Formaldehyde toxicity reports from in vitro and in vivo studies: a review and updated data.

Formaldehyde (FA) is a xenobiotic air pollutant and its universal distribution causes a widespread exposure to humans. This review aimed to bring updated information concerning FA toxicity in humans and animals based on in vitro and in vivo studies from 2013 to 2019. Researches were carried out in Pubmed, Scopus, and Science Direct databases to determine the effects of FA exposure on inflammation, oxidative stress and genotoxicity in experimental studies with animals (rats and mice) and humans. Besides, in vitro studies assessing FA cytotoxicity focusing on cell viability and apoptosis in different cell line cultures were reviewed. Studies with humans gave evidence regarding significant deleterious effects on health associated to chronic FA occupational exposure. Evaluations carried out in experimental studies showed toxic effects on different organs as lung, upper respiratory tract, bone marrow and brain as well as in cells. In summary, this study demonstrates that knowing the mechanisms underlying FA toxicity is essential to understand the deleterious effects that this xenobiotic causes on biological systems.

Does oral spirulina protect the cornea from formaldehyde exposure? Application to anatomy laboratories.

In this study, the protective effect of spirulina on corneal injury after formaldehyde (FA) exposure was assessed. Thirty adult male albino rats were divided into four groups. Group I: 12 rats were divided into two subgroups: I-a (negative control) and I-b (positive control). Group II (spirulina group): six rats received spirulina via an oral gavage feeding needle at a daily dose of 400 mg/kg b.w. Group III (FA exposure group): six rats were subjected to 10% FA inhalation for 2 h per day for 2 weeks (5 days per week). Group IV (FA exposure group treated with spirulina): six rats were exposed to 10% FA as in group III, with co-administration of spirulina as in group II. After 2 weeks, all the rats were sacrificed; the corneas were dissected and processed for paraffin sections. The sections were stained with hematoxylin and eosin (H&E), Masson's trichrome (MTC), or avidin-biotin peroxidase, and examined by light microscopy. The sections of rat cornea exposed to FA (Group III) showed disorganized and compressed epithelium with erosions. Subepithelial mononuclear cell infiltration and invasion of blood vessels were also evident. Stromal collagen fibers were disorganized and widely separated. All these changes were ameliorated by administration of spirulina (Group IV). Corneal thickness was nearly normal in Group IV, statistically significantly less than in Group III. It was concluded that spirulina protects against FA-induced corneal injury in rats. Clin. Anat. 31:830-837, 2018. © 2018 Wiley Periodicals, Inc.

A comparison of engineering controls for formaldehyde exposure during grossing activities in health care anatomic pathology laboratories.

This article for the first time reports a large set of monitoring results for formaldehyde exposure during grossing activities in health care anatomic pathology laboratories, and compares the effectiveness of different local exhaust ventilation systems on the exposure. To control the confounding effects from grossing work load, sampling duration, and the sizes of specimens grossed, only 15-min short-term personal exposure samples collected during large tissue specimen grossing were used for the comparison of the effectiveness of these local exhaust systems. While we also collected long-term 8-hr time weighted average samples, these are not treated in this analysis. The systems examined were canopy receiving hoods, slot exhausts, and commercially available pre-manufactured backdraft grossing stations, both recirculating and ducted exhaust types. Out of over 2,000 personal short-term air samples, 307 samples from 163 surveys met the data selection criteria. Over a third of the data were less than the analytical laboratory limits of detection. Using the robust maximum likelihood estimation method for multiple limits of detection, the mean and geometric mean of the dataset for each type of local exhaust system were found to be less than the short-term personal exposure regulatory limit of 2 ppm. Nonparametric Wilcoxon rank-sum pairwise tests of five types of engineering controls showed a statistically significant difference among these controls, with the most effective being the manufactured backdraft grossing stations ducted to the outside, and the least effective being canopy exhaust systems and manufactured filtered recirculating grossing stations. Finally, exposure with each of the major engineering control types was rated by the American Industrial Hygiene Association exposure control rating scheme.

