Environment International 130 (2019) 104950

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Environment International
journal homepage: www.elsevier.com/locate/envint

Melamine and cyanuric acid in foodstuffs from the United States and their T
implications for human exposure
⁎
Hongkai Zhua, Kurunthachalam Kannana,b,c,
a
Wadsworth Center, New York State Department of Health, Albany, NY 12201, United States
b
Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Albany, NY 12201, United States
c
Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi
Arabia

A R T I C LE I N FO A B S T R A C T

Handling Editor: Adrian Covaci We determined the concentrations of melamine, ammeline, ammelide, and cyanuric acid in meat, fish and
Keywords: seafood, cereal products, beverages, cooking oil, and vegetables (n = 121) collected from Albany, New York,
Foodstuff United States. In addition, food packaging (n = 24) and animal feed (n = 12) were analyzed to determine the
Melamine sources of melamine and its derivatives in foods. Among the six categories of foods analyzed, median con-
Cyanuric acid centrations of ∑melamine (sum of melamine and its three derivatives) in meat (23.6 ng/g fresh weight; fw) and
Dietary intake cereal products (20.9 ng/g fw) were significantly (p < 0.05) higher than those in other food categories
Exposure assessment Dairy (< 5.03 ng/g fw). Cyanuric acid and melamine were the major compounds, accounting for 51% and 26% of the
total ∑melamine concentrations, respectively. ∑melamine was found ubiquitously in food packaging (median:
36.2 ng/g fw) and animal feed (56.5 ng/g fw), which are two important sources of melamine found in foodstuffs.
The median estimated daily dietary intakes (including concentrations reported for dairy products in our previous
study) of melamine and cyanuric acid were in the ranges of 13.4–72.7 and 75.4–347 ng/kg body weight/day,
respectively, for various age groups. Dairy products, cereal products, and meat were major sources of dietary
melamine (~76%) and cyanuric acid (~95%) exposure. The calculated hazard quotients for dietary exposure to
melamine and cyanuric acid were well below 1.0, which suggested minimal risk from current exposures.

1. Introduction stones) account for a significant percentage of urinary stones (Cicerello,

The outbreaks of nephrolithiasis and acute kidney injury in pet
animals and humans from several countries during 2007–2008 were
associated with exposure to melamine and cyanuric acid (Bhalla et al.,
2009; Osborne et al., 2009). Since then, melamine and cyanuric acid
have been under the scrutiny of regulatory agencies throughout the
world (Dalal and Goldfarb, 2011; Hau et al., 2009; Sun et al., 2010).
The pathogenic mechanism involves precipitation of melamine and
cyanuric acid in distal renal tubules to form crystals, which, in turn,
inflict kidney injury (Brown et al., 2007). Co-exposure of melamine and
cyanuric acid was reported to exacerbate renal toxicity in comparison
with melamine or cyanuric acid alone. In addition to nephrotoxicity,
recent animal studies showed endocrine and neurotoxic potentials of
melamine (Bolden et al., 2017; Chu et al., 2018; Nuntapong et al., 2019;
Yin et al., 2013).
In the United States (US), approximately 10% of the population is
diagnosed with urolithiasis (Moses et al., 2015). Uric acid calculi (i.e.,
2018). Melamine was reported to play a key role in uric acid-related
kidney injury in humans (Zhang et al., 2015). Further, melamine and
cyanuric acid exposure is nearly ubiquitous in the US population, with
measured urinary concentrations that range from below the limit of
detection (LOD) to 1085 ng/mL (Sathyanarayana et al., 2018; Zhu and
Kannan, 2018a). Nevertheless, sources of current human exposure to
melamine and cyanuric acid are not fully understood.
The global production of melamine and cyanuric acid was > 2
million tons in 2010 (European Food Safety Authority (EFSA), 2010).
Melamine is used in dinnerware, kitchenware, adhesives, laminates,
flame retardants, coatings, plastics, and fertilizer mixtures (World
Health Organization (WHO), 2009a; Jiang et al., 2019). Cyanuric acid
is used in disinfectants, chlorine stabilizers, sanitizers, and bleaches
(Dorne et al., 2013). Ammeline and ammelide are impurities formed
during melamine production. Besides, melamine can be hydrolyzed
sequentially to ammeline, ammelide, and cyanuric acid (Gong et al.,
2016). The pathway of melamine hydrolysis is shown in Fig. S1 in the

