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Formaldehyde in the British chemical industry. An occupational cohort study.

This paper reports the mortality experience of a cohort of 7680 men who had first been employed before 1965 in one of six factories in the British chemical or plastics industry where formaldehyde had been manufactured or used. All the jobs undertaken by each man were classified, on the basis of subjective information, into four categories in terms of exposure to formaldehyde. More than 98% of the workforce were traced to the end of 1981. No deaths from nasal cancer were reported (1.07 expected), and no excess mortality was found for cancers at any of the sites previously reported to be possibly associated with formaldehyde. In one factory a significantly high mortality from lung cancer was found (standardised mortality ratio 124; 95% confidence limits 104, 148) when the mortality rates of England and Wales were used as a standard, but not when an adjustment was made based on the local area mortality. Within the factory the increased mortality was limited to men who had been exposed to "high" levels of formaldehyde. There were no trends of increasing mortality with duration of work or interval since first exposure. This result may be a chance finding or reflect the influence of smoking or some other factor. Although a carcinogenic action of formaldehyde seems less likely as an explanation it cannot be excluded. The statistical power of the study to detect various risks of nasal cancer is described.

Chemical Industry↗

Threshold responses in formaldehyde-sensitive subjects.

Patch tests with three low concentrations of formaldehyde were applied continuously in formaldehyde-sensitive subjects for 1 wk. The closed patch test method produced a response to 30 parts per million (ppm) in some subjects by 120 continuous hours of testing. Thirteen subjects then sprayed a 30-ppm formaldehyde solution in an axilla on a double-blind, controlled, 2-wk-use test. Their responses to 30 ppm aqueous formaldehyde indicate that levels below this concentration should be tolerated by sensitive subjects if repeatedly applied to normal skin. Popular formaldehyde-releasing preservatives can be above or below this threshold-eliciting response.

Clinical Trials as Topic↗

Modifications of the catalytic and binding subunits of pertussis toxin by formaldehyde: effects on toxicity and immunogenicity.

A panel of pertussis toxin (PT) preparations with varying levels of residual toxicity was prepared by treatment of native PT with formaldehyde (0-1.00% (w/v)) with the purpose of investigating the effects of residual toxicity on immunogenicity. The catalytically inactive mutant PT (PT-9K/129G) was used for comparison. Results from in vitro ADP-ribosyl transferase and Chinese hamster ovary (CHO)-cell toxicity assays demonstrated a formaldehyde-dependent reduction in PT toxicity, and implied that both A and B domain functions of PT were modified. The in vivo histamine sensitisation and leukocyte proliferation tests suggested that the formaldehyde-treated native PT preparations were subject to reversion to toxicity. Reversion was confirmed by in vitro toxicity assays, which demonstrated recovery of A and B domain functions. The presence of high molecular weight aggregated and cross-linked species of PT in these preparations did not appear to be detrimental to the production of a neutralising antibody response. IgG responses to native and non-catalytic mutant PT suggested that low levels of residual activity in the native PT enhanced the antibody response, while higher levels of activity inhibited the response. Using the non-catalytic mutant PT showed that formaldehyde-induced changes were not detrimental to the magnitude of the PT-specific antibody response but did reduce the PT-specific neutralising activity. In conclusion, the residual toxicity of PT preparations following formaldehyde treatment may play an important role in the immune response to pertussis vaccine, potentially altering the quality, class and magnitude of the antibodies produced to PT.

Animals↗

Release of formaldehyde by 4 endodontic sealers.

OBJECTIVE: The purpose of this study was to evaluate the release of formaldehyde by some root canal filling materials. STUDY DESIGN: Two older endodontic sealers, AH 26 and Endomethasone, and 2 recently available sealers, AH Plus and Top Seal, were analyzed. Infrared and electronic spectroscopy were used to determine formaldehyde content after set of the materials. RESULTS: Analysis showed that the AH 26 and Endomethasone sealers released formaldehyde. Although the AH Plus and Top Seal sealers have similar chemical composition, they released formaldehyde in a minimal concentration. CONCLUSIONS: The AH 26 and Endomethasone sealers released formaldehyde after setting; however, a minimum release was observed for the AH Plus and Top Seal sealers.

Administration, Topical↗

Laser-induced fluorescence of formaldehyde in combustion using third harmonic Nd:YAG laser excitation.

