TABLE8 DISTRIBUTION OF NEOPLASMS BY TYPEOF PLANT Type of Plant
Cancer Deaths All Deaths
Percentage of Deaths
69/324
21.3
9/58 14/62 46/204
15.5 22.6 22.6
186/943
19.7
Total smelter Primary smelter Secondary smelter Secondary refinery Battery plant
employment and tumor incidence, employees were grouped by estimated lead exposures based upon job titles; by duration of employment (more than or less than ten years) ; and by date of hire (before or after January 1, 1946). None of these showed consistent or significant relationships. Distribution of Neoplasms Based on Type of Plant Deaths due to malignant neoplasms, expressed as a proportion of total certified deaths, for primary smelters, secondary smzlters, and secondary lead 8. refineries and battery plants, are shown in TABLE Distribution of Cancer Deaths by Primary Site The proportion of all cancer deaths attributed to tumors from various 9. These have been compared with the relative primary sites is shown in TABLE proportions for the total male population of the United States for 1950, 1959, and 1969. TABLE9 PROPORTION OF DEATHS DUETO MALIGNANTNEOPLASMS ATTRIBUTEDTO VARIOUS ANATOMICAL SITES* Observed Smelters Battery
Expected
Site
%
%
1950 %
Digestive organs Respiratory system Genital organs Urinary organs Leukemia Lymphosarcoma, etc. Other
36.2 31.9 5.6 7.2 2.3 4.4 12.4
37.6 32.8 4.3 2.7 3.2 3.8 15.6
42.1 16.1 11.5 6.2 4.7 4.4 15.0
100.0
100.0
100.0
* Based on 255 deaths. 1947-1970.
1969 %
35.7 23.2 10.9 6.1 5.2 5.3 13.6
27.5 32.9 9.3 5.5 4.5 5.8 14.5
100.0
100.0
~~
~
Total
1959 %
Annals New York Academy of Sciences
256
TABLE10 DISTRIBUTION OF NEOPLASMS BY PRIMARY SITE
Site
Smelters
Battery Plants
Esophagus Stomach Large intestine Liver Pancreas Other Total
0 8 9
3 22 26 2 10 5
2 3 3
25
-
68
A more detailed analysis of site was made within each major system. The distribution by primary site of tumors reported as originating from the gastro10. Tumors of the respiratory tract were intestinal system is shown in TABLE predominantly bronchogenic carcinoma. All tumors of the genital tract were prostatic in origin. Distribution of diagnoses for tumors of the urinary tract are shown in TABLE1 1 , three having arisen from kidney, six from the urinary bladder, and one from the urethra. There were seven tumors of the central nervous system, four among smelter workers and three among battery plant 12. workers, as shown in TABLE The small numbers of tumors falling into various anatomic categories made it impossible to develop any meaningful relationships with job or exposures, particularly in view of the fact that for most deceased individuals in the study, no details of exposure were available.
TABLE1 1 URINARY TRACTNEOPLASMS (DIAGNOSES FROM DEATH CERTIFICATES)
Lead Production Facilities (342 total deaths, 69 cancer deaths) Hypernephroma with metastasis to spine (autopsy) Malignant tumor of left kidney (no autopsy) Primary adenocarcinoma of the bladder (no autopsy) Carcinomatosis of urinary bladder (no autopsy) Carcinoma of urethra (no autopsy) ~
Battery-Plants (1,014 total deaths, 186 cancer deaths) Metastatic renal adenocarcinoma (autopsy) Carcinoma of urinary bladder (autopsy) Carcinoma, bladder (autopsy) Anaplastic carcinoma bladder with metastasis to neck (autopsy?) Carcinoma of the urinary bladder (autopsy) Summary Kidney Bladder Urethra
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .....................