⁎
Corresponding author at: Wadsworth Center, Empire State Plaza, P.O. Box 509, Albany, NY 12201-0509, United States.
E-mail address: Kurunthachalam.Kannan@health.ny.gov (K. Kannan).

https://doi.org/10.1016/j.envint.2019.104950
Received 6 May 2019; Received in revised form 2 June 2019; Accepted 19 June 2019
0160-4120/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
H. Zhu and K. Kannan
Supporting information (SI). These widespread applications have re-
sulted in their occurrence in sewage sludge, irrigation water, farm soils,
and sediment (Qin et al., 2010; Zhu et al., 2019a,b,c). Our previous
study reported the occurrence of melamine and cyanuric acid in ferti-
lizers (Zhu et al., 2019b). Thus, it is reasonable to believe that farm
products contain melamine and cyanuric acid through the plant uptake
and food chain transfer. Melamine was reported to occur in infant
formula and dairy milk at concentrations on the order of several tens to
thousands of parts per billion (ng/g) (WHO, 2009a,b). The EFSA (2010)
reported median daily dietary intakes of melamine and cyanuric acid at
1640 and 1450 ng/kg body weight (bw)/day, respectively, for the po-
pulations in Europe. The earlier studies, however, were focused on
exposures related to food adulteration/scandals that occurred during
the period 2007–2008.
To date, little information is available on human exposure to mel-
amine and its derivatives through dietary sources in the US. Thus, the
objectives of this study were (1) to determine the current status of
melamine, cyanuric acid, ammeline, and ammelide concentrations in a
range of food items marketed in the US; (2) to compare the profiles of
melamine and its derivatives in different categories of foods; and (3) to
assess human dietary exposure to melamine and cyanuric acid.
Melamine was reported to migrate into foods that are prepared and
served in melamine-based kitchenware (Arce et al., 2019; Chien et al.,
2011; M.T. Wu et al., 2015). In addition, carryover of melamine from
feed to animal tissues has been documented (Chan et al., 2011; Park
and Kim, 2017). Therefore, we also analyzed select food packaging
materials and animal feed to elucidate sources of melamine and its
derivatives in foods.
2. Materials and methods
2.1. Sample collection
A total of 121 food items were purchased from several major gro-
cery stores in Albany, New York, US, from August to September 2018.
Food samples were grouped into six categories: (1) meat (n = 28;
comprised of beef, chicken, pork, and turkey); (2) fish and seafood
(n = 11; comprised of salmon, tuna, sole, and shrimp); (3) cereal pro-
ducts (n = 27; including cereals, flour, pasta, and rice), (4) vegetables
(n = 13; including mushrooms, carrots, lettuce, and cabbage); (5)
beverages (n = 32; including fruit juices and beer), and (6) cooking oil
(n = 10; including corn, vegetable, olive, and sesame oils). These food
categories were selected based on a report of the EFSA (2010), which
indicated that more than half of the human exposure dose to melamine
and cyanuric acid was contributed by these foodstuffs. Popular brands
of foods commonly consumed by the population throughout the
country were collected for analysis. In addition to foodstuffs, food
packaging (n = 24) and animal feed (n = 12) were also collected. The
food packaging materials were selected from foods that were collected
for analysis and classified into plastic (n = 8) and paper (n = 16) ma-
terials. Popular brands of concentrated swine (n = 6) and poultry
(n = 6) feeds were purchased from online retailers. Common in-
gredients listed on the feed bags include processed grains, minerals,
vitamins, and amino acids. Further details of the food samples analyzed
in this study are provided in Tables S1 and S2 in the SI. All samples
were stored at -20o C until analysis.
2.2. Chemicals
Native analytical standards of melamine (99% purity), ammeline
(97.9% purity), ammelide (98% purity), and cyanuric acid (98% purity)
were purchased from Sigma-Aldrich (St. Louis, MO, US). Isotopically-
labelled internal standards, 15N3,13C3-melamine (15N3 and 13C3 at 98%
