Sensory irritation and use of the best available science in setting exposure limits: Issues raised by a scientific panel review of formaldehyde human research studies.

As a high production volume chemical with recognized sensory irritation and widespread exposure, the human health risk potential of formaldehyde has been reviewed by many international regulatory agencies and scientific advisory bodies. A scientific panel, the Human Studies Review Board, under the auspices of the EPA's Toxic Substances Control Act (TSCA) program recently reviewed the sensory irritation studies included in the 2022 Draft Integrated Risk Information System (IRIS) Formaldehyde Hazard Assessment in the context of their use in a weight of evidence evaluation of acute inhalation health effects. This panel issued a series of recommendations on the use of these studies for the purposes of calculating exposure limits (e.g., study design preferences; uncertainty adjustment). Considering that these recommendations might reflect topic areas with varying degrees of scientific consensus, this commentary reflects on commonalities and distinctions amongst international formaldehyde exposure limits based on sensory irritation. Notably, each review panel charged with an assessment of the science recommended that no adjustment was needed to account for either exposure duration or human variability. These areas of scientific consensus should be considered as the best available science for the purposes of setting exposure limits in the anticipated TSCA Risk Evaluation on formaldehyde.

Central and peripheral mechanism of MOTS-c attenuates pain hypersensitivity in a mice model of inflammatory pain.

BACKGROUND: Inflammatory pain is caused by damaged tissue or noxious stimuli, accompanied by the release of inflammatory mediators that often leads to severe hyperalgesia and allodynia with limited therapy options. Recently, a novel mitochondrial-derived peptide (named MOTS-c) was reported to regulate obesity, metabolic homeostasis and inflammatory response. The aim of this study was to investigate the effects of MOTS-c and its related regulatory mechanisms involved in inflammatory pain. METHODS: Male Kunming mice (8-10 weeks-old) were intraplantar injected with formalin, capsaicin, λ-Carrageenan and complete Freund adjuvant (CFA) to establish acute and chronic inflammatory pain. The effects of MOTS-c on the above inflammatory pain mice and its underlying mechanisms were examined by behavioral tests, quantitative polymerase chain reaction (qPCR), western blotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry (IHC) and immunofluorescence (IF). RESULTS: Behavioral experiments investigated the potential beneficial effects of MOTS-c on multiple acute and chronic inflammatory pain in mice. The results showed that MOTS-c treatment produced potent anti-allodynic effects in formalin-induced acute inflammatory pain, capsaicin-induced nocifensive behaviors and λ-Carrageenan/CFA-induced chronic inflammatory pain model. Further mechanistic studies revealed that central MOTS-c treatment significantly ameliorated CFA-evoked the release of inflammatory factors and activation of glial cells and neurons in the spinal dorsal horn. Moreover, peripheral MOTS-c treatment reduced CFA-evoked inflammatory responses in the surface structure of hindpaw skin, accompanied by inhibiting excitation of peripheral calcitonin gene-related peptide (CGRP) and P2X3 nociceptive neurons. CONCLUSIONS: The present study indicates that MOTS-c may serve as a promising therapeutic target for inflammatory pain.

Formaldehyde aggravates airway inflammation through induction of glycolysis in an experimental model of asthma exacerbated by lipopolysaccharide.

Formaldehyde (FA) exposure has been reported to induce or aggravate allergic asthma. Infection is also a potential risk factor for the onset and aggravation of asthma. However, no study has addressed the effects of FA exposure on asthmatic patients with respiratory infection. FA is ubiquitous in environment and respiratory infections are common in clinics. Therefore, it is necessary to explore whether FA exposure leads to the further worsening of symptoms in asthma patients with existing respiratory infection. In the present study, ovalbumin (OVA) was used to establish the murine asthma model. Lipopolysaccharide (LPS) was intratracheal administrated to mimic asthma with respiratory infection. The mice were exposed to 0.5 mg/m3 FA. FA exposure did not induce a significant aggravation on OVA induced allergic asthma. However, the lung function of specific airway resistance (sRaw), histological changes and cytokines production were greatly aggravated by FA exposure in OVA/LPS induced murine asthma model. Monocyte-derived macrophages (MDMs) were isolated from asthmatic patients. Exposure of MDMs to FA and LPS resulted in increased TNF-α, IL-6, IL-1ß, and nitric oxide (NO) production. Lactate produciton and lactate dehydrogenase A (LDHA) expression were found to be upregulated by FA in OVA/LPS induced asthmatic mice and LPS stimulated MDMs. Furthermore, glycolysis inhibitor 2-Deoxy-d-glucose attenuated FA and LPS induced TNF-α, IL-6, IL-1ß, and NO production. We conclude that FA exposure can lead to the aggravation of allergic asthma with infection through induction of glycolysis. This study could offer some new insight into how FA promotes asthma development.