Use of Ozone Therapy and Thymoquinone in the Prevention of Formaldehyde Toxicity by Inhalation: An Experimental Study.

INTRODUCTION: The study determined the damage caused by formaldehyde (FA) exposure in blood and liver samples using biochemical markers. Histopathological analysis was performed using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method and measurement of CD68 cell density. To what extent the antioxidant molecules thymoquinone (TQ) and ozone (O3) reversed the damage caused by FA exposure was investigated, both when used alone and combined. METHODS: Fifty-six Sprague-Dawley male rats of eight to ten weeks of age were used in the experiment. The rats were divided into eight groups, with seven rats in each group: the untreated control group, the group treated with TQ (10 mg/kg/day), the group treated with O3 (150 µg/kg/day), the group treated with TQ+O3, the group exposed to FA (10 ppm 8 h/day), the group receiving FA+TQ, the group receiving FA+O3, and the group receiving FA+TQ+O3. Serum aspartate transaminase (AST), alanine transaminase (ALT), total antioxidant (TAS, U/mL), and total oxidant (TOS, nmol/mL) levels were analyzed. TAS and TOS levels, CD68 cell density, and apoptotic cells were determined in liver tissues. RESULTS: FA exposure caused an increase in serum AST and ALT levels of (p<0.05) experimental animals, a decrease in TAS levels in serum (p=0.03) and liver (p>0.05) and an increase in TOS levels (p>0.05), TUNEL positivity (p<0.001), and CD68 cell density (p=0.004). Administration of TQ and O3 as antioxidants significantly reversed biochemical and histopathological alterations in the serum and liver. CONCLUSION: TQ and ozone therapy suppressed oxidative stress caused by FA exposure and reversed the emerging histopathological deteriorations. Ozone therapy did not suppress the effects of TQ. Therefore, ozone therapy can be given as a supportive therapy along with the main therapeutic agents. We think TQ and ozone therapy may be useful to protect individuals exposed to FA.

A Comprehensive Literature Review on the Effects of Formaldehyde on the Upper Respiratory Tract.

Prolonged exposure to indoor air pollutants at high concentrations can have adverse health effects on the respiratory system of individuals who spend most of their time indoors. Formaldehyde (FA) is a common indoor air pollutant because of its extensive use in household products such as cleaners, floorings, and furnishings. As a chemical, FA is highly water soluble and reactive. When its airborne form is inhaled, it is mainly absorbed in the upper airways. FA has been extensively studied for its carcinogenic effects, but it can also cause inflammation in the upper airways. The objective of the current review was to assess the secondary effects of such inflammation and how it can contribute to an increased risk for upper respiratory infections, which are mostly caused by viruses. A rigorous literature review was conducted through gathering, reading, and analyzing relevant literature, including peer-reviewed articles published after 1990 and seminal literature regardless of publication date. Findings from the review provide a greater understanding of the outcomes of FA exposure, the potential accumulative damage to the upper respiratory tract, and the associated increased risk for acute infections of the upper respiratory tract. This information can help in the development and enforcement of stricter regulations for furniture and building materials for household-related products to limit exposure to indoor pollutants such as FA.

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.

Occupational Exposure to Formaldehyde and Cancer Risk Assessment in an Anatomy Laboratory.

Dissecting a human cadaver is an irreplaceable practice in general training of medical students. Cadavers in anatomy laboratories are usually preserved in formalin, an embalming fluid whose basic component is formaldehyde (FA). The aim of this study is to assess the cancer risk of employees and students that are exposed to FA based on the results of three monitoring campaigns, as well as to suggest permanent solutions to the problem of FA exposure based on the results obtained. Three sampling campaigns of formaldehyde concentration in indoor environments were conducted at five different locations at the Anatomy Department of the Faculty of Medicine with the purpose of assessing permanent employees' and medical faculty first year students' exposure to FA. Indoor air was continuously sampled during 8 h of laboratory work and analyzed in accordance with the NIOSH Method 3500. Exceeding of the 8 h time-weighted average (8 h TWA) values recommended by Occupational Safety and Health Administration (OSHA) of 0.75 ppm was recorded in 37% of the samples during the three-month monitoring campaign. Cancer risk assessment levels for permanent employees were in the range from 6.43 × 10-3 to 8.77 × 10-4, while the cancer risk assessment levels for students ranged from 8.94 × 10-7 to 1.83 × 10-6. The results of the research show that cancer risk assessment for employees is several thousand times higher than the limit recommended by the EPA (10-6) and point to the importance of reducing exposure to formaldehyde through the reconstruction of the existing ventilation system, continual monitoring, the use of formaldehyde-free products, and plastination of anatomical specimens.