3 6 1
Cooper: Mortality Patterns in the Lead Industry
257
DISCUSSION There appeared to be a slight excess of deaths due to neoplasms in a population of workers in lead production plants and lead battery plants, many of whom had been very heavily exposed to lead. This is largely explained by a slight excess of bronchogenic carcinoma and tumors of the stomach and large intestine. However, there were no consistent associations between the incidence of cancer deaths and either increased length of employment or estimated risk of exposure to lead. Studies are still under way to verify these suggestive data and to determine the possible effects of other environmental exposures associated with lead industries. The surviving population of nearly 5,000 men who were alive as of January 1, 197 1 is to remain under observation and mortality will be analyzed again as of the end of 1975. Our findings are in general agreement with those of Dingwall-Fordyce and Lane (1963) .3 Although they reported more deaths from malignant neoplasms than expected (34 vs. 26.5) in a population of 425 pensioned battery plant
TUMORS OF
THE
TABLE12 CENTRAL NERVOUS SYSTEM
(DIAGNOSES ON DEATH CERTIFICATES)
Lead Production Facilities (342 total deaths, 69 cancer deaths) Glioblastoma multiforme of frontal lobe of cerebral cortex (no autopsy) Malignant brain tumor (no autopsy) Glioma (autopsy) Astrocytoma (autopsy) Lead Battery Plants (1,014 total deaths, 186 cancer deaths) Glioblastoma multiforme (no autopsy) Malignant brain tumor (autopsy) Glioma left temple (no autopsy)
workers, the incidence was less than expected in the most heavily exposed groups (10 vs. 12.5). They concluded that malignant disease is not related to lead absorption. A case report of a cerebral tumor in a lead worker served to point out the difficulty in differentiating between intracranial tumor and lead encephalopathy but did not attempt to establish a causal relationship. It is of particular interest that renal tumors, which have been produced in experimental animals by the parenteral administration or feeding of large did not occur in excess in our series. There were only amounts of lead ~alts,S-~T three primary renal tumors reported. This supports the hypothesis of Roe et al.9 that the doses of lead received in occupational exposure are too low, contrasted with those found carcinogenic in animals, for one to expect tumors in man. It has been calculated1* that the level of human exposure equivalent to the levels of lead acetate producing renal tumors in rats is 810 mg/day, equivalent to 550 mg of lead. This greatly exceeds tolerable levels for man. An association between lead and central nervous system tumors has been suggested by the limited observations of Hass et a1.,l0?l.l who reported gliomas
258
Annals New York Academy of Sciences
in 2 of 17 rats fed 1% lead subacetate and in 3 of 41 rats given 1% lead subacetate and 1.6% indole. A 0.3% incidence of gliomas was observed in control rats. The seven central nervous system tumors (2.7% of all deaths attributed to neoplasms) observed in our series is not regarded as representing a significant excess. The present study does not suggest that lead is a potent carcinogen, in view of the relatively small excess of cancer deaths in a heavily exposed group. It does, however, suggest that in the industries studied, there are factors that may increase the cancer risk, and lead has not been ruled out as a cofactor. Continuing studies to obtain additional data and to identify causative agents are warranted. SUMMARY The mortality of 7,032 men employed for one or more years in lead production facilities (“smelters”) or battery plants was observed over a 23-year period, 1947-1970. There were 1,267 certified deaths. Lead absorption in many members of the cohort was known to have been greatly in excess of accepted standards. The standardized mortality ratio (SMR) for all causes was 107 for smelter workers and 99 for battery plant workers. Deaths from malignant neoplasms were somewhat elevated in both groups, the SMR being 133 for smelter workers and 111 for battery plants. The excesses arose largely from tumors of the digestive organs and the respiratory system. Only three deaths are attributed to malignant renal tumors and seven to tumors of the central nervous system. The latter findings were of interest in view of the experimental production of renal tumors in rats and mice by the injection or oral administration of very large doses of lead salts, and the report by one group of investigators of gliomas in rats fed lead subacetate. Studies are continuing to characterize more fully the exposure of the above lead workers to substances other than lead. Additional follow-up of the cohort is also contemplated. REFERENCES
ASSOCIATES, INC. 1974. Health Studies of Lead Workers. 1. TABERSHAW/~OOPER Prepared for The International Lead Zinc Research Organization, Inc. New York, N.Y. 2. COOPER, W. C. & W. R. GAFFEY.1975. Mortality of lead workers. J. Occup. Med. 17: 100-07. I. & R. E. LANE.1963. A follow-up study of lead workers. 3. DINGWALL-FORDYCE, Br. J. Ind. Med. 2 0 313-15. R. W. 1961. Cerebral tumour in a lead worker. Br. J. Ind. Med. 19: 4. PORTAL, 153-56. H. U. 1953. Durch chronische Bleivergiftung erzeugte Nierenade5 . ZOLLINGER, nome und -carcinome bei Ratten und ihre Beziehungen zu den entsprechenden Neubildungen des Menschen. Virchows Arch. 323: 694-710. 6. TONZ, 0. 1957. Nierenveranderungen bei experimenteller chronischer Bleivergiftung (Ratten). Z. Gesamte Hyg. 128: 361-377. E., C. E. DUKES,P. L. GROVER & B.C.V. MITCHLEY.1962. The in7. BOYLAND, duction of renal tumours by feeding lead acetate to rats. Br. I. Cancer 1 6 283-88.
