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Original article Scand J Work Environ Health 1990;16(6):381-393 doi:10.5271/sjweh.1767 Epidemiologic evidence on the relationship between formaldehyde exposure and cancer. by Blair A, Saracci R, Stewart PA, Hayes RB, Shy C
Affiliation: National Cancer Institute, Occupational Studies Section, Rockville, MD 20892.
This article in PubMed: www.ncbi.nlm.nih.gov/pubmed/2284588
Print ISSN: 0355-3140 Electronic ISSN: 1795-990X Copyright (c) Scandinavian Journal of Work, Environment & Health
REVIEWS Scand J Work En viron Health 1990;16:381-93
Epidemiologic evidence on the relationship between formaldehyde exposure and cancer by Aaron Blair , PhD,1 Rodolfo Saracci , MD,2 Patricia A Stewart, MS,1 Richard B Hayes, DDS, PhD,1 Carl Shy, MD3 BLAIR A, SARACCI R, STEWART PA, HAYES RB, SHY C. Epidemiologic evidence on the relationship between formaldehyde exposure and cancer. Scand J Work Env iron H ealth 1990;16:381- 93. Over 30 epidemiologic studies have evaluated cancer risks associated with formaldehyde exposure. Excesses were reported for several sites, leukemia and cancers of the nasal cavities, nasopharynx, lung, and brain generating the greatest interest. The excesses of leukemia and brain and colon cancer found among professionals may not be related to formaldehyde exposure, since similar excesses were not observed among industrial workers. Inconsistencies among and within studies impede assigning formaldehyde a convincing causal role for the excesses of lung cancer found among industrial workers. A causal role for formaldehyde is the most probable for cancers of the nasopharynx and, to a less extent, the nasal cavities. Evidence of exposure-response relationships, the fact that direct contact with formaldehyde may occur at these upper respiratory sites, and the consistency of these findings with experimental studies make this assumption highly probable. Key terms: lung, meta-analysis, nasal, nasopharynx, review.
An imal bio assays (I , 2) indicate that formaldeh yde ca uses nasal tumors in rats. The wide spread use of for maldehyde in ind ustry a nd in commercial products ha s heightened public health co ncern s regarding this chemical. In the United States, the National Oc cupational Ha zards Survey (3) of the National Institute for Occupational Safet y and Health indicates that 1.6 million wor kers may be expo sed to formaldehyde during the manu facture o f formaldeh yde resins, textiles, ga rments, particle bo ard and plywood, insulating materials, dinnerware, and paper a nd in health-related pro fession s. In addition , off-ga ssing of formaldehyde fro m certain co nsumer products may lead to expo sure of large numbers of th e ge neral public. The results of animal expe riments led to ep idem iologic studies on a variety of formaldehyde-exposed populations. Previous reviews of these studies have pr imarily focu sed on asses sin g th e weight of evid ence co ncern ing fo rma ldehyde as a human carcinogen witho ut a det ailed presentation of the stu dy result s. In one such review the International Agenc y for Research on Ca ncer (l ARC) concluded that th ere is sufficien t eviden ce fo r th e carcinoge nic ity of form ald eh yde in
1
2 .1
National Cancer Institute, Rockville, Maryland, United States. Internatio nal Agency for Research on Cancer, Lyon, France. University of North Carolina, Chapel Hill, North Carolina, United States.
Reprint requests to: Dr A Blair, National Cancer Institute, Occupational Studies Section, Executive Plaza North, Room 418, Rockville, MD 20892, USA.
animals, but limited evidence for humans (4). Another group co ncluded that th e evidence fo r the carcinogenicity of formaldeh yde in humans was less per suasive th an did IARC (5). In our review of th e epidemiologic literature we hav e summarized results on a site-by-site basis and have focu sed on potential expo sures to form aldehyde and other expo sures that the study populations ma y ha ve experienced to eva luate the strength o f th e evidence regarding fo rmalde hyde and human ca ncer.