A Short Critique on the Stance of the Netherlands Food and Consumer Product Safety Authority on Melamine Polymer Formaldehyde Exposures.

In February 2021, the Netherlands Food and Consumer Product Safety Authority came out with their risk assessment on formaldehyde exposure from melamine crockery with bamboo fiber to especially young children. In this short commentary, I will critique their assessment of this type of food-contact material (FCM). The main flaws are at least: (i) absence of a proper valuation of the available principal scientific literature yielding a biased risk assessment; (ii) discounting the endogenous formaldehyde formation that outweighs background exposure substantially; (iii) ad hoc positing of an unjustifiable and unfounded low background exposure levels to formaldehyde whereby risks of exposure to melamine formaldehyde is grossly exaggerated. This biased assessment has created societal unrest that is wholly uncalled for. Additionally, it has wide-ranging European consequences for the use of all melamine FCM.

Proteomic and transcriptomic changes in rat liver following oral feeding of formaldehyde.

Formaldehyde (FA), a ubiquitous volatile organic compound present in a wide range of resources, is a hazardous chemical and human carcinogen. Contamination of FA in food, especially perishable commodities like fish and meat, is a major source of exposure, although it is not recommended for use in food and food products owing to its carcinogenicity. Effects of oral feeding of FA have been studied by evaluating general health, haematology and clinical chemistry in rat. Recent studies have shown that FA exposure leads to detrimental cardiovascular effects. It regulates vascular tensions through nitric oxide-cGMP signalling pathway and ion channels in rats. Although FA is an established carcinogen, molecular studies on carcinogenic potential with dose dependency are meagre. In this context, the present study was undertaken to investigate the toxicogenomic and proteomic alterations in liver of rats fed FA through drinking water. By proteomic analysis, 621 proteins/protein-subunits showed differential abundance (proteome data available via ProteomeXchange with identifier PXD010534), whereas 536 differentially-expressed-genes were identified by transcriptome analysis (data available via Sequence Read Archive with identifier SRR7974113). Gene ontology analysis showed that binding, catalysis, signal transduction were affected in formaldehyde-fed rats. Pathway analysis revealed that formaldehyde-exposure activated PI3K-AKT pathway that leads to inhibition of caspase activity thereby assisting cells to survive against apoptosis. Decreased abundance/down-regulation of ANGPT, eNOS, STAT3 proteins/transcripts and increased abundance of EDN1 indicated decrease in angiogenesis and vasodilatation that restricted hepatic cells from becoming tumorigenic; thus, indicating FA could be less toxic and non-tumorigenic at low concentrations.

Recommendations of the working group of the Anatomische Gesellschaft on reduction of formaldehyde exposure in anatomical curricula and institutes.