Formaldehyde (CH2O) is an important intermediate species in combustion processes and it can through laser-induced fluorescence measurements be used for instantaneous flame front detection. The present study has focussed on the use of the third harmonic of a Nd:YAG laser at 355 nm as excitation wavelength for formaldehyde, and different dimethyl ether (C2H6O) flames were used as sources of formaldehyde in the experiments. The investigations included studies of the overlap between the laser profile and the absorption lines of formaldehyde, saturation effects and the potential occurrence of laser-induced photochemistry. The technique was applied for detection of formaldehyde in an internal combustion engine operated both as a spark ignition engine and as a homogenous charge compression ignition engine.

Fluorescence↗

Formaldehyde as a probe of DNA structure. I. Reaction with exocyclic amino groups of DNA bases.

A comprehensive description is given of both the equilibrium and the kinetic aspects of the reaction of formaldehyde with the exocyclic amino groups of derivatives of adenine, cytosine, and guanine; the results extend previous data in the literature to the point where formaldehyde can now be used as a quantitative probe of DNA structure and dynamic behavior. The main results are: (i) the reaction product is proven (by isolation followed by nuclear magnetic resonance (NMR) spectroscopy) to be a hydroxymethyl group; (ii) a dihydroxymethyl adduct is shown to exist at high formaldehyde concentrations; (iii) equilibrium constants at 25 degrees for forming the monoadduct with adenine and cytosine compounds are about 12 (M-1), while those for forming the dihydroxymethyl adduct are about 0.4 (M-1); (iv) the standard enthalpies for forming the monoadducts with adenine and cytosine compounds are about minus 4 to minus 6 kcal/mol; (v) indirect evidence is presented suggesting that a monohydroxymethyl group on adenine or cytosine derivatives exists preferentially as that rotational isomer which blocks Watson-Crick hydrogen bonding; (vi) in derivatives of guanine, it is shown that the N-1 endocyclic imino group can react with formaldehyde, as well as the amino group, the overall equilibrium constant being about 6 (M-1); (vii) all rate constants are reported, as well as their response to temperature, pH, and various solvent additives known to perturb DNA structure; (viii) using a series of substituted anilines, a linear free energy relation is obtained between the logarithm of both the forward and the reverse rate constant for the formaldehyde reaction and the amine pK, over a range of 10-8 change in amie basicity; (ix) using this relation, the pK's for protonating the nucleoside amino groups are estimated to lie in the range of minus 2 to minus 4; (x) a reaction mechanism is proposed; and (xi) some implications of these results forpolynucleotide studies are discussed.

Adenine↗

Removal of formaldehyde by hydroxyapatite layer biomimetically deposited on polyamide film.

Some harmful volatile organic compounds (VOCs), such as formaldehyde, are regulated atmospheric pollutants. Therefore, development of a material to remove these VOCs is required. We focused on hydroxyapatite, which had been biomimetically coated on a polyamide film, as an adsorbent and found that formaldehyde was successfully removed by this adsorbent. The amount of formaldehyde adsorbed increased with the area of the polyamide film occupied by hydroxyapatite. The amount of adsorbed formaldehyde and its rate of adsorption were larger for hydroxyapatite deposited on polyamide film than for the commercially available calcined hydroxyapatite powder. This high adsorption ability is achieved by the use of nanosized particles of hydroxyapatite with low crystallinity and containing a large number of active surface sites. Therefore, hydroxyapatite biomimetically coated on organic substrates can become a candidate material for removing harmful VOCs such as formaldehyde.

Adsorption↗

Controlling formaldehyde emissions with boiler ash.

Fluidized wood ash reduces formaldehyde in air from about 20 to <1 ppmv. Methanol is removed to a much lower extent. The efficiency of formaldehyde reduction increases with increasing moisture content of the ash. Sorption of formaldehyde to ash can be substantially accounted for by partitioning to the water contained in the ash followed by rate-controlling binding to the ash solids. Adsorption occurs at temperatures of up to 165 degrees C; oxidation predominates thereafter. It is proposed that formaldehyde could be stripped from an air stream in a fluidized bed containing ash, which could then be returned to a boiler to incinerate the formaldehyde.

Adsorption↗

Effect of various cryostabilizers on the production and reactivity of formaldehyde in frozen-stored minced blue whiting muscle.