Cooper: Mortality Patterns in the Lead Industry
259
8. VAN ESCH,G. J., H. VAN GENDEREN& H. H. VINK. 1962. The induction of renal tumours by feeding of basic lead acetate to rats. Br. J. Cancer 16: 28997. 9. ROE, F. J. C., E. BOYLAND, C. E. DUKES& B.C.V. MITCHLEY. 1965. Failure of testosterone or xanthopterin t o influence the induction of renal neoplasms by lead in rats. Br. J. Cancer 19: 860-66. R. OYASU,H. A. BATTIFORA& J. T. PALOUCEK. 10. HASS, G. M., J. H. MCDONALD, 1967. Renal neoplasia induced by combinations of dietary lead subacetate and N-2-fluorenylacetamide. In International Symposium on Renal Neoplasia. J. S. Knig, Jr., Ed. : 377-412. Brasilia, Brazil, 1965. Little Brown and Co., Inc. Boston, Mass. I I . MAO. P. & J. J. MOLNAR.1967. The fine structure and histochemistrv of leadinduced renal tumors in rats. Am. J. Pathol. 50: 571-603. B. & K. MEDRAS.1968. Tumoren and Storungen des Porphyrinstoff12. ZAWIRSKA, wechsels bei Ratten mit chronischer experimenteller Bleiintoxikation. Zentralbl. Allg. Pathol. 111: 1-12. 13. VANESCH,G. J . & R. KROES. 1969. The induction of renal tumours by feeding basic lead acetate to mice and hamsters. Br. J. Cancer 23: 765-71. 14. OYASU,R., H. A. BATTIFORA, R. A. CLASEN,J. H. MCDONALD& G. M. HASS. 1960. Induction of cerebral gliomas in rats with dietary lead subacetate and 2acetylaminofluorene. Cancer Res. 30: 1248-6 1. B. & K. MEDRAS. 1972. The role of the kidneys in disorders of 15. ZAWIRSKA, porphyrin metabolism during carcinogensis induced with lead acetate. Arch. Immunol. Ther. Exp.20: 257-272. P. S . 1973. Lead-induced renal carcinoma. Proc. Inst. Med. Chic. 29: 16. COOGAN, 309. 17. ITO,N. 1973. Experimental studies on tumors of the urinary system of rats induced by chemical carcinogens. Acta Pathol. Jap. 23: 87-109. AGENCYFOR RESEARCH O N CANCER.1972. IARC Monographs 18. INTERNATIONAL on the Evaluation of Carcinogenic Risk of Chemicals to Man. Vol. I: 40-50. Lyon, France.
