Annals of Oncology Advance Access originally published online on September 25, 2007
Annals of Oncology 2008 19(1):29-43; doi:10.1093/annonc/mdm202
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Formaldehyde and cancer risk: a quantitative review of cohort studies through 2006
1 Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy
2 International Epidemiology Institute, Rockville, MD
3 Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
4 Dipartimento di Traumatologia, Ortopedia e Medicina del Lavoro, Università di Torino, Turin
5 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy
* Correspondence to: Dr C. Bosetti, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Masa 19, 20156 Milan, Italy. Tel: +39 02-39014526; Fax: +39 02-33200231; E-mail: bosetti{at}marionegri.it
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Background: Occupational exposure to formaldehyde has been associated with excess risk of nasopharyngeal and selected other cancers.
Patients and methods: We reviewed and pooled the results of cohort studies published through February 2007.
Results: There were 5651 deaths from all cancers observed in six cohorts of industry workers and six of professionals, with a pooled relative risk (RR) of 0.95 for industry workers and of 0.87 for professionals. Nine deaths from nasopharyngeal cancer in three cohorts of industry workers yielded a pooled RR of 1.33, which declined to 0.49 after excluding six cases from one US plant. The pooled RR for lung cancer was 1.06 in industry workers and 0.63 in professionals. Corresponding values were 1.09 and 0.96 for oral and pharyngeal, 0.92 and 1.56 for brain, 0.85 and 1.31 for all lymphatic and hematopoietic cancers, and 0.90 and 1.39 for leukemia.
Conclusions: Comprehensive review of cancer in industry workers and professionals exposed to formaldehyde shows no appreciable excess risk for oral and pharyngeal, sinonasal or lung cancers. A non-significantly increased RR for nasopharyngeal cancer among industry workers is attributable to a cluster of deaths in a single plant. For brain cancer and lymphohematopoietic neoplasms there were modestly elevated risks in professionals, but not industry workers.
Key words: formaldehyde, neoplasm, occupational exposure, review, risk assessment
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introduction |
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Formaldehyde occurs as a natural product in most living systems and in the environment. It has also been long used in aqueous solution as a disinfectant and preservative and, more recently, in several industrial applications, including the production of adhesives and binders for wood, plastic, textiles and leather, and in the manufacture of chemical products [1].
Studies on experimental animals have shown that inhalation of formaldehyde at high levels induces squamous-cell carcinomas of the nasal cavity in rats, but not in mice and hamsters [1]. Animal studies also indicated that, besides the respiratory tract, other organs, which do not come directly in contact with formaldehyde, are unlikely to be targets of a carcinogenic effect, since formaldehyde is highly reactive and rapidly metabolized locally [1].
Several epidemiological studies have analyzed the potential association between formaldehyde and cancer risk in humans. These have been reviewed in three consecutive monographs of the International Agency for Research on Cancer (IARC) [1–3], which classified formaldehyde as ‘probably carcinogenic to humans’ (Group 2A), due to an excess risk of nasopharyngeal cancer. The most recent evaluation by IARC classified formaldehyde as ‘carcinogenic to humans’ (Group 1) [4–6], and concluded that there is evidence that formaldehyde causes nasopharyngeal cancer. The working group also concluded that there is strong but not sufficient evidence for leukemia and limited evidence for sinonasal cancer.
An independent review of the epidemiologic evidence on formaldehyde and cancer risk, however, cast some doubt on the causal association between formaldehyde and nasopharyngeal cancer risk [7], since the excess risk of nasopharyngeal cancer was restricted to a single cohort study of industry workers at one facility [8–13]. A meta-analysis reported a relative risk (RR) of 1.3 for nasopharyngeal cancer, but concluded that the available studies did not support a causal relation between formaldehyde and nasopharyngeal cancer risk [14]. Some excess risk of leukemia has been reported in studies of pathologists, anatomists, and embalmers and other professionals exposed to formaldehyde [1], but evidence supporting a causal relation between formaldehyde exposure and leukemia remains weak [15, 16].
