Formaldehyde: exposure and genotoxicity assessments and potential health effects

Worldwide formaldehyde is manipulated with diverse usage properties, since industrial purposes to health laboratory objectives, representing the economic importance of this chemical agent. Therefore, many people are exposed to formaldehyde environmentally and/or occupationally. Considering the latter, there was recommended occupational exposure limits based on threshold mechanisms, limit values and indoor guidelines. Formaldehyde is classified by the International Agency for Cancer Research (IARC) as carcinogenic to humans (group 1), since a wide range of epidemiological studies in occupational exposure settings have suggested possible links between the concentration and duration of exposure and elevated risks of nasopharyngeal cancer, and others cancers, and more recently, with leukemia. Although there are different classifications, such as U.S. EPA that classified formaldehyde as a B1 compound, probable human carcinogen under the conditions of unusually high or prolonged exposure, on basis of limited evidence in humans but with sufficient evidence in animals. Formaldehyde genotoxicity is well-known, being a direct-acting genotoxic compound positively associated for almost all genetic endpoints evaluated in bacteria, yeast, fungi, plants, insects, nematodes, and cultured mammalian cells. There are many human biomonitoring studies that associate formaldehyde occupational exposure to genomic instability, and consequently possible health effects. Besides the link with cancer, also other pathologies and symptoms are associated with formaldehyde exposure, namely respiratory disorders such as asthma, and allergic contact dermatitis. Nowadays, there are efforts to reduce formaldehyde exposure, namely indoor. Europe and United States developed more strict regulation regarding formaldehyde emissions from materials containing this agent. Despite the regulations and restrictions, formaldehyde still continues to be difficult to eliminate or substitute, being biomonitoring an important tool to control possible future health effects.

Differential effects of formaldehyde exposure on the cell influx and vascular permeability in a rat model of allergic lung inflammation

Exposure to air pollutants such as formaldehyde (FA) leads to inflammation, oxidative stress and immune-modulation in the airways and is associated with airway inflammatory disorders such as asthma. The purpose of our study was to investigate the effects of exposure to FA on the allergic lung inflammation. The hypothesized link between reactive oxygen species and the effects of FA was also studied. To do so, male Wistar rats were exposed to FA inhalation (1%, 90 min daily) for 3 days. and subsequently sensitized with ovalbumin (OVA)-alum by subcutaneous route One week later the rats received another OVA-alum injection by the same route (booster). Two weeks later the rats were challenged with aerosolized OVA. The OVA challenge of rats upon FA exposure induced an elevated release of LTB(4). TXB(2), IL-1 beta, IL-6 and VEGF in lung cells, increased phagocytosis and lung vascular permeability, whereas the cell recruitment into lung was reduced. FA inhalation induced the oxidative burst and the nitration of proteins in the lung Vitamins C, E and apocynin reduced the levels of LTB(4) in BAL-cultured cells of the FA and FA/OVA groups, but Increased the cell influx into the lung of the FA/OVA rats. In OVA-challenged rats, the exposure to FA was associated to a reduced lung endothelial cells expression of intercellular cell adhesion molecule 1 (ICAM-1) In conclusion, our findings suggest that FA down regulate the cellular migration into the lungs after an allergic challenge and increase the ability of resident lung cells likely macrophages to generate inflammatory mediators, explaining the increased lung vascular permeability Our data are indicative that the actions of FA involve mechanisms related to endothelium-leukocyte interactions and oxidative stress, as far as the deleterious effects of this air pollutant on airways are concerned. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Reduced allergic lung inflammation in rats following formaldehyde exposure: Long-term effects on multiple effector systems

