Formaldehyde and Cancer - Advances in Chemistry (ACS Publications)

20 Formaldehyde and Cancer An Epidemiologic Perspective M A U R E E N T. O’BERG

Downloaded by FUDAN UNIV on March 18, 2017 | http://pubs.acs.org Publication Date: August 21, 1985 | doi: 10.1021/ba-1985-0210.ch020

Ε. I. Du Pont De Nemours & Company, Wilmington, D E 19898 A review of epidemiologic findings has thus far failed to demon strate a causal relationship between formaldehyde and cancer. Ex cesses of brain cancer and leukemia have occurred, mainly among anatomists and pathologists; however, diagnostic and social class bias may explain these excesses. Industrial groups have shown defi cits of these cancer types. The lack of a causal relationship must be viewed cautiously, as most of the studies have low power to detect increased risks 20 or more years after first exposure. epidemiolo gists look statistically at patterns of what specific diseases occur, in what groups of people, where, and when, to identify risk factors. This review is directed at the issue of how epidemiologic research has contributed to an understanding of whether formaldehyde is a human car cinogen. The task is made simpler in that several people have looked care fully at this subject within the last few years; thus, a literature base has been established, and much careful thought and discussion can be refer enced. One major convocation on the topic was held in October 1983. At that time, a panel of epidemiologists convened in Little Rock, Arkansas, as one part of the larger "Consensus Workshop on Formaldehyde." This panel was charged with the responsibility to review the current epidemiologic research and then specifically address the question, "What evidence exists concerning the relationship between formaldehyde exposure and illness?" Furthermore, because public attention has focused on the issue of cancer, the panel spent almost all of its time considering this disease. The available literature further restricted this review primarily to mortality studies of adult working males. The panel consisted of eight individuals from various organizations in government, academia, and private consulting, with a potpourri of per spectives. Some panel members were very familiar with the scientific liter ature on formaldehyde; others were not. Also, it soon became apparent I J P I D E M I O L O G Y IS T H E S T U D Y O F T H E O C C U R R E N C E O F D I S E A S E ;

0065-2393/85/0210/0289$06.00/0 © 1985 American Chemical Society

Turoski; Formaldehyde Advances in Chemistry; American Chemical Society: Washington, DC, 1985.

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that some important studies were in progress, with late-breaking preliminary findings. These studies, previously not publicly released, were presented from the floor at the workshop. After an update of the current research, the panel made an attempt to pool results from the various studies and reach consensus on their overall meaning. The highlights of their conclusions about cancer are as follows: The data are sparse and conflicting and do not yet provide persuasive evidence of a causal relation between exposure to formaldehyde and cancer in people. As far as nasal cancer is concerned, the evidence is against a substantial (e.g., tenfold) immediate increase in risk, but sufficient information is not yet available to exclude such an effect if risk starts to increase 20 or more years after first exposure. An increase in risk of brain cancer and leukemia is noted among each of three professional groups who preserve human tissues with solutions containing formaldehyde and other chemicals. In view of the small numbers of person-years of follow-up in subjects followed for 20 years or more and various methodological limitations of the studies, it is not possible from the available epidemiological data to exclude the possibility that formaldehyde is a human carcinogen (la). Nasal cancer was of special interest to this panel because the nose was the target organ in the animal studies. No cases of nasal cancer were seen in the dozen or so epidemiologic studies the panel reviewed. A total of approximately three cases would have been expected across these studies. A l though the absence of nasal cancer is encouraging, the findings must be viewed cautiously because very few of the studies have traced persons for more than 20 years. The panel was aware of some case reports of nasal cancer in persons with potential exposure to formaldehyde. However, these case reports were dismissed as not informative on the issue of cause and effect. For brain cancer and leukemia, significant excesses were seen in several professional groups having potential formaldehyde exposures (lb-7). Industrial groups did not experience these excesses. In fact, chemical workers had a marked deficit of brain cancer. A major study of industrial workers from Great Britain revealed 5 brain cancer deaths, with more than 12 expected (8). The D u Pont case control study also showed decreased risks on the basis of smaller numbers (9). The excess of brain cancer and leukemia in professionals represents a new finding, seen mainly in three large studies, two of which were then unpublished. The first is a mortality study of anatomists, conducted by Stroup at the Centers for Disease Control (CDC) (5). Stroup presented the preliminary unpublished results of her study at the workshop. This study included 2239 male anatomists enrolled in the American Anatomists Society for at least 1 year between 1889 and 1969. These men were all physicians or had PhDs



