CORRESPONDENCE

Re: Mortality From Lymphohematopoietic Malignancies Among Workers in Formaldehyde Industries

Mercedes Casanova, Philip Cole, James J. Collins, Rory Conolly, Elizabeth Delzell, Henry d' A. Heck, Robin Leonard, Rick Lewis, Gary M. Marsh, M. Gerald Ott, Tom Sorahan, Charles W. Axten

Correspondence to: Charles W. Axten, PhD, CIH, Health Risk Solutions, LLC, 1606 Maddux Lane, McLean, VA 22101-3200 (e-mail: chuckaxten{at}cox.net)

The study described in the article by Hauptmann et al. (1) has several strengths, including large size, long follow-up, and attempts to control for potentially important confounding factors. However, the study does not provide conclusive evidence of a causal association between formaldehyde exposure and leukemia for several reasons. In particular, the large relative risks (RRs) reported for the internal comparison stratified by exposure category need to be reconciled with the external comparisons in which the standardized mortality ratio (SMR) for all lymphohematopoietic neoplasms in formaldehyde-exposed workers is 0.8 (95% confidence interval [CI] = 0.7 to 0.9). We have estimated SMRs for leukemia and other lympohematopoietic malignancies for the peak formaldehyde exposure categories shown in table 3 of Hauptmann et al. (1). These SMRs (Table 1) suggest that mortality from lymphohematopoietic malignancies is not higher than would be expected in those workers with a peak formaldehyde exposure of 4 ppm or more, but rather is lower than would be expected in workers in the lowest exposure category of less than 2 ppm (SMR = 0.6, 95% CI = 0.4 to 0.7). Similar conclusions may be drawn from the leukemia findings.


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Table 1. Estimated standardized mortality ratios (SMRs) for selected lymphohematopoietic cancers by formaldehyde peak exposure*

 
Additionally, we point out that the assignment of peak exposure was based primarily on professional judgment, not on actual measurements. Such an assignment makes this exposure the weakest of the four exposure metrics used in the study by Hauptmann et al. (1) relative to supporting data, and this exposure is typically the most difficult exposure metric to estimate in the absence of detailed measurements.

Hauptmann et al. (1) briefly discuss the biologic evidence relevant to their hypothesis of formaldehyde-induced lymphohematopoietic cancer, but they conclude that the evidence is inconsistent. However, this conclusion is in conflict with substantial experimental data showing that, under controlled exposures, there is no increase in the concentration of formaldehyde in the blood of humans (2 ppm), monkeys (6 ppm), or rats (15 ppm) (2,3) and that formaldehyde does not appear to induce cancer via inhalation at sites other than the respiratory tract (4). These results strongly suggest that inhaled formaldehyde is rapidly metabolized in the respiratory tract, does not reach the bone marrow, and is therefore unlikely to induce distant-site toxicity including leukemia.

Finally, discrepancies in the data from available industrial studies suggest that the findings of Hauptmann et al. (1) may be due to chance, some uncontrolled confounding exposure, or an inappropriate comparison group. For example, a large study of workers exposed to formaldehyde in the U.K. (5) reports no increased risk for leukemia in the entire study cohort (SMR = 0.9, 95% CI = 0.6 to 1.3) or among workers with the highest formaldehyde exposures (SMR = 0.7, 95% CI = 0.3 to 1.4).

Thus, we believe that the findings of Hauptmann et al. (1) need to be critically assessed in light of external comparisons, existing biologic evidence, the findings of other studies, and a more complete understanding of the exposure metrics and classification parameters used. Until these issues are meaningfully addressed, questions will continue to be raised about the overall significance of the findings reported.

NOTES

M. Casanova and H. d'A. Heck have served as consultants to the Formaldehyde Epidemiology, Toxicology, and Environmental Group. P. Cole currently conducts research sponsored by the Formaldehyde Council. R. Leonard is currently employed by DuPont Haskell Laboratory, a business unit of E. I. DuPont de Nemours and Co., which produces and uses formaldehyde. R. Lewis is currently employed by Solutia Inc., which produces and uses formaldehyde. G. M. Marsh has received funding from Cytec Industries for research relating to nasopharyngeal carcinoma and formaldehyde but not for lymphohematopoietic malignancies and formaldehyde. M. G. Ott is employed by BASF Corp., a user of formaldehyde in the United States, and holds stock in BASF AG, a manufacturer and user of formaldehyde outside the United States.

REFERENCES

1 Hauptmann M, Lubin JH, Stewart PA, Hayes RB, Blair, A. Mortality from lymphohematopoietic malignancies among workers employed in formaldehyde industries. J Natl Cancer Inst 2003;95:1615–23.[Abstract/Free Full Text]

2 Heck H d'A, Casanova-Schmitz M, Dodd PB, Schachter EN, Witek TJ, Tosun T. Formaldehyde (CH2O) concentrations in the blood of humans and Fischer-344 rats exposed to CH2O under controlled conditions. Am Ind Hyg Assoc J 1985;46:1–3.[ISI][Medline]

3 Casanova M, Heck H d'A, Everitt JI, Harrington WW Jr, Popp JA. Formaldehyde concentrations in the blood of Rhesus monkeys after inhalation exposure. Food Chem Toxicol 1988;26:715–6.[CrossRef][ISI][Medline]

4 Wood dust and formaldehyde. International Agency for Research on Cancer (IARC) Monograph on the Evaluation of Carcinogenic Risks to Humans. Vol 62. 1995. p. 282–94.

5 Coggon D, Harris EC, Poole J, Palmer KT. Extended follow-up of a cohort of British chemical workers exposed to formaldehyde. J Natl Cancer Inst 2003;95:1608–15.[Abstract/Free Full Text]



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