Clinical and experimental evidences show that formaldehyde (FA) exposure has an irritant effect on the upper airways. As being an indoor and outdoor pollutant, FA is known to be a causal factor of occupational asthma. This study aimed to investigate the repercussion of FA exposure on the course of a lung allergic process triggered by an antigen unrelated to FA. For this purpose, male Wistar rats were subjected to FA inhalation for 3 consecutive days (1%, 90-min daily), subsequently sensitized with ovalbumin (OVA)-alum via the intraperitoneal route, and 2 weeks later challenged with aerosolized OVA. The OVA challenge in rats after FA inhalation (FA/OVA group) evoked a low-intensity lung inflammation as indicated by the reduced enumerated number of inflammatory cells in bronchoalveolar lavage as compared to FA-untreated allergic rats (OVA/OVA group). Treatment with FA also reduced the number of bone marrow cells and blood leukocytes in sensitized animals challenged with OVA, which suggests that the effects of FA had not been only localized to the airways. As indicated by passive cutaneous anaphylactic reaction, FA treatment did not impair the anti-OVA IgE synthesis, but reduced the magnitude of OVA challenge-induced mast cell degranulation. Moreover, FA treatment was associated to a diminished lung expression of PECAM-1 (platelet-endothelial cell adhesion molecule 1) in lung endothelial cells after OVA challenge and an exacerbated release of nitrites by BAL-cultured cells. Keeping in mind that rats subjected solely to either FA or OVA challenge were able to significantly increase the cell influx into lung, our study shows that FA inhalation triggers long-lasting effects that affect multiple mediator systems associated to OVA-induced allergic lung such as the reduction of mast cells activation, PECAM-1 expression and exacerbation of NO generation, thereby contributing to the decrease of cell recruitment after the OVA challenge. In conclusion, repeated expositions to air-borne FA may impair the lung cell recruitment after an allergic stimulus, thereby leading to a non-responsive condition against inflammatory stimuli likely those where mast cells are involved. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Differential effects of female sex hormones on cellular recruitment and tracheal reactivity after formaldehyde exposure

Female sex hormones (FSHs) exert profound regulatory effects on the course of lung inflammation due to allergic and non-allergic immune responses. As pollution is one of the pivotal factors to induce lung dysfunction, in this study we investigated the modulatory role of FSHs on lung inflammation after a formaldehyde (FA) exposure. For this purpose, lung and systemic inflammatory responses were evaluated in terms of leukocytes countings in bronchoalveolar lavage (BAL), peripheral blood and bone marrow lavage from 7-day ovariectomized (OVx) and Sham-OVx rats subjected to FA inhalation for 3 consecutive days. The hypothesized link between effects of FSHs on expression of adhesion molecules and mast cells degranulation was also studied. Once exposed to FA, Sham-OVx rats increased the number of total cells recovered in BAL and of leukocytes in peripheral blood, and decreased the counts in bone marrow. By contrast, in OVx rats upon FA exposure there was a reduction of the total cells counts in BAL and of blood leukocytes: lung expressions of ICAM-1 and Mac-1 were depressed, but the number of bone marrow cells did not vary. Estradiol treatment of OVx rats increased the total cells in BAL and decreased the number of blood leukocytes, whereas the number of bone marrow cell remained unaltered. Progesterone treatment, in turn increased the total cells in BAL and blood leukocytes, but decreased the number of bone marrow cells. OVx rats exposed to FA developed tracheal hyperresponsiveness to methacholine (MCh). A similarly altered response was found between the tracheal segments of Sham-OVx rats after FA exposure and that found in tracheae of naive rats. Estradiol treatment prevented FA-induced tracheal hyperresponsiveness to MCh whereas progesterone was ineffective in this regard. In addition, OVx rats upon FA exposure significantly increased both, the ability of mast cell degranulation and serum corticosterone levels. In conclusion, it was found that FSHs act by distinct control mechanisms on FA-induced lung inflammation and tracheal hyperresponsiveness, since at low circulating levels of FSHs (such as those after OVx) there is some resistance to the development of a lung inflammatory response, but the cholinergic tracheal responsiveness is exacerbated. Our data also help to understand the involvement of FSHs on mast cells activity after pollutants exposure and add information regarding the role of FSHs on the mechanisms related to endothelium-leukocyte interactions. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Reduced allergic lung inflammation in rats following formaldehyde exposure: Long-term effects on multiple effector systems

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

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

Genotoxic effects in occupational exposure to formaldehyde: A study in anatomy and pathology laboratories and formaldehyde-resins production

