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Mortality from respiratory cancers (including lung cancer) among workers employed in formaldehyde industries.

A joint study on effects of formaldehyde exposure in industrial populations by the National Cancer Institute and the Formaldehyde Institute, Inc. (Blair et al. [1986]: J Natl Cancer Inst 76: 1071-1084; Blair and Stewart [1989]: J Occup Med 31: 881, Blair et al. [1990]: Am J Ind Med 17:683-700) reported no significant elevation in risk ratios standardized to the general population. Using the same data as Blair et al., we compared more exposed to less exposed workers to compute relative risk for respiratory and lung cancers using a multivariate, log-linear model incorporating factors for job type (hourly vs. salaried), cumulative exposure (0.1-0.5, 0.5-2, 2+ vs. < 0.1 ppm/years), length of exposure (1-5, 5-10, 10+ vs. < 1 years), and age. Models were fit for all workers, all males, all workers less than 65 years of age, and for all males less than 65 years of age. Hourly workers have a significantly elevated relative risk when compared to salaried workers. While only high levels of cumulative exposure show a significant elevation in relative lung cancer risk, trend analyses of the coefficients of a log-linear model show a significant trend of increasing risk with increasing formaldehyde exposure. The significantly elevated respiratory and lung cancer risk for workers younger than 65 may indicate a shift of respiratory cancer mortality towards younger ages among those occupationally exposed to formaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Reducing the levels of formaldehyde exposure in gross anatomy laboratories.

BACKGROUND: A method is described in which formaldehyde levels are greatly reduced in our gross anatomy laboratory in order to comply with increasingly severe safety and health regulations. METHODS: A novel type of dissection "bed" has been introduced which incorporates an internal motor that causes a downflow of formaldehyde-rich vapors, which are absorbed by a replaceable active carbon filtration system. RESULTS: Use of the new dissection "beds" has resulted in the recirculated air being virtually formaldehyde-free. Formaldehyde vapor levels in our gross anatomy laboratory have been greatly reduced and are typically in the range of 0.03-0.09 ppm. CONCLUSIONS: The new system allows us to comply with safety and health regulations and provide a dissection room with an excellent working environment.

Air Pollution, Indoor↗

Cancer risks due to occupational exposure to formaldehyde: results of a multi-site case-control study in Montreal.

A case-control study was undertaken in Montreal to investigate the possible associations between occupational exposures and cancers of the following sites: oesophagus, stomach, colo-rectum, liver, pancreas, lung, prostate, bladder, kidney, melanoma and lymphoid tissue. In total, 3,726 cancer patients and 533 population controls were interviewed to obtain detailed lifetime job histories and information on potential confounders. Each job history was translated into a history of occupational exposures. Because of current concerns about formaldehyde carcinogenicity, we carried out a special analysis of the association between exposure to formaldehyde and each type of cancer covered by this study. Separate statistical analyses were carried out for each type of cancer using population controls as well as a control series drawn from among the other cancer sites in the study. Although nearly a quarter of all subjects had undergone occupational exposure to formaldehyde, the levels of exposure were in general quite low. There was no persuasive evidence of an increased risk of any type of cancer among men exposed to these levels of formaldehyde. However, the possibility of a small increase in risk could not be ruled out.

Adult↗

One-year inhalation toxicity study of formaldehyde in male rats with a damaged or undamaged nasal mucosa.

