                                                                                       EFSA Journal 2014;12(2):3550
                                      SCIENTIFIC REPORT OF EFSA
  Endogenous formaldehyde turnover in humans compared with exogenous
                                    contribution from food sources1
                                     European Food Safety Authority2, 3
                             European Food Safety Authority (EFSA), Parma, Italy
ABSTRACT
The FEEDAP Panel received a request to deliver a scientific opinion on the safety and efficacy of formaldehyde
used in feed for all animal species based on dossiers submitted by applicants. In parallel, the ANS Panel
evaluated the safety of formaldehyde formed from endogenous production and from dietary sources of methanol,
including aspartame. In order to support both evaluations, assistance was requested to the SCER unit to evaluate
the oral internal dose of formaldehyde in humans from endogenous production, food-derived from target animals
exposed to formaldehyde-treated feed and formaldehyde generated from dietary sources of methanol, including
from food additives such as aspartame. Endogenous turnover of formaldehyde was estimated to be
approximately 0.61-0.91 mg/kg bw per minute and 878-1310 mg/kg bw per day assuming a half life of
1-1.5 min. Compared with formaldehyde turnover and the background levels of formaldehyde from food
sources (1.7-1.4 mg/kg b. w per day for a 60-70 kg person), including from dietary methanol, the relative
contribution of exogenous formaldehyde from consumption of animal products (milk, meat) from target animals
exposed to formaldehyde-treated feed was negligible (<0.001 %). Oral exposure to formaldehyde from
aspartame involves metabolism to methanol and further oxidation to formaldehyde. At the current ADI of
40 mg/kg bw per day for aspartame, formaldehyde would be approximately 4 mg/kg bw per day and represent
only 0.3-0.4 % of the endogenous turnover of formaldehyde.
© European Food Safety Authority, 2014
KEY WORDS
formaldehyde, endogenous, background levels, carry-over, aspartame, methanol
1
  On request from EFSA, Question No EFSA-Q-2013-01033, approved on 28 January 2014.
2
  Correspondence: scer@efsa.europa.eu
3
  Acknowledgement: EFSA wishes to thank EFSA staff: Jean Lou Dorne, Camille Bechaux, Georges Kass and Matteo
  Innocenti for the support provided to this scientific output. EFSA greatly acknowledges Jan Alexander, David Gott and
  Georges Bories for reviewing this scientific report.
Suggested citation: European Food Safety Authority, 2014. Endogenous formaldehyde turnover in humans compared with
exogenous contribution from food sources. EFSA Journal 2014;12(2):3550, 11 pp. doi:10.2903/j.efsa.2014.3550
Available online: www.efsa.europa.eu/efsajournal
© European Food Safety Authority, 2014

                                                               Endogenous versus exogenous formaldehyde
SUMMARY
Formaldehyde is an important metabolic intermediate that is physiologically present in all cells. The
electrophilic nature of formaldehyde makes it reactive towards a variety of endogenous molecules,
including glutathione, proteins, nucleic acids and folic acid.
In order to estimate the synthesis and metabolism of formaldehyde in the human body, authors in the
scientific literature have assumed that it is present in all aqueous body fluids because of its water
solubility and have estimated its half life in humans as 1-1.5 min. Blood and intracellular steady state
concentrations of formaldehyde have been estimated in humans to be around 2.6 mg/L (87 µM) and
12 mg/L (400 µM), respectively. Based on blood steady state concentrations and half life values in
humans of 1-1.5 min, formaldehyde turnover was estimated to be approximately 0.61-0.91mg/kg bw
per minute corresponding to a daily turnover of 878-1310 mg/kg bw per day.
Background levels in food products of formaldehyde are very variable and range from values around
0.1-0.3 mg/kg in milk to over 200 mg/kg in some fish species. Considering such wide variability in
formaldehyde concentrations and assuming a person would be eating one kilogram of food per day, it
was assumed that oral exposure to formaldehyde in humans would not exceed 100 mg formaldehyde
per day, corresponding to 1.7 and 1.4 mg/kg bw per day for 60 kg and 70 kg respectively. Carry over
in animal tissues has been measured in a few limited tissue deposition studies, mostly in cows and the
data showed a maximum increase in formaldehyde concentration between 0.1-0.2 mg/kg milk or meat.
