RESERVE THIS SPACE

Formaldehyde – all-rounder or toxicant

Minh Tuyen Mai

Martin-Luther-University Halle-Wittenberg, Institute of Chemistry, Food

Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany,
minh.mai@student.uni-halle.de

The simplest member of the aldehyde family, formaldehyde, or

so-called methanal has a very strong reactivity. It is a colorless,
pungent, and toxic gas. There are sources: natural which can occur
in all living organisms and anthropogenic which comes from all
kinds of combustion mainly fuel combustion and emissions from
house components as well as indoor activities such as cooking.
Besides irritating characteristics, it is even considered a
carcinogen and a neural toxin. Human is exposed mostly through
ingestion compared to inhalation. Through inhalation and
ingestion, formaldehyde is rapidly absorbed and transported, and
converted throughout the body. There are so many pathways to
detoxify formaldehyde, in which glutathione (GSH)-dependent
pathway catalyzed by ADH3 and S-formyl GSH hydrolase plays
the main role. At last, the metabolites are eliminated through
exhalation (CO2), urine, and feces (HCOO-). Formaldehyde is one
of the most 50 produced chemicals. Its use is widely expanded in
all areas of life, in which the resin industry plays an essential role.

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 Introduction

The simplest member of the aldehyde family, formaldehyde, or so-called

methanal has a very strong reactivity due to the strong electrophilic property of the
carbonyl group. Formaldehyde is colorless, pungent, and has a low molecular
weight. The first report of formaldehyde was in 1859 by Aleksandr Butlerov, a
Russian chemist who accidentally misinterpreted the compound as dioxymethylen. 1
It was finally identified as formaldehyde by August Wilhelm von Hofmann, a
German chemist whose method of producing formaldehyde is, with additional
enhancements, still in use.2,3 So many studies have shown that it is a very toxic gas
and even considered a human carcinogen and a neural poison. The question is if
formaldehyde is such a very toxic substance, why is its use intensively wide? And is
it so poisonous that it should not appear in any living organism? If formaldehyde is
unfortunately consumed, what would happen next? In this essay, detailed
information about the definition, properties, usage areas, and harmful effects of
formaldehyde will be discussed.

Production and chemical/physical properties

Production
Formaldehyde is one of the 25 most produced chemicals in the world.4 The
increase in worldwide production of formaldehyde firmly is almost double from
1992 (12 million tons)5 to 2000 (21.5 million tons)6. This indicates that the need for
formaldehyde is significantly bigger. There are several ways to produce
formaldehyde. However, the primal manufacture is the oxidation of methanol, in
which methanol is firstly generated from synthesis gas.7 The method using red-hot
metal (e.g., silver nowadays, before copper)5 as catalysts to form formaldehyde from
methanol, which had been found by A.W. von Hoffmann a hundred years ago, is
primarily widely used today.7,8 The overall yield of formaldehyde can go up to 86–
90%.7 An alternative method is using metal oxide (e.g., iron-promoted molybdenum
oxide) as the catalyst with a yield of more than 90%.9
Properties
The enormous production volume of formaldehyde implies that the demand for
its use is intensively growing. On the other hand, it exhibits many toxic
characteristics.10 Therefore, its properties were extensively investigated in the
following decades.11 Its solubility in hydrogen-bond donor solvents, and a bipolar
solvent such as water6 is an important factor in the formaldehyde’s toxicokinetics.

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Besides that, its strong reactivity (e.g., association with itself and association with
water,5 amines leading to cross-links proteins11, etc.) also plays a deciding role.

Occurrences of formaldehyde

cigarette cosmetics

textiles
chip-
board

clean air
indoor air

Figure 1: Schematic representatives of formaldehyde-releasing products12

Figure 1 shows the overview of formaldehyde occurrences, which humans are in
close contact with.
Natural sources
Formaldehyde can be found in almost all of earth’s living organisms (e.g.,
amount from 0.1-0.4 mM in human body fluids and tissues)11. It is also a product of
many natural processes5 (e.g., volatile organic compounds13 (most important:
methane) oxidation in the troposphere and as an intermediate product of the radical
reaction of terpenes as well as isoprenes)6. Formaldehyde’s natural occurrence in
food also is concerned, which is elucidated in the section “Formaldehyde and food”.
Anthropogenic sources
Besides natural backgrounds, anthropogenic activities also contribute to the huge
amount of formaldehyde. There are direct and indirect sources in this category.
Industrial onsite uses and fuel combustion play a major part as direct sources.13
According to the data reported to the National Pollutant Release Inventory of
Canada, the largest direct source is on-road mobile vehicles.5 277 million kg/year is
the amount emitted from automobiles that have engines not equipped with catalytic
converters.7 Gasoline-powered and diesel-powered vehicles account for 40% and
60% of the on-road automotive exhausts, respectively.5 Speaking of non-direct