The data to be presented in this report were obtained during a study of the mortality of 7,032 men who had been employed for at least one year in either a lead production facility or a lead battery plant during the years 1947 through 1970. The findings have been presented in considerably more detail elsewhere; 1v the emphasis in this report will be upon deaths attributed to malignant neoplasms. Several points should be emphasized with respect to the occupational exposures of the individuals who were studied. First, actual exposures to lead and other substances could not be quantitatively described for most of the individuals whose mortality patterns were studied. However, information that was obtained on urinary and blood lead concentrations in the same plants indicates that a great many had absorbed lead considerably in excess of currently acceptable standards. Second, the population studied, particularly those in lead production facilities, was potentially exposed to many substances other than lead, including arsenic, cadmium, and sulfur dioxide. Therefore, although many of them had high lead exposures, one is not warranted in attributing all effects to lead alone. METHODS
The cohort studied was derived from microfilmed personnel records of six smelters and ten battery plants, which had been selected from 84 plants that had responded affirmatively to a preliminary questionnaire. Participating plants were selected on the basis of size, geographic distribution, the adequacy of records, and the length of time they had been in operation. No attempt was made to get either a representative sample or a random sample. From a total of 24,494 individuals who had been employed by the 16 plants during the period 1946 through 1970, 7,032 met criteria for inclusion in the mortality study, i.e., they were male, had been employed for one year or more, and had complete data on hire date and birth date. Follow-up of these individuals was pursued through company employment records and the usual techniques for tracing individuals. Death certificates were requested for all known deaths, and these were coded by the rules of the Seventh (1955) Revision of the International Classification of Diseases, Injuries and Causes of Death. Proportionate mortality for twelve selected causes was compared with the distribution for United States male deaths in 1959. Standardized mortality ratios (SMR’s) were calculated for a 35-cause list (plus some causal groups related to infectious diseases and to renal disease). Data on urinary and blood-lead concentrations were available from six battery plants, which had contributed 89% of the study population, and from four lead-producing plants, which had contributed 80% of the smelter workers in the study. 250
Cooper: Mortality Patterns in the Lead Industry
25 1
RESULTS Follow-up to determine vital status was successful for 96% of the study population, i.e., 98% of smelter workers and 95% of battery plant workers. The 1,356 deaths during the 23-year period 1947-1970 were the basis for mortality analyses. Death certificates were obtained for 1,267, or 93% of the known deaths. FicuRe 1 summarizes the establishment of the study population and the subsequent follow-up.
Women ca. 950 q1 y r ca. 16,000 Missing data ca. 350 Alive 5,387(77%)
Certificate received 1,267
Dead 1,356(19%)
V i t a l status
No c e r t i f i c a t e 89(73)
FIGURE1. Summary of the study population and follow-up, 1947-1970. Of the 289 unknown, 193 were from two smaller plants, where there was no Social Security follow-up. Of the 89 with no certificate, 70 were from one plant in Pennsylvania. (By permission of the publisher of J. Occup. Med.2)
Indicators of Probable Exposure The population studied included more than 3,000 men who had been working on January 1, 1946, and exposures extended back to 1920 or earlier for some individuals. No quantitative data on lead absorption existed for the period before 1948, and for most plants it began later. TABLE 1 summarizes the employment history of the 7,032 men in the study, based on date of termination or December 3 1, 1970, whichever came first. This indicates a high percentage who had worked for 20 or more years.
Annals New York Academy of Sciences
252
TABLE1 DISTRIBUTION BY NUMBEROF YEARS EMPLOYED FOR SMELTER AND BA~TERYPLANTWORKERS Percentage of population with more than indicated number of years Smelters Battery Plants
Years Employed * Over 5
54.0 39.6 3 1.7 24.0 15.3 9.4 4.7
10 15 20 25 30 35
* As of date of termination or Dec.
69.9 53.0 41.1 35.2 29.3 19.2 10.0
31, 1970, whichever came first.