Background - According to the Report on Carcinogens, formaldehyde ranks 25th in the overall U.S. chemical production, with more than 5 million tons produced each year. Given its economic importance and widespread use, many people are exposed to formaldehyde environmentally and/or occupationally. Presently, the International Agency for Research on Cancer classifies formaldehyde as carcinogenic to humans (Group 1), based on sufficient evidence in humans and in experimental animals. Manyfold in vitro studies clearly indicated that formaldehyde can induce genotoxic effects in proliferating cultured mammalian cells. Furthermore, some in vivo studies have found changes in epithelial cells and in peripheral blood lymphocytes related to formaldehyde exposure. Methods - A study was carried out in Portugal, using 80 workers occupationally exposed to formaldehyde vapours: 30 workers from formaldehyde and formaldehyde-based resins production factory and 50 from 10 pathology and anatomy laboratories. A control group of 85 non-exposed subjects was considered. Exposure assessment was performed by applying simultaneously two techniques of air monitoring: NIOSH Method 2541 and Photo Ionization Detection equipment with simultaneously video recording. Evaluation of genotoxic effects was performed by application of micronucleus test in exfoliated epithelial cells from buccal mucosa and peripheral blood lymphocytes. Results - Time-weighted average concentrations not exceeded the reference value (0.75 ppm) in the two occupational settings studied. Ceiling concentrations, on the other hand, were higher than reference value (0.3 ppm) in both. The frequency of micronucleus in peripheral blood lymphocytes and in epithelial cells was significantly higher in both exposed groups than in the control group (p < 0.001). Moreover, the frequency of micronucleus in peripheral blood lymphocytes was significantly higher in the laboratories group than in the factory workers (p < 0.05). A moderate positive correlation was found between duration of occupational exposure to formaldehyde (years of exposure) and micronucleus frequency in peripheral blood lymphocytes (r = 0.401; p < 0.001) and in epithelial cells (r = 0.209; p < 0.01). Conclusions - The population studied is exposed to high peak concentrations of formaldehyde with a long-term exposure. These two aspects, cumulatively, can be the cause of the observed genotoxic endpoint effects. The association of these cytogenetic effects with formaldehyde exposure gives important information to risk assessment process and may also be used to assess health risks for exposed workers.

Genotoxic effects in occupational exposure to formaldehyde: A study in anatomy and pathology laboratories and formaldehyde-resins production

ABSTRACT – Background: According to the Report on Carcinogens, formaldehyde ranks 25th in the overall U.S. chemical production, with more than 5 million tons produced each year. Given its economic importance and widespread use, many people are exposed to formaldehyde environmentally and/or occupationally. Presently, the International Agency for Research on Cancer classifies formaldehyde as carcinogenic to humans (Group 1), based on sufficient evidence in humans and in experimental animals. Manyfold in vitro studies clearly indicated that formaldehyde can induce genotoxic effects in proliferating cultured mammalian cells. Furthermore, some in vivo studies have found changes in epithelial cells and in peripheral blood lymphocytes related to formaldehyde exposure. Methods: A study was carried out in Portugal, using 80 workers occupationally exposed to formaldehyde vapours: 30 workers from formaldehyde and formaldehyde-based resins production factory and 50 from 10 pathology and anatomy laboratories. A control group of 85 non-exposed subjects was considered. Exposure assessment was performed by applying simultaneously two techniques of air monitoring: NIOSH Method 2541 and Photo Ionization Detection equipment with simultaneously video recording. Evaluation of genotoxic effects was performed by application of micronucleus test in exfoliated epithelial cells from buccal mucosa and peripheral blood lymphocytes. Results: Time-weighted average concentrations not exceeded the reference value (0.75 ppm) in the two occupational settings studied. Ceiling concentrations, on the other hand, were higher than reference value (0.3 ppm) in both. The frequency of micronucleus in peripheral blood lymphocytes and in epithelial cells was significantly higher in both exposed groups than in the control group (p < 0.001). Moreover, the frequency of micronucleus in peripheral blood lymphocytes was significantly higher in the laboratories group than in the factory workers (p < 0.05). A moderate positive correlation was found between duration of occupational exposure to formaldehyde (years of exposure) and micronucleus frequency in peripheral blood lymphocytes (r = 0.401; p < 0.001) and in epithelial cells (r = 0.209; p < 0.01). Conclusions: The population studied is exposed to high peak concentrations of formaldehyde with a long-term exposure. These two aspects, cumulatively, can be the cause of the observed genotoxic endpoint effects. The association of these cytogenetic effects with formaldehyde exposure gives important information to risk assessment process and may also be used to assess health risks for exposed worker

Exposure assessment: the influence of environmental monitoring methodology

Exposure assessment is an important step of risk assessment process and has evolved more quickly than perhaps any aspect of the four-step risk paradigm (hazard identification, exposure assessment, dose-response analysis, and risk characterization). Nevertheless, some epidemiological studies have associated adverse health effects to a chemical exposure with an inadequate or absent exposure quantification. In addition to the metric used, the truly representation of exposure by measurements depends on: the strategy of sampling, random collection of measurements, and similarity between the measured and unmeasured exposure groups. Two environmental monitoring methodologies for formaldehyde occupational exposure were used to assess the influence of metric selection in exposure assessment and, consequently, in risk assessment process.