Study designs Over 30 reports fro m epidemiologic studies on form ald ehyde have been published (table I) . These reports hav e focused on professional groups such as funeral directors and embalmers, anatomists, pathologists, and workers in formaldeh yde facilities producing formaldeh yde , resins, plastic molding, decorative laminates , plywood , particle bo ard , and apparel. These studies, as well as relevant broad surveys of cancer risk by occupation in the United States, Canada, a nd Swed en, a re included in thi s review. The studies ha ve been conducted in eight countries (United States, Canada, Great Britain , Denmark, The Netherlands, Finland, Sweden , and Italy) and ha ve emplo yed standardized mortal ity ratio (SMR), proportionate mortality ratio (PMR), standardized incidence ratio (SIR), and case-referent des ign s. The total number of cancer cases with potential exp osur e to formald eh yde in thes e studies is now large enough to provide considerable statistical po wer for evalu ating the ca rci nogenicity o f formaldeh yde in humans for all but rare sites. 38 1
Table 1. Des c ri p t ion o f th e epidem io log ic s tu dies on formald eh yde. (PMR i n ci d e n c e ra ti o, SMR stand a rdized mortali ty rat io)
=
Author
Study des ign
Populat ion stu died
Time period
=p ro portionate mort a li t y ra t io, SIR =stan dardized
Exposu re evaluation
Diseases report ed
1959- 1961
Number of subjec ts
. Contr ol of Compar.'son smoking populat ion
Professiona l and nonoccupational exposures Peter sen & Milham (6)
PMR
None
All
No
Cali fornia
Jensen & Andersen (7)
Physicians Casereferent SIR Pharmacy users
t 943-1 976
Specialty
Lung cancer
84 cases , 252 referents
No
Ot her cancers
1969-1978
None
Lung All cancer
557
No
All pharmacy users
Friedman & Ury (8)
Funerai direc to rs
Milham (9)
PMR
Funeral directors
1959-1979
None
All
333
No
Washington
Walrath & Fraumeni (48)
PMR
Funeral directors, embalmers
1925- 1980
Type of lice nse
All
1132
No
United States
Harringt on & Shannon (65)
SMR
Pat hologists
1955- 1973
None
2079
No
United Kingdom
Harringto n & Oakes (64)
SMR
Patholo gist s
1974- 1980
None
13 selec ted causes 13 selected
2307
No
Unit ed King dom
causes
Levine et al (47)
SMR
Undertakers
1928- 1977
Latency
All
1477
No
Ontario
Walrat h & Fraumeni (10)
PMR
Embalmers
1925- 1980
Duratio n
All
1007
No
United St ates
Gallagher et al (11)
PMR
Funeral directors
1950-1978
None
All
No
British Columb ia
Logue et al (12)
SMR
Path ologi sts
1962- 1977
None
Selected
St roup et a! (49)
SMR
Anato mis ts
1888-1 979
All
No No
United States
Walrath et al (67)
SM R
Funeral directors,
1954- 1970
Speci alty, durati on None
5585 2317
All
408
No
Other vete rans
Funera l direct ors
1975- 1985
None
All
4046
No
United States
Chemic al workers Casereferent
1957- 1979
Level, duration
All cancer
Yes
Oth er wo rkers
emba lmers
Hayes et al (63)
PMR
Industrial workers Fayerwe ather et al (40)
481 cases 481 referents
Marsh (35)
PMR
Chemic al worker s
1950-1976
Duration
32 cause s
603
No
United Stat es
Wong (36)
SMR
Chemical work ers
1940- 1977
Durat ion
23 causes
2026
No
United States
9 ca uses All
24 256
No No
Unit ed States Unite d States
13 causes
7680
No
United Kingdom, local
Lung, bladder
889 cases 1758 refere nts
No
Oth er death s
Nasal,
839 cases 2465 ref erent s
No
Oth er cancers
No
Sweden
Yes
Other workers
1332
No
Italy
26561
No
Unite d Stat es, unexposed
Liebli ng et al (37)
PMR
Chemical workers
1976- 1980
None
Stayner et al (33)
PMR
Garment workers
1959- 1980
Durati on, latency
Acheson et al (23, 68)
SMR
Chemic al workers
1937- 1981
Coggon et al (41)
Brit ish de aths Casereferen t Danish Cancer Casereferent Registry
1975-1979
Level, dura tio n Level
1970-1982
Duration
Ol sen et al (44)
Malke r & Weiner (13)
Partanen et al (31)
SIR
Nested case-
Swedis h CancerEnvironment Regist ry Finnis h woodworkers
naso1961- 1979
None
pharynx 6 cancers
1957-1 980
Level, duration
Respiratory cancer
67378
60 cases 171 referents
referent
Bert azzi et al (30, 50)
SMR
Resin workers
1959- 1986
Duration
14 cau ses
Blair et al (24- 28)
SMR
10 plant s
1934-1 980
Level,
All
duration
Bond et al (43)
Nest ed Chemical worker s
1940-1980
Latency
Lung
308 cases 588 referents
Yes
Oth er workers
1978- 1981
Level
Nasal cancer
91 cases 195 referents
Yes
Populat ion referents
1979- 1983
Levell duration
Nasa l,
285 cases, 552 referents
Yes
pharyn x
Populat ion referents
Probability of expo sure
Nasal, nasopharyn x
371 cases, 605 referents
No
Othe r deaths
casereferent
Hayes et al (42) Vaughan et al (45, 62)
The Netherland's Casereferent hosp ita ls Washington Casereferent Tumor Regis try
Rou sh et al (59)
Connec tic ut Casereferent Tumor Registry
1935- 1975
Stayner et al (34)
SMR
1959--1982
Duration
All
Gerin et al (39)
Mont real Caserefere nt
1979- 1985
Level, duration
19 cancers
Garment worker s
Exposure information
Formaldehyde is ubiquitous in the environment. For th e assessment of can cer risk s asso ciated with form aldehyde exposure, it is of paramount importance that the level of expos ure o f study subjects be determined.