To study the effect of bilateral intranasal electrocoagulation damage on the susceptibility of rats to formaldehyde vapour, male Wistar rats with a damaged or undamaged nasal mucosa were exposed to atmospheres containing 0, 0.1, 1 or 10 ppm formaldehyde vapour during 6 h/day, 5 days/wk for 13 or 52 weeks. Electrocoagulation damage was induced in the anterior third part of the nose. The repair process followed the pattern of wound healing. Loss of turbinates and perforation of the septum were common irreversible findings. After 13 weeks basal cell hyperplasia and squamous metaplasia of the respiratory epithelium, and rhinitis were still visible. After 52 weeks effects attributable to electrocoagulation were slight basal cell hyperplasia and some rhinitis. Major formaldehyde-related adverse effects in the 10 ppm group not subjected to electrocoagulation included growth retardation, reduced urine production, and rhinitis accompanied by squamous metaplasia of the nasal respiratory epithelium. No adverse effects were seen at 0.1 or 1 ppm in rats with an intact nasal mucosa. The principal untoward effects of formaldehyde in electrocoagulation-treated rats seen after 13 and/or 52 weeks comprised increase in basal cell hyperplasia, squamous metaplasia of the nasal respiratory epithelium, damage to the olfactory epithelium at 10 ppm, and focal squamous metaplasia of nasal respiratory epithelium at 0.1 and 1 ppm.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

Differential mutagenicity of two dihydrophenalene congeners: examination of formaldehyde generation and reactive intermediate formation as possible mechanisms.

Compounds in the dihydrophenalene series are currently under investigation as potential antipsychotic agents. The mutagenicity of two compounds in this series was evaluated in several strains in the Ames Salmonella (2,3-dihydro-N,N-dimethyl-1H-phenalen-2-amine:HCI) was less mutagenic than its monomethyl analogue, U-64,273A. Two hypothesis-the of formaldehyde and release of formaldehyde and the formation of macromolecular reactive intermediates--were evaluated as possible mechanisms for the observed mutagenicity. Formaldehyde release during biotransformation of U-65,556A but not U-64,273 was demonstrated, as measured by trapping with the Nash reagent. Thus, formaldehyde release does not correlate with the mutagenic potency of these compounds. Covalent binding of U-65,556A-[3H] equivalents to rat hepatic protein was observed, but binding to DNA, which is considered the more critical target molecule, was not observed. These data suggest that reactive intermediate formation does not explain the mutagenicity of U-65,556A in the Ames Salmonella assay. Follow-up studies were conducted to assess the possible contribution of tritium exchange to the observed covalent binding to protein by quantitatively recovering 3H2O from incubations containing U-65,556A-[3H] and rat liver microsomes. Data indicate that enzyme-dependent formation of 3H2O does occur but that this phenomenon does not account for U-65,556A-[3H]-derived, protein-bound tritium in covalent binding studies.

Animals↗

Tympanoplasty using formaldehyde formed fascia grafts.

The closure of total perforations of the tympanic membrane has always been more difficult than lesser eardrum defects. Postoperative anterior sulcus blunting and graft lateralization occur with greater frequency in this situation and thus compromise results. In 1975, Rodney Perkins developed and described a technique for the closure of such total perforations which involved the use of formaldehyde treated temporalis muscle fascia, shaped by means of a metal mold into the configuration of a normal tympanic membrane and medial end of the bony external ear canal. This formaldehyde formed fascia (FFF) graft impressed us with its adaptability and logic. This article is a review of 139 cases involving the use of formaldehyde treated grafts not only for closure of total performations, but also for closure of total performations with concomitant middle ear ossicular reconstruction. The postoperative nonperforation rate in this series is 96.4%; blunting and/or graft lateralization was absent in 94.2% of cases. Closures of the air-bone gap to within 20 db occurred in 74% of cases with an overall gain in hearing for all cases of 84%. We believe that formaldehyde formed fascia grafts are an effective tool for the closure of total tympanic membrane perforations with or without concomitant ossicular chain reconstruction.

Adolescent↗

A cell biosensor specific for formaldehyde based on pH-sensitive transistors coupled to methylotrophic yeast cells with genetically adjusted metabolism.