In order to further investigate the relation between formaldehyde exposure and the risk of cancers of interest (mainly those of the oral cavity and pharynx, nasopharynx, sinus and nasal cavity, lung, brain and leukemia), we reviewed in detail cohort studies published between 1994 and 2006, and we briefly summarized the main results of earlier studies included in the review by McLaughlin [7]. We also computed quantitative estimates of the overall risk of selected cancers by pooling the results from cohort studies of industry workers and professionals exposed to formaldehyde.
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materials and methods |
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The studies included are all original cohort investigations published through February 2007, which provide information on formaldehyde exposure and cancer risk. These included cohort studies of formaldehyde-exposed industry workers and cohort studies of professionals who used formaldehyde, such as pathologists, anatomists and embalmers. They were identified through searches of the MEDLINE database, using the keywords ‘formaldehyde’, ‘neoplasm’ and ‘risk'. Papers were also identified through the reference lists of the retrieved studies, as well as through other reviews and meta-analyses on the issue. A total of 30 publications were identified, including the results of seven cohorts of formaldehyde industry workers and nine cohorts of professionals. Most case-control studies were community-based, and had no formaldehyde workers nor direct measure of formaldehyde exposure, but rather classified workers primarily by their job titles, using ad hoc exposure matrices. Thus, actual formaldehyde exposure is uncertain, since only a minority of jobs classified as implying formaldehyde exposure actually entail measurable levels of exposure. As a result, case-control studies provide less valid and reliable information on this issue than cohort studies, and are therefore not included in the present review [17].
To provide quantitative pooled estimates of the standardized mortality ratios (SMR) for selected cancers in relation to formaldehyde exposure, the number of cancer deaths observed and the SMRs or proportionate mortality ratios (PMR) were abstracted from each study. The expected number of deaths in each study was also abstracted or obtained from the ratio of observed deaths over SMR, and the pooled SMR for each cancer of interest and corresponding 95% confidence intervals (CI) were calculated. For cancer sites with more than 10 observed deaths, pooled RRs and corresponding 95% CI were also computed as a weighted average of the SMRs, using the inverse of the variance of the logarithm of the SMRs as weight (fixed-effects model) and the sum of the inverse of the variance and the moment estimator of the variance between studies (random-effects model) in case of significant heterogeneity between studies [18, 19]. Chi-square tests were used to evaluate the heterogeneity between studies. For cohort studies with subsequent updates, only the most recent results were considered for the pooled estimates.
The results of the meta-analysis were also presented graphically, plotting the SMR for each single study as a black square, whose size was inversely proportional to the variance of the logarithm of the SMR. For some studies, the 95% CI slightly differed from those published in the original papers because of rounding. Diamonds were used to plot the pooled RRs, whose centres represent the RRs and their extremes the CIs. A graph was not provided for nasal cancer, because few deaths were observed in the studies under review.
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cohort studies of industry workers
The most informative studies on formaldehyde and cancer risk are cohort studies of industry workers employed in the manufacture of formaldehyde and formaldehyde-containing products. These workers have a definite exposure to formaldehyde, although there is wide heterogeneity of jobs considered, and hence of exposure circumstances in industrial workers.
There are four primary cohorts of formaldehyde industry workers [20–23], plus a small cohort from Sweden [24], whose main results have already been included in the review by McLaughlin [7] (Table 1). The four studies included a collaborative study conducted by the US National Cancer Institute (NCI) based on 26 561 workers at 10 formaldehyde-producing or using facilities in the USA [20]; a cohort study of 14 017 British workers at six plants [22]; a study of 1322 resin workers in Italy [21]; and a study of 11 030 textile workers in the USA [23]. No significant excess of cancer mortality overall was reported in any of these studies [7]. There was, however, increased mortality from nasopharyngeal cancer (6 observed deaths versus 2.0 expected) in the NCI study [20], and excess mortality from lung cancer (18 observed deaths versus 9.7 expected) in the first report of the Italian study [21], which was, however, no longer observed in a subsequent update of the same cohort (24 observed versus 23.9 expected) [25].
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Since 1994, updates of the two cohorts from the USA [26–28], and the British cohort [29] have been published, as were results from two additional cohort studies of industrial workers [30, 31] (Table 1).
