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Abstract
Formaldehyde (FA) is a mutagenic chemical – a property mitigated in vivo by rapid detoxification and limited tissue distribution following inhalation of the free agent. Endogenously produced FA is necessary for life and required for one-carbon transfer reactions; however, FA derived from external sources (exogenous FA), which may be in the form of methanol, may increase in vivo concentrations above naturally occurring physiological levels. Both endogenous and exogenous FA produce DNA monoadducts, DNA–DNA and DNA–protein cross-links (DDX and DPX) but, when exposed to exogenously-derived free FA, DNA monoadducts, DDX, and DPX are only produced at initial sites of contact. In contrast, methanol may systemically induce DNA adducts distally. FA also induces oxidative stress/lipid peroxidation with some individuals suggesting the resulting reactive aldehydes may have the potential to induce distal site DNA damage with the resulting reactive aldehydes having the potential to induce distal site DNA damage. Chromosome changes in the form of aberrations or micronuclei in blood cells have been studied in FA-exposed animals and humans, with most of the former being negative. Human occupational studies have given mixed results for such changes in peripheral blood lymphocytes (PBLs) which circulate widely but do not reflect recent bone marrow (BM) events. Recent studies reporting changes in human BM or hematopoietic precursor cells (HPCs) either have had confounding exposures or could not distinguish in vivo from in vitro occurrences. The reported genetic changes in circulating blood cells do not provide convincing support for FA’s classification as a human leukemogen.
Notes
Acknowledgements
The authors gratefully acknowledge the extensive comments offered by 8 reviewers selected by the Editor presented anonymously to the authors. These comments were useful in revising the paper.
Declaration of interest
The conclusions of this review are those of the authors. DK is employed by Ramboll Environ, a global environmental consultancy. RJA served as in independent contractor to Ramboll Environ, and as such was compensated for his time. As such the University of Vermont has no responsibility for this paper.
This project was undertaken with funds provided to Ramboll Environ by Hexion Inc., a global manufacturer operating approximately 60 industrial facilities around the world with interest in FA and FA derivatives. Hexion participates in the American Chemistry Council Formaldehyde Panel. Although employees of Hexion Inc. and the American Chemistry Council had the opportunity to review early draft material, the analyses, opinions, and conclusions presented in this paper are exclusively those of the authors and do not necessarily represent the views of Hexion Inc. or the American Chemistry Council.
During the course of writing this review, early results were presented at the 2013 annual meeting of the Society of Risk Analysis, as well as at an US EPA-sponsored public workshop “State of the Science Workshop to Discuss Issues Relevant to Assessing the Health Hazards of Formaldehyde Inhalation” (30 April–1 May 2014), where funders and others were present. Neither RJA nor DK have appeared in legal proceedings that involve the contents of this review.
Notes
1 MAK values are set by the German Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission). A MAK value is the maximum permissible concentration of a substance as a gas, vapor or aerosol in the air at the workplace which, according to current knowledge, does not normally affect worker health or cause unreasonable nuisance even with repeated and long-term exposure, usually 8 hours a day, but assuming an average weekly working time of 40 hours.