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Formaldehyde and Cancer: An Epidemiologic Perspective 291

and thus represented a high social class. They were traced during the years 1925-79 to determine whether they were dead or alive. As of the end of 1979, approximately 35% had died. These 738 deaths compare with 1130.3 expected on the basis of U.S. general population rates for the years 1925-75. The ratio of observed to expected deaths reveals approximately a 30% deficit. A deficit of this order is commonly seen when workers are compared to the general population and is referred to as the "healthy worker effect." Among the deaths, 10 were due to brain cancer, and 3.7 were expected. This result is a statistically significant finding of nearly a threefold increase. Leukemia deaths numbered 10, and 6.7 were expected. This 50% excess is not statistically significant. The two other major studies were proportionate mortality studies of embalmers done by Walrath at the National Cancer Institute (NCI) (6-7). Walrath's results from the New York study had been published, but the California data were, again, presented publicly for the first time at this meeting. In each study, the names of deceased white male embalmers were obtained from the State Bureau of Licenses, Division of Embalmers, for the years 1925-80. In New York, 1132 deaths had occurred; in California, 1007 deaths had occurred. The number of deaths from brain cancer and leukemia are shown in Table I for each group. Also shown are the numbers expected on the basis of the proportions seen in the U.S. population for the years 1925-75. Nine deaths from brain cancer occurred in each group; 5.8 were expected in the New York study and 4.7 were expected in the California study. These numbers represent a 60-90% increase, as shown in the ratio of observed to expected deaths. Each study had 12 deaths from leukemia; 8.5 were expected in New York, and 6.9 were expected in California. These numbers, while not statistically significant, do represent a consistent 50% excess. In reviewing these results, one must recognize that proportionate analyses have limitations. In particular, in these studies one cannot deterTable I. Deaths from Brain Cancer and Leukemia of White Male Embalmers in New York and California, 1925-80 California

New York

Cause of Death

Observed

Expected

Ratio

Observed

Expected

Ratio

Brain cancer Leukemia

9 12

5.8 8.5

1.6 1.4

9 12

4.7 6.9

1.9 1.7

0

b

0

b

°Expected deaths are based on the proportions seen in the U.S. population for the years 1925-75. Ratio of observed to expected deaths. fo



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mine whether a specific excess is indicative of a real increase in risk, or is instead the result of deficits in other causes of death. Walrath acknowledges these limitations, but the lack of a readily available and suitable database forced her to use proportionate analyses. Tables II and III summarize the findings from the three studies just reviewed, plus a few other smaller studies of embalmers and pathologists. The results of the studies shown in Tables II and III were pooled in a crude fashion by adding the columns of observed and expected numbers. On the basis of the total observed versus expected comparison, the panel made the statement that excesses of brain cancer and leukemia were seen in professional groups. A few important concepts may explain why such excesses occurred in these studies of professionals. The first issue is diagnostic bias. Evidence of diagnostic bias can be seen in a 1981 publication by Greenwald who suggested that a "diagnostic sensitivity bias" exists for brain cancer (10). He stated that an apparent initial excess of diagnosed brain tumors may have resulted from a diagnostic sensitivity bias arising from the more complete medical evaluation of Kodak employees, as compared with the general population. In a follow-

Table II. Summary of Deaths from Brain Cancer in Professional Groups Professional Group Researcher (Ref.) Observed Expected Anatomists Embalmers, N.Y. Embalmers, Calif. Embalmers, Ontario Pathologists Pathologists