The practice of human and veterinary medicine is based on the science of anatomy and dissection courses are still irreplaceable in the teaching of anatomy. Embalming is required to preserve body donors, for which process formaldehyde (FA) is the most frequently used and well characterized biocidal substance. Since January 2016, a new occupational exposure limit (OEL) for FA of 0.37mg/m3 issued by the European Committee on Hazardous Substances is obligatory since FA has been classified as a human 1B carcinogen. The anatomical institutes in the German-speaking region are called upon to consolidate efforts to reduce use of FA in anatomical curricula and body donations. As a result, the Anatomische Gesellschaft (AG) has formed a "Working Group for Reduction of Formaldehyde Exposure in Dissection Courses" tasked with discussion and recommendation of measures to reduce FA. Based on the assessment of the Working Group, the AG has issued an official opinion to the effect that, at this point in time, embalming of body donors without FA completely is not feasible. Therefore, a combination of approaches are to be used to reduce FA exposure, including technical and structural (architectural) adaptations, modification of protocols for fixation and preservation as well as organizational measures. One structural measure considered unavoidable is the integration of air supply and exhaust of individual dissecting tables into the ventilation system of the anatomy building. To embalm human body donors, intra-arterial perfusion fixation with up to 4% FA and a total fluid volume of 150mL/kg body weight will suffice. For animals where body weights and biology of bodies vary widely (i.e. special needs of fixation for ruminants, large animals as horses) perfusion fixation with up to 4% FA and a quantity of fixative solution of 10-15% of the body weight may be required. Preservation of body donors in storage (immersion) can be done with 40% ethanol or in a full bath preservation containing up to 2% FA. Corpse humidification in the dissecting room is possible with 2% phenoxyethanol, in each case without FA. In veterinary anatomy, microbiological burden is often higher and therefore might lead to a need of FA in long-time storage. Compliance with the current OEL in all institutes would appear to be feasible in combination with various organizational measures.

Formaldehyde Exposure in Indoor Air From Public Places and Its Associated Health Risks in Kunshan City, China.

This study assessed the noncarcinogenic and carcinogenic health risks associated with formaldehyde exposure for employees working in 4 categories of public places in Kunshan City in China. A total of 564 different public places, which can be divided into 4 categories (hotel and social interaction places, bathing and beauty places, cultural and entertainment places, and shopping places), and 2716 indoor air samples in those places were measured from January 1, 2010, to December 31, 2015. The average concentration of formaldehyde was 0.57 mg/m3, which is 5.7 times the acceptable concentration level (0.1 mg/m3). The noncarcinogenic risk assessment index for the 4 categories of places tested was above 1. The carcinogenic risk of formaldehyde for employees of the 4 categories of public places was 4.70 × 10-5 to 1.57 × 10-4, which was greater than the acceptable carcinogenic risk probability (1 × 10-6) from the US Environmental Protection Agency. The highest carcinogenic risk occurred in bathing and beauty places, and male employee carcinogenic risk was greater than that of females. Occupational formaldehyde exposure has serious noncarcinogenic and carcinogenic health risks for employees, and further research is needed to improve indoor air quality in the workplace environment.

Effects of formaldehyde exposure on the development of pulmonary fibrosis induced by bleomycin in mice.

Environmental and Occupational pollution has been extensively studied because of its serious implications on the human health. Formaldehyde (FA) is a pollutant widely employed in several industries and also in anatomy, pathology and histology laboratories. Studies have shown the correlation between FA exposure and development or worsening of asthma. However, the effect of FA exposure on the pulmonary fibrosis (PF) is unknown. PF is a progressive and chronic lung disease with high incidence and considerable morbidity and mortality. Few studies have shown a worsening of PF after pollutants exposure such as ozone and nitrogen dioxide. Therefore, our objective was to assess the effects of FA on the PF. Male mice C57BL6 were treated or not with bleomycin (1,5 U/kg) and exposed or not to FA inhalation (0.92 mg/m3, 1 h/day, 5 days/week during 2 weeks). Non-manipulated mice were used as control. Our data showed that FA exposure in fibrotic mice increased the number of granulocytes in the bronchoalveolar lavage followed by elevated levels of interleukin 1 beta and interleukin 17. In addition, FA exposure in fibrotic mice enhanced the gene expression of C-X-C motif chemokine ligand 1 (CXCL1) and tumor necrosis factor alpha (TNF-α) in the lung. We also showed an increase in the collagen production, while lung elastance was reduced. No differences were found in the mucus production, oedema and interstitial thickening in the lung tissue of fibrotic mice after FA exposure. In conclusion our study showed that FA exposure aggravates the lung neutrophils influx and collagen production, but did not alter the lung elastance, mucus production, oedema and interstitial tickening. This work contributes to understand the effects of pollution in the development of PF.

