Review
Formaldehyde exposure and leukemia: A new meta-analysis and potential mechanisms

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Abstract

Formaldehyde is an economically important chemical, to which more than 2 million U.S. workers are occupationally exposed. Substantially more people are exposed to formaldehyde environmentally, as it is generated by automobile engines, is a component of tobacco smoke and is released from household products, including furniture, particleboard, plywood, and carpeting. The International Agency for Research on Cancer (IARC) recently classified formaldehyde as a human carcinogen that causes nasopharyngeal cancer and also concluded that there is “strong but not sufficient evidence for a causal association between leukemia and occupational exposure to formaldehyde”. Here, we review the epidemiological studies published to date on formaldehyde-exposed workers and professionals in relation to lymphohematopoietic malignances. In a new meta-analysis of these studies, focusing on occupations known to have high formaldehyde exposure, we show that summary relative risks (RRs) were elevated in 15 studies of leukemia (RR = 1.54; confidence interval (CI), 1.18–2.00) with the highest relative risks seen in the six studies of myeloid leukemia (RR = 1.90; 95% CI, 1.31–2.76). The biological plausibility of this observed association is discussed and potential mechanisms proposed. We hypothesize that formaldehyde may act on bone marrow directly or, alternatively, may cause leukemia by damaging the hematopoietic stem or early progenitor cells that are located in the circulating blood or nasal passages, which then travel to the bone marrow and become leukemic stem cells. To test these hypotheses, we recommend that future studies apply biomarkers validated for other chemical leukemogens to the study of formaldehyde.

Section snippets

History and chemistry of formaldehyde

Formaldehyde is the most simple yet most reactive of all aldehydes, with the chemical formula CH2O [1], [2]. It exists as a colorless gas at room temperature and has a strong pungent smell. Aleksandr Butlerov synthesized the chemical in 1859, but it was August Wilhelm von Hofmann who identified it as the product formed from passing methanol and air over a heated platinum spiral in 1867. This method is still the basis for the industrial production of formaldehyde today, in which methanol is

Formaldehyde is classified as a human carcinogen

Formaldehyde was long considered as a probable human carcinogen (Group 2A chemical) based on experimental animal studies and limited evidence of human carcinogenicity. However, the International Agency for Research on Cancer (IARC) reclassified formaldehyde as a human carcinogen (Group 1) in June 2004 based on “sufficient epidemiological evidence that formaldehyde causes nasopharyngeal cancer in humans”. The sufficient evidence comes from six major cohort studies of industrial workers and seven

Summary of previous meta-analyses and approach to the current review

Previous meta-analyses of leukemia and formaldehyde exposure have shown mixed results [91], [110], [111]. Blair et al. [110] first reported a summary relative risk (RR) of 1.6 for studies of professional workers with formaldehyde exposures and 1.1 for studies of industrial formaldehyde exposures. In a subsequent meta-analysis involving more recent studies, Collins and Lineker [111] reported a summary RR of 1.1 (95% CI, 1.0–1.2) for 18 studies of formaldehyde exposure or associated job titles,

Formaldehyde-induced hematotoxicity and genotoxicity

Most chemically induced human leukemias are acute myeloid leukemia (AML) and precursor myelodysplastic syndromes (MDS). Leukemia arises through damage to early stem or progenitor cells in the bone marrow (detailed in next section). Such damage to the bone marrow often manifests itself as hematotoxicity and/or genotoxicity, both of which occur following exposure to chemicals that cause leukemia. Established chemical leukemogens, such as chemotherapeutic drugs (alkylating agents and topoisomerase

Potential mechanisms of formaldehyde-induced leukemia

Leukemias and related disorders originate in pluripotent precursor cells located in the bone marrow that normally give rise to all blood cells [189], [190]. Disruptions of the normal hierarchy of maturation result in hematological disorders characterized by either excesses or deficiencies of mature effector cells [191], [192]. The disorders of myeloid origin include acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative disorders such as chronic myeloid leukemia

Conclusions and future directions

In this review we have performed a comparative global survey of formaldehyde occupational and environmental exposure limits. We concluded that: (1) the U.S. OEL (0.75 ppm, 8h TWA, OSHA PEL) has remained at the same high level since 1992, in comparison to other countries who have lowered their OELs; (2) the U.S. has no regulation for non-occupational indoor formaldehyde exposure limits, while other developed and developing nations have established such standards, according to the recommendations

Conflict of interest statement

None.

Acknowledgements

We are grateful to Dr. Cliona McHale, Jed Guevara, and Aisha Qamar for assistance in preparing the manuscript. Dr. Xiaojiang Tang and Anh Duong compiled the information regarding formaldehyde exposure limits and levels. We truly appreciate valuable discussions and insightful comments provided by Profs. Stephen Rappaport and Kirk Smith of UC Berkeley, and Dr. Martha Sandy of OEHHA, California EPA.

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