and 99% purities, respectively), 13C3-ammeline (13C3 at 99% purity),
13
C3-ammelide (13C3 at 99% purity), and 15N3,13C3-cyanuric acid (15N3
and 13C3 at 98% and 99% purities, respectively) were purchased from
2
Environment International 130 (2019) 104950
Cambridge Isotope Laboratories (Andover, MA, US). High-purity sol-
vents and reagents were purchased from J.T. Baker (including me-
thanol, acetonitrile, water, and formic acid) and Sigma-Aldrich (am-
monium formate and ammonium hydroxide). Solid phase extraction
(SPE) cartridges, Oasis MAX® and Oasis MCX® (150 mg, 6 mL, 30 μm
particle size), were purchased from Waters Corporation (Milford, MA,
US).
2.3. Sample analysis
The method for the extraction of melamine and its derivatives from
foodstuffs, food packaging, and animal feed was similar to that de-
scribed earlier, with minor modifications (Zhu and Kannan, 2018b; Zhu
et al., 2019a). For the analysis of meat, fish and seafood, cereal pro-
ducts, vegetables, cooking oil, food packaging, and animal feed, ap-
proximately 0.2–0.5 g (fresh weight; fw) of homogenized/chopped/
ground samples were weighed into a 15 mL polypropylene (PP) conical
tube and fortified with 10 ng each of the internal standards. Samples
were extracted twice with a mixture of methanol/water (4,1, v/v, 5 mL
each) by shaking in an orbital shaker (Eberbach, Ann Arbor, MI, US) at
250 oscillations/min for 60 min. The sample mixture was centrifuged at
4000 ×g for 10 min (Eppendorf Centrifuge 5804, Hamburg, Germany),
and the supernatant was combined in a new PP tube. The combined
extract was concentrated to 2 mL under a gentle nitrogen stream and
divided into two equal aliquots; one aliquot was alkalized with 2 mL of
5% ammonium hydroxide in water (for the analysis of cyanuric acid),
and the other aliquot was acidified with 2 mL of 5% formic acid in
water (for the analysis of melamine, ammeline, and ammelide). The
extracts were purified by passage through mixed-mode SPE cartridges
(Oasis MAX and Oasis MCX for alkalized and acidified aliquots, re-
spectively).
For the analysis of beverages, two 5-g aliquots of samples were
transferred into PP tubes; one aliquot was alkalized by the addition of
200 μL of ammonium hydroxide, and the other aliquot was acidified by
the addition of 150 μL of formic acid. The samples were then purified by
passage through mixed-mode SPE cartridges, as described above. The
eluates were concentrated to near dryness under a gentle nitrogen
stream, reconstituted with 250 μL of the mobile phase solution (de-
scribed below), and filtered through a 0.2 μm nylon syringe filter
(Corning, NY, US) directly into a glass vial for high-performance liquid
chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis.
A Shimadzu LC-30AD Series HPLC system (Shimadzu Corporation,
Kyoto, Japan) coupled with an AB Sciex 5500 triple-quadrupole mass
spectrometer (Applied Biosystems, Foster City, CA, US) was used in the
identification and quantification of target compounds. A Kinetex hy-
drophilic-lipophilic interaction liquid chromatography column
(100 mm × 2.1 mm, 2.6 μm particle size; Phenomenex, Torrance, CA,
US), serially connected to a Betasil C18 guard column
(20 mm × 2.1 mm, 5 μm particle size; Thermo Scientific), was used for
chromatographic separation of target analytes. The mobile phase
comprised of acetonitrile and 5 mM ammonium formate buffer
(pH = 4.0). Further details of the mobile phase gradient flow and MS/
MS parameters are provided in the SI (Table S3).
2.4. Quality assurance (QA)/quality control (QC)
A ten-point calibration curve that ranged in concentrations of target
analytes from 0.01 to 100 ng/mL (regression coefficient > 0.996) was
used in the quantification. The limits of quantification (LOQs) were
derived from the lowest point in the calibration standard with a signal-
to-noise ratio of 10 and a nominal sample weight (Table S3). With every
batch of 40 samples, procedural blanks (n = 2), spiked blanks (n = 2),
and matrix spikes (n = 2) were analyzed. Trace levels of cyanuric acid