Role and mechanism of miR-871-3p/Megf8 in regulating formaldehyde-induced cardiomyocyte inflammation and congenital heart disease.

OBJECTIVE AND DESIGN: We aimed to investigate the molecular mechanism underlying formaldehyde (FA)-induced congenital heart disease (CHD) using in vitro and in vivo models. MATERIALS AND SUBJECTS: Neonatal rat heart tissues and H9C2 cells were used for in vitro studies, while FA-exposed new-born rats were used for in vivo studies. TREATMENT: H9C2 cells were exposed to FA concentrations of 0, 50, 100 and 150 µM/mL for 24 h. METHODS: Whole transcriptome gene sequencing identified differentially expressed miRNAs in neonatal rat heart tissues, while Real-time quantitative PCR (RT-qPCR) assessed miR-871-3p and Megf8 expression. RNA pull-down and dual-luciferase reporter assays determined miR-871-3p and Megf8 relationships. Inflammatory cytokine expression was assessed by western blotting. A FA-induced CHD model was used to validate miR-871-3p regulatory effects in vivo. RESULTS: We identified 89 differentially expressed miRNAs, with 28 up-regulated and 61 down-regulated (fold change ≥ 2.0, P < 0.05). Inflammation (interleukin) and signalling pathways were found to control FA-induced cardiac dysplasia. miR-871-3p was upregulated in FA-exposed heart tissues, modulated inflammation, and directly targeted Megf8. In vivo experiments showed miR-871-3p knockdown inhibited FA-induced inflammation and CHD. CONCLUSION: We demonstrated miR-871-3p's role in FA-induced CHD by targeting Megf8, providing potential targets for CHD intervention and improved diagnosis and treatment strategies.

Influence of formaldehyde exposure on the molecules of the NO/cGMP-cAMP signaling pathway in different brain regions of Balb/c mice.

This toxicology study was conducted to assess the impact of formaldehyde, a common air pollutant found in Chinese gymnasiums, on the brain function of athletes. In this research, a total of 24 Balb/c male mice of SPF-grade were divided into four groups, each consisting of six mice. The mice were exposed to formaldehyde at different concentrations, including 0 mg/m3, 0.5 mg/m3, 3.0 mg/m3, and 3.0 mg/m3 in combination with an injection of L-NMMA (NG-monomethyl-L-arginine), which is a nitric oxide synthase antagonist. Following a one-week test period (8 h per day, over 7 days), measurements of biomarkers related to the nitric oxide (NO)/cGMP-cAMP signaling pathway were carried out on the experimental animals post-treatment. The study found that: (1) Exposure to formaldehyde can lead to brain cell apoptosis and neurotoxicity; (2) Additionally, formaldehyde exposure was found to alter the biomarkers of the NO/cGMP-cAMP signaling pathway, with some changes being statistically significant (p < 0.05 or p < 0.01); (3) The use of L-NMMA, an antagonist of the NO/cGMP-cAMP signaling pathway, was found to prevent these biomarker changes and had a protective effect on brain cells. The study suggests that the negative impact of formaldehyde on the brain function of mice is linked to the regulation of the NO/cGMP-cAMP signaling pathway.

Aldehyde dehydrogenase 2 deficiency reinforces formaldehyde-potentiated pro-inflammatory responses and glycolysis in macrophages.