The production of formaldehyde in frozen-stored minced blue whiting muscle was described by a rectangular hyperbolic model, and the effectiveness of each cryostabilizer is discussed in terms of its parameters. The maltodextrins assayed noticeably inhibited formaldehyde production, this effect being greater at -20 degrees C than at -10 degrees C. Sucrose was only effective at -20 degrees C. It seems that these compounds act by restricting molecular diffusion. The effect of each cryostabilizer on formaldehyde binding was closely regulated by its effect on production. This is discussed in terms of the binding equation parameters. The binding of formaldehyde during frozen storage was dependent on protein rearrangements leading to reactive groups becoming available. The constraints of cryostabilizers on molecular diffusion reduced the exposure of these groups. Consequently, the interpretation of formaldehyde reactivity was biased, leading to conclusions different from those that would be obtained from a study done under standard conditions.

Animals↗

Doxoform and Daunoform: anthracycline-formaldehyde conjugates toxic to resistant tumor cells.

The recent discovery that the clinically important antitumor drugs doxorubicin and daunorubicin alkylate DNA via catalytic production of formaldehyde prompted the synthesis of derivatives bearing formaldehyde. Reaction of the parent drugs with aqueous formaldehyde at pH 6 produced in 40-50% yield conjugates consisting of two molecules of the parent drug as oxazolidine derivatives bound together at their 3'-nitrogens by a methylene group. The structures were established as bis(3'-N-(3'-N,4'-O-methylenedoxorubicinyl)) methane (Doxoform) and bis(3'-N-(3'-N,4'-O-methylenedaunorubicinyl))methane (Daunoform) from spectroscopic data. Both derivatives are labile with respect to hydrolysis to the parent drugs. 3'-N,4'-O-Methylenedoxorubicin and 3'-N,4'-O-methylenedaunorubicin are intermediates in the hydrolysis. Daunoform reacts with the self-complementary deoxyoligonucleotide (GC)4 faster than the combination of daunorubicin and formaldehyde at an equivalent concentration to given drug-DNA adducts. In spite of hydrolytic instability, Doxoform is 150-fold more toxic to MCF-7 human breast cancer cells and 10000-fold more toxic to MCF-7/ADR resistant cells. Toxicity to resistant cancer cells is interpreted in terms of higher lipophilicity of the derivatives and circumvention of catalytic formaldehyde production.

Alkylation↗

Studies on the nitroso-glyoxylate reaction. Relative hydroxamic acid production by glyoxylate, pyruvate, and formaldehyde in reactions with 4-nitrosobiphenyl.

The pH rate profiles for the reactions of 4-nitrosobiphenyl with three carbonyl substrates in aqueous buffers were determined by use of chromatographic and spectrophotometric methods. Glyoxylate and formaldehyde caused the conversion of 4-nitrosobiphenyl to N-(4-biphenyl)-formohydroxamic acid, while pyruvate resulted in the production of N-(4-biphenyl)acetohydroxamic acid. The dramatic effect of pH on the kinetics of these reactions provided considerable information concerning the nature of these reactions. The reactions with pyruvate and formaldehyde displayed similar pH rate profiles and were significant only at acidic pH. Glyoxylate displayed a pH rate profile that differed markedly from those of pyruvate and formaldehyde as the pH was increased beyond 2.0. The ability of glyoxylate to convert 4-nitrosobiphenyl to the hydroxamic acid increased rapidly in the pH range 2.0-4.0, above which the pH dependency was constant. This biphasic appearance of the pH rate profile was unique to glyoxylate, since the reactions of pyruvate and formaldehyde became extremely slow as solution neutrality was approached. A second substrate, 4-chloronitrosobenzene, displayed similar pH rate profiles in its reactions with these carbonyl substrates. For 4-nitrosobiphenyl, hydroxamic acid formation by glyoxylate was 10(4) times faster than that by pyruvate at neutral pH, but only about 3-fold faster at pH 1.0. The appearance of the pH rate profile for glyoxylate suggested that this alpha-oxo acid reacts with nitrosoarenes at neutrality via a pathway that is insignificant for pyruvate or formaldehyde. Thus, the nitroso-glyoxylate reaction is unique to this alpha-oxo acid under physiological pH conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Biphenyl Compounds↗

Maize glutathione-dependent formaldehyde dehydrogenase cDNA: a novel plant gene of detoxification.