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sources, man-made products, and uses13 must be mentioned (e.g., formaldehyde-
based products: buildings, plastic, etc.)14.
Next to outdoor, formaldehyde is also a major indoor released pollutant.15
Formaldehyde could be released by all parts of a house (e.g., painted walls, clothing,
and furniture) and consumer products.14 Generally, the formaldehyde content in
these products is less than 1%.7

Toxicity

Formaldehyde is listed as an irritant gas. In the case of irritant gases, the

localization of damage in the respiratory tract is determined by their water
solubility.16 With decreasing water solubility, they tend to attack deeper and deeper
"airway floors", which is largely independent of the damage mechanism. This
observation is explained by the rapid decrease in the concentration of water-soluble
gases along the airways through interaction and absorption from the mucous
membranes.16 It is unknown how exactly the formaldehyde toxicity mechanism
works. However, there is an interaction with molecules on cell membranes, in
tissues, and in some parts of body fluids (e.g., proteins and DNA). Moreover,
disruption of cell functions is also observed.4
Conversion factors: at the atmosphere pressure and 20°C 1 ppm = 1.249 mg/m3,
and at 25°C 1 ppm = 1.228 mg/m3.13
Acute and chronic toxicity

Figure 2: Acute and chronic toxicity of formaldehyde12

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 Figure 2 demonstrates the overview of the toxicities of formaldehyde. Irritation
of the mucous membranes, eyes, and respiratory tract as well as skin symptoms are
the consequences of acute and chronic inhalation.12 NOAEL-value is 0.63 mg/m3
sensory irritation occurs at the concentration in range 0.15-1.25 mg/m3; and
respiratory effects occur at the concentration in range 0.08–11.2 mg/m3. 13
The chronic effects on the neural cells are the first point that would be taken a
more detailed look at. An increase in brain formaldehyde levels will likely change
brain cell metabolism. In that case, the function of the brain might be affected. The
results of different studies show a connection between neurodegenerative conditions
and a higher level of formaldehyde found in the brain. Furthermore, other studies
correlated those neuro-diseases with oxidative stress and impaired energy
metabolism.7 Results of studies, in which Tau protein was examined, suggest that
excess formaldehyde (abnormal elevation of extrinsic and intrinsic formaldehyde)
leads to hyper-modification and misfolding of proteins.17 Clinical studies, as well as
studies in mice, point out that formaldehyde can also induce chronic impairment and
sporadic senile dementia.17
The Department of Health and Human Services has determined that
formaldehyde may reasonably be anticipated to be a carcinogen. 4 After being
lifelong exposed to 5 ml/m3 and more, rats and mice showed carcinogenic effects in
the nasal area.16 The first symptom was always the destruction of local tissue
followed by the appearance of tumors.16 This cytotoxic effect leads to increased cell
division in the undamaged cells, which can ultimately lead to tumor formation. 16
Moreover, exposure to formaldehyde leads to an increased occurrence of DNA-
protein crosslinks.16 At the concentration of 2ppm, crosslinks are observed and
when the concentration is ≥ 4 ppm, tumors are observed.13

Toxicokinetics

Absorption and Exposures

As mentioned above, formaldehyde‘s solubility in water plays an important role
in its absorption which explains it is rapidly absorbed in the respiratory and
gastrointestinal systems of humans and animals.18 Besides that, absorption through
the skin is of less concern. Therefore, the two following main routes of exposure
would be further discussed below.
Although a study in Canada reveals that the daily formaldehyde inhalation intake
is lower compared to the intake from food, inhalation and ingestion are normally
concerned separately due to the relation between critical effects and attacked
positions.13 Table 1 shows the value of exposure by different types.

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Table 1:General world population exposure to formaldehyde categorized by media
and activity19
Media/Activity Exposure Exposure per kg
[µg/day] body weight
[µg/kg]
Air: Inhalation exposure 1542 24
Food products Range: low 4350 68
Range: high 41900 655
Inhalation exposure
The ratio of formaldehyde concentration between indoor concentration and
outdoor concentration is always bigger than 1.14 To come to this statement, so many
surveys, as well as studies, have been carried out. Specifically, here, the following
data13 are reported: 15 and 32 μg/m3 (50th and 95th percentiles, respectively) in 100
office buildings in the United States (1994-1998), 14 μg/m3 in winter, and 30 μg/m3
in summer in 50 schools in Japan (2000), and 28 μg/m3 in 419 rooms in Germany
(2001-2004). Meanwhile, from the outdoor concentration, ambient concentrations
are 1.5–16.4 μg/m3 with a mean value of 7.2 μg/m3.13 Another study in China
strengthening this statement shows that in 6000 recently refurbished dwellings
(1999-2006) the indoor and outdoor average concentration was 238 μg/m 3 and 12
μg/m3, respectively.14 Moreover, due to this ratio, formaldehyde is considered an
indoor pollutant.13 Indoor inhalation accounts for 98% of total inhalation, the rest for
outdoor inhalation and inhalation from traffic is 1% each. 19 Guidelines for indoor
exposure according to WHO is 0.1 mg/m3 (30-minute average concentration).13
Distribution and Elimination
Figure 3 shows a general distribution and elimination of a substance when it is
absorbed.
After the absorption by inhalation and ingestion, formaldehyde is then
transported into arterial bloodstreams. After that, it is continuously transported to
different organs (e.g., liver) and tissues (except fat tissue4). As mentioned above,
formaldehyde is then primarily eliminated from the body as CO 2 through the lungs.7
In most studies, radioactive substance 14C would be used to examine the distribution
and elimination. An observation of 6-hour inhalation exposure of rats shows that
about 40% was eliminated as CO2 over 70 hours; 17% as formate6 in the urine, 5%
in the feces, and 35–39% remained in the tissues and carcass.13 In the case of
ingestion, a study in rats shows that within 12 hours, 40 % of the radioactive 14C-
formaldehyde was eliminated as CO 2, 10% in the urine, and 1% in the feces; after
24 hours total body 14C-residues were 20%.20

