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The formaldehyde-donating activity of N5,N10-methylene tetrahydrofolic acid in xenobiotic biotransformation.

Reaction of reproterol, (7-(3-[2-(3,5-dihydroxyphenyl)-2-hydroxyethylamino]propyl)theophyl line (I), with formaldehyde liberated in a solution of N5,N10-methylene tetrahydrofolic acid at pH 7.3 led to the formation of 7-[3-(4,6,8-trihydroxy-1,2,3,4-tetrahydroisoquinolinyl-2)propyl]th eophylline (II), but no such reaction was observed in a solution of N5-methyl tetrahydrofolic acid. Compound II was also formed by incubation of I with rat-liver subcellular fractions. The highest formaldehyde-donating activity was found in the soluble fraction but some activity was also observed with washed mitochondria and microsomes. Dimedone was transformed to methylene bisdimedone by incubation with the soluble fraction. The amount of formaldehyde liberated in the soluble fraction during a four hour incubation at 22 degrees C was 1-3.6 mumol/g of liver. Metaproterenol and terbutaline, structurally related to I, reacted with formaldehyde to yield the corresponding tetrahydro-isoquinolines. The rate of this chemical reaction for the three drugs correlated with the amount of the tetrahydroquinolines formed by incubation with the soluble fraction and in orally dosed rats.

Animals↗

Effects of formaldehyde treated soybean meal on milk yield, milk composition, and nutrient digestibility in the dairy cow.

The nutritional value of soybean meal that had been treated with formaldehyde (.3 g/100 g) to inhibit microbial degradation of soybean meal protein in the rumen was investigated. Four experimental diets were fed ad libitum during wk 4 to 43 of lactation to Holstein cows randomly assigned to diets in a 2 x 2 factorial arrangement of dietary crude protein (12 and 14%) and formaldehyde treatment (untreated and treated soybean meal). Concentrate, corn silage, and alfalfa-grass hay provided 53.0, 35.4, and 11.6% of the daily intake of dry matter. Analysis of covariance revealed that digestibility of dietary crude protein by cows fed formaldehyde treated soybean meal was lower than by cows fed untreated soybean meal (62.4 versus 65.4%). Similar quantities of milk, 4% fat-corrected milk, milk fat, and milk solids-not-fat (overall means of 7998, 7402, 281, and 660 kg/301 days of lactation) were produced by cows fed different diets. This was true whether the data were summarized during peak production (day 22 to 63), during days 22 to 119 when crude protein intake did not meet requirements, or during the complete experiment (days 22 to 301 of lactation). Milk protein (total nitrogen x 6.38) produced by cows fed soybean meal treated with formaldehyde was less than by cows fed untreated soybean meal during days 22 to 63 and during days 22 to 119 (47 versus 44 kg/cow and 103 versus 97 kg/cow). Changes in body weight of cows during lactation were similar among treatments. Treating soybean meal with .3 g formaldehyde/100 g may decrease availability of soybean meal protein for use by lactating dairy cows.

Ammonia↗

Exposure to formaldehyde and cancer mortality in a cohort of workers producing resins.

The mortality of 1,332 male workers employed at least 30 days in 1959-1980 in a resins-manufacturing plant was examined. Ambient measurements taken in the plant between 1974 and 1979 documented a potential for exposure to levels of formaldehyde as high as greater than 3.0 mg/m3. Vital status was ascertained for 98.6% of the cohort members, and their mortality was compared with expected deaths drawn from the national and local population rates. A statistically significant increase in lung cancer was observed, based on 18 deaths, which was not fully accounted for by possible confounding factors linked to personal habits or sociocultural characteristics. This elevated risk, however, could not be attributed specifically to exposure to formaldehyde. Mortality from digestive cancer (14 deaths observed) and hematologic neoplasms (5 deaths observed) was not substantially higher than expected. The study was limited by information bias due to incomplete work histories, by the small number of deaths from some relevant causes, and by the possibly insufficient length of the observation period. Therefore these results do not provide sufficient grounds either to link formaldehyde exposure in the plant to the increased cancer risk noted or to exclude that formaldehyde might pose such a risk to humans under certain exposure circumstances.