Such levels of formaldehyde resulting from the consumption of milk or meat from animals fed with
formaldehyde-supplemented feed would represent 0.1-0.3 % of human oral exposure from background
levels in food products and would be below 0.001 % considering the endogenous formaldehyde
turnover. Such levels were considered negligible.
Based on the analysis of the EFSA Scientific Panel on Food Additives and Nutrient Sources added to
Food using actual usage data, methanol from aspartame was estimated to contribute to 0.5-9.7 % of
the total daily exposure to endogenous and exogenous methanol. For formaldehyde, and assuming
exposure to aspartame at the current Acceptable Daily Intake of 40 mg/kg bw per day together with a
10 % conversion to methanol with further conversion to formaldehyde, a daily exposure of 4 mg/kg
bw per day is estimated. This exposure would only contribute to approximately 0.3-0.4 % of human
oral exposure from background levels in food products and endogenous turnover.
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                                                                                             Endogenous versus exogenous formaldehyde
TABLE OF CONTENTS
Abstract .................................................................................................................................................... 1
Summary .................................................................................................................................................. 2
Table of contents ...................................................................................................................................... 3
Background as provided by EFSA ........................................................................................................... 4
Terms of reference as provided by EFSA ................................................................................................ 4
Assessment ............................................................................................................................................... 5
1. Introduction ..................................................................................................................................... 5
2. Endogenous turnover of formaldehyde in humans .......................................................................... 5
3. Background levels of formaldehyde in food.................................................................................... 5
4. Tissue deposition studies of formaldehyde in animal species ......................................................... 6
5. Comparison of endogenous formaldehyde with oral exposure from food sources.......................... 7
  5.1.      Endogenous formaldehyde versus background levels in food and carry over from animal
  products ................................................................................................................................................ 7
  5.2.      Aspartame-derived methanol/formaldehyde versus endogenous and background levels in
  food       ................................................................................................................................................ 7
Conclusions .............................................................................................................................................. 8
References ................................................................................................................................................ 9
Abbreviations ......................................................................................................................................... 11
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                                                               Endogenous versus exogenous formaldehyde
BACKGROUND AS PROVIDED BY EFSA
Formaldehyde, a known carcinogen, is currently being considered in ongoing evaluations by the ANS
and FEEDAP Panels. The ANS Panel has re-evaluated, among others, the artificial sweetener
aspartame that forms formaldehyde as part of its metabolism (EFSA-Q-2011-00406). The FEEDAP
Panel is currently evaluating formaldehyde as a preservative for feed, and their terms of reference
include both consumers and users and target species (EFSA-Q-2013-00763). In addition, both the
ANS Panel and the FEEDAP Panel are re-evaluating hexamethylenetetramine (EFSA-Q-2011-00458
and EFSA-Q-2012-00415), that is also partially metabolised to formaldehyde. The SCER unit has
produced an internal report resulting from an assistance request from the FEEDAP and the FIP unit.
The report evaluated the internal exposure to formaldehyde in humans from food derived from target
animals exposed to formaldehyde-treated feed and compare this to (i) the endogenous production of
formaldehyde and (ii) the internal exposure to formaldehyde from aspartame and other dietary or
endogenous sources (performed by the ANS Panel).
TERMS OF REFERENCE AS PROVIDED BY EFSA
The SCER unit is requested to produce a scientific report from the internal report on “endogenous
formaldehyde synthesis and metabolism in humans compared with exogenous contribution from food
sources”, by 31 January 2014. In order to follow the EFSA procedure for scientific reports, the SCER
unit should have the report reviewed by at least two external reviewers with relevant expertise.