A cell biosensor specific for formaldehyde was developed using double-mutant cells of the methylotrophic yeast Hansenula polymorpha A3-11. The activities of some of the enzymes in the metabolic pathway of the wild-strain cells were deliberately suppressed by introducing respective genetic blocks to optimize the selectivity and acidification rate. Mutant yeast cells produced in this way were immobilized in Ca-alginate gel on the gate of a pH-sensitive field effect transistor. The local acidification of the extracellular medium due to specific conversion of formaldehyde was recorded. The steady-state response time of the biosensor was 2-3 min, i.e., about 10 times shorter than the response time for the alcohol-specific cell biosensors described earlier. The linear dynamic range of the sensor's response corresponds to formaldehyde concentrations of 2 to 200 mM. The operational stability of the sensor was not less than 4 h. The biosensor demonstrated high specificity to formaldehyde with no response to several organic acids, methanol, and other alcohols, except for low sensitivity to ethanol. The influence of sample buffer capacity and pH on the sensor response, as well as thermostability, was investigated.

Biosensing Techniques↗

Formaldehyde and cancer morbidity among male employees in Denmark.

Formaldehyde, a genotoxic and potent animal carcinogen, is widespread in the working environment as well as in private homes. The risk for cancer morbidity in Denmark during 1970-84 was estimated from standardized proportionate incidence ratios (SPIR) among men whose longest employment had been held since 1964, at least 10 years before diagnosis, in 265 companies in which exposure to formaldehyde was identified. The results do not support the hypothesis that formaldehyde is associated with lung cancer (SPIR = 1.0, 410 cases). Significantly elevated risks were found for cancers of the colon (SPIR = 1.2, 166 cases), kidney (SPIR = 1.3, 60 cases), and sino-nasal cavities (SPIR = 2.3, 13 cases). For sino-nasal cancer, a relative risk of 3.0 (95 percent confidence interval = 1.4-5.7) was found among blue-collar workers with no probable exposure to wood dust, the major confounder. This study provides further evidence that occupational exposure to formaldehyde increases the risk for sino-nasal cancer.

Adult↗

Formaldehyde-induced sister chromatid exchanges in vitro and the influence of the exogenous metabolizing systems S9 mix and primary rat hepatocytes.

Formaldehyde-induced sister chromatid exchanges (SCE) in vitro and the influence of the exogenous metabolizing systems, S9 mix and primary rat hepatocytes, were studied. The SCE-frequency in V79 cells was dose dependent. A three- to four-fold increase at non-toxic doses was observed. However, in the presence of an exogenous metabolizing system, the number of formaldehyde-induced SCE decreased. S9 mix as well as hepatocytes reduced the SCE frequency to nearly that of the control range. It could be demonstrated that the reduction was not due to an unspecific binding of formaldehyde to macromolecules of the added S9 mix. The decrease in genotoxic effects, due to rapid metabolisation of formaldehyde in vitro and in vivo, explains the differences between results obtained in the in vitro experiments--performed without metabolizing systems--and in vivo results.

Animals↗

Oxidation of formaldehyde by alcohol oxidase of Candida boidinii.

A fromaldehyde oxidase activity was found in cellfree extracts of methanol-grown yeast Candida boidinii. Loss of alcohol oxidase activity in a mutant, 48, led to loss of the formaldehyde oxidase activity, indicating that the same enzyme is probably responsible for both activities. This could be demonstrated with the purified alcohol oxidase which oxidizes, besides lower primary alcohols, formaldehyde to formate. The Km value for formaldehyde is 5.7 mM. It seems that alcohol oxidase is not implicated in formaldehyde oxidation in vivo.

Alcohol Oxidoreductases↗

Formaldehyde fixation of cGMP in distinct cellular pools and their recognition by different cGMP-antisera. An immunocytochemical study into the problem of serum specificity.

Three different antisera raised against the same formaldehyde fixed cGMP conjugate were tested for their specificity in two non-biological and two biological model systems. The first non-biological model system was based on nucleotides fixed to gelatin by formaldehyde and the other non-biological model was nitrocellulose paper as a carrier for nucleotides coupled to proteins by formaldehyde. All antisera proved specific for cGMP in both models. As biological models we used the in vitro incubated hippocampus slice and the in vitro incubated aortic ring. In hippocampus slices all three antisera showed cGMP-producing cells after atrial natriuretic factor stimulation. However, there were significant differences in the visualization of cGMP-immunoreactivity between the three antisera when sodium nitroprusside or potassium were used to stimulate cGMP production. Nevertheless, these differential staining patterns all showed cGMP-immunoreactivity using the conventional immunocytochemical control tests. In the aorta ring all three antisera showed the same strong increase in cGMP-immunoreactivity after in vitro stimulation with sodium nitroprusside. These results were corroborated by biochemical assay of cGMP. We conclude that these three antisera all demonstrate cGMP-immunoreactivity in the biological models used. The different staining patterns that occur are caused by differences in the microchemical milieu of the formaldehyde-fixed cGMP. The use of different antibodies to cGMP may give information about this microchemical milieu which may eventually contribute to a better understanding of different intracellular cGMP pools.