Follow-up of the NCI cohort of US workers employed at 10 formaldehyde-producing or using facilities prior to 1966 [20] was extended by 15 years through 1994, yielding a total of 865 708 person-years [26, 27]. The results of this cohort were given separately for subjects exposed and for those non-exposed to formaldehyde. Compared with the US population, total cancer mortality was not increased among subjects exposed to formaldehyde (SMR = 0.90, based on 1723 deaths), nor was mortality from most cancer sites, including those of the oral cavity and pharynx (SMR = 1.01, based on 49 deaths), nasal cavity (SMR = 1.19, based on 3 deaths), lung (SMR = 0.97, based on 641 deaths) and brain (SMR = 0.92, based on 43 deaths). Excess mortality was observed for nasopharyngeal cancer among those exposed to formaldehyde, with 8 deaths observed versus 3.8 expected, corresponding to a SMR of 2.1. Two deaths from nasopharyngeal cancer were also found in subjects not exposed to formaldehyde (SMR = 1.56). The RR for nasopharyngeal cancer was 1.67 for the highest average intensity exposure (
1.0 ppm), 1.83 for the highest peak exposure (4.0 ppm), 4.14 for the highest cumulative exposure (5.5 ppm-years) and 4.18 for the highest duration of exposure (15 years). The trends in risk for peak and cumulative exposure were statistically significant, but not those for average intensity and duration of exposure.
As pointed out in the NCI study [27], and confirmed in re-analyses of the same cohort [10, 11], 6 of the 8 nasopharyngeal cancer deaths observed in exposed workers occurred in a single plant in Wallingford, Connecticut (Plant 1), while the remaining 4 cases (including 2 in unexposed workers) occurred in four of the other nine plants. Thus, the SMR for nasopharyngeal cancer in exposed workers was 9.13 in Plant 1 (based on 6 deaths), and 0.64 in Plants 2–10 (based on 2 deaths), with similar results when using local rates, instead of national ones, for computing expected number of deaths. Using an external comparison group, the SMRs for Plant 1 were also markedly elevated compared to SMRs for Plants 2–10 at the highest exposure levels for average intensity, peak, cumulative and duration (6.2-fold, 6.7-fold, 3.5-fold and 9-fold, respectively) [32]. Because of the few nasopharyngeal cancer deaths in Plant 2–10, only the SMR for the highest category of peak exposure was significantly higher in Plant 1. Moreover, the SMRs for the highest level of exposure metrics in Plants 2–10 were only slightly elevated compared to the SMR of 1.9 (based on 2 deaths) for unexposed workers in the same plants. Thus, the significant exposure-risk relation observed using internal comparisons for peak exposure in Plants 1–10 was almost entirely due to the large excess risk in Plant 1, while for other measures of exposure (i.e. average intensity, cumulative exposure, and duration of exposure), no significant trends in risk were reported in separate analyses of Plant 1 and Plants 2–10 [10].
An independent and larger cohort study of Plant 1 [9, 33, 34] was also conducted. The latest update of this study [34], including 7328 workers first employed prior to 1985 with follow-up through 1998, reported 7 deaths from nasopharyngeal cancer as compared to 1.4 expected (the additional death in a worker first employed the year after the latest year of employment defining the original NCI cohort), corresponding to a SMR of 4.94, based on national rates, and of 5.00, based on local rates. The highest excess risk was found in workers hired between 1947 and 1956 (SMR = 8.13, based on 6 deaths), when formaldehyde exposures were probably higher. Moreover, there was some suggestion of an increased risk with cumulative exposure and duration of exposure, particularly in workers with exposure levels >0.2 and >0.7 ppm, although based on very small numbers. Only 3 of the 7 nasopharyngeal cancers were, however, exposed to formaldehyde longer than 8 months, and each had a low average intensity of exposure (0.03–0.60 ppm). Moreover, short-term workers had higher excess risk (SMR = 5.35) than long-term ones (SMR = 4.59).
With reference to leukemia, no overall excess mortality was reported in the updated follow-up of the NCI cohort (SMR = 0.85, based on 65 deaths) [26]. However, internal comparisons showed a significant trend of increasing risk in relation to peak exposure (RR = 2.46, 95% CI 1.31–4.62 for 4.0 ppm as compared to 0.1–1.9 ppm), particularly for myeloid leukemia (RR = 3.46, 95% CI 1.27–9.43). Excess risks were also found for the highest level of average exposure intensity (RR = 1.68 for 1.0 ppm), and for the longest duration of exposure (RR = 1.39 for 15 years), although the trends in risk were not significant. No dose-risk relation was found for cumulative dose of exposure. Moreover, a re-analysis of data on leukemia showed that the elevated RR for all leukemias and myeloid leukemia in relation to peak exposure occurred because of a significant reduced mortality in the reference category, and the associations with average intensity and duration of exposure were weakened using different categorizations [35].