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Figure 3: Conceptual Representation of a Physiologically Based Pharmacokinetic
(PBPK) Model for a Hypothetical Chemical Substance 4

Metabolism

Figure 4: Metabolism: the fate of formaldehyde3

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 Figure 4 shows some endogenous pathways elucidating the fate of formaldehyde
in the human body worth discussing. These pathways are the repair mechanisms to
prevent the lethal and mutagenic damage21 because they help to transform
formaldehyde into metabolites (CO2 and HCOO-), which are later either eliminated
or further used.
Generation of formaldehyde from methanol
To understand the issue simpler, methanol will be examined in this part. Besides
other formaldehyde sources, methanol is consumed from fruits, vegetables,
fermented beverages, soft drinks, and aspartame-sweetened foods or as an
endogenous product of a carboxyl methyl esters’ hydrolyzation is also an important
source to form formaldehyde.10 Three main pathways accounting for the generation
of formaldehyde from methanol in vivo are: catalytic oxidation in the presence of
hydroperoxide (H2O2) with side product water (H2O), radical reaction (hydroxyl
radicals (•OH) originating from methanol through the help of Fe2+ and H2O2) with
side product O2 and enzymatic oxidation through ADH1 and NAD +.14
Mitochondrial Aldehyde dehydrogenase-2 (ALDH2) Pathway
This first pathway is a single-step glutathione (GSH)-independent process
reaction, in which aldehyde dehydrogenase enzymes (ALDH) play as catalysts. 11
This enzyme family is responsible for the oxidation of aldehyde into the salt of the
corresponding carboxylic acid.22 Specifically, aldehyde dehydrogenase class I,
member A1 (ALDH1A1) and ALDH2.6 They are both tetrameric enzymes,
however, ALDH1A1’s location is in the cytosol and ALDH2 in the mitochondrial
matrix.23 These ALDHs have an affinity for free formaldehyde.6
More clearly, ALDH2 would catalyze further oxidation of the generated
formaldehyde to formic acid in the presence of NAD + with the by-products NADH
and H+.14 Nevertheless, the physiological relevance of ALDH2 in formaldehyde
biology is little understood.24
Glutathione-Dependent Pathway
Glutathione (GSH) is a thiol-containing tripeptide, which is able to act as an
important antioxidant to prevent carbonyl derivatives generated through lipid
peroxidation.14 Figure 5 shows the molecular structure of GSH.

Figure 5: Glutathione molecule25

In this pathway, class III alcohol dehydrogenase (ADH3 or FDH10) and S-
formylglutathione hydrolase play the main role.6 Compared to ALDH2, ADH3
(cytosolic ADH), also known as GSH-dependent formaldehyde dehydrogenase,

