A review and meta-analysis of formaldehyde exposure and leukemia

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Abstract

Most reviews on the carcinogenicity of formaldehyde have focused on cancers of the respiratory tract because these cancer sites were thought to be most biologically plausible. However, two recent updated large industrial studies have found positive associations between some measures of formaldehyde exposure and increased leukemia, although another recent update of a large study did not find any association. We examine 18 epidemiology studies of workers exposed to formaldehyde where leukemia rates were reported. We summarize the findings across studies by using meta-analytic techniques to calculate the meta-relative risk values (mRR), confidence intervals, and heterogeneity of the risk estimates for several study characteristics. We also determine if publication or reporting biases may be affecting the estimates. We found a small increase in rate of leukemia overall among embalmers (mRR=1.6, 95%CI 1.2–6.0), and pathologists/anatomists (mRR=1.4, 95%CI 1.0–1.9). Industrial workers, who have been reported to have the highest formaldehyde exposures, had a mRR of 0.9 (95%CI 0.8–1.0). There was increased risk with increasing exposure in two large industrial studies, although the increased risk is one of these studies was not seen when an external comparison group is used. Also, another large industrial study with more highly exposure workers found decreased risk of leukemia among the highest exposed group. The long latency for leukemia deaths observed in the two industrial studies that reported increased risk was not consistent with a chemical carcinogen such as benzene. We found limited evidence of publication or reporting bias. On balance, these data do not provide consistent support for a relationship between formaldehyde exposure and leukemia risk.

Introduction

Formaldehyde is currently classified as a probable human carcinogen based on animal studies with neoplastic lesions at the point of contact, the nasal cavity, and limited evidence of human respiratory tract carcinogenicity (IARC, 1995). Increased leukemia rates have been observed in some studies of anatomists, pathologist, and embalmers who often have formaldehyde exposure, but industrial workers have not consistently reported increased leukemia rates (Blair et al., 1990). However, two recent updated large industrial studies have found a positive association between some measures of formaldehyde exposure and increased leukemia rates (Hauptmann et al., 2003; Pinkerton et al., 2004), although another recent update of a large study did not find any association (Coggon et al., 2003). Increased leukemia rates among workers with formaldehyde exposure deserve further examination because of these new findings. Since many epidemiology studies have examined cancer rates among workers with exposure to formaldehyde, there may be sufficient information to determine if there is a consistent relationship between leukemia and formaldehyde exposure across worker studies. Several authors have reviewed these worker studies focusing on cancers of the respiratory tract (Blair et al., 1990; Collins et al., 1997; IARC, 1995; Liteplo and Meek, 2003; McLaughlin, 1994; Nelson et al., 1986; Partanen, 1993), but only the review of Blair et al. (Blair et al., 1990) formally examined leukemia rates. Because no review on leukemia rates has been published since new information from the three large study updates, we re-examined the studies of workers exposed to formaldehyde where leukemia rates were reported and use meta-analytic techniques to summarize the findings. We also examine exposure-response and the induction latency periods in these studies to further evaluate the findings of the meta-analysis.

Section snippets

Methods and materials

We performed a search of MEDLINE and Toxline using the keywords formaldehyde and cancer from January 1, 1975, the year of the first published formaldehyde worker study, to December 1, 2003. We also included an update of a study which was in press (Pinkerton et al., 2004). We used meta-analytic techniques to evaluate the studies on leukemia examining the heterogeneity of results across studies.

A description of 47 cancer studies published before 1995 is given in a previous review (Collins et al.,

Results

Table 1 provides selected details of the studies used in the analysis. The studies were published from 1975 to 2003. The studies include a wide range of potential formaldehyde exposure including tissue preservation (embalmers, pathologists, and anatomists), garment making, formaldehyde monomer production, core making in foundries, and other industrial applications such as plastic resins production.

Fig. 1 presents the relative risks and confidence intervals for leukemia for each study by date of

Discussion

The possible connection between formaldehyde exposure and leukemia rates has not been previously evaluated across studies using a formal meta-analysis approach although the study of Blair et al. did sum observed and expected leukemias to provide a crude estimate of risk (Blair et al., 1990). We examined 18 studies that reported leukemia rates among workers exposed to formaldehyde using a formal meta-analysis. We also examined exposure-response and time from first exposure for the studies where

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