CORRESPONDENCE

RESPONSE: Re: Mortality From Lymphohematopoietic Malignancies Among Workers in Formaldehyde Industries

Michael Hauptmann, Jay H. Lubin, Patricia A. Stewart, Richard B. Hayes, Aaron Blair

Correspondence to: Dr. Michael Hauptmann, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Blvd., EPS/8050, Bethesda, MD 20892-7244 (e-mail:hauptmann{at}nih.gov)

We agree with Casanova et al. that our study (1) does not provide conclusive evidence of a causal association between formaldehyde exposure and leukemia. However, it is difficult to conceive how our findings of an increasing risk of lymphohematopoietic malignancies, especially leukemia, with increasing average intensity and peak levels of exposure to formaldehyde could be explained solely by bias due to imprecision of exposure metrics or uncontrolled confounding, in the absence of a causal association.

The availability of the peak exposure metric is a unique feature of our study, and peak exposure is the metric that best characterizes exposure patterns similar to those experienced by pathologists and embalmers (2), for whom increased leukemia mortality has been observed in several studies (35). Estimates of peak exposure were based on the judgment of experts using information on job titles and tasks in combination with measurements of formaldehyde concentrations at selected workplaces. Uncertainties in estimating levels of peak exposure are unlikely to have induced the observed exposure–response gradient because the assessment was done before determining vital status and cause of death and was therefore unlikely to be differential with respect to disease outcome. We also observed increasing risks for average exposure intensity and duration of exposure, although not for cumulative exposure.

Confounding from unobserved factors is always a possibility in observational studies. Benzene is the only established risk factor for leukemia that could confound our analysis at a level sufficient to explain our results. However, after we excluded all 586 workers (2% of the cohort) with potential exposure to benzene from the analysis, we still observed an association between levels of peak exposure and leukemia.

We disagree with Casanova et al. that external comparisons are the method of choice for an exposure–response evaluation when there is an adequate reference group within the study population. Other workers are the best comparison group because of the healthy worker bias associated with standardized mortality ratios (SMRs). Even though the overall reduced SMR for leukemia is interesting, the patterns of increasing risk with increasing measures of exposure, as seen for both relative risks and SMRs, are the most important element in support of an exposure–response relationship.

Biologic explanations for formaldehyde effects beyond the upper respiratory tract are uncertain. However, there is evidence that genotoxic effects of inhaled formaldehyde can be detected in vivo in the bone marrow of rats and in human peripheral lymphocytes [cited in (1)].

We agree that our findings could be due to chance. However, chance could also explain the failure to see an association between formaldehyde exposure and leukemia mortality in a British cohort study (6) that included approximately half as many leukemia deaths as in our study. Increased mortality from leukemia was observed among textile workers (7), pathologists (3), and embalmers (4,5) exposed to formaldehyde. Many questions remain about possible links between formaldehyde exposure and risk of lymphohematopoietic malignancies, and we support further epidemiologic, toxicologic, and mechanistic research.

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 Stewart PA, Herrick RF, Feigley CE, Utterback DF, Hornung R, Mahar H, et al. Study design for assessing exposures of embalmers for a case-control study. Part I. Monitoring results. Appl Occup Environ Hyg 1992;7:532–40.

3 Harrington JM, Shannon HS. Mortality study of pathologists and medical laboratory technicians. Br Med J 1975;4:329–32.[Medline]

4 Walrath J, Fraumeni JF Jr. Cancer and other causes of death among embalmers. Cancer Res 1984;44:4638–41.[Abstract]

5 Hayes RB, Blair A, Stewart PA, Herrick RF, Mahar H. Mortality of U.S. embalmers and funeral directors. Am J Ind Med 1990;18:641–52.[ISI][Medline]

6 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]

7 Pinkerton LE, Hein MJ, Stayner LT. Mortality among a cohort of garment workers exposed to formaldehyde: an update. Occup Environ Med 2004;61:193–200.[Abstract/Free Full Text]



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