Adolescent↗

Formaldehyde exposure in work and the general environment. Occurrence and possibilities for prevention.

Formaldehyde is extensively used for many different purposes. For this reason, serious concern has been expressed about the health hazards related to its potent irritating and sensitizing properties. Recently published information about the potential carcinogenicity of formaldehyde has generated further discussion of the potential health hazards of this compound. This article briefly reviews the health hazards of formaldehyde, the occurrence of formaldehyde in the environment, and general aspects of the prevention of existing hazards.

Air Pollutants↗

[Formaldehyde exposure and multiple chemical sensitivity].

Multiple chemical sensitivity (MCS) is characterized by various somatic symptoms which cannot be explained organically and by sensitivity to extremely low concentrations of chemicals including formaldehyde. In the absence of a widely accepted definition of MCS, contradictory etiological hypotheses and therapeutic suggestions are discussed. Formaldehyde is a flammable, colorless and readily polymerized gas at ambient temperature. It is present in the environment as a result of natural processes and from man-made sources, including motor vehicle exhaust, residues, emissions, or wastes produced during the manufacture of formaldehyde, and cigarette smoke. Formaldehyde exposure is considered to be one of the causes of MCS. This review describes the current knowledge about MCS and preventive measures of the administration.

Air Pollution, Indoor↗

[Measurement of emission rate of formaldehyde and volatile organic compounds(VOCs) from building materials by the small chamber method].

A small chamber for measuring the emission rate of formaldehyde gas and volatile organic compounds(VOCs) from building materials was developed, and formaldehyde and VOCs (toluene and xylene) concentrations emitted from particle boards(PB), medium density fiber-boards(MDF) and wall papers were measured. The emission rates measured by the chamber method were compared with the values by the desiccator method, several modified desiccator methods and the perforator method. The emission rate of formaldehyde increased with time and it became constant after about 20 hours. On the other hand, the emission rate of VOCs decreased with time. A good correlation was obtained on the emission rate of formaldehyde between the chamber method and the conventional desiccator method. The correlation coefficient between the perforator method and the chamber method was also high, but the correlation was low for surface treated materials.

Air Pollution, Indoor↗

[Free formaldehyde determination in cosmetic products by the HPLC method].

In order to standardize the analytical methods and procedures with the ones used in the EU, a method of free formaldehyde determination in cosmetic products preserved with formaldehyde donors, recommended by Commission Directive (90/207/EEC of 4th April, 1990), has been tested. The free formaldehyde level is determined by HPLC using post column derivatisation with acetylacetone. Formaldehyde content was determined in 44 fortified samples of cosmetic emulsions and shampoos. Recoveries ranged from 94.8-97.5%. Relative Standard Deviation 1-2.3%.

Chromatography, High Pressure Liquid↗

[Effect of corticotrophin on formaldehyde-induced somatostatin of spinal cord in rats].

AIM: To study the effect of corticotrophin (Cor) on somatostatin (Som) and its synthesis in spinal dorsal horn induced by formaldehyde in rats. METHODS: Using double immunohistochemical stainings, and in situ hybridization. RESULTS: Two hours after s.c. formaldehyde (5%, 200 microL) in one hindpaw of rats, the neurons of c-fos-like immunoreactivity (FLI), somatostatin-like immunoreactivity (Som-LI), Som-LI/FLI, and perprosomatostatin mRNA (PPS-mRNA) in ipsilateral spinal dorsal horn were increased obviously, as compared with the control group. The FLI and Som-LI of spinal cord were not changed by i.p. Cor. Cor (25 or 12.5 U.kg-1, i.p.) inhibited the formaldehyde-evoked FLI, Som-LI, Som-LI/FLI, and PPS-mRNA of spinal cord in a dose-dependent manner. The decrease of c-fos or Som level due to i.p. Cor in rats of chronic pain was prevented by raphe nuclei injected cyproheptadine, but not by bicuculline, naloxone, or phentolamin injected to raphe nuclei. CONCLUSION: The formaldehyde-evoked c-fos expression, Som, and Som synthesis of spinal cord were suppressed by Cor through the serotonin receptor of raphe nuclei.

