Does formaldehyde cause nasopharyngeal cancer In man?

Cancer Letters, 46 (1989) 79-85 Elsevier Scientific Publishers Ireland Ltd. 79 Review Letter Does formaldehyde cause nasopharyngeal cancer In man? I.F.H. Purchase and G.M. Paddle ICI Central Toxicology Laboratory and Epidemiology Unit, Alderley Park, Macclesfield, Cheshire, SK10 4TJ (U.K) (Received 6 March 1989) (Accepted 8 March 1989) Summary Formaldehyde is a widely used industrial chemical, which also has uses in consumer products, and hence large numbers of people are exposed to it. It is also an endogenous metabolite with measurable levels in body fluids and tissues. The reports of its carcinogenicity to rats have raised concern about its potential to cause a carcinogenic response in exposed populations. This letter reviews the information on the carcinogenicity of formaldehyde, particularly to the upper respiratory tract, in animals and man. Keywords: formaldehyde exposure; upper respiratory tract tumours; lung tumours; humans; rodents. Animal studies Male and female rats were exposed to 2.0, 5.6 or 14.3 ppm formaldehyde in air for 8 h a day, 5 days a week, for up to 24 months. Squamous cell carcinoma of the nasal passages was induced in the F344 rats (44% at 14.3 ppm, 0.85% at 5.6 ppm and none at 2 ppm) [1]. A number of polyploid adenomas were also observed in the exposed rats. Similar neoplasms were also observed in Sprague Dawley rats exposed to 14.1 ppm [2]. Mice (B6C3F1) developed a low incidence (0.93 %) of squamous cell carcinomas of the nasal cavities at 14.3 ppm, but not at 5.6 or 2.0 ppm [1]. Hamsters exposed to 10 ppm did not develop neoplasms of the nasal cavity [3]. Relatively short-term exposure is capable of inducing nasal cancer in rats. Rats exposed for up to 13 weeks to 10 or 20 ppm formaldehyde were kept for periods of up to 126 weeks [4]. The non-neoplastic histological changes in the nasal respiratory and olfactory epithelium did not recover over the 126-week period and 4.5% of the rats exposed to 20 ppm for 13 weeks developed nasal adenomas or carcinomas by 126 weeks. Shorter term studies in rats [5] have demonstrated that the concentration rather than the total quantity (concentration X time) is the critical factor in determining the severity of cytotoxicity in the nasal cavity. These studies demonstrate that high concentrations of formaldehyde cause irreversible damage to the nasal epithelium of rats and that in some cases rats exposed to these concentrations develop neoplasia. At lower doses (below 5 ppm) there is some evidence of cytotoxicity demonstrated by an increase in cell turnover [5], but no evidence of a carcinogenic effect [1]. Mechanism of action of formaldehyde Studies of the physiological response following exposure to formaldehyde and its Published and Printed in Ireland

80 mechanism of action provide evidence which helps to explain the large differences in susceptibility between rat and mouse and suggest that there will be differences in susceptibility between man and rats [6]. The amount of formaldehyde reaching the tissue is likely to be the most important determinant in the response of that tissue and this may explain the difference between the response of the mouse and rat. On exposure to formaldehyde the mouse reduces its minute volume by a substantially larger amount than the rat, thereby reducing the amount of formaldehyde available for absorption. Rodents are obligatory nose breathers with the consequence that formaldehyde, being water soluble, is absorbed predominantly through the anterior mucosal surfaces of the nasal cavity. This is precisely the point at which squamous carcinomas develop in the rat. Since man breathes both through the nose and the mouth, tissue concentrations may be higher lower down the respiratory tract thereby increasing the number of potential target sites. This may reduce the tissue concentration of formaldehyde but increase the number of sites exposed to high atmospheric concentrations. Hence epidemiological studies should examine all sites in the respiratory tract. Formaldehyde produces toxic effects on the mucociliary apparatus in both rats and man. At levels of greater than 2 ppm there are clear signs of cilia stasis in rats and at lower levels (0.38-1.63 ppm) there is evidence of reduced mucus flow in man. The mucus coating of the nasal epithelium is likely to be a significant barrier to the penetration of formaldehyde and the induction of epithelial lesions at specific sites in the nasal cavity at high doses may be associated with disruption of the mucociliary junction at these sites. Formaldehyde is an endogenous metabolite which appears to be present in all biological tissues. Cells survive in spite of the presence of chemically reactive and cytotoxic formaldehyde as a consequence of active enzymatic pathways for its removal. Even at the highest levels of exposure to formaldehyde used in the long-term studies (15 ppm) there is no increase in the concentration of free or reversibly bound formaldehyde in rat nasal mucosa. There is also no increase in blood concentrations of formaldehyde in rats exposed to 15 ppm. Nevertheless it is possible to measure the binding of exogenous formaldehyde to proteins and nucleic acids. There is, however, less binding in the nasal cavity at concentrations below 2 ppm than would be predicted from binding studies carried out at higher concentrations. There is also less hyperplasia of the respiratory mucosa at low levels than would be predicted from high level exposure or DNA binding [7]. The proportionately lower nasal tissue doses and hyperplasia at low inhaled doses may be due to the disruption of normal respiratory mechanisms at high doses. The importance of the observation lies in the absence of acute or chronic tissue responses at low doses, suggesting that human populations exposed to these low doses would not be susceptible to the responses observed at high doses. Epidemiology The upper respiratory tract and lung are the likely target sites for the action of formaldehyde when exposure is by inhalation. The lung may be a more likely site for the effects of formaldehyde in man than in rats, owing to the difference in breathing habits. A recent review has been carried out of 12 reports of cohort studies and 3 of proportionate mortality studies [8]. As would be expected for such a large number of studies, some statistically significant differences between observed and expected lung cancer cases were reported, but often it was impossible to take into account the confounding effects of cigarette smoking. In other studies the necessary exposure duration and dose effects expected from a causal association were not observed. The study group concluded that 'overall, the evidence is not indicative of an association between formaldehyde exposure and lung cancer risk' [8]. A summary of the principal results from