Aldehyde dehydrogenase 2 (ALDH2) deficiency caused by   genetic variant is present in more than 560 million people of East Asian descent, which can be identified by apparent facial flushing from acetaldehyde accumulation after consuming alcohol. Recent findings indicated that ALDH2 also played a critical role in detoxification of formaldehyde (FA). Our previous studies showed that FA could enhance macrophagic inflammatory responses through the induction of HIF-1α-dependent glycolysis. In the present study, pro-inflammatory responses and glycolysis promoted by 0.5 mg/m3 FA were found in mice with Aldh2 gene knockout, which was confirmed in the primary macrophages isolated from Aldh2 gene knockout mice treated with 50 µM FA. FA at 50 and 100 µM also induced stronger dose-dependent increases of pro-inflammatory responses and glycolysis in RAW264.7 murine macrophages with knock-down of ALDH2, and the enhanced effects induced by 50 µM FA was alleviated by inhibition of HIF-1α in RAW264.7 macrophages with ALDH2 knock-down. Collectively, these results clearly demonstrated that ALDH2 deficiency reinforced pro-inflammatory responses and glycolysis in macrophages potentiated by environmentally relevant concentration of FA, which may increase the susceptibility to inflammation and immunotoxicity induced by environmental FA exposure.

K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.

Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and they accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA-protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA (mRNA) are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-between-RING (RBR) E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and they suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.

Antinociceptive effect of intermittent fasting via the orexin pathway on formalin-induced acute pain in mice.

It has been suggested that stress responses induced by fasting have analgesic effects on nociception by elevating the levels of stress-related hormones, while there is limited understanding of pain control mechanisms. Here, we investigated whether acute or intermittent fasting alleviates formalin-induced pain in mice and whether spinal orexin A (OXA) plays a role in this process. 6, 12, or 24 h acute fasting (AF) and 12 or 24 h intermittent fasting (IF) decreased the second phase of pain after intraplantar formalin administration. There was no difference in walking time in the rota-rod test and distance traveld in the open field test in all groups. Plasma corticosterone level and immobility time in the forced swim test were increased after 12 h AF, but not after 12 h IF. 12 h AF and IF increased not only the activation of OXA neurons in the lateral hypothalamus but also the expression of OXA in the lateral hypothalamus and spinal cord. Blockade of spinal orexin 1 receptor with SB334867 restored formalin-induced pain and spinal c-Fos immunoreactivity that were decreased after 12 h IF. These results suggest that 12 h IF produces antinociceptive effects on formalin-induced pain not by corticosterone elevation but by OXA-mediated pathway.

N-acetylcysteine modulates redox imbalance and inflammation in macrophages and mice exposed to formaldehyde.

This study aimed to evaluate the protective role of N-acetylcysteine (NAC) in cells and mice exposed to formaldehyde. For the in vitro study, J774A.1 macrophages cells were incubated for 8, 16 and 24 h with formaldehyde or NAC to assess cell viability and reactive oxygen species (ROS). In the in vivo study, C57BL/6 mice (n = 48) were divided into 6 groups: control (CG), vehicle (VG) that received saline by orogastric gavage, a group exposed to formaldehyde 1% (FG) and formaldehyde exposed groups that received NAC at doses of 100, 150 and 200 mg/Kg (FN100, FN150 and FN200) for a period of 5 days. In vitro, formaldehyde promoted a decrease in cell viability and increased ROS, while NAC reduced formaldehyde-induced ROS production. Animals exposed to formaldehyde presented higher leukocyte counts in the blood and in the bronchoalveolar lavage fluid, and promoted secretion of inflammatory markers IL-6, IL-15, and IL-10. The exposure to formaldehyde also promoted redox imbalance and oxidative damage characterized by increased activities of superoxide dismutase, catalase, decreased GSH/GSSG ratio, as well as it increased levels of protein carbonyls and lipid peroxidation. NAC administration after formaldehyde exposure attenuated oxidative stress markers, secretion of inflammatory mediators and lung inflammation. In conclusion, both in in vitro and in vivo models, NAC administration exerted protective effects, which modulated the inflammatory response and redox imbalance, thus preventing the development airway injury induced by formaldehyde exposure.

Formaldehyde regulates S-adenosylmethionine biosynthesis and one-carbon metabolism.