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oxidizes formaldehyde to formate in a multistep process.6 Members of the ADH
family are homodimer enzymes with the subunits consisting of two domains: a
coenzyme binding domain and a distal catalytic domain and between these domains
in the cleft there is an active site.26
Firstly, a spontaneous enzyme-independent reaction between formaldehyde and
glutathione to form S-hydroxymethylglutathione (HMGSH) initially takes place.
10,11
HMGSH as ADH3 substrate is subsequently oxidized to generate S-
formylglutathione in the presence of electron acceptor NAD +.6,11,14,24 At last, S-
formylglutathione is further irreversibly metabolized by S-formylglutathione
hydrolase (FGH) yielding formate and regenerating reduced GSH.6,14,24
Due to a very low Michaelis-Menten constant (Km)-value for S-hydroxymethyl
glutathione (4 μM) of ADH3 compared to that of ALDH2 for formaldehyde (0.2–
0.5 µM), ADH3 is likely to be especially important for the oxidation of low
concentrations of formaldehyde.6,11 Meanwhile, the low Km-value of ALDHs leads
to its increasing contribution, when the concentrations of formaldehyde increase.6
Formaldehyde and Formate in One-Carbon (1C) Circle
One-carbon units which are in the form of methyl (−CH3), methylene (−CH2-),
methenyl (−CH=), formyl (−CHO), and forming (−CH = NH) groups can be
transferred from one compound to another.14 In the presence of serine
hydroxymethyl transferase (SHMT), 1C units are produced primarily by the
enzymatic cleavage of serine, which might generate glycine and formaldehyde.24
This formaldehyde rapidly reacts with tetrahydrofolate (THF) to form 5,10-
methylene-THF14 entering the 1C cycle.24 The oxidized form of methylene-THF is
10-formyl-THF contributing to MET-tRNA formylation for mitochondrial protein
synthesis. 27 Alternatively, formate from hydrolyzed 10-formyl-THF will enter the
1C-cycle in the cytoplasm.27
Under physiological conditions, formic acid is usually dissociated into formate
and hydrogen ions.14 Carbon dioxide (CO2) is the oxidation product of the neurotoxic
formate by a THF-dependent multistep pathway.28 During this reaction cycle,
formate could be firstly ATP-independently converted to 10-formyl-THF by binding
to THF, in which 10-formyl-THF synthetase (either the cytosolic methylene
tetrahydrofolate dehydrogenase (MTHFD) 1 or its mitochondrial isoform
MTHFD1L) plays the role as a catalyst.11,14
There are 3 biosynthetic pathways in the cytoplasm. First, there is the de novo
purine biosynthesis, where 10-formyl-THFise is needed for the C2 and C8 carbons
of the purine ring. Then there is the de novo thymidylate biosynthesis for which
methylene-THF is necessary for the reductive methylation of deoxyuridylate
(dUMP) to create thymidylate (dTMP). The third pathway is the remethylation of
homocysteine to methionine, for which one needs 5-methyl-THF. 27
On the other hand, the cytosolic 10-formyl THF dehydrogenase, also known as
ALDH1L1, or its mitochondrial isoform ALDH1L2 oxidizes the formyl group on

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10-formyl-THF with help of the cofactor NADP+ to CO2.11 Figure 6 shows the
pathway for the convert of formic acid in 10-formyl-THF and later to CO2.
All the pathways mentioned above not only detoxify formaldehyde but also
supports essential metabolism by providing 1C units for nucleotide biosynthesis.24
Consequently, this circle provides cellular components including proteins, lipids,
and nucleic acids for cell growth and proliferation.14

Figure 6:Fate of the generated formate11

Use of formaldehyde

Formaldehyde is a chemical that is widely used due to its chemical properties

and is also found in the natural structure of the organism. It is particularly important
in the chemical industry because it is an inexpensive starting material for several
chemical reactions.29 It is applied in almost all life areas, e.g., resins industry,
chemical compound, food industry, medical fields, agriculture, etc. In these areas, it
can play a role as a reactant, preservative, disinfectant, insecticide, etc. Table 3
shows more details about its use in selected fields. The use of formaldehyde in
medical and other fields is 1.5% of the total production compared with its use in the
manufacture of synthetic resins and chemical compounds.29 Therefore, it is worth
discussing its role in the resin industry.
By the 20th century, development in chemistry and physics coming along with the
demand for innovative products led to the explosion in formaldehyde’s usage in the
newborn area “plastic”.15 Throughout the flow of history, there are four types of
formaldehyde-based plastic products: casein formaldehyde, phenolic resins, urea-
formaldehyde, and melamine-formaldehyde. Table 2 summarizes the use of resin
types.
Phenol formaldehyde (PF) is considered the first completely synthetic plastic
resin, which is the product of polycondensation. 15,30 In the past, it was called

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“Bakelite”.15,31 This resin consists of two main types: novolic resin, which is a
preconddensate with a high degree of crosslinking in acidic explaining for the
hardness and low deformation after curing; resolic resin, which is formed in alkaline
solution, reactive and self-curing.31,32 Figure 7 shows the basic product between one
formaldehyde and one phenol molecule. Meanwhile, figure 8 indicates the two
product types of the condensation process.

Figure 7: Reaction between phenol and formaldehyde31

Figure 8: Basic resin types: Resol and Novlak33

Urea-formaldehyde (UF), which is similar to phenolic resin, is a polymer of a
condensation reaction after the first step (Mannich reaction). 15,31 Due to hydrolysis
of C-N-bond releasing formaldehyde, this resin has very poor water resistance. 15,31
The reaction between formaldehyde and urea molecule is shown in figure 9.

Figure 9: Reaction between urea and formaldehyde31

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 Melamine formaldehyde (MF): initiation by methylation of the melamine
molecule then the formation of a methylene bridge and a methylene ether bridge,
resulting in a three-dimensional polymer network.34 These resins are nearly identical
to UF resins, except they have high resistance to heat, water, and detergents.15 Figure
10 demonstrates a simple reaction between melamine and formaldehyde molecule.
One possibility of the final product is presented in figure 11.