Formaldeyde exposure during animal macroscopic examination

Results of research work developed in anatomy and pathology laboratories have indicated that “macroscopic examination” is the task involving the highest exposure to formaldehyde. This is probably because precision and very good visibility are needed and, therefore, pathologists must lean over the specimen with consequent increase of proximity. With this research we aimed to know formaldehyde exposure in case of animal’s macroscopic examination. Three macroscopic examinations were considered and exposure assessment performed with photo ionization detection (PID) direct-reading equipment (with an 11.7 eV lamp) designated by First-Check, from Ion Science. Higher values of formaldehyde concentration (ceiling values) were register in each exam.

Parasitology of juvenile mullet (Mugil liza) and effect of formaldehyde on parasites and host

Few studies have been performed with parasites of marine and estuarine fish in southern Brazil. In the present study, unpublished results show the ways of parasitism of juvenile mullet by parasites. The toxicity of formaldehyde and the effectiveness of this chemotherapy in controlling parasites in reared juvenile mullet Mugil liza were also studied. Juvenile mullets (1 +/- 0.26 g; 4.1 +/- 0.4 cm) were exposed to different concentrations of 37% formaldehyde: control group and five formaldehyde concentrations which were tested: T1 (13.5), T2 (21.6), T3 (40.5), T4 (81) and T5 (135) mg L-1 with 8 fish per repetition in triplicate. To verify the drug effectiveness in parasitic control, juvenile mullets were exposed to 1 h prophylactic bath of 37% formaldehyde with a control group and five formaldehyde concentrations: T1 (67.5), T2 (135), T3 (270), T4 (405) and T5 (540) mg L-1, 8 fish per repetition in triplicate. Ligophorus cf. uruguayensis (Monogenoidea: Ancyrocephalidae) and Solostamenides cf. platyorchis (Monogenoidea: Microcotylidae) were identified in the gills. Digenea and Nematoda were observed in the intestines. This is the first occurrence of S. cf. platyorchis in Brazil. During the toxicity test, the LC50-96 h was estimated at 20.77 mg L-1 of formaldehyde. During the 1 h formaldehyde prophylactic bath, all parasites were eliminated in formaldehyde concentrations between 135 and 540 mg L-1. High survival rate was observed in all treatments. Values of prevalence and intensity of infestation observed in this study showed the potential damage caused by Monogenoidea to mullet. Formaldehyde baths with 135 mg L-1 are recommended to control Monogenoidea in mullet and the safe limits for formaldehyde use were presented. Besides, the endoparasites were tolerant to formaldehyde exposure. (C) 2012 Elsevier B.V. All rights reserved.

Parasitology of juvenile mullet (Mugil liza) and effect of formaldehyde on parasites and host

Few studies have been performed with parasites of marine and estuarine fish in southern Brazil. In the present study, unpublished results show the ways of parasitism of juvenile mullet by parasites. The toxicity of formaldehyde and the effectiveness of this chemotherapy in controlling parasites in reared juvenile mullet Mugil liza were also studied. Juvenile mullets (1 +/- 0.26 g; 4.1 +/- 0.4 cm) were exposed to different concentrations of 37% formaldehyde: control group and five formaldehyde concentrations which were tested: T1 (13.5), T2 (21.6), T3 (40.5), T4 (81) and T5 (135) mg L-1 with 8 fish per repetition in triplicate. To verify the drug effectiveness in parasitic control, juvenile mullets were exposed to 1 h prophylactic bath of 37% formaldehyde with a control group and five formaldehyde concentrations: T1 (67.5), T2 (135), T3 (270), T4 (405) and T5 (540) mg L-1, 8 fish per repetition in triplicate. Ligophorus cf. uruguayensis (Monogenoidea: Ancyrocephalidae) and Solostamenides cf. platyorchis (Monogenoidea: Microcotylidae) were identified in the gills. Digenea and Nematoda were observed in the intestines. This is the first occurrence of S. cf. platyorchis in Brazil. During the toxicity test, the LC50-96 h was estimated at 20.77 mg L-1 of formaldehyde. During the 1 h formaldehyde prophylactic bath, all parasites were eliminated in formaldehyde concentrations between 135 and 540 mg L-1. High survival rate was observed in all treatments. Values of prevalence and intensity of infestation observed in this study showed the potential damage caused by Monogenoidea to mullet. Formaldehyde baths with 135 mg L-1 are recommended to control Monogenoidea in mullet and the safe limits for formaldehyde use were presented. Besides, the endoparasites were tolerant to formaldehyde exposure. (C) 2012 Elsevier B.V. All rights reserved.