One-carbon metabolism is an essential branch of cellular metabolism that intersects with epigenetic regulation. In this work, we show how formaldehyde (FA), a one-carbon unit derived from both endogenous sources and environmental exposure, regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells. FA reacts with privileged, hyperreactive cysteine sites in the proteome, including Cys120 in S-adenosylmethionine synthase isoform type-1 (MAT1A). FA exposure inhibited MAT1A activity and decreased SAM production with MAT-isoform specificity. A genetic mouse model of chronic FA overload showed a decrease n SAM and in methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a and related genes function as compensatory mechanisms for FA-dependent SAM depletion, revealing a biochemical feedback cycle between FA and SAM one-carbon units.

Margin of exposure to free formaldehyde in personal care products containing formaldehyde-donor preservatives: Evidence for consumer safety.

Formaldehyde has been classified as carcinogenic to humans by International Agency for Research on Cancer and found in personal care (PC) products containing formaldehyde-donor (FD) preservatives. However, the cancer risk associated with the use of FD-containing PC products has not been well established. Our study provides the quantitative cancer risk assessment of formaldehyde in FD-containing PC products. The carbon-13 nuclear magnetic resonance (13C-NMR) spectroscopy was used in this risk assessment to provide reliable exposure information to formaldehyde in PC products and aqueous solutions containing sodium hydroxymethylglycinate. The risk assessment was conducted using the margin of exposure (MOE) approach with benchmark doses (BMDs) for 10% effect. For hemolymphoreticular neoplasias in male rats, a BMD of 28.03 mg/kg/day and a BMD lower confidence limit (BMDL) of 2.52 mg/kg/day were calculated from available long-term animal experiments. The worst-case consumer exposure to formaldehyde from FD-containing PC products was 0.007 µg/kg/day. Comparing the consumer exposure with BMDL, the resulting MOE was 360,000 for the worst-case scenario. The consumer exposure to formaldehyde (0.007 µg/kg/day) from using FD-containing PC products represents less than 1.0 × 10-6 % of background level endogenous formaldehyde (878-1310 mg/kg/day). The cancer risk from formaldehyde to consumers using FD-containing PC products is negligible.

Effect of pachymaran on oxidative stress and DNA damage induced by formaldehyde.

To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by formaldehyde. 40 adult Kunming male mice were randomly divided into four groups with different interventions. One week later, the contents of serum SOD, GR, MDA, DNA-protein crosslink (DPC), 8-hydroxydeoxyguanosine (8-OHDG) and DNA adduct were determined by ELISA. The results showed that there were statistically significant differences in the contents of SOD, GR and MDA among the four groups (P < 0.01). The activity of SOD and GR increased along with the increase of pachymaran dosage (SOD: rs = 0.912, P < 0.01; GR: rs = 0.857, P < 0.01), while the content of MDA showing a significant negative correlation (rs = - 0.893, P < 0.01). There were statistically significant differences in the levels of DPC, 8-OHDG and DNA adduct among the four groups (DPC and DNA adduct: P < 0.01, 8-OHDG: P < 0.05), the concentration decreased along with the increase of pachymaran dosage (DPC: rs = - 0.855, P < 0.01; 8-OHDG:rs = - 0.412, P < 0.05, DNA adduct: γs = - 0.869, P < 0.01). It can be inferred that pachymaran can inhibit oxidative stress and DNA damage induced by formaldehyde with the dose-effect relationship.

Silencing of peroxiredoxin III inhibits formaldehyde-induced oxidative damage of bone marrow cells in BALB/c mice.