The US cohort study of 11 030 workers exposed to formaldehyde in three garment plants [23] conducted by the National Institute for Occupational Safety and Health (NIOSH) was updated though 1998 [28], including a total of 339 241 person-years. In this updated analysis, mortality from all cancers was less than expected (SMR = 0.89, based on 608 deaths) based on national rates. No excess mortality was found from cancers of the oral cavity and pharynx (SMR = 0.79, based on 8 deaths), lung (SMR = 0.98, based on 147 deaths), brain (SMR = 1.09, based on 19 deaths), lymphatic and hemopoietic system (SMR = 0.97, based on 59 deaths) and leukemia (SMR = 1.09, based on 24 deaths). No nasopharyngeal cancer deaths were observed compared with 0.96 expected. A non-significant excess risk was, however, found for myeloid leukemia, with 15 deaths observed versus 10.4 expected (SMR = 1.44). Mortality from myeloid leukemia was highest among workers first exposed prior to 1963 (SMR = 1.61), among those with 10 years of exposure (SMR = 2.19), and among those with 20 years since first exposure (SMR = 1.91), but the trends in risk were not significant.
In the extended follow-up [29] of a cohort of 14 014 men employed after 1937 in six British factories [22], excess mortality from all cancers was reported (SMR = 1.10, based on 1511 deaths) compared with national rates. This excess was, however, restricted to deaths before 1990 (the SMR was 1.03 over the period 1990–2000). Twenty-six deaths from cancer of the oral cavity and pharynx were observed compared to 19.7 expected (SMR = 1.32), one of the nasopharynx compared to 2.0 expected (SMR = 0.5), and two of the nose and nasal sinus compared to 2.3 expected (SMR = 0.87). The worker dying from nasopharyngeal cancer was not highly exposed to formaldehyde [11, 29]. Significant excess mortality was found for lung cancer, with an SMR of 1.22 based on 594 deaths observed, particularly in workers in the highest exposure category (>2 ppm) (SMR = 1.58, 95% CI 1.40–1.78). The excess risk in highly exposed workers was reduced when estimates were adjusted for local variations in mortality (SMR = 1.28, 95% CI 1.13–1.44). Although lung cancer mortality was higher in workers exposed before 1965 (SMR = 1.65), it was also higher in workers with <1 year of high exposure (SMR = 1.78), and there was no clear pattern of risk with time since first exposure in a job with high levels of exposure. No excess mortality was found for brain cancer (SMR = 0.85, based on 30 deaths), and leukemia (SMR = 0.91, based on 31 deaths).
In a subset of 3929 of 8147 workers at a US automotive iron foundry exposed to formaldehyde between 1960 and 1987 [30], and followed-up for mortality through 1989, there was no excess mortality from all cancers combined (SMR = 0.99, based on 127 deaths observed). No deaths from nasopharyngeal or nasal cancer were observed. The SMR was slightly above unity for cancers of the oral cavity and pharynx (SMR = 1.31, based on 6 deaths) and of the lung (SMR = 1.20, based on 51 deaths). However, no relation with time since first employment or duration of employment was observed for either of these types of cancers. Mortality from these neoplasms was higher among smokers (SMR = 1.99 and 1.44, respectively, for cancers oral cavity and pharynx and lung) than among non-smokers (SMR = 0.0 and 0.74, respectively). Thus, tobacco smoking, as well as exposure to silica in foundry workers, may explain at least in part the excess lung cancer risk. Mortality was non-significantly below unity for cancers of the brain (SMR = 0.62, based on 2 deaths), lymphatic and hemopoietic system (SMR = 0.59, based on 7 deaths) and leukemia (SMR = 0.43, based on 2 deaths).