Figure 10: Initial reaction between melamine and formaldehyde31

Figure 11: Melamine resin molecule with possible crosslinks34

Table 2: Formaldehyde resins appliances15,35,36

Resin types Use
Casein formaldehyde small plastic items such as buttons, buckles, and
knitting needles
Phenolic resins wood and foundry adhesives, laminates, molding,
composites protective coatings, electrical insulators
Urea-formaldehyde adhesives, binders, emulsion paints, foundry sands,
resins electrical applications
Melamine resins production of dishes and kitchen utensils

Table 3: Overview of the use of formaldehyde-based products in some selected

areas29
Area Use

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 Agriculture Seed dressing, soil disinfection, protection of dietary protein in
ruminants (animal nutrition), fumigant, preventative for mildew
in wheat and rot in oats, a germicide, and fungicide for plants, an
insecticide, and in the manufacture of slow-release fertilizers.
Cleaning The preservative in soaps, detergents, and cleaning agents
agent against microbial contamination
industry
Cosmetics The preservative in soaps, deodorants, shampoos, etc. against
industry microbial contamination; additive in nail hardeners, products for
oral hygiene, makeup, hand cream, and shaving cream; and plant
and equipment sanitation
Food industry Preservation of dried foods, disinfection of containers, and
preservation of fish and certain oils and fats, modifying starch
for cold swelling
Medicine Disinfection, sterilization, and preservation of preparations
Sugar Infection inhibitor in producing juices
industry

Formaldehyde and Food

Sources
As mentioned above, formaldehyde is also found in fruit, vegetables, or other
kinds of foods (e.g., seafood with an average amount of 2.177 ± 1.414 mg/kg)15 and
plant residues, which are still in the early stages of decomposition.6 A study in 2007
showed that sixty different fresh fruits were found to have a formaldehyde content
of below 2.74 mg/kg, but with refrigeration, this value increased by 2.3–3.8 times.15
Table 4 summarizes the concentrations in food and drink.
Table 4: Background levels range of formaldehyde in food and drink 37
Food product Formaldehyde content
[mg/kg]
Meat and poultry 5.7-20
Fish 6.4-293
Milk and milk products 0.01-0.80
Sugar and sweeteners 0.75
Fruit and vegetables 6-35
Coffee 3.4-16
Alcohol beverages 0.27-3.0

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 Not only products are the contributor, but also the processes such as cooking 5
account for indoor emission of formaldehyde. Firstly, the term cooking emissions
must be explained. Simply understand, it consists of “the gas and air fumes that are
expelled during cooking activities”38. In the cooking process, heat is a factor that
promotes the oxidation of fatty acids in edible oils.39 Consequently, primary
products, peroxides, would be converted to aldehydes. 40 The relation between
various cooking styles, food types, and formaldehyde emission has been studied.
Xiang et al. examined four different styles: barbeque, teppanyaki, frying, and stir-
frying. It was found that C1-C3 aldehydes account for 80% of released carbonyl
compounds. Based on the data of this study, formaldehyde is the most released one
and barbecue-style as well as frying-style have the biggest emission.41 Table 5 shows
the results of this study.
Table 5:Formaldehyde emission by cooking styles41
Cooking Styles Emission [µg/kg]
Barbecue 0.750 ± 0.106
Teppanyaki 0.664 ± 0.078
Frying 0.747 ± 0.112
Stir-frying 0.418 ± 0.127
Exposure
Oral exposure
When it comes to oral exposure, food exposure, which is an important natural
source, deserves the most attention. The average concentration is 1,5-14 mg/d
according to WHO.42 Depending on the individual's ability to consume, the exposure
concentrations [µg/d] should be classified in the high or low range.19 (see ranges in
table 1) Data on average exposure per person [µg/kg body weight] are provided as
follows: in the drink category, values from representatives such as alcoholic
beverages, coffee, and drinking water are 0.08-15, 14-65, and 0.3, respectively; in
the food category, values from representatives such as fruits and vegetables, meat
and poultry, and fish and shellfish are 24-436, 14.3-50.3, and 0.52-50.5,
respectively.19
Use
Formaldehyde is used as a preservative. Formalin is the 37-40% of
formaldehyde solution.5 Some studies show that formalin is used to prolong the shelf
life of fish, fruits, and vegetables in tropical countries.42 It also can be found in dried
foods, Italian cheeses, and many more products.14 Two different studies pointed out
that formaldehyde levels were also measured in vermicelli noodles in the ranges
0.011–2.859 mg/kg and 1.0–3.38 mg/kg, respectively.15