Data on urinary or blood-lead concentrations were obtained from nine of the 15 plants that had routine monitoring programs as of 1970 (TABLE2). Many workers had no levels recorded because their entire work experience had been before their individual plant began monitoring. PbU levels were available for less than 10% of deceased workers; PbB values were available for less than 2%. Study of the urine and blood lead concentration did, however, provide valuable indirect information regarding the relatively high levels of lead absorption by a substantial portion of the workers in the plants under study. TABLE 3 summarizes the numbers of men whose mean PbU values over a working lifet h e exceeded certain indicated values. TABLE 4 summarizes similar information on blood-lead concentrations. Proportionate mortality, i.e., the relative proportion of the 1,267 certified deaths which fell into each of 12 major categories when compared with male deaths in 1959, is shown in TABLE5. There were slight excesses for some types of cardiovascular renal disease and for certain malignancies. Since such a proportional mortality table does not take into account the age of the population at risk, it is regarded as only a suggestive indicator. The total mortality of the 7,032 individuals as summarized in TABLE 6 was approximately the same as that of the general population, 1,356 deaths having occurred where 1,348 were expected, giving a standardized mortality ratio (SMR) for all causes of 101. The SMR for smelter workers was 107, that for TABLE2 SUMMARY OF URINARY LEADAND BLOODLEADDETERMINATIONS
PbU PbB
Number of Analyses
Number of Men
Analyses/man (average)
97,002 16,152
2,274 1,860
43 9
Percentage of total (7032) 32% 26%
Cooper: Mortality Patterns in the Lead Industry
25 3
TABLE 3 NUMBEROF WORKERS WITH TEN OR MORE PBU DETERMINATIONS OR EXCEEDED INDICATED CONCENTRATIONS WHOSEMEANVALUESEQUALED (!a/L) (UNCORRECTED)
Type of Plant
Numbers of Workers with over 10 determinations
2150
2200
2250
2 300 pg/liter
Smelters Battery plants
497 1,053
289 249
164 59
70 17
27 7
Total
1,550
538
223
87
34
Number with mean values
TABLE 4 OF WORKERS WHOSEMEANPBB VALUESOVERA WORKINGLIFETIME NUMBER EQUALED OR EXCEEDED THE INDICATED CONCENTRATIONS Number with mean values Type of Plant
No. of Workers
2 40
270
280
2 100 wglloog
Smelters Battery plants
534 1316
457 976
138 350
83 105
25 52
1850
1433
488
188
77
Totals
TABLE 5 IN
PERCENTAGES OF 1267 CERTIFIED DEATHS SMELTERAND BATTERY-PLANT WORKERS,DUE TO SELECTEDCAUSES, WITH PERCENTAGES AMONG US. MALES FOR 1959 COMPARED (PROPORTIONATE MORTALITY) Cause of Death
Major cardiovascular-renal Vascular lesions of CNS Hypertensive heart disease Other hypertensive disease Chronic and unspecified nephritis Malignant neoplasms Respiratory tract Urinary organs Cirrhosis of liver Suicide Motor vehicle accidents Other
U.S. Males
53.9
Smelter Workers 45.7
9.7 3.2 0.7 0.7 14.6
57.3 7.4 3.1 2.2 2.2
21.3 3.4 0.9
1.3 1.5 3.0 25.7
Battery-Plant Workers 7.1 3.1 1.4 1.5 19.7
6.8 1.5 0.6 4.0
4.6 23.8
6.5 0.5 2.8 1.7 1.9 16.6
Annals New York Academy of Sciences
254
TABLE6 EXPECTEDAND OBSERVED DEATHSBY CAUSE JAN. 1, 1947-DEC. 31, 1970 FOR LEADSMELTER AND BATTERY-PLANT WORKERS Cause of Death Tuberculosis, all forms Bacterial and viral diseases plus influenza and pneumonia Malignant neoplasms Major cardiovascular renal disease Violent deaths All other certified causes Total for certified causes All causes including uncertified Number of workers Person-years
* Correction of
+5.55%
Obs.
Smelters Exp. SMR*
Battery Plants Obs. Exp. SMR t
4.55
23
5
14.84
37
8 8.17 69 54.95 151 165.29 59 40.52 36 46.15 324 319.64 342 319.64 2352 33482
103 133 96 154 82 107
23 186 540 62 127 943 1014
26.82 180.34 575.21 89.63 141.45 1028.37 1028.37 4680 69828
92 111 101 74 97 99
1
applied for 18 missing death certificates.
t Correction of +7.52% applied for 71 missing death certificates.
battery plant workers 99. The SMR for all malignant neoplasms was 133 for smelter workers and 111 for battery plant workers. This group of deaths was studied in more detail, based upon anatomical site, as shown in TABLE 7. Tumors arising in the digestive organs and in the respiratory system were slightly elevated in both groups, the excess being close to significance at the 5% level. No other sites showed appreciable deviations from expected numbers. In attempts to demonstrate relationships between TABLE7 EXPECTED AND OBSERVED DEATHSFOR MALIGNANT NEOPLASMS JAN. 1, 1947-DEC. 31, 1970 LEADSMELTER AND BATTERY-PLANT WORKERS Smelters Battery-Plant Obs. Exp. SMR * Obs. Exp. SMR t
Cause of Death All Malignant Neoplasms (140-205)
Buccal cavity and pharynx (140-148) Digestive organs, peritoneum (150-159) Respiratory system ( 160-1 64) Genital organs (170-179) Urinary organs (180-181) Leukemia (204) Lymphosarcoma, lymphatic and hematopoietic (200-203, 205) Other sites
* Correction of
+5.55%
69 54.95
133
186 180.34
111
0 25 22 4 5 2
1.89 17.63 15.76 4.15 2.95 2.40
150 148 101 179 88
6 6.02 70 61.48 61 49.51 8 18.57 5 10.33 6 7.30
107 123 132 46 52 88
3 8
3.46 6.71
92 126
7 23
9.74 17.39
17 142
applied for 18 missing death certificates.