Stroup (5) Walrath (6) Walrath (7) Levine (3) Harrington (2) Matanoski (4)

10 9 9

3.7 5.8 4.7

3 4 5

2.6 1.2 4.7

Table III. Summary of Deaths from Leukemia in Professional Groups Professional Group Researcher (Ref.) Observed Expected Anatomists Embalmers, N.Y. Embalmers, Calif. Embalmers, Ontario Pathologists

Stroup (5) Walrath (6) Walrath (7) Levine (3) Harrington (I, 2)

10 12 12

6.7 8.5 6.9

4 2

2.5 2.6


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up article in 1982, he reinforced his original idea and stated the following (11):


The possibility of a diagnostic sensitivity bias remains an important con sideration, particularly where the study population has liberal access to high-quality diagnostic testing, employee insurance coverage, occupa tional medical referrals, and the impact of neurologic and neurosurgical specialists in a university school setting. A social class bias may also influence brain cancer and leukemia. Sup port can be found in published data from the Registrar General's reports from Great Britain (12). Shown in Table IV are the rates for men below and above 64 years of age by social class for all cancers and for brain cancer and leukemia. Social Class I comprises professional occupations; Social Class V consists of unskilled occupations. A decreasing social class gradient exists between Social Class I and Social Class V . One can see trends in ratios for both standardized mortality ratio (SMR) and proportionate mortality ratio (PMR) analyses. For brain cancer and leukemia, higher social classes show increased risks; lower social classes show decreased risks. This result is in marked contrast with cancer overall, where higher social classes have decreased risks. Looking back to the studies in question, one notes that they primarily included anatomists and pathologists. These people are highly educated, well-paid professionals. They work in a medically related specialty; many even work in medical facilities. Their awareness of medical diagnostics and their access to high-quality medical care is certainly well above average. As a group, they have shown excesses of brain cancer and leukemia. This result is not surprising because of their greater access to medical care due to their income, their education, and their regular interface with the medical environment. A third source of bias may result from the increased diagnosis of brain cancer over the past decade. This increase is partially due to improved di agnostic capabilities. C A T scans and other new technologic advances now make it easier to identify brain tumors that in the past may have been mis diagnosed as strokes or neurologic disorders. Table IV. Mortality Among Males in Great Britain and Wales, 1970-72 Ages 16-64, SMRs by Social Class

Ages 65-74, PMRs by Social Class

0

Cause of Death

I

II

All cancers 75 80 Brain cancer 108 101 Leukemia 113 100 a

III Ν III M IV 91 111 107

113 105 101

0

V

I

II

116 131 96 98 100 92 225 137 104 95 138 124

III Ν HIM 99 109 108

102 99 98

I is the highest social class; V is the lowest.


