Using mechanistic information to support evidence integration and synthesis: a case study with inhaled formaldehyde and leukemia

Abstract

Formaldehyde is one of the most comprehensively studied chemicals, with over 30 years of research focused on understanding the development of cancer following inhalation. The causal conclusions regarding the potential for leukemia are largely based on the epidemiological literature, with little consideration of cancer bioassays, dosimetry studies, and mechanistic research, which challenge the biological plausibility of the disease. Recent reanalyzes of the epidemiological literature have also raised significant questions related to the purported associations between formaldehyde and leukemia. Because of this, considerable scientific debate and uncertainty remain on whether there is a causal association between formaldehyde inhalation exposure and leukemia. Further complexity in evaluating this association is related to the endogenous production of formaldehyde. Multiple modes of action (MOA) have been postulated for the development of leukemia following formaldehyde inhalation that includes unsupported hypotheses of direct or indirect toxicity to the target cell population. Herein, the available evidence relevant to evaluating the postulated MOAs for leukemia following formaldehyde inhalation exposure is organized in the IPCS MOA Framework. The integration of all the available evidence clearly highlights the limited amount of data that support any of the postulated MOAs and demonstrates a significant amount of research supporting the null hypothesis that there is no causal association between formaldehyde inhalation exposure and leukemia. These analyses result in a lack of confidence in any of the postulated MOAs, increasing confidence in the conclusion that there is a lack of biological plausibility for a causal association between formaldehyde inhalation exposure and leukemia.

Electrochemical and Optical Sensors for the Detection of Chemical Carcinogens Causing Leukemia

“…Formaldehyde enters the body mainly during breathing and it is absorbed in the upper and lower respiratory tract, where it is rapidly metabolized, thanks to which its concentration in the blood is relatively constant [ 34 , 39 , 45 , 58 ]. A small amount of formaldehyde penetrates the body through the skin and is ingested with food and drink [ 41 , 59 ].…”

“…One study showed that exposure to formaldehyde increases the risk of chromosomal aberrations occurring in the course of AML (chromosome 7 monosomy and chromosome 8 trisomy); however, the methodology of the study is now questioned and the need to repeat it is indicated [ 62 , 63 , 64 , 65 , 66 ]. The IARC classified formaldehyde as a human carcinogen (group 1), capable of inducing nasopharyngeal cancer (2004) and leukemia (2012), especially AML [ 8 , 39 , 45 , 47 , 58 ]. Despite the toxic effect of formaldehyde on cells, the mechanism by which it can induce leukemia is unclear [ 39 , 58 ].…”

“…The IARC classified formaldehyde as a human carcinogen (group 1), capable of inducing nasopharyngeal cancer (2004) and leukemia (2012), especially AML [ 8 , 39 , 45 , 47 , 58 ]. Despite the toxic effect of formaldehyde on cells, the mechanism by which it can induce leukemia is unclear [ 39 , 58 ]. Potential mechanisms have been proposed in which formaldehyde may contribute to the development of leukemia: direct damage to bone marrow stem cells, damage to hematopoietic stem cells circulating in the blood or present in the nasal passages, which are then transported with the blood to the bone marrow and initiate the development of cancer [ 39 , 62 , 66 ].…”

A Review of Stable Isotope Labeling and Mass Spectrometry Methods to Distinguish Exogenous from Endogenous DNA Adducts and Improve Dose–Response Assessments

“…56,58,144−147 It remains highly debatable whether FA causes nasopharyngeal cancer and leukemia in humans. 148,149 FA is a highly reactive chemical, and its DNA-damaging ability is well documented. 49,55,57,58,79,92,145,146 FA can directly target DNA to form diverse DNA lesions, including DNA monoadducts, DNA−DNA cross-links and DNA−protein cross-links (DPC), as illustrated in Figure 3.…”

“…FA, one of the top 20 highest volume production industrial chemicals, induces nasal tumors in rats at high doses (6 ppm and above) and has been classified as a Group 1 Human Carcinogen by International Agency for Research on Cancer (IARC), whereas European Chemical Agency (ECHA) classifies FA as a Group 1b carcinogen, solely based on its potential to cause nasal tumors. ,,− It remains highly debatable whether FA causes nasopharyngeal cancer and leukemia in humans. , FA is a highly reactive chemical, and its DNA-damaging ability is well documented. ,,,,,,, FA can directly target DNA to form diverse DNA lesions, including DNA monoadducts, DNA–DNA cross-links and DNA–protein cross-links (DPC), as illustrated in Figure .…”