Adrenocorticotropic Hormone↗

Identification and measurement of resveratrol and formaldehyde in parts of white and blue grape berries.

The phytoalexin resveratrol (3,5,4'-trihydroxy-trans-stilbene) and formaldehyde (as its dimedone adduct, formaldemethone) have been identified and measured in the extracts of parts of white and blue grapes as well as in white and red wines by overpressured layer chromatography (OPLC), high performance liquid chromatography (HPLC) and from matrix assisted laser desorption/ionization mass spectrometric data. It has been established that the level of resveratrol was very high in skin and in some cases in the stem. Blue grape varieties and red wines always contained a considerably higher amount of resveratrol than white grapes and wines. The measurable level of formaldehyde as well as the resveratrol content was always parallelly high in the same parts of the berries, however, the formaldehyde level was higher in white grapes than in blue ones. The simultaneous occurrence of resveratrol and formaldehyde gives a possibility for interaction between these two special molecules, consequently, hydroxymethyl derivatives of resveratrol can be formed. These resveratrol derivatives may be responsible for special biological activities of resveratrol in grapes and dietetically (cardioprotective effect and chemopreventive effect against cancer) in the human organism.

Chromatography, High Pressure Liquid↗

Alteration of endogenous formaldehyde level following mercury accumulation in different pig tissues.

The effect of mercury accumulation on the formaldehyde cycle of different pig tissues resulted by a single dose of mercury (0.4 mg mercury in Hg(II)-chloride form, 500 kBq Hg-203/animal) has been studied. Daily mercury excretion was tracked, and having reached the steady-state mercury level of the body (10th day), samples were taken from the liver, kidney and muscle (musculus longissimus dorsi). After reaction with dimedone the endogenous formaldehyde levels in the samples were measured by high performance liquid chromatography. Our results show that the endogenous formaldehyde level decreased by more than 50% in the liver and the kidney, where the average mercury accumulation was the highest (1017 Bq/100 g and 625 Bq/100 g, respectively). In contrast, the muscle tissues, with a low mercury level (139 Bq/100 g), responded to the stress effect by about a 30% increase in their endogenous formaldehyde level.

Animals↗

Microbial urea-formaldehyde degradation involves a new enzyme, methylenediurease.

The enzymic mechanism of metabolization of urea-formaldehyde condensation products (methyleneureas; MU) and the fate of the degradation products ammonium, urea and formaldehyde were studied in bacteria isolated from garden soil, which were able to use methyleneureas as the sole source of nitrogen for growth. An organism identified as Ochrobactrum anthropi completely degraded methylenediurea (MDU) and dimethylenetriurea (DMTU) to urea, ammonia, formaldehyde and carbon dioxide. An enzyme designated as methylenediurease (methylenediurea deiminase; MDUase) was responsible for the degradation of both MDU and DMTU as well as higher polymerized MU. Growth on MU as the nitrogen source specifically induced the synthesis of this enzyme, which seems to be located in the periplasm of the bacterium. Under these growth conditions, urease as well as NAD-specific formaldehyde and formiate dehydrogenase were expressed to high levels, efficiently using the products of MU degradation, and high-affinity transport systems for urea and ammonia were synthesized scavenging the environment for these products.

Amidohydrolases↗

Comparison of the allospecific and viral-specific immune responses to irradiated versus formaldehyde-fixed allogeneic Moloney lymphoma cells in CBA mice.