IV

V

100 101 85 56 90 77


294


Because the computerized statistical packages psed by epidemiologists had rates current only through 1975, they have underestimated the numbers expected for the late 1970s. Deaths, however, continued to accrue through 1979 or 1980 in the major studies reported. For this reason, the risk of brain cancer in the studies reviewed may not really be as high as reported. Leukemia rates have also increased during the past decade, though not as dramatically, so the same bias may apply to leukemia risks. Without more information on the studies reported, it is not possible to determine to what extent the sources of bias just described contribute to the excesses of brain cancer and leukemia seen in professionals, but they clearly could account for much of it. And finally, even if one ignores the potential biases and accepts the findings of increased brain cancer and leukemia in professionals, it must be noted that these persons were exposed to many substances other than formaldehyde. The issue of lung cancer has also been a topic of much discussion. Only one of the several studies discussed by the panel showed any increase in lung cancer. In the British study conducted by Acheson, the excess was seen in one (the largest) of five plants analyzed. Furthermore, the number of lung cancer deaths was high compared with national rates, but not compared with local rates. Local rates are likely to be more representative of the plant population with regard to cigarette smoking patterns, which clearly influence lung cancer. The professional groups discussed earlier showed a significant deficit of lung cancer. This decrease is probably due to less cigarette smoking in these highly educated, medically oriented groups. This summary has highlighted several specific areas of focus that emerged at the consensus workshop regarding cancer. The present lack of a causal relationship between formaldehyde and cancer was stated with guarded optimism because not enough is known about formaldehydeexposed populations that have been followed for more than 20 years. The consensus workshop in Little Rock has provided a thorough review of epidemiologic research on formaldehyde. A few months prior to the consensus workshop, another group of experts convened in July 1983 in Oxford, England, to review the relevant available epidemiologic studies on formaldehyde, as well as several other agents. Sir Richard Doll chaired this "Symposium on Interpretation of Epidemiological Evidence." The conclusions of this symposium, although not quite as current as those of the Little Rock consensus workshop, were similar. The symposium participants stated that the evidence was inadequate to permit firm conclusions, but that it suggested that formaldehyde is unlikely to have produced a quantitatively large increased risk of cancer under the conditions of exposure that have operated in the past. Looking ahead, new results continue to be reported as additional stud-


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Formaldehyde and Cancer: An Epidemiologic Perspective

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ies are completed. One project on the horizon is a large study of approxi mately 30,000 workers exposed to formaldehyde at 10 plant locations in the United States. This interindustry mortality study is being conducted coop eratively by the National Cancer Institute and the Formaldehyde Institute. Because this is a large, statistically powerful study of formaldehyde work ers, we can anticipate that it will provide important input to the question of whether formaldehyde causes cancer in humans.


Literature Cited 1a. Report on the Consensus Workshop on Formaldehyde Environ. Health Perspect. 1984, 58, 339. 1 b . Harrington, J. M.; Shannon, H . S. Br. Med. J. 1974, 2, 329-34. 2. Harrington, J. M.; Oakes, D . Br. J. Ind. Med. 1984, 41, 188-91. 3. Levine, R. J.; Andjelkovich, D . Α.; Shaw, L . K. In “Formaldehyde Toxicology, Epidemiology and Mechanisms”; Clary, J. J.; Gibson, J. E . ; Waritz, R. S., Eds.; Marcel Dekker: New York, 1983; pp. 127-40. 4. Matanoski, G . M . Preliminary studies. Letter to Martonik, John, Occupa tional Safety and Health Administration, 1982. 5. Stroup, N., personal communication, 1983. 6. Walrath, J.; Fraumeni, J. F. Int. J. Cancer 1983, 31, 4 0 7 - 1 1 . 7. Walrath, J.; Fraumeni, J. F. Cancer Res. 1984, 44, 4 6 3 8 - 4 1 . 8. Acheson, E . D.; Gardner, M . J.; Pannett, B.; Barnes, H . R.; Osmond, C . ; Taylor, C . P. Lancet 1984, 611-16. 9. Fayerweather, William E . In “Formaldehyde: Toxicity, Epidemiology and Mechanisms”; Clary, J. J.; Gibson, J. E . ; Waritz, R. S., Eds.; Marcel Dekker: New York, 1983; 4 7 - 1 2 1 . 10. Greenwald, Peter; Greenwald, P.; Friedlander, B. R.; Lawrence, C . E.; Hearne, T.; Earle, K. J. Occup. Med. 1981, 23, 690-94. 11. Greenwald, Peter; Greenwald, P.; Friedlander, B. R.; Lawrence, C . E.; Hearne, T.; Earle, K . J. Occup. Med. 1982, 24, 4 2 8 - 3 2 . 12. “Registrar General’s Decennial Supplement for England and Wales, 1970-72: Occupational Mortality”; Her Majesty’s Stationery Office: London, Series DS No. 1. RECEIVED

for review September

2 8 , 1984. A C C E P T E D

February

2 1 , 1985.


Formaldehyde and Cancer - Advances in Chemistry (ACS Publications)

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