Indoor formaldehyde concentrations in urban China: Preliminary study of some important influencing factors.

The Huai River and Qingling Mountain divide (H-Q) divide China into north and south with respect to public policies for building construction and operation practises. China's building energy efficiency standard mandates that air exchange rates be 0.5h-1 north of the H-Q divide and 1h-1 south of the divide. China's heating policy allows space heating systems only north of the H-Q divide. Consequently, indoor temperature and humidity differ considerably between north and south. A theoretical model using indoor temperature, humidity, and air change rate was developed to predict indoor formaldehyde concentrations. Data for 39 cities were obtained from 42 studies. There was good agreement between the literature and modelling in a theoretical reference room. The United States Environmental Protection Agency (U.S.EPA) model was applied to estimate cancer risk from formaldehyde exposure indoors. The median indoor formaldehyde concentration for renovation ever from 2002 to 2015 in Chinese cities was 125µg/m3, which is higher than the WHO threshold, 100µg/m3. The median indoor formaldehyde concentrations in the north were higher than in the south (0.5 times higher for dwellings renovated within the past year and 0.2 times higher for renovation ever), driven by the much higher northern winter concentrations (40-1320%). The U.S.EPA model predicts that the lifetime formaldehyde related cancer risk for people living north of the H-Q divide is 1.2 times greater than for people living south. This can be partly explained by greater indoor exposure to formaldehyde for Chinese living north of the H-Q divide.

Evaluation of subchronic formaldehyde exposure in rats with open field test / Evaluación de la exposición al formaldehído subcrónico en ratas con prueba de campo abierto

SUMMARY: Formaldehyde (FA), which is an indispensable chemical substance in anatomy and pathology, is a very harmful substance for living things. In our study, the purpose was to investigate the changes in behavior of rats exposed to subchronic formaldehyde with open field test. We divided 24 Wistar-Albino rats into 3 groups. The first group (n=8) was identified as the control group, and normal air breathing was ensured. Low-dose FA (mean 1 ppm) was inhaled in the second group, and high-dose FA (mean 10 ppm) was inhaled in the third group. FA exposure was done for 4 hours, 12 weeks, and 5 days a week. The rats were subjected to open field test during the first week and the last week of FA exposure. We observed significant decreases in the number of vertical movements and grooming in rats in the experimental group compared to the control group in the open field test (p 0.05). As a conclusion, we can argue that FA causes changes in the behaviors of rats regardless of dose and duration.

RESUMEN: El formaldehído (FA), una sustancia química indispensable en la anatomía y patología, pero es un elemento sumamente nocivo para todos los seres vivos., El objetivo de nuestro estudio fue investigar los cambios en el comportamiento de ratas expuestas a formaldehído subcrónico con prueba de campo abierto. Utilizamos 24 ratas Wistar-Albino divididas en 3 grupos. El primer grupo (n = 8) se identificó como el grupo de control y se aseguró una respiración normal de aire. En el segundo grupo se inhalaron dosis bajas de FA (media de 1 ppm) y en el tercer grupo se inhalaron dosis altas de FA (media de 10 ppm). La exposición a FA se realizó durante 4 horas, 12 semanas y 5 días a la semana. Las ratas fueron sometidas a una prueba de campo abierto durante la primera semana y la última semana de exposición a FA. Observamos disminuciones significativas en el número de movimientos verticales y acicalamiento en ratas en el grupo experimental en comparación con el grupo control en la prueba de campo abierto (p 0,05). Como conclusión, podemos argumentar que la AF provoca cambios en el comportamiento de las ratas independientemente de la dosis y la duración.