Using the Danish Cancer Registry, cancer incidence during 1970–84 was investigated among 2041 Danish men employed since 1964, at least 10 years before diagnosis, in 265 companies where exposure to formaldehyde was identified [31]. There was no excess risk for cancers of the oral cavity and pharynx (standardized proportionate incidence ratios, SPIR, 1.1, based on 23 cases observed), but a non-significant excess of nasopharyngeal (SPIR = 1.3, based on 4 cases) and particularly of nasal cancer (SPIR = 2.3, based on 13 cases) was found. Nasal cancer risk was elevated both in workers exposed to formaldehyde and wood dust (SPIR = 5.0), and in those exposed to formaldehyde but not to wood dust (SPIR = 3.0). No excess was found for cancer of the lung (SPIR = 1.0, based on 410 cases), brain (SPIR = 1.1, based on 54 cases) or leukemia (SPIR = 0.8, based on 39 cases). This study was not included in the pooled estimate, since there was no direct measure of formaldehyde exposure, which was mainly derived from job histories, and SPIRs were used as measures of the RRs.
One additional study analyzed the risk of various cancers in relation to self-reported formaldehyde exposure in a group of 45 399 men from the American Cancer Society's Cancer Prevention Study II employed in wood-related occupations [36]. This study was mainly designed to evaluate exposure to wood dust, and occupational exposure to various other industrial chemicals or agents was ascertained using a limited questionnaire. Consequently, this study was not included in the pooled estimates. Overall, 104 lung cancers were observed among subjects who reported to be exposed to formaldehyde, with a RR of 0.93, as compared with subjects not employed in wood occupations nor exposed to wood dust. Twenty-eight lymphatic and hemopoietic cancers were observed among those exposed to formaldehyde (RR = 1.22), of which 12 were leukemias (RR = 0.96).
cohort studies of professionals exposed to formaldehyde
Professionals, such as pathologists, anatomists and embalmers, have used formaldehyde as a preservative and disinfectant for more than 100 years. These workers have thus been exposed to formaldehyde, often at relatively high levels, as well as to several other chemicals.
The results from 10 studies of nine cohorts of professionals [37–46] have already been summarized by McLaughlin [7] (Tables 2 and 3). No further study on professionals exposed to formaldehyde has been published since 1994.
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In short, no risk estimate for nasopharyngeal or sinonasal cancer was reported in the published studies, with the exception of a non-significantly increased PMR in a US study of embalmers and funeral directors [45]. None of the other studies reported the presence of a nasopharyngeal death. Mortality from cancers of the upper respiratory tract was generally lower than expected. Some excess risk was found for brain cancer [38–41, 43] and leukemia [38, 39, 41–43, 45]. However, formaldehyde exposure was not directly measured in any of the studies, and a few of them used proportional mortality analyses, which may be biased by differences in total mortality in those highly selected professionals groups. Further, whether these apparent excess risks of brain cancer and leukemia are attributable to formaldehyde exposure or to other chemical or viral exposures is still unclear.
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A summary of the main results of cohort studies regarding total cancer mortality and mortality from seven cancers or groups of cancers of interest is presented in Table 4, which includes the number of cohorts providing data, the number of observed and expected deaths, the overall SMR and the pooled RR, based on the inverse of the variance of each study estimate. The study by Marsh at al. [34], which is an update of Plant 1 of Hauptmann et al. [27], was not included in summary calculations.
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Overall, 5651 deaths from all cancers were observed in six cohorts of industry workers and six of professionals (Figure 1). The pooled RR was 0.95, based on 4048 deaths, for industry workers, 0.87, based on 1603 deaths, for professionals, and 0.63 based on 153 deaths, for studies of professionals providing SMRs only. The latter estimate was based on one study in embalmers and two in pathologists, and likely reflects more favorable exposure to tobacco and other lifestyle factors in those professionals.
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One hundred and fifty deaths from cancers of the oral cavity and pharynx were observed in ten cohorts (Figure 2). The pooled RR was 1.09 for industry workers, 0.96 for professionals and 0.49 for studies on professionals providing SMR only. The significantly reduced RR among professionals based on three studies providing SMRs is also likely attributable to the lower tobacco and alcohol consumption of pathologists and other professionals compared with the general population.