Two groups of adult CBA mice were immunized with 10-7 allogeneic Moloney lymphoma (YAC) cells. These YAC (H-2a) cells, which were either irradiated with 6000 R (Group i) or were formaldehyde fixed (Group II), were injected i.p. at weekly intervals for 3 weeks. Four days following the last injection, sera and lymphocytes were collected and tested in vitro for activity against either allospecific antigens (H-2d target cells) or viral-specific antigens, namely, Moloney leukemia virus (MLV). Both groups of animals developed measurable cellular and humoral immunity to the virally determined antigens. However, only the animals in Group i, immunized with irradiated cells, developed detectable immunity to H-2d. Immune and control lymphocytes were tested in microcytotoxicity tests and by 51Cr release. Antibody was assessed by complement-dependent cytotoxicity, indirect membrane immunofluorescence, virus neutralization, and antibody-dependent lymphocyte cytotoxicity. Group I serum, which had both anti-MLV and anti-H-2 antibodies, was absorbed with either living or formaldehyde-fixed YAC cells. The living cells were able to remove both H-2 and MLV antibodies. On the other hand, the formaldehyde-fixed cells removed no H-2 antibody but were able to remove MLV antibody, although less efficiently than living cells. These data indicate that formaldehyde fixation selectively impaired the H-2 antigens, leaving the viral antigenicity relatively intact. Differences between the immune responses to MLV-determined antigens and to H-2 antigens were demonstrated in many of the parallel in vitro tests.

Animals↗

A study on dust emission, particle size distribution and formaldehyde concentration during machining of medium density fibreboard.

A study to characterise the quantity, particle size distribution and morphology of dust created during the machining of MDF was carried out. Four different types of MDF boards were included in this study, including a 'zero-formaldehyde' board that contains isocyanate-based resin, rather than urea-formaldehyde resin. In addition, natural softwood (pine) and natural hardwood (oak) were included in the study, for comparison with MDF. The results show that in general, the dust generated by machining MDF is comparable in terms of particle size distribution and morphology with the dust generated by similarly machining hardwood or softwood. The quantity of dust generated during sanding is higher for sanding MDF compared with sanding either hardwood or softwood. However, for sawing there is no significant difference between MDF and natural woods, in terms of the quantity of dust generated. Free formaldehyde in the air was less than 0.17mg m(-3) during machining of the Class B (higher formaldehyde potential) MDF board. There was no measurable isocyanate in the dust generated from the boards.

Air Pollutants, Occupational↗

Formaldehyde-mediated aggregation of protein antigens: comparison of untreated and formalinized model antigens.

A formaldehyde-mediated aggregation pathway (FMAP) is suggested as being primarily responsible for the aggregation of lyophilized tetanus toxoid (TT; a formalinized antigen) in the presence of moisture. The general occurrence of the FMAP was examined by using bovine serum albumin (BSA) and ribonuclease A (RNase) as model antigens; both protein antigens were formalinized according to a method commonly used to detoxify bacterial toxins. To clearly delineate the FMAP from other aggregation mechanisms, the aggregation kinetics and mechanism of both unmodified antigens (BSA and RNase) and formalinized antigens (f-BSA and f-RNase) were evaluated. We report that formaldehyde treatment introduces more rapid and extensive aggregation in antigens under conditions that favor the FMAP (i.e., 80% relative humidity and 37 degrees C). Consistent with formaldehyde-mediated crosslinking, f-antigen aggregates were covalent and non-disulfide-bonded, whereas BSA aggregates were disulfide-linked and RNase even did not aggregate under the same conditions. Coincorporation of amino acids (histidine and lysine), which strongly interact with formaldehyde, as well as prior antigen reduction with cyanoborohydride, significantly inhibited f-BSA aggregation, but showed no selective effect on BSA aggregation. Mechanistic analysis of f-BSA aggregates, inhibition studies, and similar reactivity of f-BSA with TT all confirmed the existence of the FMAP at moisture levels intermediate between the dry and solution state. This study demonstrates the potential for covalent reactions between formalinized protein antigens and neighboring chemical or biochemical species even after formalinization, and provides a general approach to inhibit the FMAP.

Amino Acids↗

[Measurement of formaldehyde in disinfectant with spectrophotometry].