81 Table 1. Summary of epidemiological studies on the association between occupational exposure to formaldehyde and sinonasal and nasopharyngeal cancer. Author (Ref.) Study design Study result Cohort studies Acheson et al. (1984) [15] Blair et al. (1986) [9J Case-control studies Brinton et al. (1984) [16] Hayes et al. (1986) [ 17] Hernberg et al. (1983) [18] Olsen et al. (1984) [11] Cohort study in 6 plants 7680 men uith 98% follow-up Mixed exposure: for HCHO 4 exposure categories estimated 605 men in highest category (> 2.0 ppm) for 20 years Cohort study in 10 plants 24,717 persons with 95 % follow-up included 5 exposure categories 11 % - no exposure 12% - < 0.1 TWA ppm 34% - 0.1-0.5 TWA ppm 40% - 0.5-2.0 TWA ppm 4% - > 2.0 TWA ppm 160 sinonasal cancer cases 91 male nasal cancer cases 2 independent assessments of exposure based on interview information on work history Adjusted for smoking and wood-dust exposure 167 nasal cancer referrals (matched with colon or rectal cases) Occupational history obtained by telephone interview 754 sinonasal and nasopharyngeal carcinoma cases No increased cancer mortality Sinonasal OlE 0/ 1.1 Nasopharynx Ol E Ol not given White men - all cancers Ol E 570/566 Sinonasal Ol E 2/ 2.2 Nasopharynx OlE 6/2.0 2 cases exposed to HCHO giving relative risk of 0.35 (0.1-l.8) Relative risk for HCHO exposure was 2.5 (significant) for exposure assessment A and 1.9 (not significant) for B. When restricted to squamous carcinoma RR was 3.0 (33 cases) and 1.9 (26 cases) (both significant) respectively Given the limitations of the study the authors consider it is not conclusive No nasal cancer patients exposed to HCNO Relative risk for HCNO related sinonasal cancer in males 2.8 (33 exposed cases, significant).

82 (Table 1 contd.) Author (Ref.) Study design Study result Olsen et al. (1986) [19] Roush et al. (1987) [14] Vaughan et al. (1986a,b) [20] Assessment of HCHO exposure for 6-18 years 215 male squamous cell cancer cases of the nasal cavity and paranasal sinuses 159 male squamous cell cancer cases of the nasopharynx Study of occupational exposure to HCHO among 198 sinonasal and 173 nasopharyngeal cancer cases Study of occupation, smoking and residential details among 285 cases of cancer of pharynx, sinus and nasal cavity When adjusted for exposure to wood-dust, RR = 1.6 (not significant) No excess RR for nasopharyngeal cancer RR of 2.3 for 13 sinonasal cases (not significant). Introduction of 10 year latency did not result in significantly increased RR No association demonstrated for nasopharynx Odds ratio for lower levels of exposure close to unity For 7 nasopharyngeal cases with high exposure 20 + years before death, odds ratio 2.3 (0.9-6.0) A further sub-group of 6 cases aged 68 + at death, the odds ratio was significant at 4.0 (1.3-12.0) No significantly increased RR for occupational HCHO exposure. Increased risk of nasopharyngeal cancer in those living in mobile homes studies of sinonasa] and nasopharyngeal cancer are given in Table 1. In the two large cohort studies there was no excess of sinonasal cancer, but in one [9] there was a statistically significant excess of nasopharyngeal cancer (Observed/Expected, 6/2.0). This was reported not to be positively associated with cumulative exposure [9] but further work reported that 5 of the cases occurred in dusty conditions and for these cases, there was a non-significant positive trend with cumulative exposure [10]. In the case-control studies, two showed an increased relative risk of sinonasal cancer (Table 1). In the first [11] there was a significantly increased relative risk of 2.8 which, when adjusted for wood-dust exposure was reduced. to 1.6 (non-significant). In the second [12] two independent methods of assessing potential exposure to formaldehyde were used. By one method there was a Significantly increased relative risk of 2.5 and by the other a non-significant relative risk of 1.6. The difficulty of assessing formaldehyde exposure accurately limits the usefulness of these results. For nasopharyngeal cancer, one of the studies [13] showed an increased odds ratio of