t Correction of +7.52% applied for 71 missing death certificates.
Cooper: Mortality Patterns in the Lead Industry
255
TABLE8 DISTRIBUTION OF NEOPLASMS BY TYPEOF PLANT Type of Plant
Cancer Deaths All Deaths
Percentage of Deaths
69/324
21.3
9/58 14/62 46/204
15.5 22.6 22.6
186/943
19.7
Total smelter Primary smelter Secondary smelter Secondary refinery Battery plant
employment and tumor incidence, employees were grouped by estimated lead exposures based upon job titles; by duration of employment (more than or less than ten years) ; and by date of hire (before or after January 1, 1946). None of these showed consistent or significant relationships. Distribution of Neoplasms Based on Type of Plant Deaths due to malignant neoplasms, expressed as a proportion of total certified deaths, for primary smelters, secondary smzlters, and secondary lead 8. refineries and battery plants, are shown in TABLE Distribution of Cancer Deaths by Primary Site The proportion of all cancer deaths attributed to tumors from various 9. These have been compared with the relative primary sites is shown in TABLE proportions for the total male population of the United States for 1950, 1959, and 1969. TABLE9 PROPORTION OF DEATHS DUETO MALIGNANTNEOPLASMS ATTRIBUTEDTO VARIOUS ANATOMICAL SITES* Observed Smelters Battery
Expected
Site
%
%
1950 %
Digestive organs Respiratory system Genital organs Urinary organs Leukemia Lymphosarcoma, etc. Other
36.2 31.9 5.6 7.2 2.3 4.4 12.4
37.6 32.8 4.3 2.7 3.2 3.8 15.6
42.1 16.1 11.5 6.2 4.7 4.4 15.0
100.0
100.0
100.0
* Based on 255 deaths. 1947-1970.
1969 %
35.7 23.2 10.9 6.1 5.2 5.3 13.6
27.5 32.9 9.3 5.5 4.5 5.8 14.5
100.0
100.0
~~
~
Total
1959 %
Annals New York Academy of Sciences
256
TABLE10 DISTRIBUTION OF NEOPLASMS BY PRIMARY SITE
Site
Smelters
Battery Plants
Esophagus Stomach Large intestine Liver Pancreas Other Total
0 8 9
3 22 26 2 10 5
2 3 3
25
-
68
A more detailed analysis of site was made within each major system. The distribution by primary site of tumors reported as originating from the gastro10. Tumors of the respiratory tract were intestinal system is shown in TABLE predominantly bronchogenic carcinoma. All tumors of the genital tract were prostatic in origin. Distribution of diagnoses for tumors of the urinary tract are shown in TABLE1 1 , three having arisen from kidney, six from the urinary bladder, and one from the urethra. There were seven tumors of the central nervous system, four among smelter workers and three among battery plant 12. workers, as shown in TABLE The small numbers of tumors falling into various anatomic categories made it impossible to develop any meaningful relationships with job or exposures, particularly in view of the fact that for most deceased individuals in the study, no details of exposure were available.
TABLE1 1 URINARY TRACTNEOPLASMS (DIAGNOSES FROM DEATH CERTIFICATES)
Lead Production Facilities (342 total deaths, 69 cancer deaths) Hypernephroma with metastasis to spine (autopsy) Malignant tumor of left kidney (no autopsy) Primary adenocarcinoma of the bladder (no autopsy) Carcinomatosis of urinary bladder (no autopsy) Carcinoma of urethra (no autopsy) ~
Battery-Plants (1,014 total deaths, 186 cancer deaths) Metastatic renal adenocarcinoma (autopsy) Carcinoma of urinary bladder (autopsy) Carcinoma, bladder (autopsy) Anaplastic carcinoma bladder with metastasis to neck (autopsy?) Carcinoma of the urinary bladder (autopsy) Summary Kidney Bladder Urethra
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .....................