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There were 13 deaths from nasopharyngeal cancer in four cohorts. The SMR was 1.33 for industry workers (Figure 3); a PMR of 2.16 was observed in one cohort of professionals (Table 3). Excluding a cluster of 6 deaths from a single plant of the NCI study, the pooled RR among industry workers declined to 0.49, based on 3 deaths. The studies by Bertazzi et al. [21], Edling et al. [24] and Andjelkovich et al. [30] were not included in the computation of the pooled estimates, since they reported the observed (0,1 and 0, respectively) but not the expected number of nasopharyngeal cancer deaths. If these studies were taken into consideration, and approximating the number of expected deaths from nasopharyngeal cancer as a proportion of expected total cancer deaths, the pooled SMR would be 1.40 (95% CI 0.67–2.57).
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The SMR was 1.05 for sinus and nasal cavity cancer among industry workers, based on 5 deaths. No death from sinonasal cancer was observed among professionals, compared to 0.35 expected.
Lung cancer mortality was slightly but significantly above unity among industry workers (RR = 1.06, based on 1459 deaths from six studies), and below unity in professionals (RR = 0.63, based on 562 deaths from eight studies) (Figure 4). The difference between the results of industry workers and professionals is again likely attributable to different smoking habits, as also indicated by the substantially reduced lung cancer RR (0.46) among the five studies of professionals providing SMRs.
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Data on brain cancer were provided by four studies on industry workers, including 94 deaths, with an overall RR of 0.92 (Figure 5). The pooled RR for brain cancer was 1.56 (significant) from seven studies of professionals including 74 deaths, and 1.80 (significant) from four studies of professionals giving estimates of SMRs based on 32 deaths. The RRs for industry workers and professionals were significantly heterogeneous, and there is no clear interpretation of the excess risk of brain cancer among pathologists and other professionals.
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There were 234 deaths from all lymphatic and hemopoietic neoplasms in four cohorts of industry workers, corresponding to a RR of 0.85 (Figure 6). Based on eight cohorts of professionals, there was a significant pooled RR of 1.31, based on 263 deaths. The corresponding value for the five cohorts of professionals with SMR estimates was 1.27, still significant. With reference to leukemia only, there were 122 deaths in four cohorts of industry workers, corresponding to a pooled RR of 0.90 (Figure 7). Although, internal comparisons of the NCI cohort study [26] showed a significant trend of increasing risk in relation to peak exposure, this should be interpreted cautiously in view of the reduced leukemia mortality observed in the reference group [35]. The pooled RR was significantly elevated (1.39), based on 106 deaths from eight cohorts of professionals, and 1.36, still significant, in the five cohorts giving SMRs.
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Thus, as for brain cancer, an excess risk of all lymphoid neoplasms combined and of leukemia was observed among professionals only, while the RRs for industry workers were below unity. This weighs against a causal role of formaldehyde exposure on these neoplasms, together with the short half-life of formaldehyde in plasma of experimental animals, the failure of inhaled formaldehyde to increase concentration in the blood of humans, monkeys or rats, and the lack of detectable protein adducts in bone marrow [1, 5, 47–49].
In conclusion, this comprehensive qualitative and quantitative view of cancer risk among industry workers and professionals exposed to formaldehyde shows no appreciable excess risk for cancers of the oral cavity and pharynx, sinus and nasal cavity and lung. The slight excess risk of nasopharyngeal cancer found in industry workers, based on 9 deaths, is due to a cluster of 6 deaths in a single plant in North America. Recent evidence suggests that this cluster may be explained by prior exposure to metal working [50]. For brain cancer, lymphoid neoplasms and leukemia there were excess risks among pathologists and other professionals, whereas the overall RRs were, if anything, below unity in industry workers. This indicates that other occupational or lifestyle characteristics of pathologists, anatomists and embalmers, rather than formaldehyde, are likely to be the underlying factors associated with the excess risk of these neoplasms among these professionals.
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This work was conducted with the contribution of the Italian Association for Cancer Research, and the Italian League Against Cancer. This work was undertaken while CLV was a senior fellow at the International Agency for Research on Cancer. The authors thank Mr Martin Plummer from the International Agency for Research on Cancer for providing the R function to plot the graphs, and Mrs Ivana Garimoldi for editorial assistance.
Received for publication November 9, 2006. Revision received March 29, 2007. Accepted for publication April 18, 2007.
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