We have previously shown that intact plants and cultured plant cells can metabolize and detoxify formaldehyde through the action of a glutathione-dependent formaldehyde dehydrogenase (FDH), followed by C-1 metabolism of the initial metabolite (formic acid). The cloning and heterologous expression of a cDNA for the glutathione-dependent formaldehyde dehydrogenase from Zea mays L. is now described. The functional expression of the maize cDNA in Escherichia coli proved that the cloned enzyme catalyses the NAD(+)- and glutathione (GSH)-dependent oxidation of formaldehyde. The deduced amino acid sequence of 41 kDa was on average 65% identical with class III alcohol dehydrogenase from animals and less than 60% identical with conventional plant alcohol dehydrogenases (ADH) utilizing ethanol. Genomic analysis suggested the existence of a single gene for this cDNA. Phylogenetic analysis supports the convergent evolution of ethanol-consuming ADHs in animals and plants from formaldehyde-detoxifying ancestors. The high structural conservation of present-day glutathione-dependent FDH in microorganisms, plants and animals is consistent with a universal importance of these detoxifying enzymes.

Alcohol Dehydrogenase↗

Formation of formaldehyde from adrenaline in vivo; a potential risk factor for stress-related angiopathy.

Cardiovascular and cerebrovascular disorders are well known to be associated with stress related behaviors. Stress enhances excretion of adrenaline, which is deaminated by monoamine oxidase and methylamine is formed. This product can be further deaminated by semicarbazide-sensitive amine oxidase (SSAO) and converted to toxic formaldehyde, hydrogen peroxide and ammonia. SSAO is located in the cardiovascular smooth muscles and circulated in the blood. We investigated whether formaldehyde can be derived from adrenaline in vivo. Methylamine was confirmed to be a product of adrenaline catalyzed by type A monoamine oxidase (MAO-A). Irreversible and long-lasting radioactive residual activity was detected in different tissues following administration of 1-[N-methyl-3H]-adrenaline. Such irreversible linkage could be blocked by selective MAO-A or SSAO inhibitors. Endothelial cells are quite sensitive to formaldehyde and relatively resistant to hydrogen peroxide. It is possible that stimulation of adrenaline excretion by chronic stress could increase the levels of circulatory formaldehyde. Such chronic "formaldehyde" stress may be involved in the initiation of endothelial injury and subsequently angiopathy.

Amine Oxidase (Copper-Containing)↗

Primary oxidation products affect the quantification of formaldehyde in autoxidized fatty alcohol ethoxylates when using DNPH derivatization.

Non-ionic surfactants, e.g. fatty alcohol ethoxylates, are considered to cause less skin irritation than other types of surfactants. However, the autoxidation of alcohol ethoxylates generates products that are both skin irritating and sensitizing, such as formaldehyde. It has been suggested that formaldehyde be used as an indicator of the degree of autoxidation of fatty alcohol ethoxylates, and thus also as an indicator of the sensitizing capacity of the product. Attempts to analyse formaldehyde in autoxidized ethoxylates using 2,4-dinitrophenylhydrazine derivatization resulted in formation of the corresponding hydrazone not only from free formaldehyde but also from autoxidation products during the derivatization reaction. Consequently, this derivatizing agent is inappropriate for the determination of formaldehyde in autoxidized fatty alcohol ethoxylates. Focus on the content of primary oxidation products, i.e. hydroperoxides/peroxides, is suggested, particularly as they also are potent sensitizers.

Alcohols↗

Sources of formaldehyde, other aldehydes and terpenes in a new manufactured house.

Formaldehyde, less volatile aldehydes, and terpene hydrocarbons are generally the predominant air contaminants in new manufactured and site-built houses. This study was conducted to identify the major sources of these compounds in a typically constructed, new manufactured house and to evaluate several source reduction practices. Specimens of materials used within the house were collected. These were individually pre-conditioned for 19 +/- 4 days, and tested for emissions of formaldehyde and other target compounds using small-scale chambers. Several cabinetry materials, passage doors, and the plywood subfloor were the predominant sources of formaldehyde and other aldehydes. The plywood subfloor was the predominant terpene source. Whole-house emission rates for combined materials were predicted based on the emission factors and the corresponding material quantities. These predicted rates were compared with whole-house emission rates derived from measurements made at the house 3 months after its installation. For 10 of 14 target compounds including formaldehyde, the predicted and derived rates were within a factor of two. Four emission barriers applied to plywood were shown to reduce emission factors for formaldehyde, hexanal, and other aldehydes.

Air Pollution, Indoor↗

Formaldehyde levels in Sweden: personal exposure, indoor, and outdoor concentrations.