Formaldehyde in disinfectant was measured by acetylacetone spectrophotometry. The regression equation was linear when the formaldehyde concentration was smaller than 10 micrograms/ml. The detection limit was 0.08 microgram/ml. The accuracy was less than 3.9% and the recovery varied between 100.2%-108.2% for formaldehyde disinfectant with different concentration, which was similar to titrimetry. It was demonstrated that the method was simple, reproducible, sensitive, precise and accurate, making it important for assay of formaldehyde in disinfectant when disturbance caused titrimetry unavailable.

Disinfectants↗

Doxorubicin-formaldehyde conjugate, doxoform: induction of apoptosis relative to doxorubicin.

BACKGROUND: The anthracycline antitumor drug, doxorubicin (DOX), is proposed to catalyze the production of formaldehyde and bond to the formaldehyde at its amino sugar to produce an active metabolite that subsequently crosslinks DNA as part of the cytotoxic mechanism. Doxoform (DOXF), a synthetic formaldehyde conjugate of DOX, exhibits enhanced toxicity to numerous sensitive and resistant cancer cell lines. The aim of this study was to demonstrate that DOXF, at much lower drug levels, retains the apoptosis-inducing characteristics of DOX, consistent with DOXF being a prodrug to the DOX active metabolite. MATERIALS AND METHODS: HeLa S3 and MCF-7 cells were treated with IC50-equivalent concentrations of DOX and DOXF and analyzed for DNA fragmentation and phosphatidylserine externalization, common morphological features of apoptosis. DNA fragmentation was detected by gel electrophoresis and TUNEL assay; phosphatidylserine externalization was detected by annexin V binding. RESULTS: DNA fragmentation and phosphatidylserine externalization were detected in HeLa S3 cells following a 3 h treatment with either 86 nM equiv. DOXF or 1 microM DOX. No apoptotic features were observed for MCF-7 cells following a 3 h treatment with either DOXF (100 nM equiv.) or DOX (1 microM). CONCLUSIONS: DOXF induced cell death in both cell lines at drug levels an order of magnitude lower than DOX. The similar behavior of DOXF and DOX supports the role of formaldehyde in the cytotoxic mechanism of the clinical anthracycline antitumor agents and provides further support for the proposition that DOXF is a prodrug to the DOX active metabolite.

Annexin A5↗

IgE-mediated urticaria from formaldehyde in a dental root canal compound.

A patient had suffered twice from an acute urticaria after treatment with two different dental root canal compounds (RCC). Skin prick tests with the single components and formaldehyde 1%aq. were positive to formaldehyde 1%aq., but irritant with formaldehydeRCC. Specific IgE to formaldehyde were positive. Patch tests were positive to formaldehydeRCC only. In the literature 28 patients with immediate symptoms to formaldehyde containing RCC have been described.

Adult↗

Activation of adriamycin by the pH-dependent formaldehyde-releasing prodrug hexamethylenetetramine.

Previous studies have shown that Adriamycin can react with formaldehyde to yield an activated form of Adriamycin that can further react with DNA to yield Adriamycin-DNA adducts. Because hexamethylenetetramine (HMTA) is known to hydrolyze under cellular conditions and release six molecules of formaldehyde in a pH-dependent manner, we examined this clinical agent for its potential as a formaldehyde-releasing prodrug for the activation of Adriamycin. In IMR-32 neuroblastoma cells in culture, increasing levels of HMTA resulted in enhanced levels of Adriamycin-DNA adducts. These adducts were formed in a pH-dependent manner, with 4-fold more detected at pH 6.5 compared with pH 7.4, consistent with the known acid lability of HMTA. The resulting drug-DNA lesion was shown to be cytotoxic, with combined Adriamycin and prodrug treatment resulting in a 3-fold lower IC(50) value compared with that of Adriamycin alone. Given the acidic nature of solid tumors and the preferential release of formaldehyde from HMTA in acidic environments, HMTA therefore has some potential for localized activation of Adriamycin in solid tumors.

Antineoplastic Agents↗