382
11030
No
United Stat es
4259
Yes
Populat ion and other cance r
In epidemiologic studies of forma ldehyde exposure and cancer risk variou s ap proaches to exposure assessment have been taken, largely dict ated by th e cons traints of the study design. Mortality surveys, such as of profe ssional groups, have relied upo n quali tat ive assessme nt
of exposure based upon job title or similar designations. Mortality studies of individual industrial facilities have generally provided more-detailed exposure estimates based on industrial exposure measurements and ancillary information. Case-referent studies composed of persons from a variety of occupations have generally relied on indirect exposure assessment based on knowledge of work practices and exposures in formaldehyde-related jobs .
Study groups
Professionals Embalmers may come in contact with a variety of chemicals, including formaldehyde, pheno l, dyes and stains, glutaraldehyde, glycol, glycerol, xylene, alcohols, and particulates, and also with biologic material and gamma radiation (14). Levels of 2.0
35 % > 2.0 ppm
Asb estos
Dust in all plants
< 0.1- >2.0, peaks > 4.0
3 % > 2.0 ppm
Alcohol , ureas, anti oxidants, plast iciz ers, dyes , asbes tos , wood dust , pheno l, stearat es, amides , and others
Dust in many plants
None
Higher in past
Blai r et al (24-27)
Stayner et al (34)
3 garment manufactur ing plants
Partanen et al (31) and Kauppi nen & Niem ela (32)
19 particleboard , ply wood, glue , sawm ill plants
Bertazzi et al (30)
1 resin pla nt
Current geometric mean=0.14 -0.17, no peaks measure d 9 % > 1.5 (average expo sure)
1974- 1979 mean levels = 0.2-3.8
Wood dust, glues , pesticides, pheno l, te rpenes, solvents, exhaust gases, molds Urea, melamine, styrene, expo xy resins, solvents , epic hlorhydrin
Past levels higher
383
data available since 1970 and interviews with management and long-term employees about process changes and controls were used to estimate the exposure levels. Twenty-five percent of the subjects were unexposed. Among those holding jobs where exposure occurred, 35 070 had their highest exposed job in the low-exposure category, 14 0J0 had their highest exposed job in the moderate category, and 51 0J0 had their highest exposed job in the high category (> 2.0 ppm). The authors specifically mentioned the presence of only one other substance, asbestos, but we assume that many of the chemicals identified in the formaldehyde and resin plants studied by Blair et al (24-27), such as wood dust, phenol, melamine, and urea, may have also been present in the formaldehyde and resin plants in this study. Blair et al (24-29) studied IO plants producing a variety of products, including formaldehyde, formaldehyde resins and molding compounds, decorative laminates, photographic film, and plywood. The estimates of formaldehyde levels for each unique combination of job, department, plant, and calendar-year combination were based on the results of monitoring conducted by the investigators (about 2000 full-shift personal samples) (27), company monitoring results (over 4500 results dating back to the 1960s for some plants), plant visits, job descriptions, and interviews with management and long-term employees regarding changes in the process, controls, work practices, and sensory perceptions (26). With the use of these estimates jobs were assigned to categories of trace, ~ 0.1, 0.1- 1.00 and total number of studies 6/9 7/9 Professionals 0/3 1/4 Industrial wor kers
2/5 1/4
9
0.8
14
10 1.4
7.9 1.1 8 16.0 0.5
122 114.4 1.1
22 26.0 0.8
11/13 2/3
1/6 1/2
a Data in italics are included in the summary stat istics.
Colon and rectal cancer. Melanoma. , P 0- 5.5 ppm-years , hi gh level 2:5.5 ppm-yea rs. b Lower level = all exp osed , high er leve l = p robab ly exposed t o high leve ls for at least one year. C On a scal e of 1- 9, lower level = 1-2 and higher level = 2:3 (all among th ose exposed to lower levels of wood dusts) . d Exposu re esti mat es fr om industrial hyg ienist A. e Ex pos ure es ti mates from industrt at hygienist B. f Lower level ver sus me diu m to high level s. 9 Usin g data f rom in d ustr ial hyg ienist B for H ayes et al (42). , P ,;0.05.
Table 6. Rel at ive risks fo r naso pha ryn geal ca ncer by level or duration of exposure to form alde hyde . (0 cases, E expected number of cases , RR relative risk)
=
=
Un exposed
Lower level/d ur at ion
=o bserv ed num ber o f
Hi gher level/du rat io n
Au tho r
0
E
RR
0
E
RR
Blair et al (28)" Roush et al (59)b Vaug han et al (45)C
1 126 16
0.5 126 16
2.0 1.0 1.0
2 21 7
0.5 21 5.8
4.0 1.0 1.2
Tot al
143
142.5
1.0
30
27.3
1,1
0
X for t rend
E
RR
2 7 4
0.3 3.1 2.9
7.5 2.3 * 1.4
0.83 1.29 0.65
13
6.3
2.1 '
2.02'
a Unexposed =