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 It is also used clean the machines of food production and be washed with water
afterward. Due to mistakes in the cleaning process, there is always a chance that
some of those substances for disinfection could be in the products. In 1985 for
example formaldehyde was found in sausages in Pfalz/Germany with a value of
70mg/kg.43

Conclusion
It can be seen that as much is produced, as much is consumed. According to
WHO, formaldehyde was consumed about 21 million tons (in 2000)6, accounting for
97% of production. The reason for the explosion of growth and consumption of
formaldehyde is the simplicity of production, low cost, and, most importantly, its
own physicochemical characteristics. Unfortunately, that glamor doesn't mean it's
harmless as it is present in every living organism's own body and is a component or
product of all the smallest things that humans come into direct contact with. In terms
of sources, for example, there are two main sources: natural and anthropogenic, in
which anthropogenic sources dominate. Eating is perhaps the most essential need
after breathing, so here, food, natural sources, and food processing, anthropogenic
sources are discussed in more detail. Different cooking styles in China have been
studied and it is shown that barbecue is the process that releases the largest amount
of formaldehyde among other styles because the food exposed to high temperatures
for a long period of time leads to the formation of toxic substances. The question is:
is formaldehyde itself really toxic? To answer this question is not simple. All aspects
must be considered. First, about its toxicity, formaldehyde is the simplest of the
aldehyde family, it is also its simple structure (when only one carbonyl group is
directly bonded to two hydrogen atoms) that is responsible for the high reactivity
because its electrophilicity is now unaffected by electron repulsive groups as in other
aldehydes. Formaldehyde itself is a hydrogen-bond acceptor, which explains its high
solubility in water. This is also the reason why it is absorbed rapidly through the
inspiratory and gastrointestinal systems but not much through the skin, which is a
semi-permeable membrane. As mentioned, the main anthropogenic source is
dominance which also means that the natural source is secondary and in addition,
human exposure through ingestion is much more than inhalation. Therefore, it can
be said that fortunately until now formaldehyde has not been a major risk. However,
the concentration of indoor air guidelines should be 0.1 mg/m3 and the dietary
exposure should not exceed 100 mg/d42. Turning back to toxicokinetics, after being
absorbed, it will be eliminated as metabolites (CO2 and HCOO-), the remaining rate
is about 20-40% in mice and rats. The question is: is it bad to get to know that this
toxic substance remains in the body? The answer is no. These data are the result of
studies based on measuring the signal of a radioactive substance, which doesn't

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directly indicate the original form of formaldehyde. In simpler words, formaldehyde
is now incorporated. To support this argument, the metabolism of formaldehyde has
been studied. Through the Mitochondrial ALDH2 pathway, glutathione (GSH)-
dependent pathway catalyzed by ADH3 and S-formyl GSH hydrolase formaldehyde
will be converted to formate then CO2 leaving the body through exhalation and urine.
A part of formate or formaldehyde itself will be converted and enter the 1C-cycle,
which is responsible for the manufacturing of essential functional products in the
body such as proteins, lipids, nucleotides, etc. Another bright side of formaldehyde
is its use in all areas in nowadays life, in which the resin industry has the most
important role. Imagine a life without any plastic items, or all the parts are separate
due to no adhesives, it can be seen that formaldehyde is an indispensable part, and it
is difficult to find a more perfect replacement. Nevertheless, its toxicity due to its
high reactivity still must be taken care of and strictly controlled, as there have been
numerous reports of carcinogenicity as well as being neurotoxic besides other effects
on health. To conclude, formaldehyde is both an all-rounder and a toxicant. The main
point is the knowledge of it must be learned and it must be consumed properly.

References

1. Butlerow, A. Ueber einige Derivate des Jodmethylens. Justus Liebigs

Ann. Chem. 1859, 111 (2), 242–252. DOI: 10.1002/jlac.18591110219.
2. Patterson, T. S. A text-book of organic chemistry: Historical, structural
and economic. By John Read, M.A., Ph.D., B.Sc. Pp. xii+679. London: G.
Bell & Sons, Ltd., 1926. Price 12s. 6d. J. Chem. Technol. Biotechnol.
1926, 45 (39), 703. DOI: 10.1002/jctb.5000453906.
3. Hofmann, A. W. Beiträge zur Kenntniss des Methylaldehyds. J. Prakt.
Chem. 1869, 107 (1), 414–424. DOI: 10.1002/prac.18691070161.
4. Agency for Toxic Substances and Disease Registry : ATSDR. Medical
Management Guidelines for Formaldehyde. https://wwwn.cdc.gov/TSP/
MMG/MMGDetails.aspx?mmgid=216&toxid=39 (accessed 2022-06-26).
5. Liteplo, R. G.; Beauchamp, R.; Meek, B.; Chénier, R. Concise
International Chemical Assessment Document 40: Formaldehyde. IPCS
Concise International Chemical Assessment Documents 2002.
6. World Health Organization/International Agency for Research on Cancer,
Ed. Volume 88: Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropan-
2-ol; IARC monographs on the evaluation of carcinogenic risks to
humans; International Agency for Research on Cancer, 2004.
7. Agency for Toxic Substances and Disease Registry : ATSDR.
Toxicological profile for formaldehyde; U.S. Department of Health and
Human Services, Public Health Service, 1999.