EFSA Journal 2014;12(2):3550                                                                          4

                                                                Endogenous versus exogenous formaldehyde
ASSESSMENT
1.        Introduction
This Scientific report summarises the scientific support provided by the SCER unit after receiving an
assistance request from the FEEDAP and FIP unit, for the evaluation and comparison of the internal
dose to formaldehyde in humans from endogenous turnover, background levels in food, food-derived
from target animals exposed to formaldehyde-treated feed and formaldehyde derived from aspartame-
derived methanol.
2.        Endogenous turnover of formaldehyde in humans
Formaldehyde is an essential metabolic intermediate estimated from measurements in nasal tissue to
be present in cells at an intracellular concentration of around 12 mg/L (400 µM) (EFSA, 2013). There
are numerous sources of endogenous formaldehyde including the one carbon pool, amino acid
metabolism (serine, glycine, methionine, and choline), methanol metabolism, lipid peroxidation, and
P450 dependent demethylation (e.g. O-, N-, and S-methyl) (Dhareshwar and Stella, 2008; Swenberg et
al., 2011). The metabolism of formaldehyde is rapid and catalysed by glutathione-dependent
formaldehyde dehydrogenase (which is also known as alcohol dehydrogenase 5, ADH5) and S-
formyl-glutathione hydrolase to formic acid. Formic acid then enters the one-carbon pool where it can
be incorporated as a methyl group into nucleic acids and proteins and is either excreted in the urine or
oxidised to carbon dioxide and exhaled at a significantly slower rate than its formation from
formaldehyde (formic acid halflife in plasma is between 1 and 6 h) (Dhareshwar and Stella, 2008).
ADH5 has been detected in all human tissues at all stages of development, from embryo through adult.
The electrophilic nature of formaldehyde makes it reactive towards a variety of endogenous
molecules, including glutathione, proteins, nucleic acids and folic acid. (NTP, 2011). Ideally, an
evaluation of the fate of formaldehyde in vivo requires a distinction between products which are
normal cellular metabolites, those which are detoxification products and those which are formed
chemically in localized tissues due to the reactivity of formaldehyde (Dhareshwar and Stella, 2008).
Formaldehyde concentration in the blood of mammals resulting from endogenous production is similar
in different species with 2.2, 2.4 and 2.6 mg/L in the rat, monkey and humans, respectively (Heck et
al., 1982; 1985; Casanova et al., 1988). In order to estimate the total content of formaldehyde in the
human body, authors have assumed that it is present in all aqueous body fluids because of its water
solubility and have estimated its half life in humans as 1-1.5 min (Sullivan and Krieger, 2001) with a
volume of distribution as approximately total body water (42 and 49 L for an adult of 60 and 70 kg,
respectively), giving a total body content of 1.82 mg/kg bw and using the steady state concentration of
2.6 mg/L. Based on the latter total body formaldehyde content and the reported half-lives of 1 and
1.5 min (Clary and Sullivan, 2001), there would be a turnover of 0.61-0.91 mg formaldehyde/kg bw
per minute or 878-1310 mg formaldehyde/kg bw per day to maintain a formaldehyde steady state
concentration of 2.6 mg/L in the blood stream (Cascieri and Clary, 1992; Dhareshwar and Stella,
2008).
3.        Background levels of formaldehyde in food
Background levels of formaldehyde have been measured in milk, meat, plant material, mushrooms and
fish.
Formaldehyde is present in the milligram range with the lowest level measured in fresh milk
(0.013 - < 1 mg/kg) (Kaminski et al. 1993; Trezl et al., 1997).
In pig tissues, background formaldehyde levels (n=3) has been measured with values of 11.8±0.17,
8.75±0.28, 6.24±0.12 mg/kg in liver, kidney and muscle, respectively (Retfalvi et al., 1998). In meat,
background levels of formaldehyde ranged from 2.5 mg/kg in sandwich paste from poultry, 2.9-4.6
EFSA Journal 2014;12(2):3550                                                                           5

                                                                Endogenous versus exogenous formaldehyde
mg/kg in cold meat cuts, ham from poultry, turkey, up to 10-20.7 mg/kg in sausages and up to
224-267 mg/kg in the outer layer of smoked ham (Brunn and Klostermeyer, 1984; Trezl et al., 1997).