Animals↗

The formaldehyde-fluorescamine method. An investigation of reaction mechanisms and optimization of the method.

Formaldehyde reacts with primary amino groups to derivatives which are unable to react with the fluorogenic primary amino group probe, fluorescamine. Paradoxically, however, certain specific cell systems continue to display strong fluorescamine-induced fluorescence after formaldehyde pretreatment. Among such formaldehyde-fluorescamine (FF) positive cell systems are certain peptide- and protein-secreting cells as well as all hitherto investigated types of cancer cells. We have now optimized the cytochemical FF method by using microfluorometry in combination with systematically varied reaction conditions. In addition, the quantitative data indicate that in FF positive cells, formaldehyde pretreatment causes a paradoxical increase in the fluorescence yield with fluorescamine. This has tentatively been ascribed to quenching phenomena, associated with closely spaced primary amino groups. Work with alternative fluorogenic amino group probes (MDPF and OPT) show that these display the same spectrum of tissue selectivity as fluorescamine, but that the latter remains the reagent of choice for the cytochemical FF reaction.

Adenocarcinoma↗

Effect of urinary acidifiers on formaldehyde concentration and efficacy with methenamine therapy.

Twenty-seven patients with indwelling urinary catheters and chronic bacteriuria were studied for methenamine efficacy. In a crossover fashion, each patient received methenamine mandelate granules 4 g/day alone, with ascorbic acid 4 g/day, and with ascorbic acid 4 g/day plus cranberry cocktail one 1/day. Proteus vulgaris, Pseudomonas aeruginosa, and E. coli were the common pathogens. Urinary acidifiers had no significant effect on mean urine pH, however, high urinary formaldehyde concentrations were associated with the use of ascorbic acid. Bacteriocidal formaldehyde levels were more frequently present in patients with acidic urine pH than those with alkaline pH. Although ascorbic acid increased formaldehyde levels, additional cranberry cocktail had no further effect. Despite higher formaldehyde levels, urine culture results were positive in most cases with or without urine acidification. Methenamine therapy may be of limited value in asymptomatic chronic bacteriuric patients with indwelling catheters.

Aged↗

IgE-mediated 14C-serotonin release from passively sensitized rat mast cells: comparative kinetic study with formaldehyde and ice-cold methods.

The kinetics of IgE-mediated release of serotonin from passively sensitized rat mast cells in vitro was studied by stopping 14C-serotonin release with the application of formaldehyde fixative or ice-cold mast cell medium (MCM). Antigen dose-release curves of 14C-serotonin and/or histamine were comparable when mediator release was terminated with either formaldehyde at a final concentration of 1% or ice-cold MCM 15 min after antigen challenge. However, the kinetic study of immunological mediator release stopped by formaldehyde showed that the addition of antigen resulted in a progressive increase of released 14C-serotonin for 7 min, the release curve being sigmoidal, whereas the application of ice-cold MCM artificially enhanced 14C-serotonin and histamine release in the first 2 min. The results suggest that stopping IgE-mediated release of 14C-serotonin with formaldehyde is a simple, rapid and accurate method of studying the kinetics of mediator release from mast cells.

Animals↗

Formaldehyde-fluorescamine-induced fluorescence as a property of carcinoma cells.