BACKGROUND: Formaldehyde (FA) is associated with the occurrence of leukemia, and oxidative stress is considered to be a major reason. As an endogenous biomarker of oxidative stress, few studies focus on the relationship between peroxiredoxin III (PrxIII) and FA toxicity. Our previous research observed high expression of PrxIII occurred in the process of apoptosis of bone marrow cells (BMCs) induced by FA, however the exact mechanism is unclear. Therefore, this paper aimed to explore the possible association between FA toxicity and PrxIII gene. METHODS: We first, used a Cell Counting Kit-8 (CCK-8) to detect the viability of BMCs after they were exposed to different doses of FA (50, 100, 200 µmol/L) for different exposure time (12, 24, 48 h), then chose 24 h as an exposure time to detect the expression of PrxIII for exposing different doses of FA by Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analysis. Based on our preliminary experimental results, we chose 100 µmol/L FA as an exposure dose to expose for 24 h, and used a small interfering RNA (siRNA) to silenced PrxIII to examine the cell viability by CCK-8, reactive oxygen species (ROS) level by DCFH-DA, apoptosis by Annexin V/PI double staining and cell cycle by flow cytometry (FCM) so as to explore the possible regulatory effect of PrxIII silencing on FA-induced bone marrow toxicity. RESULTS: High expression of PrxIII occurred in the process of FA-induced oxidative stress. Silencing of PrxIII prevented FA from inducing oxidative stress, thus increasing cell viability, decreasing ROS level, rescuing G0 -G1 and G2 -M arrest, and reducing cell apoptosis. CONCLUSION: PrxIII silencing might be a potential target for alleviating FA-induced oxidative damage.

GRPR down-regulation inhibits spermatogenesis through Ca2+ mediated by PLCß/IP3R signaling pathway in long-term formaldehyde-exposed rats.

Formaldehyde (FA), which is known as an air pollutant, has been proven to induce male infertility. However, the underlying mechanism of FA-induced male infertility remains elusive. In this study, 24 male SD rats were exposed to different levels of FA (0, 0.5, 2.46, and 5 mg/m3) for eight consecutive weeks. Through HE staining and sperm smear, we observed that FA exposure resulted in spermatogenic injury and the sperm quality decreased in rats. The qRT-PCR and Western blot analysis further revealed that GRPR was down-regulated in testicular tissues of FA-exposed rats as well as primary spermatogenic cells. Meanwhile, ZDOCK uncovered an interaction between GRPR and PLCß. In addition, the CCK8, Fluo 3-AM and Flow cytometry results showed that FA exposure suppressed the expression of GRPR, PLCß and IP3R, consequently reducing the Ca2+ concentration in spermatogenic cells, inducing apoptosis and inhibiting proliferation of spermatogenic cells. Moreover, rescue experiments confirmed that promoting GRPR could improve intracellular Ca2+ concentration by upregulating PLCß and IP3R, partially reducing the apoptosis and promoting the proliferation of FA-treated spermatogenic cells. These findings revealed that GRPR participates in spermatogenesis through Ca2+ mediated by the PLCß/IP3R signaling pathway in FA-exposed rats.

Quantitative Risk Assessment of Dermal Sensitization Potential Following Use of Shampoo Products Containing the Formaldehyde Releasing Preservative DMDM Hydantoin.

Historically, formaldehyde was used as a preservative in personal care products to extend product shelf-life; however, given its skin sensitization potential it has been phased out of use and replaced with formaldehyde-releasing preservatives, such as Dimethyloldimethyl hydantoin (DMDMH). A relationship has been established between positive patch test results following exposure to DMDMH and previous sensitization to formaldehyde. Upon direct contact with the skin, formaldehyde can react with skin proteins and cause an acute inflammatory reaction, which may progress to skin sensitization following repeated exposure. This quantitative risk assessment (QRA) aimed to assess the risk of skin sensitization induction following use of shampoo products containing the maximum allowable concentrations of DMDMH in formulation (1% w/v), translating to a free formaldehyde concentration of 0.02%. To determine a margin of safety (MOS) for exposure to DMDMH from use of shampoo products, consumer exposure levels (CEL) were estimated based on typical use scenarios and then benchmarked against an acceptable exposure level (AEL). The AEL was derived using a weight of evidence approach where a range of no expected sensitization induction levels (NESILs) was utilized. The MOS values for a shampoo product containing 1% DMDMH (.02% formaldehyde) was above 1 for the typical use scenario indicating a low likelihood of skin sensitization induction among healthy individuals. Thus, it can be concluded that shampoo products containing DMDMH at or below current allowable concentrations are not expected to increase the risk of skin sensitization induction.

Inhalational exposure to formaldehyde, carcinogenic, and non-carcinogenic risk assessment: A systematic review.