(~0.15 to 0.43 ng/g) were found in one batch of procedural blanks, and
background subtraction was performed for that batch of food samples.
Absolute recoveries of internal standards spiked into each sample
H. Zhu and K. Kannan
ranged from 49 ± 12 (cyanuric acid) to 71 ± 6.1% (melamine), and
the average recoveries of native standards fortified in foods, packaging
materials, and feeds (two levels of fortified concentrations and eight
matrixes) were in the range of 73 ± 8.5% (ammeline) to 83 ± 12%
(cyanuric acid) (Table S4). A midpoint calibration standard was in-
jected after every 20 samples to monitor for drift in instrumental sen-
sitivity. Several randomly selected samples were analyzed in duplicate
(n = 5 for each batch), and the coefficient variation in concentrations
between samples was < 10% for each of the target compounds.
Concentrations in foods and feed are reported on a fresh-weight basis.
2.5. Data analysis
For the calculation of dietary intake, food consumption data were
obtained for seven broad categories of foods (including dairy products,
analyzed in our previous study), which were multiplied by the mea-
sured chemical concentrations, as shown in Eq. (1):
EDI = ∑ Ci × FIRi (1)
where EDI (ng/kg bw/day) is the estimated daily intake of melamine
and cyanuric acid for age groups of infants (< 1 year old), toddlers (1
to < 6 yrs), children (6 to < 11 yrs), teenagers (11 to < 21 yrs), and
adults (21 yrs and older); C (ng/g fw) is the melamine and cyanuric acid
concentrations measured in foods, and FIR (g/kg bw/day) is the daily
food ingestion rate. Two scenarios were considered: (i) an “average”
exposure scenario on the basis of median concentrations measured in
foodstuffs and (ii) a “high” exposure scenario on the basis of 95th
percentile concentrations in foodstuffs. The FIR values for various food
and age groups (Table S5) were obtained from the US Environmental
Protection Agency (USEPA, 2011) Exposure Factors Handbook 2011.
The risks from exposure to melamine and cyanuric acid were esti-
mated as hazard quotients (HQ), as shown in Eq. (2):
EDI
HQ =
TDI (2)
where TDI is the tolerable daily intake of melamine and cyanuric acid
(ng/kg bw/day). The reported TDI values for melamine and cyanuric
acid are currently under debate and vary by two orders of magnitude
(Chen et al., 2009; Choi et al., 2010; Hsieh et al., 2009; Ingelfinger,
2008; Wang et al., 2011). In this study, a TDI value of 63,000 ng/
kg bw/day for melamine and 1,500,000 ng/kg bw/day for cyanuric
acid, as recommended by the US Food and Drug Administration (FDA)
(Hsieh et al., 2009) and the WHO (2009b), respectively, were applied.
An HQ value of ≥1 indicates the existence of a potential risk from
exposure to melamine and cyanuric acid.
Values below the LOD and between the LOD and LOQ were sub-
stituted with zero and 1/2-LOQ, respectively, for statistical analysis.
Differences in concentrations between food groups were tested by one-
way ANOVA. Statistical analyses were performed with the SPSS 17.0
software package. All of the plots were created using Origin version 8.1.
The probability value of p ≤ 0.05 was set for statistical significance.
3. Results and discussion
3.1. Melamine and its derivatives in foodstuffs
The concentrations and detection frequencies (df) of four target
compounds in six food categories are summarized in Table 1. All food
samples (n = 121) contained measurable concentrations of Σmelamine
(sum of four compounds) that ranged from 0.14 to 305 ng/g fw, with an
overall median value of 9.42 ng/g fw. These concentrations were well
below the tolerance limit of 2.5 mg/kg set by the USFDA for melamine
in food (Gossner et al., 2009). The measured concentrations of Σme-
lamine were lower than those reported for food samples analyzed
during the food scandal that involved melamine adulteration in the
period 2007–2008 at concentrations on the order of several tens to
3
Environment International 130 (2019) 104950
thousands of ng/g fw (Araujo et al., 2012; EFSA, 2010). Nevertheless,
our study establishes baseline levels of melamine and its derivatives in
foodstuffs.