16
Formaldehyde_Tuyen Mai Printed 6/29/2022
 8. Sperber, H. Herstellung von Formaldehyd aus Methanol in der
BASFHerrn Professor Dr. B. Timm zum 60. Geburtstag. Chemie
Ingenieur Technik - CIT 1969, 41 (1969), 962–966. DOI:
10.1002/cite.330411705.
9. Hader, R. N.; Wallace, R. D.; McKinney, R. W. Formaldehyde from
methanol. Industrial & Engineering Chemistry 1952, 44 (7), 1508–1518.
10. Manahan, S. E. Toxicological chemistry and biochemistry, 3rd ed.; Lewis
Pub, 2003.
11. Tulpule, K.; Dringen, R. Formaldehyde in brain: an overlooked player in
neurodegeneration? Journal of neurochemistry 2013, 127 (1), 7–21. DOI:
10.1111/jnc.12356.
12. Reichl, F.-X.; Benecke, J.; Hammelehle, R.; Zilker, T. R.; Benecke, M.;
Eckert, K.-G.; Erber, B.; Golly, I.; Kreppel, H.; Liebl, B.; Mückter, H.;
Szinicz, L., Eds. Taschenatlas der Toxikologie:Substanzen, Wirkungen,
Umwelt, 2., aktualisierte Aufl.; Thieme, 2002.
13. World Health Organization. Regional Office for Europe. WHO guidelines
for indoor air quality: selected pollutants; World Health Organization.
Regional Office for Europe, 2010.
14. He, R. Formaldehyde and Cognition; Springer eBook Collection;
Springer, 2017. DOI: 10.1007/978-94-024-1177-5.
15. Zhang, L. Formaldehyde:Exposure, toxicity and health effects / Luoping
Zhang; Issues in Toxicology, Vol. 37; Royal Society of Chemistry, 2018.
16. Greim, H., Ed. Das Toxikologiebuch:Grundlagen, Verfahren, Bewertung;
Wiley-VCH Verlag GmbH & Co. KGaA, 2017.
17. He, R.; Lu, J.; Miao, J. Formaldehyde stress. Science China Life Sciences
2010, 53 (12), 1399–1404. DOI: 10.1007/s11427-010-4112-3.
18. Talaiekhozani, A and Fulazzaky, MA and Ponraj, M and Abd Majid, ZM,
Ed. Formaldehyde from production to application, 2013.
19. Joint Research Centre; Institute for Health and Consumer Protection;
Kotzias, D.; Bruinen de Bruin, Y.; Kephalopoulos, S. HEXPOC -- human
exposure characterization of chemical substances : quantification of
exposure routes; Publications Office, 2005.
20. European Chemical Agency. Formaldehyde:Product-type 02.
Disinfectants and algaecides not intended for direct application to humans
or animals. https://echa.europa.eu/documents/10162/59c9d260-a4a7-
0b0e-dbd6-972470a84066.
21. Gonzalez, C. F.; Proudfoot, M.; Brown, G.; Korniyenko, Y.; Mori, H.;
Savchenko, A. V.; Yakunin, A. F. Molecular basis of formaldehyde
detoxification. Characterization of two S-formylglutathione hydrolases
from Escherichia coli, FrmB and YeiG. The Journal of biological