83 1.6 (not significant) with occupational exposure. Only when occupational and mobile-home exposure were combined was a significant odds ratio of 6.7 observed. There were only 27 cases in this study and a number of sources of potential bias were inherent in the study design [8]. A second study of 173 cases of nasopharyngeal cancer had an odds ratio close to unity [14]. For 7 nasopharyngeal cases with more than 20 years exposure and a further sub-group of 6 cases aged over 68 at death, higher odds ratios were observed, with that for the 6 cases being significantly higher (Table 1). The remaining case control studies showed no increased risk (Table 1). In reviewing the epidemiological studies of the association between formaldehyde exposure and sinonasal and nasopharyngeal cancer, there is a lack of consistency in the findings. For sinonasal cancer there is insufficient evidence to demonstrate an association with formaldehyde exposure, but equally the absence of an association is not a justifiable conclusion. For nasopharyngeal cancer, the key observation is in the cohort study of Blair et al. [9], as other studies are negative or, in the positive case-control study, had inherent problems in the study design. Blair et al. [9] report that the excess of nasopharyngeal cancer was statistically significant but that the increase for the oropharynx and hypopharynx cancers were not significant (Table 2). It is also interesting to note that of the 11.4 expected cases of pharyngeal cancer, 4.4 were unspecified, while only 1 of the 15 cases observed was of unspecified site. This suggests that the attribution of the precise site of origin of pharyngeal tumours is difficult and also that the difference in proportion of unspecified cancers in the expected and observed groups may be a source of bias. One way of correcting for bias would be to reallocate the unspecified cases to the 3 categories of pharyngeal cancer in proportion to the number of cancers seen at the 3 sites. Such a calculation can be done using either the observed or the expected values as a basis for the correction. Both sets of values are shown in Table 2. The correction by either method reduces the difference between the observed and expected and, in common with the figure for total pharyngeal cancers, there is no significant difference between observed and expected for any site. The use of a correction of this type is suggested by the difficulty of diagnosing the site of origin of pharyngeal cancer and the substantial difference in the unspecified site cases in Blair's study. The corrected values weaken the evidence suggesting an association between respiratory tract cancer and exposure to formaldehyde in man. Table 2. Cancer of the buccal cavity and pharynx in white men (from Ref. 9). Observed Expected Ob Lip 2 0.6 Tongue 2 5.6 Mouth 2 1.6 Nasopharynx 7 2.2 Oropharynx 5 2.9 Hypopharynx 2 1.9 Unspecified 1 4.4 7.31 3.58 7.50 4.40 5.41 4.72 5.36 4.47 2.27 3.09 2.14 2.53 Total 15 11.4 'Corrected using the distribution seen in the expected column. bcorrected using the distribution seen in the observed column.