Formaldehyde is a ubiquitous environmental pollutant and is probably carcinogenic to humans. Exposure to formaldehyde was investigated in the general population with personal as well as stationary measurements. The results from two campaigns in two Swedish cities are presented, including measurements of personal exposure among a total of 65 randomly selected subjects together with simultaneous measurements of individual indoor and outdoor concentrations. Diffusive GMD samplers were placed in the breathing zone, in the participants' bedrooms, and outside their homes for 24 h in campaign A and six days in campaign B. Repeated measurements were also conducted in order to study the variability between and within individuals. Median personal exposure to formaldehyde was 22 microg/m(3) (campaign A) and 23 microg/m(3) (campaign B), which is within the guideline value range of 12-60 microg/m(3) proposed in Sweden. Bedroom concentrations were generally slightly higher than personal exposure, while outdoor concentrations (measured only in campaign B) were low. In campaign B, the stationary measurements were used to model personal exposure. Bedroom concentrations were found to explain 90% of the variation of the measured personal exposure and predicted personal exposure nearly as well as an extended model that also included the outdoor contribution. Subjects living in single-family houses had significantly higher exposure to formaldehyde compared with subjects living in apartments. The 24-h and 6-day sampling periods yield a relatively low within-individual variability for formaldehyde measurements with GMD samplers.

Adult↗

Formaldehyde determination in seawater. Preliminary application to coastal samples at Terra Nova Bay (Antarctica).

A sensitive spectrofluorimetric-FIA (flow injection analysis) method for formaldehyde (HCHO) determination was improved with the aim of analysing seawater samples. The fluorescence emission versus HCHO concentration shows a linear pattern from sub microg L(-1) to about 1000 microg L(-1). The reproducibility at 15 ppb level is about 2%. Interferences from other aldehydes were checked; only glyoxal shows a significative interference, but only when its concentration is about 6000 times higher than that of formaldehyde. Superficial (microlayer, just sub-pack or sea-ice free sea surface) and deep (along the water column, sub-pack or in sea-ice free areas) seawater samples were collected near the coast at Terra Nova Bay (Ross Sea, Antarctica) during the 1998/1999 and 2001/2002 Italian Antarctic Expedition. We report here the preliminary results of the spectrofluorimetric-FIA determination of the HCHO content. The mean seawater superficial formaldehyde concentration was 15 microg L(-1); the concentration along the water column ranged between 4.5 to over 40 microg L(-1)(20 microg L(-1) mean concentration), usually with a maximum value for the 30 m depth, corresponding to a fluorescence maximum. The sampling was repeated 7 times in the austral summer in order to evaluate seasonal changes in the formaldehyde concentration/seawater depth profiles. The results show changes in the formaldehyde concentration at different depths.

Antarctic Regions↗

Stimulation by paraquat of microsomal and cytochrome P-450-dependent oxidation of glycerol to formaldehyde.

Glycerol can be oxidized to formaldehyde by microsomes in a reaction that is dependent on cytochrome P-450. An oxidant derived from the interaction of H2O2 with iron was responsible for oxidizing the glycerol, with P-450 suggested to be necessary to produce H2O2 and reduce non-haem iron. The effect of paraquat on formaldehyde production from glycerol and whether paraquat could replace P-450 in supporting this reaction were studied. Paraquat increased NADPH-dependent microsomal oxidation of glycerol; the stimulation was inhibited by glutathione, catalase, EDTA and desferrioxamine, but not by superoxide dismutase or hydroxyl-radical scavengers. The paraquat stimulation was also inhibited by inhibitors, substrate and ligand for P-4502E1 (pyrazole-induced P-450 isozyme), as well as by anti-(P-4502E1) IgG. These results suggest that P-450 still played an important role in glycerol oxidation, even in the presence of paraquat. Purified NADPH-cytochrome P-450 reductase did not oxidize glycerol to formaldehyde; some oxidation, however, did occur in the presence of paraquat. Reductase plus P-4502E1 oxidized glycerol, and a large stimulation was observed in the presence of paraquat. Rates in the presence of P-450, reductase and paraquat were more than additive than the sums from the reductase plus P-450 and reductase plus paraquat rates, suggesting synergistic interactions between paraquat and P-450. These results indicate that paraquat increases oxidation of glycerol to formaldehyde by microsomes and reconstituted systems, that H2O2 and iron play a role in the overall reaction, and that paraquat can substitute, in part, for P-450 in supporting oxidation of glycerol. However, cytochrome P-450 is required for elevated rates of formaldehyde production even in the presence of paraquat.

Animals↗