In fish, formaldehyde background levels show the highest values measured in food with extreme
values 232-293 mg/kg in deep frozen hake, lowest values in haddock and mullet 1.47-4.87 mg/kg and
average values in cod around 100 mg/kg (Bianchi et al. 2007; Weng et al. 2009). It has been noted that
the post-mortem formation of formaldehyde in fish is the result of the reduction of trimethylamine-N-
oxide to formaldehyde and dimethylamine (Sotelo et al., 1995; Badii and Howell, 2002)
In plant material such as fruit vegetables, background formaldehyde levels (mg/kg) range from 6.3 and
6.8 in apples and carrots, 9.0 in fresh water melon, 9.5 in apricot to 13.3 in tomatoes, 16.3 in bananas,
19.5 in potatoes to 26.9, 31 and 35 in cauliflower, kohlrabi and large beetroot respectively (Trezl et al.,
1997).
From these figures, background levels in food products of formaldehyde are very variable and range
from values below1 mg/kg in milk to over 200 mg/kg in some fish species (Kaminski et al., 1993;
Trezl et al., 1997; Bianchi et al., 2007; Dhareshwar and Stella, 2008; Weng et al., 2009). Providing a
precise exposure assessment was not the purpose of this report but assuming a person would be eating
one kilogram of food per day (including milk, fish, meat, ham, vegetables, fruit) and giving of the
variability of background formaldehyde concentration in raw commodities and food products, it was
assumed that oral exposure to formaldehyde in humans from dietary sources would not exceed 100 mg
formaldehyde per day corresponding to 1.7 and 1.4 mg/kg bw per day for 60 kg and 70 kg
respectively. It should be noted that these exposure estimates do not include endogenously produced
formaldehyde from dietary and endogenous sources of methanol. Table 1 summarises the background
levels of formaldehyde in a range of food commodities as described in literature.
Table 1:      Background levels of formaldehyde in food
                             Formaldehyde
        Food Product
                             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
4.        Tissue deposition studies of formaldehyde in animal species
Few tissue deposition studies investigating the internal dose of formaldehyde in the bloodstream of
animal species after supplementation of feed treated with formaldehyde were available. In cows,
Buckley et al. (1988) supplemented whey forage with formaldehyde at increasing levels ranging from
0, 185, 370 or 555 mg /kg whey given to cows at 75 kg per day corresponding to 13900, 27800, 41600
mg per cow, respectively, or 21.4, 42.8, 64 mg/kg bw per day for a 650 kg cow. Overall, maximum
formaldehyde levels in the milk of cows receiving 0, 21.4, 42.8 and 64 mg/kg bw per day for 33 days
were < 0.026 mg/kg (below limit of detection), 0.052, 0.094 and 0.193 mg/kg giving maximum
incremental increase of formaldehyde in milk of 0.02,0.07, 0.17 mg/kg milk. In addition, the authors
concluded that it was likely that storage and pasteurisation of milk resulted in a reduction of free
formaldehyde through irreversible binding to milk protein. Average blood concentration in cows was
also measured and was only slightly higher at 64 mg/kg bw per day after 33 days but not significant
(P>0.05) compared with controls (0.831 vs 0.615).
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                                                                Endogenous versus exogenous formaldehyde
In addition, a trial was performed in 6 calves per treatment (0, 24.1 and 45.0 mg/kg bw per day
(average) calves or 185 and 370 mg/kg feed respectively) for 95 days and two calves from each
treatment group were slaughtered at days 81, 88, and 95 days after the beginning of the trial. Tissue
samples of heart, kidney, liver, and muscle (M. longissimus dorsi) were collected and frozen until
subjected to formaldehyde analysis (limit of detection 0.026 mg/kg) The only significant difference
between control and the highest dose group (P<0.05), was found for the muscle (0.256 mg/kg vs
0.158 mg/kg, respectively for the 45.0 mg/kg bw per day (370 mg/kg) versus controls) but for no other
organs (heart, kidney, liver) or blood levels. It is worth noting that there is considerable uncertainty in
the data since only two animals per group were used (Buckley et al., 1988).