84 Conclusion On the basis of the animal studies, it might be considered likely that epidemiological studies would reveal an increased risk of respiratory tract cancer in people exposed to formaldehyde. One possible reason for not observing an increase in cancer incidence relates to the statistical power of the studies which are available on formaldehyde. One of the cohort studies [15] could detect a relative risk of 10 with a 94% chance of success. On the other hand the larger epidemiological studies were more sensitive to increases in the incidence of more common cancers. For example the case control study [11] had an 80% chance of detecting at least a 2-fold excess of lung cancer with 5 or more years of exposure. Given the incidences of cancer observed in rats, and the levels of exposure experienced in the population groups studied and summarized in Table 1, stronger evidence of an increased risk of cancer would be expected if man had the same susceptibility to formaldehyde as rats. The largely negative results from epidemiological studies taken with evidence of differences in the physiological mechanisms affected by formaldehyde in rats and man, suggest that man is much less susceptible to formaldehyde exposure and that at low occupational and domestic exposures, the risk, if any, will be so low as to be unobservable. References Kerns, W.D., Pavkov, KL, Donofrio, D.J. and Gralla, E.J.(1983) Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure, Cancer Res., 43, 4382-4392. 2 Albert, R.E., Sellakamur, AR., Laskin, S., Kuschner, M. Nelson, N. and Sugden, C.A. (1982) Nasal cancer in the rat induced by gaseous formaldehyde and hydrogen chloride, J. Natl. Cancer Ins!., 68, 597-603. 3 Dalbey, W.E. (1982) Formalde hyde and tumors in hamster respiratory tract, Toxicology, 24, 9-14. 4 Feron, V.J., Bruyntjes, J.P., Woutersen, R.A, Immel, H.R. and Appelman, LM. (1988) Nasal tumours in rats after short-term exposure to a cytotoxic concentration of formaldehyde, Cancer Lett., 39, 10 1-111. 5 Wilmer, J.W.G.M., Wouterson, R.A, Appelman, LM., Leeman, W.R. and Feron, V.J. (1987) Subacute (4-week) inhalation toxicity study of formaldehyde in male rats: 8 hour intermittent versus 8-hour continuous exposures, J. Appl. Toxicol., 7 (1) 15-16. 6 Swenberg, J.A, Barrow, C.S., Borerko, C.J., Heck, H.d'A, Levine, R.J., Morgan, KT. and Starr, T.B. (1983) Non-linear responses to formaldehyde and their implications for carcinogenic risk assessment, CarCinogenesis, 4, 945-952. 7 Casanova-Schmitz, M., Starr T.B. and Heck, H.d'A. (1984) Differentiation between metabolic incorporation and covalent binding in the labelling of macromolecules in the rat nasal mucosa and bone marrow by inhaled [l4ciand PH) formaldehyde, Toxicol. Appl. Pharmacol., 76, 26-44. 8 UAREP. (1988) Universities Association for Research and Education in Pathology Inc. Epidemiology of chronic occupational exposure to formaldehyde : report of the ad hoc panel on health aspects of formaldehyde, Tox. and Ind. Health, 4, 77-90. 9 Blair, A, Stewart, P., O'Berg, M., Gaffey, W., Walrath, J., Ward, J., Bales, R., Kaplan, S. and Cubit, D. (1986) Mortality among industrial workers exposed to formaldehyde, J. Natl. Cancer Ins!., 76, 1071-1084. 10 Blair, A., Stewart, P.A., Hoover, R.N., Fraumeni, J.F., Jr., Walrath, J., O'Berg, M. and Gaffey, W. (1987) Cancers of the nasopharynx and oropharynx and formaldehyde exposure, J. Natl. Cancer Ins!., 78, 191. 11 Olsen, J.H., Jensen, S.P., Hink, M., Faurbo, K, Breum, N.O. and Jensen, O.N. (1984) Occupational formaldehyde exposure and increased nasal cancer risk in man, In!. J. Cancer, 34, 639-644. 12 Hayes, R.B., Raatgever, J.W., de Bruyn, A and Gerin, M. (1986) Cancer of the nasal cavity and paranasal sinuses, and formaldehyde exposure, In!. J. Cancer, 37, 487-492. 13 Vaughan, T.L, Strader, C., Davis, S. and Daling, J.R. (1986a) Formaldehyde and cancers of the pharynx, sinus, and nasal cavity: I. Occupational exposures, In!. J. Cancer, 38, 677-683. 14 Roush, G.C., Walrath, J., Stayner, LT., Kaplan, S.A. and Flannery, J. T. (1989) Nasopharyngeal cancer, sinonasal cancer, and occupations related to formaldehyde : a casecontrol study, J. Natl. Cancer Ins!., 79, in press. 15 Acheson, E.D:, Barnes, H.R., Gardner, M.J., Osmond, c., Pannet, B. and Taylor, C.P. (1984) Formaldehyde in the British chemical industry: an occupational cohort study, Lancet, i, 611-616. 16 Brinton, I.A., Blot, W.J., Becker, J.A., Winn, D.M. Browder, J.P., Farmer, J.C., Jr. and Farmer, J.F., Jr., (1984) A case-control study of cancers of the nasal cavity and paranasal sinuses, Am. J. Epidemiol., 119, 896 906. 17 Hayes, R.B., Raatgever, J.W., de Bruyn, A. and Gerin, M. (1986) Cancer of the nasal cavity and paranasal sinuses and formaldehyde exposure, Int. J. Cancer, 37, 487 492.

85 18 Hernberg, S., Westerholm, P., Schultz-Larsen, K. Degerth, R, Kuosma, E., Englund, A., Engzell, U., Hansen H.S. and Mutanen, P. (1983) Nasal and sinonasal cancer. Connection with occupational exposures in Denmark, Finland and Sweden, Scand. J. Work Environ. Health, 9, 315-326. 19 Olsen, J.H. and Asnaes, S. (1986) Formaldehyde and the risk of squamous cell carcinoma of the sinonasal cavities, fu. J. ~d. Med., 43, M9-7M. 20 Vaughan, T.l., Strader, c., Davis, S. and Daling, J.R. (l986b) Formaldehyde and cancers of the pharynx, sinus and nasal cavity: II. Residential exposures, Int. J. Cancer, 38, 685-688.