3 6 1
Cooper: Mortality Patterns in the Lead Industry
257
DISCUSSION There appeared to be a slight excess of deaths due to neoplasms in a population of workers in lead production plants and lead battery plants, many of whom had been very heavily exposed to lead. This is largely explained by a slight excess of bronchogenic carcinoma and tumors of the stomach and large intestine. However, there were no consistent associations between the incidence of cancer deaths and either increased length of employment or estimated risk of exposure to lead. Studies are still under way to verify these suggestive data and to determine the possible effects of other environmental exposures associated with lead industries. The surviving population of nearly 5,000 men who were alive as of January 1, 197 1 is to remain under observation and mortality will be analyzed again as of the end of 1975. Our findings are in general agreement with those of Dingwall-Fordyce and Lane (1963) .3 Although they reported more deaths from malignant neoplasms than expected (34 vs. 26.5) in a population of 425 pensioned battery plant
TUMORS OF
THE
TABLE12 CENTRAL NERVOUS SYSTEM
(DIAGNOSES ON DEATH CERTIFICATES)
Lead Production Facilities (342 total deaths, 69 cancer deaths) Glioblastoma multiforme of frontal lobe of cerebral cortex (no autopsy) Malignant brain tumor (no autopsy) Glioma (autopsy) Astrocytoma (autopsy) Lead Battery Plants (1,014 total deaths, 186 cancer deaths) Glioblastoma multiforme (no autopsy) Malignant brain tumor (autopsy) Glioma left temple (no autopsy)
workers, the incidence was less than expected in the most heavily exposed groups (10 vs. 12.5). They concluded that malignant disease is not related to lead absorption. A case report of a cerebral tumor in a lead worker served to point out the difficulty in differentiating between intracranial tumor and lead encephalopathy but did not attempt to establish a causal relationship. It is of particular interest that renal tumors, which have been produced in experimental animals by the parenteral administration or feeding of large did not occur in excess in our series. There were only amounts of lead ~alts,S-~T three primary renal tumors reported. This supports the hypothesis of Roe et al.9 that the doses of lead received in occupational exposure are too low, contrasted with those found carcinogenic in animals, for one to expect tumors in man. It has been calculated1* that the level of human exposure equivalent to the levels of lead acetate producing renal tumors in rats is 810 mg/day, equivalent to 550 mg of lead. This greatly exceeds tolerable levels for man. An association between lead and central nervous system tumors has been suggested by the limited observations of Hass et a1.,l0?l.l who reported gliomas
258
Annals New York Academy of Sciences
in 2 of 17 rats fed 1% lead subacetate and in 3 of 41 rats given 1% lead subacetate and 1.6% indole. A 0.3% incidence of gliomas was observed in control rats. The seven central nervous system tumors (2.7% of all deaths attributed to neoplasms) observed in our series is not regarded as representing a significant excess. The present study does not suggest that lead is a potent carcinogen, in view of the relatively small excess of cancer deaths in a heavily exposed group. It does, however, suggest that in the industries studied, there are factors that may increase the cancer risk, and lead has not been ruled out as a cofactor. Continuing studies to obtain additional data and to identify causative agents are warranted. SUMMARY The mortality of 7,032 men employed for one or more years in lead production facilities (“smelters”) or battery plants was observed over a 23-year period, 1947-1970. There were 1,267 certified deaths. Lead absorption in many members of the cohort was known to have been greatly