In another study, five grams of formaldehyde per day from formaldehyde treated soybean meal was
administered to dairy cows in a 10 week feeding study and an slight increase in the formaldehyde
concentration of milk from initial 0.023 - 0.039 mg/L to 0.095 - 0.114 mg/L (three weeks) and to
0.25 mg/L after 10 weeks (Pinault, 1989, cited from AFSSA, 2004). This data gives an incremental
increase of 0.1 mg/L after three weeks and around 0.2 mg/L of milk after 10 weeks.
A 12-month feeding study in beef cattle administered 1 g formaldehyde/day from formalin treated
soybean meal showed a slight increase in formaldehyde muscle content from 0.065 mg/kg to
0.167 mg/kg (incremental increase of 0.102 mg/kg) (Pinault, 1989, cited from AFSSA, 2004).
From the limited studies available describing formaldehyde deposition in animal-tissues or milk and
muscle after supplementation of feed with formaldehyde, it can be concluded that formaldehyde
concentrations in milk and muscle have been shown to increase slightly (0.1-0.2 mg/L milk and
muscle at minimum levels of exposure >300 mg formaldehyde per kg feed with a minimum of 33 day
of exposure). Such levels are well below the background levels of formaldehyde in food (0.1-0.3 %).
5.        Comparison of endogenous formaldehyde with oral exposure from food sources
5.1.      Endogenous formaldehyde versus background levels in food and carry over from
          animal products
The turnover of endogenous formaldehyde to maintain the human blood steady state concentration of
2.6 mg/l has been estimated to be approximately 0.61-0.91 mg/kg bw per minute equivalent to 878-
1310mg/kg bw per day for half lives of 1-1.5 min. (Section 2).
Background levels of formaldehyde have been shown to be very variable in food ranging from
<0.1 mg/kg in milk to >200 mg/kg in fish) and taking a consumption scenario of 1 kg of food per
person (including milk, fish, meat, ham, vegetables, fruit), it was assumed that oral exposure to
formaldehyde in humans from background levels in food would not exceed 100 mg/kg food per person
per day corresponding to 1.7 and 1.4 mg/kg bw per day for a 60 kg and 70 kg person, respectively
(Section 3).
Carry over in animal tissue or products of formaldehyde has been measured in a few limited tissue
deposition studies mostly available in cows and showed that the maximum increase in formaldehyde
concentration was between 0.1-0.2 mg/kg milk or meat (muscle) (Section 4). Such levels of
formaldehyde resulting from the consumption of milk or meat from animals fed with formaldehyde-
supplemented feed would represent 0.1-0.3 % of human oral exposure to formaldehyde from
background levels of formaldehyde in food products (100 mg person per day or 1.7 and 1.4 mg/kg bw
per day for 60 kg and 70 kg person) and would be below 0.001 % considering the daily turnover of
formaldehyde (874-1310 mg/kg bw per day). Such levels were considered negligible.
5.2.      Aspartame-derived methanol/formaldehyde versus endogenous and background levels
          in food
With regards to aspartame, the Scientific Panel on food additives and nutrients in its scientific opinion
on the re-evaluation of aspartame has discussed that aspartame is partially metabolised into methanol
EFSA Journal 2014;12(2):3550                                                                              7

                                                               Endogenous versus exogenous formaldehyde
(10 % of a dose per weight) which is then further oxidised sequentially to formaldehyde by alcohol
dehydrogenase in humans, formic acid or formate in a pH-dependent manner and finally to carbon
dioxide (EFSA, 2013). Endogenous methanol production also occurs and the Panel estimated the basal
endogenous methanol production to range from a minimum of 2 to a maximum of 9 mg/kg bw per day
in adults. In addition, pectin degradation from fruit and vegetables has been shown to be a source of
methanol and the Panel has estimated that the body increases in methanol production following
consumption of pectin-containing foods such as apples would range by an additional 6-20 mg/kg bw
per day. On a daily basis, endogenous methanol and methanol from pectin degradation would range
from 8 to about 34 mg/kg bw per day (mean to high level exposure) (EFSA, 2013). Based on actual
usage data, methanol from aspartame (8-34 mg/kg b.w per day) only contributes 0.5-9.7 % of the total
exposure to methanol from endogenous and exogenous sources (EFSA, 2013). Assuming exposure to
aspartame at the current Acceptable Daily Intake (ADI) of 40 mg/kg bw per day and a 10 %
conversion to methanol additional exposure to methanol (4 mg/kg bw per day) would be well below
endogenous and background levels in food (2 to 9-fold). Further conversion of methanol to
formaldehyde would yield a daily exposure of 4 mg/kg bw per day, which would only represent
0.3-0.4 % of the total formaldehyde exposure, based on a daily turnover of formaldehyde of
878-1310 mg/kg bw per day (EFSA, 2013).