17
Formaldehyde_Tuyen Mai Printed 6/29/2022
 chemistry 2006, 281 (20), 14514–14522. DOI: 10.1074/jbc.M600996200.
Published Online: Mar. 27, 2006.
22. Jelski, W.; Szmitkowski, M. Alcohol dehydrogenase (ADH) and aldehyde
dehydrogenase (ALDH) in the cancer diseases. Clinica Chimica Acta
2008, 395 (1), 1–5. DOI: 10.1016/j.cca.2008.05.001.
23. Danquah, K. O.; Gyamfi, D. Chapter 3 - Alcohol and Aldehyde
Dehydrogenases: Molecular Aspects. In Molecular Aspects of Alcohol
and Nutrition; Patel, V. B., Ed.; Academic Press, 2016; pp 25–43. DOI:
10.1016/B978-0-12-800773-0.00003-3.
24. Reingruber, H.; Pontel, L. B. Formaldehyde metabolism and its impact on
human health. Current Opinion in Toxicology 2018, 9, 28–34. DOI:
10.1016/j.cotox.2018.07.001.
25. Yurimoto, H.; Kato, N.; Sakai, Y. Assimilation, dissimilation, and
detoxification of formaldehyde, a central metabolic intermediate of
methylotrophic metabolism. Chem Record 2005, 5 (6), 367–375. DOI:
10.1002/tcr.20056.
26. Sanghani, P. C.; Bosron, W. F.; Hurley, T. D. Human Glutathione-
Dependent Formaldehyde Dehydrogenase. Structural Changes Associated
with Ternary Complex Formation. Biochemistry 2002, 41 (51), 15189–
15194. DOI: 10.1021/bi026705q.
27. Stover, P. J. One-Carbon Metabolism–Genome Interactions in Folate-
Associated Pathologies. J Nutr 2009, 139 (12), 2402–2405. DOI:
10.3945/jn.109.113670.
28. Noker, P. E.; Tephly, T. R. The role of folates in methanol toxicity.
Advances in experimental medicine and biology 1980, 132, 305–315.
DOI: 10.1007/978-1-4757-1419-7_32.
29. Ince, M.; Kaplan Ince, O.; Ondrasek, G., Eds. Biochemical
Toxicology:Heavy Metals and Nanomaterials; IntechOpen, 2020.
30. Dodiuk, H.; Goodman, S. H., Eds. Handbook of Thermoset Plastics
(Third Edition); William Andrew Publishing, 2014.
31. Salthammer, T.; Mentese, S.; Marutzky, R. Formaldehyde in the Indoor
Environment. Chemical Reviews 2010, 110 (4), 2536–2572. DOI:
10.1021/cr800399g.
32. Fink, J. K., Ed. Reactive Polymers Fundamentals and Applications
(Second Edition) : Plastics Design Library; William Andrew Publishing,
2013.
33. Fink, J. K. Chapter 4 - Phenol/Formaldehyde Resins. In Reactive
Polymers Fundamentals and Applications (Second Edition) : Plastics
Design Library; Fink, J. K., Ed.; William Andrew Publishing, 2013; pp
155–177. DOI: 10.1016/B978-1-4557-3149-7.00004-8.

18
Formaldehyde_Tuyen Mai Printed 6/29/2022
 34. Ebner, I.; Haberer, S.; Sander, S.; Kappenstein, O.; Luch, A.; Bruhn, T.
Release of Melamine and Formaldehyde from Melamine-Formaldehyde
Plastic Kitchenware. Molecules (Basel, Switzerland) 2020, 25 (16). DOI:
10.3390/molecules25163629.
35. Pizzi, A.; Ibeh, C. C. 2 - Phenol–Formaldehydes. In Handbook of
Thermoset Plastics (Third Edition); Dodiuk, H., Goodman, S. H., Eds.;
William Andrew Publishing, 2014; pp 13–44. DOI: 10.1016/B978-1-
4557-3107-7.00002-6.
36. Fink, J. K. Chapter 5 - Urea/Formaldehyde Resins. In Reactive Polymers
Fundamentals and Applications (Second Edition) : Plastics Design
Library; Fink, J. K., Ed.; William Andrew Publishing, 2013; pp 179–192.
DOI: 10.1016/B978-1-4557-3149-7.00005-X.
37. European Food Safety Authority. Endogenous formaldehyde turnover in
humans compared with exogenous contribution from food sources. EFSA
Journal 2014, 12 (2), 3550. DOI: 10.2903/j.efsa.2014.3550.
38. Gokhale, M.; Salimifard, P. Cooking Emissions, 2019. DOI:
10.13140/RG.2.2.14138.21448.
39. Choe, E.; Min, D. B. Mechanisms and Factors for Edible Oil Oxidation.
Comprehensive Reviews in Food Science and Food Safety 2006, 5 (4),
169–186. DOI: 10.1111/j.1541-4337.2006.00009.x.
40. Zhang, D.-C.; Liu, J.-J.; Jia, L.-Z.; Wang, P.; Han, X. Speciation of VOCs
in the cooking fumes from five edible oils and their corresponding health
risk assessments. Atmospheric Environment 2019, 211, 6–17. DOI:
10.1016/j.atmosenv.2019.04.043.
41. Xiang, Z.; Wang, H.; Stevanovic, S.; Jing, S.; Lou, S.; Tao, S.; Li, L.; Liu,
J.; Yu, M.; Wang, L. Assessing impacts of factors on carbonyl compounds
emissions produced from several typical Chinese cooking. Building and
Environment 2017, 125, 348–355. DOI: 10.1016/j.buildenv.2017.08.045.
42. Nowshad, F.; Islam, M. N.; Khan, M. S. Concentration and formation
behavior of naturally occurring formaldehyde in foods. Agriculture &
Food Security 2018. DOI: 10.1186/s40066-018-0166-4.
43. Diehl, J. F. Chemie in Lebensmitteln:Rückstände, Verunreinigungen,
Inhalts- und Zusatzstoffe, Nachdr. 2001; Wiley-VCH, 2001. DOI:
10.1002/9783527624607.

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Formaldehyde_Tuyen Mai Printed 6/29/2022