The median concentrations of Σmelamine in meat and cereal pro-
ducts were 23.6 (range: 1.75–305) and 20.9 (5.81–81.3) ng/g fw, re-
spectively, which were significantly (p < 0.05) higher than those
measured in fish and seafood (5.03; 0.60–210 ng/g fw), beverages
(4.04; 1.53–45.1 ng/g fw), cooking oil (3.30; 0.14–44.1 ng/g fw), and
vegetables (2.17; 0.68–71.5 ng/g fw) in that decreasing order (Table 1).
ΣMelamine was reported in infant formula and dairy products (e.g.,
milk, yogurt, cheese, butter) collected from Albany, New York, in 2018,
at median concentrations of 2.70 ng/g fw and 6.28 ng/g fw, respec-
tively. The Σmelamine concentrations reported for infant formula and
dairy products were lower than those found in other food categories
analyzed in this study. Infant formula and dairy products have been the
focus of regulatory attention since the melamine scandal in 2007–2008
(Braekevelt et al., 2011; Maleki et al., 2018). Our results imply that
regulatory actions are effective in reducing melamine contamination of
dairy products and infant formula. Our results indicate that ingestion of
certain types of foods, such as meat and cereal products, can contribute
to high Σmelamine exposures.
Melamine was frequently found in all food categories at detection
rates above 80%. Meat (median: 1.77 ng/g fw) and cereal products
(1.61 ng/g fw) contained higher concentrations of melamine than fish/
seafood (1.01 ng/g fw), beverages (0.87 ng/g fw), vegetables (0.80 ng/g
fw), and cooking oil (0.68 ng/g fw). Meat products were characterized
by the highest overall median concentrations of cyanuric acid (21.5 ng/
g fw; df: 75%), followed by cereal products (12.0 ng/g fw; 96%) and
beverages (2.82 ng/g fw; 97%). The detection frequencies of cyanuric
acid were low in fish and seafood (45%), vegetables (30%), and cooking
oil (10%), with median concentrations below the LOQ. The highest
cyanuric acid concentration of 303 ng/g fw was found in a chicken
sample. Ammeline was detected in cooking oil (median: 1.69 ng/g fw;
df: 90%) and cereal products (1.11 ng/g fw; 81%), whereas ammelide
was found in cereal products (1.47 ng/g fw; df: 100%) and vegetables
(0.74 ng/g fw; 100%).
The percentage composition of melamine and its derivatives to
Σmelamine concentrations is shown in Fig. 1. Cyanuric acid was the
major derivative, accounting for, on average, 43 ± 50% (in fish and
seafood) to 88 ± 50% (in chicken) of Σmelamine concentrations in
foods, with the exception of pork, cooking oil, and vegetables. Mela-
mine was the second major derivative, accounting for 25 ± 15% of
Σmelamine concentrations. The overall contributions of ammeline and
ammelide to Σmelamine concentrations were ~10% each. Interestingly,
ammeline was found at a high proportion in cooking oil (64 ± 25%).
Ammeline has been reported to be used in lubricating greases (Dorne
et al., 2013). The presence of ammeline in cooking oil may be due to
contamination during the production of oil. Earlier studies have shown
that cyanuric acid was the most abundant analogue in human and an-
imal urine (70–97% of total), infant formula (80%), and dairy products
(68–82%) (Karthikraj et al., 2018; Sathyanarayana et al., 2018; Zhu and
Kannan, 2018a,b; Zhu et al., 2019d). In contrast, melamine was the
major compound in sewage sludge (46%), indoor dust (59%), soil
(63%), and sediment (87%) (Zhu and Kannan, 2018c; Zhu et al.,
2019a,b,c). The predominance of cyanuric acid in foodstuffs suggests a
contribution from sources such as nitrogenous fertilizers (such as urea),
its direct incorporation into animal feed, and degradation of melamine
to cyanuric acid in plants and animals (Hatakeyama and Takagi, 2016;
Zhu et al., 2019d).
3.2. Melamine and cyanuric acid in food packaging and animal feed
Food packaging has been recognized as a source of contamination of
several man-made chemicals in foods (Liao and Kannan, 2013; Pocas
and Hogg, 2007; Wang and Kannan, 2018). Melamine and its deriva-
tives were found ubiquitously in all food packaging materials analyzed,
H. Zhu and K. Kannan Environment International 130 (2019) 104950