Formaldehyde is one of the most widely used substances in a variety of industries, although it was classified as a human carcinogen by the International Agency for Research on Cancer (IARC). The present systematic review was conducted to retrieve studies related to occupational exposure to formaldehyde until November 2, 2022. Aims of the study were to identify workplaces exposed to formaldehyde, to investigate the formaldehyde concentrations in various occupations and to evaluate carcinogenic and non-carcinogenic risks caused by respiratory exposure to this chemical among workers. A systematic search was done in Scopus, PubMed and Web of Science databases to find the studies done in this field. In this review, studies that did not meet the criteria specified by Population, Exposure, Comparator, and Outcomes (PECO) approach were excluded. In addition, the inclusion of studies dealing with the biological monitoring of FA in the body and review studies, conference articles, books, and letters to the editors were avoided. The quality of the selected studies was also evaluated using the Joanna Briggs Institute (JBI) checklist for analytic-cross-sectional studies. Finally, 828 studies were found, and after the investigations, 35 articles were included in this study. The results revealed that the highest formaldehyde concentrations were observed in waterpipe cafes (1,620,000 µg/m3) and anatomy and pathology laboratories (4237.5 µg/m3). Carcinogenic and non-carcinogenic risk indicated the potential health effects for employees due to respiratory exposure as acceptable levels of CR = 1.00 × 10-4 and HQ = 1, respectively were reported to be exceeded in more than 71% and 28.57% of the investigated studies. Therefore, according to the confirmation of formaldehyde's adverse health effects, it is necessary to adopt targeted strategies to reduce or eliminate exposure to this compound from the occupational usage.

Hydrogen sulfide antagonizes formaldehyde-induced ferroptosis via preventing ferritinophagy by upregulation of GDF11 in HT22 cells.

Formaldehyde (FA) has neurotoxic characteristics and causes neurodegenerative disease. Our previous study demonstrated the neuroprotective effects of hydrogen sulfide (H2S) on FA-induced neurotoxicity in HT22 cells. Emerging evidence have supported that ferroptosis is involved in FA-induced neurotoxicity. To understand the mechanism of the protection of H2S against FA-induced neurotoxicity, this study explored the regulatory effect of H2S on FA-induced ferroptosis and the underlying mechanisms. The researcher found that H2S (100, 200, and 400 µM, 30 min) reverses the ferroptosis induced by FA (100 µM, 24 h) in HT22 cells (a cell line of mouse hippocampal neurons), including decreases in free iron, reactive oxygen species (ROS), 4-hydroxy-2-trans-nominal (4-HNE), and malondialdehyde (MDA) contents, as well as an increase in glutathione (GSH) content. H2S (100, 200, and 400 µM, 30 min) also inhibited ferritinaphagy in FA-exposed HT22 cells, as evidenced by the downregulation of the ferritinophagy receptor nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain-3B (LC3B) as well as the upregulation of the main iron storage protein ferritin heavy chain 1 (FTH1) and p62. H2S (100, 200, and 400 µM, 30 min) also up-regulated the expression of growth differentiation factor-11 (GDF11) in FA-exposed HT22 cells. Furthermore, knockdown of GDF11 in HT22 cells cancelled the beneficial effects of H2S in FA-induced ferroptosis and ferritinaphagy. These data indicated that the protective mechanism underlying H2S-prevented neurotoxicity of FA is involved in alleviating FA-induced ferroptosis via inhibiting ferritinaphagy by upregulation of GDF11.

Formaldehyde exacerbates asthma in mice through the potentiation of HIF-1α-mediated pro-inflammatory responses in pulmonary macrophages.

Exposure to formaldehyde (FA) has been indicated to be positively correlated with increased incidence of allergic asthma in many epidemiological and experimental studies. However, few studies have ever addressed the molecular basis of the correlation. In the present study, it was found that inhaling 2.0 mg/m3 FA for 2 weeks could exacerbate the pulmonary inflammation and mucus over-accumulation in OVA-induced murine asthmatic model. The pro-inflammatory cytokines, such as IL-1ß, TNF-α, IL-6 and IL-8, were increased in lung and serum of FA-exposed asthmatic mice. The contribution of HIF-1α signaling in FA-exacerbated allergic asthma was confirmed by bioinformatic analysis. HIF-1α and its downstream proteins, which are known as mediators of glycolysis, were found to be upregulated by 50 µM FA, and the FA-enhanced of glycolysis was reversed by inhibition of HIF-1α with PX-478 in vitro and YC-1 in vivo. Furthermore, it was confirmed that inhibition of HIF-1α signaling could restrain the macrophagic inflammatory responses and asthma exacerbation induced by FA. Collectively, these results revealed that FA could exacerbate asthma through the potentiation of HIF-1α-mediated inflammatory responses in macrophages, which also indicated the universal roles of FA-triggered macrophage metabolic and functional alterations in inflammatory or allergic diseases.