The putative role of ovary removal and progesterone when considering the effect of formaldehyde exposure on lung inflammation induced by ovalbumin

OBJECTIVE: Formaldehyde exposure during the menstrual cycle is known to affect the course of allergic lung inflammation. Because our previous data demonstrated that formaldehyde combined with an ovariectomy reduced allergic lung inflammation, we investigated the putative role of ovary removal and progesterone treatment when considering the effect of formaldehyde on allergic lung inflammation. METHOD: Ovariectomized rats and their matched controls were exposed to formaldehyde (1%, 3 days, 90 min/day) or vehicle, and immediately after exposure, the rats were sensitized to ovalbumin by a subcutaneous route. After 1 week, the rats received a booster by the same route, and after an additional week, the rats were challenged with ovalbumin (1%) by an aerosol route. The leukocyte numbers, interleukin-10 (IL-10) release, myeloperoxidase activity, vascular permeability, ex vivo tracheal reactivity to methacholine and mast cell degranulation were determined 24 h later. RESULTS: Our results showed that previous exposure to formaldehyde in allergic rats decreased lung cell recruitment, tracheal reactivity, myeloperoxidase activity, vascular permeability and mast cell degranulation while increasing IL-10 levels. Ovariectomy only caused an additional reduction in tracheal reactivity without changing the other parameters studied. Progesterone treatment reversed the effects of formaldehyde exposure on ex vivo tracheal reactivity, cell influx into the lungs and mast cell degranulation. CONCLUSION: In conclusion, our study revealed that formaldehyde and ovariectomy downregulated allergic lung inflammation by IL-10 release and mast cell degranulation. Progesterone treatment increased eosinophil recruitment and mast cell degranulation, which in turn may be responsible for tracheal hyperreactivity and allergic lung inflammation. .

Histopathologic Changes of Rat Tracheal Mucosa Following Formaldehyde Exposure / Cambios Histopatológicos de la Mucosa Traqueal de la Rata Seguidos a la Exposición de Formaldehído

Formaldehyde is a chemical, which is used traditionally for fixing the cadaver. It is vaporized during dissection and practical studying on cadaver. Studies show that this vapor can cause some clinical symptoms such as throat, eye, skin and nasal irritation. This study was designed to determine the histopathologic changes of rat tracheal mucosa while all of the experiments were exposed to formaldehyde for 18 weeks. This study was performed on 28, 6-7 weeks postnatal albino Wistar rats. The rats were divided into 3 case groups (E1: 4h/d, 4d/w; E2: 2h/d, 4d/w; E3: 2h/d, 2d/w) and 1 control group. The tracheal specimens were sectioned and stained with H&E technique for histopathologic study. An epithelial disorganization, cilia disappearance, slight dysplastic changes and slight subepithelial lymphocytic infiltration were observed in the case of E1. Epithelial disorganization, irregular cilia and slight subepithelial infiltration were seen in E2 and E3 groups. The results of this study show that "the more exposure to formaldehyde vapor, the more intense epithelial changes".

El formaldehido es un producto químico que se usa tradicionalmente para la fijación de cadáveres. Éste se vaporiza durante la disección y los estudios prácticos en el cadáver. Investigaciones han mostrado que este vapor puede causar algunos síntomas clínicos como la irritación de garganta, ojos, piel y mucosa nasal. Este estudio tuvo como objetivo determinar los cambios histopatológicos en la mucosa de la tráquea de la rata para lo cual todos los animales fueron expuestos al formaldehído, durante 18 semanas. El estudio fue realizado en 28 ratas albinas Wistar, con 6-7 semanas de vida. Las ratas fueron divididas en 3 grupos (E1: 4h/día, 4días/semana; E2: 2h/día, 4días/semana; E3: 2h/día, 2días/semana) y un grupo control. Fueron seccionadasas las tráqueas de los especímenes y teñidas con H&E para su estudio histopatológico. Una desorganización epitelial, desaparición de cilios, leves cambios dispásticos y leve infiltración linfocítica subepiteial fueron observados en el grupo E1. Desorganización epitelial, cilios irregulares y leve infiltración subepitelial fueron observados en los grupos E2 y E3. Los resultados de este estudio muestran que a mayor exposición al vapor del formaldehido, más intensos son los cambios epiteliales de la mucosa traqueal.