in excess of accepted standards. The standardized mortality ratio (SMR) for all causes was 107 for smelter workers and 99 for battery plant workers. Deaths from malignant neoplasms were somewhat elevated in both groups, the SMR being 133 for smelter workers and 111 for battery plants. The excesses arose largely from tumors of the digestive organs and the respiratory system. Only three deaths are attributed to malignant renal tumors and seven to tumors of the central nervous system. The latter findings were of interest in view of the experimental production of renal tumors in rats and mice by the injection or oral administration of very large doses of lead salts, and the report by one group of investigators of gliomas in rats fed lead subacetate. Studies are continuing to characterize more fully the exposure of the above lead workers to substances other than lead. Additional follow-up of the cohort is also contemplated. REFERENCES
ASSOCIATES, INC. 1974. Health Studies of Lead Workers. 1. TABERSHAW/~OOPER Prepared for The International Lead Zinc Research Organization, Inc. New York, N.Y. 2. COOPER, W. C. & W. R. GAFFEY.1975. Mortality of lead workers. J. Occup. Med. 17: 100-07. I. & R. E. LANE.1963. A follow-up study of lead workers. 3. DINGWALL-FORDYCE, Br. J. Ind. Med. 2 0 313-15. R. W. 1961. Cerebral tumour in a lead worker. Br. J. Ind. Med. 19: 4. PORTAL, 153-56. H. U. 1953. Durch chronische Bleivergiftung erzeugte Nierenade5 . ZOLLINGER, nome und -carcinome bei Ratten und ihre Beziehungen zu den entsprechenden Neubildungen des Menschen. Virchows Arch. 323: 694-710. 6. TONZ, 0. 1957. Nierenveranderungen bei experimenteller chronischer Bleivergiftung (Ratten). Z. Gesamte Hyg. 128: 361-377. E., C. E. DUKES,P. L. GROVER & B.C.V. MITCHLEY.1962. The in7. BOYLAND, duction of renal tumours by feeding lead acetate to rats. Br. I. Cancer 1 6 283-88.
Cooper: Mortality Patterns in the Lead Industry
259
8. VAN ESCH,G. J., H. VAN GENDEREN& H. H. VINK. 1962. The induction of renal tumours by feeding of basic lead acetate to rats. Br. J. Cancer 16: 28997. 9. ROE, F. J. C., E. BOYLAND, C. E. DUKES& B.C.V. MITCHLEY. 1965. Failure of testosterone or xanthopterin t o influence the induction of renal neoplasms by lead in rats. Br. J. Cancer 19: 860-66. R. OYASU,H. A. BATTIFORA& J. T. PALOUCEK. 10. HASS, G. M., J. H. MCDONALD, 1967. Renal neoplasia induced by combinations of dietary lead subacetate and N-2-fluorenylacetamide. In International Symposium on Renal Neoplasia. J. S. Knig, Jr., Ed. : 377-412. Brasilia, Brazil, 1965. Little Brown and Co., Inc. Boston, Mass. I I . MAO. P. & J. J. MOLNAR.1967. The fine structure and histochemistrv of leadinduced renal tumors in rats. Am. J. Pathol. 50: 571-603. B. & K. MEDRAS.1968. Tumoren and Storungen des Porphyrinstoff12. ZAWIRSKA, wechsels bei Ratten mit chronischer experimenteller Bleiintoxikation. Zentralbl. Allg. Pathol. 111: 1-12. 13. VANESCH,G. J . & R. KROES. 1969. The induction of renal tumours by feeding basic lead acetate to mice and hamsters. Br. J. Cancer 23: 765-71. 14. OYASU,R., H. A. BATTIFORA, R. A. CLASEN,J. H. MCDONALD& G. M. HASS. 1960. Induction of cerebral gliomas in rats with dietary lead subacetate and 2acetylaminofluorene. Cancer Res. 30: 1248-6 1. B. & K. MEDRAS. 1972. The role of the kidneys in disorders of 15. ZAWIRSKA, porphyrin metabolism during carcinogensis induced with lead acetate. Arch. Immunol. Ther. Exp.20: 257-272. P. S . 1973. Lead-induced renal carcinoma. Proc. Inst. Med. Chic. 29: 16. COOGAN, 309. 17. ITO,N. 1973. Experimental studies on tumors of the urinary system of rats induced by chemical carcinogens. Acta Pathol. Jap. 23: 87-109. AGENCYFOR RESEARCH O N CANCER.1972. IARC Monographs 18. INTERNATIONAL on the Evaluation of Carcinogenic Risk of Chemicals to Man. Vol. I: 40-50. Lyon, France.