Relationship between formaldehyde exposure, respiratory irritant effects and cancers: a review of reviews.

OBJECTIVES: Formaldehyde is an organic compound used in the production of resins, paper, wood plywood, solvents and cleaning products. Formaldehyde is also present when tobacco is smoked. Formaldehyde has been defined as an irritant and is classified as a human carcinogen by the International Agency for Research on Cancer. The purpose of this study was to demonstrate the following two distinct correlations: (1) the association between formaldehyde exposure and development of irritant diseases affecting the respiratory tract, mainly asthma; and (2) the association between formaldehyde exposure and development of neoplastic diseases. STUDY DESIGN: This was an umbrella review. METHODS: A search was conducted in the three main electronic databases of scientific literature: PubMed, Scopus and Web of Science. The search included systematic reviews and meta-analyses published in the previous 10 years. Initially, titles and abstracts of retrieved articles were evaluated, then full-text assessments of selected articles took place. Data extraction and quality assessment were performed according to Assessing the Methodological Quality of Systematic Reviews (AMSTAR) score. RESULTS: A total of 630 articles were initially collected. Nine articles concerning the association between formaldehyde exposure and asthma were included in the present review, and the majority of these reported good association. In addition, 27 articles investigating the association between formaldehyde exposure and neoplastic diseases were included in the review. These studies showed that nasopharyngeal cancer and leukaemia were the most represented neoplastic diseases; however, only a weak association was reported between formaldehyde exposure and cancer. CONCLUSIONS: Although the studies included in this review did not show a strong association between exposure to formaldehyde and irritant or neoplastic diseases, the World Health Organisation recommends that levels of formaldehyde do not exceed the threshold value of 0.1 mg/m3 (0.08 ppm) for a period of 30 min. It is recommended that preventive measures, such as ventilation in workplaces with high exposure to formaldehyde and environmental monitoring of formaldehyde concentrations, are implemented.

Updating the biologically based dose-response model for the nasal carcinogenicity of inhaled formaldehyde in the F344 rat.

Chronic inhalation of formaldehyde by F344 rats causes nasal squamous cell carcinoma (SCC). This outcome is well-characterized: including dose-response and time course data for SCC, mechanistic endpoints, and nasal dosimetry. Conolly et al. (Toxicol. Sci. 75, 432-447, 2003) used these resources to develop a biologically based dose-response (BBDR) model for SCC in F344 rats. This model, scaled up to humans, has informed dose-response conclusions reached by several international regulatory agencies. However, USEPA concluded that uncertainties precluded its use for cancer risk assessment. Here, we describe an updated BBDR model that addresses uncertainties through refined dosimetry modeling, revised analysis of labeling index data, and an extended dataset where both inhaled (exogenous) and endogenous formaldehyde (exogF, endoF) form DNA adducts. Further, since Conolly et al. (ibid) was published, it has become clear that, when controls from all F344 inhalation bioassays are considered, accounting for over 4000 rats, at most one nasal SCC occurred. This low spontaneous incidence constrains possible contribution of endoF to the formation of nasal SCC via DNA reactivity. Further, since both exogF and endoF form DNA adducts, this constraint also applies to exogF. The revised BBDR model therefore drives SCC formation through the cytotoxicity of high concentration exogF. An option for direct mutagenicity associated with DNA adducts is retained to allow estimation of an upper bound on adduct mutagenicity consistent with the lack of a spontaneous SCC incidence. These updates represent an iterative refinement of the 2003 model, incorporating new data and insights to reduce identified model uncertainties.