CONCLUSIONS
        Formaldehyde is an essential metabolic intermediate present in all cells at an intracellular
        concentration of around 400 µM (12 mg/L) which is synthesised endogenously. Sources of
        endogenous formaldehyde include the one carbon pool, amino acid metabolism, methanol
        metabolism, lipid peroxidation, and P450 dependent demethylation.
        Formaldehyde metabolism is rapid and catalysed by glutathione-dependent formaldehyde
        dehydrogenase and S-formyl-glutathione hydrolase to formic acid. Formic acid then enters the
        one-carbon pool and is either excreted in the urine or oxidised to carbon dioxide and exhaled.
        The electrophilic nature of formaldehyde makes it reactive with a variety of endogenous
        molecules, including glutathione, proteins, nucleic acids, and folic acid.
        Formaldehyde concentration in the blood of mammals resulting from endogenous production
        is similar in different species with 2.2, 2.4 and 2.6 mg/L in the rat, monkey and humans
        respectively. Formaldehyde half life in humans is very short and has been estimated to be
        within 1-1.5 min associated with a volume of distribution approximately corresponding to
        total body water (49 L). Total content of formaldehyde in the human body has been estimated
        assuming its presence in all aqueous body fluids and a range of half-lives of 1 and 1.5 min,
        daily endogenous turn over of formaldehyde has been estimated to be around 878-1310 mg/kg
        bw per day.
        Background levels in food products of formaldehyde are very variable and range from values
        below 1 mg/kg in milk to over 200 mg/kg in some fish species. Considering the wide
        variability of formaldehyde concentrations in food, daily exposure to formaldehyde from
        would not exceed 100 mg per kilogram of food and per person.
        Carry over in animal tissue or products of formaldehyde has been measured in a few limited
        tissue deposition studies mostly available in cows and showed a maximum increase in
        concentration between 0.1-0.2 mg/kg milk or meat (muscle). The levels of formaldehyde
        resulting from the consumption of milk or meat from animals fed with formaldehyde-
        supplemented feed would be around 0.1 % of the background levels of formaldehyde in food
        products and below 0.001 % of daily endogenous turnover of formaldehyde. Such levels are
        considered negligible.
        Oral exposure to formaldehyde derived from aspartame-derived methanol at the current
        acceptable daily intake of aspartame would be 4 mg/kg bw per day assuming a 10 %
        conversion. Such exposure only represents 0.3-0.4 % of the combined background level in
        food and the daily turnover of formaldehyde for an adult.
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                                                               Endogenous versus exogenous formaldehyde
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ABBREVIATIONS
ADI             Acceptable daily intake
ANS             Scientific Panel on Food Additives and Nutrient Sources added to Food of the
                European Food Safety Authority
EFSA            European Food Safety Authority
SCER            EFSA’s Scientific Committee and Emerging Risks Unit
FEEDAP          Scientific Panel on Additives and Products or Substances used in Animal Feed of the
                European Food Safety Authority
FIP             EFSA’s Food Ingredients and Packaging’s Unit
EFSA Journal 2014;12(2):3550                                                                      11