Caracterización de la exposición ocupacional a formaldehído en trabajadores del sector salud y educación en Colombia 2004-2013.

El Formaldehído es una sustancia química de amplio uso a nivel mundial con efectos documentados en personas expuestas entre los cuales se destacan irritación de la piel, mucosas, tracto respiratorio y ojos. Según la Agencia Internacional para la Investigación del Cáncer (IARC) el formaldehido se encuentra clasificado en el grupo 1 como agente cancerígeno con suficiente evidencia de producir neoplasias en humanos. Los sectores industriales en Colombia que utilizan de forma frecuente el formaldehído incluyen los fabricantes de maderas, los servicios funerarios, y los sectores de salud y educación. El presente estudio de corte transversal pretende, con base en mediciones históricas (2004-2013) construir un perfil de exposición a formaldehído en trabajadores vinculados al sector de salud y educación en Colombia, divididos y analizados según actividades de trabajo similares (Patólogos, Histotecnólogos, Auxiliares de laboratorio, Docentes y Estudiantes), con el fin de establecer una línea base de diagnóstico para la orientación acciones dirigidas al control del riesgo. Con base en los hallazgos y soportados en estimadores estadísticos aplicables a los grupos de exposición, en general existe un tendencia de no conformidad al comparar los resultados aplicables con valores de referencia de larga duración definidos para el agente por autoridades internacionales. De forma complementaria se encontraron brechas significativas respecto a la implementación de controles administrativos y técnicos que sugieren circunstancias de exposición no controladas en los colectivos de interés.

Genotoxicity biomarkers in occupational exposure to formaldehyde: the case of histopathology laboratories

Formaldehyde, classified by the IARC as carcinogenic in humans and experimental animals, is a chemical agent that is widely used in histopathology laboratories. The exposure to this substance is epidemiologically linked to cancer and to nuclear changes detected by the cytokinesis-block micronucleus test (CBMN). This method is extensively used in molecular epidemiology, since it provides information on several biomarkers of genotoxicity, such as micronuclei (MN), which are biomarkers of chromosomes breakage or loss, nucleoplasmic bridges (NPB), common biomarkers of chromosome rearrangement, poor repair and/or telomere fusion, and nuclear buds (NBUD), biomarkers of elimination of amplified DNA. The aim of this study is to compare the frequency of genotoxicity biomarkers, provided by the CBMN assay in peripheral lymphocytes and the MN test in buccal cells, between individuals occupationally exposed and non-exposed to formaldehyde and other environmental factors, namely tobacco and alcohol consumption. The sample comprised two groups: 56 individuals occupationally exposed to formaldehyde (cases) and 85 unexposed individuals (controls), from whom both peripheral blood and exfoliated epithelial cells of the oral mucosa were collected in order to measure the genetic endpoints proposed in this study. The mean level of TWA8h was 0.16±0.11ppm (exposure to formaldehyde and the presence of genotoxicity biomarkers.

Effects of exposure to formaldehyde and tobacco smoking on genotoxicity biomarkers

Formaldehyde (FA) is a colour less gas widely used in the industry and hospitals as an aqueous solution, formalin. It is extremely reactive and induces various genotoxic effects in proliferating cultured mammalian cells. Tobacco smoke has been epidemiologically associated to a higher risk of development of cancer, especially in the oral cavity, larynx and lungs, as these are places of direct contact with many carcinogenic tobacco’s compounds. Approximately 90% of human cancers originate from epithelial cells. Therefore, it could be argued that oral epithelial cells represent a preferred target site for early genotoxic events induced by carcinogenic agents entering the body via inhalation and ingestion. The cytokinesis-blocked micronucleus assay (CBMN) in human lymphocytes is one of the most commonly used methods for measuring DNA damage, namely the detection of micronucleus, nucleoplasmic bridges, and nuclear buds.