Fluorescamine is a sensitive cytochemical probe for primary amino groups and produces an intense general fluorescence in unfixed tissue sections reflecting the ubiquitous occurrence of such groups. Following treatment with formaldehyde, most primary amino groups react to form derivatives unable to yield fluorescence with fluorescamine. Certain cell systems, however, contain amino groups which do not react with formaldehyde but display strong reactivity with fluorescamine. In formaldehyde- and fluorescamine-treated specimens such cell systems display an intense fluorescence, whereas the majority of tissue constituents are non-fluorescent. Fluorescent cell systems include certain protein- and peptide-secreting cells and a large number of different types of carcinoma cells. In some cases it appears that neoplastic transformation is necessary before the cells display formaldehyde-fluorescamine-induced fluorescence. Available data indicate that the reactive substance(s) are peptide in nature and that the production of such substance(s) may be a general property of carcinoma cells.

Carcinoma↗

Carbonyls in the metropolitan area of Mexico City: calculation of the total photolytic rate constants Kp(s(-1)) and photolytic lifetime (tau) of ambient formaldehyde and acetaldehyde.

A great number of studies on the ambient levels of formaldehyde and other carbonyls in the urban rural and maritime atmospheres have been published because of their chemical and toxicological characteristics, and adverse health effects. Due to their toxicological effects, it was considered necessary to measure these compounds at different sites in the metropolitan area of Mexico City, and to calculate the total rate of photolytic constants and the photolytic lifetime of formaldehyde and acetaldehyde. Four sites were chosen. Sampling was carried out at different seasons and atmospheric conditions. The results indicated that formaldehyde was the most abundant carbonyl, followed by acetone and acetaldehyde. Data sets obtained from the 4 sites were chosen to calculate the total rate of photolysis and the photolytic lifetime for formaldehyde and acetaldehyde. Maximum photolytic rate values were obtained at the maximum actinic fluxes, as was to be expected.

Acetaldehyde↗

Formaldehyde activating enzyme (Fae) and hexulose-6-phosphate synthase (Hps) in Methanosarcina barkeri: a possible function in ribose-5-phosphate biosynthesis.

Formaldehyde activating enzyme (Fae) was first discovered in methylotrophic bacteria, where it is involved in the oxidation of methanol to CO2 and in formaldehyde detoxification. The 18 kDa protein catalyzes the condensation of formaldehyde with tetrahydromethanopterin (H4MPT) to methylene-H4MPT. We describe here that Fae is also present and functional in the methanogenic archaeon Methanosarcina barkeri. The faeA homologue in the genome of M. barkeri was heterologously expressed in Escherichia coli and the overproduced purified protein shown to actively catalyze the condensation reaction: apparent Vmax = 13 U/mg protein (1 U = micromol/min); apparent Km for H4MPT = 30 microM; apparent Km for formaldehyde = 0.1 mM. By Western blot analysis the concentration of Fae in cell extracts of M. barkeri was determined to be in the order of 0.1% of the soluble cell proteins. Besides the faeA gene the genome of M. barkeri harbors a second gene, faeB-hpsB, which is shown to code for a 42 kDa protein with both Fae activity (3.6 U/mg) and hexulose-6-phosphate synthase (Hps) activity (4.4 U/mg). The results support the recent proposal that in methanogenic archaea Fae and Hps could have a function in ribose phosphate synthesis.

Aldehyde-Lyases↗

Spectrofluorimetric determination of formaldehyde by a flow-injection method based on its catalytic effect on the acridine yellow-bromate reaction.

A flow-injection configuration for the determination of formaldehyde is proposed. The method is based on the enhancing effect of formaldehyde on the oxidation of acridine yellow by bromate in acidic medium. The proposed procedure is simple, inexpensive, sensitive and suitable for concentrations of formaldehyde between 1 and 56 microg mL(-1). A sampling-rate of 60 samples h(-1) was achieved. The effect of several organic and inorganic species was studied. The method was applied to the determination of formaldehyde in pharmaceuticals, milk and air in work environments. The accuracy of the method was confirmed by comparing the results with those obtained using the standard acetylacetone method.

Air Pollutants↗