Table 1
Concentrations (ng/g fresh weight) and detection frequencies (df/%) of melamine and its derivatives in foodstuffs, food packaging, and animal feed collected from
Albany, New York, the United States.
Melamine Ammeline Ammelide Cyanuric acid ∑melamine

Meat (n = 28) Median/range 1.77 (0.34–6.42) < 0.20 (< 0.20–5.23) 0.66 (< 0.10–4.50) 21.5 (< 0.25–303) 23.6 (1.75–305)
df/% 100 21 93 75
Fish/seafood (n = 11) Median/range 1.01 (< 0.12–2.34) < 0.20 (< 0.20–1.47) 0.49 (< 0.10–7.16) < 0.25 (< 0.25–206) 5.03 (0.60–210)
df/% 82 9 73 45
Cereal products (n = 27) Median/range 1.61 (0.15–9.33) 1.11 (< 0.20–8.75) 1.47 (0.39–7.19) 12.0 (< 0.25–72.9) 20.9 (5.81–81.3)
df/% 100 81 100 96
Vegetables (n = 13) Median/range 0.80 (0.23–67.3) < 0.20 (< 0.20–1.90) 0.74 (0.17–4.20) < 0.25 (< 0.25–3.08) 2.17 (0.68–71.5)
df/% 100 20 100 30
Cooking oil (n = 10) Median/range 0.68 (< 0.12–7.16) 1.69 (< 0.20–43.1) < 0.10 (< 0.10–0.23) < 0.25 (< 0.25–2.61) 3.30 (0.14–44.1)
df/% 80 90 40 10
Beverages (n = 32) Median/range 0.87 (0.05–12.1) < 0.02 (< 0.02–3.49) 0.34 (< 0.01–1.90) 2.82 (< 0.03–28.4) 4.04 (1.53–45.1)
df/% 100 44 75 97
a
Dairy products (n = 34) Median/range 1.19 (0.48–3.66) 0.17 (0.04–0.41) 0.43 (0.03–5.44) 4.69 (< 0.06–52.7) 6.28 (0.61–54.3)
df/% 100 100 100 91
Food packaging (n = 25) Median/range 17.5 (0.76–1290) 2.46 (< 0.20–39.2) 1.35 (< 0.10–11.8) 3.60 (< 0.25–254) 36.2 (7.86–1570)
df/% 100 100 83 58
Animal feed (n = 12) Median/range 4.78 (2.25–18.7) < 0.02 (< 0.02–1.25) 4.22 (2.88–18.0) 41.6 (5.95–285) 56.5 (13.9–294)
df/% 100 25 100 100

a
Occurrences of melamine and its derivatives in dairy products were reported in our previous study (Zhu and Kannan, 2018b) and were also presented here for
comparison. Dairy products included dairy milk, yogurt, cheese, and butter.

with a df of 100% for melamine and > 58% for other derivatives
(Table 1). The median concentration of ∑melamine in food packaging
was 36.2 (7.86–1570) ng/g fw. The highest concentration of 1570 ng/g
fw of ∑melamine was found in a pasta packaging material (Table S2).
Melamine (median: 17.5 ng/g fw) was the predominant compound
found in all food packaging analyzed, followed by cyanuric acid
(3.60 ng/g fw), ammeline (2.46 ng/g fw), and ammelide (1.35 ng/g fw).
This distribution pattern of melamine and its derivatives in food
packaging was slightly different from what was found in foodstuffs, in
which cyanuric acid was the predominant compound. In the US, mel-
amine is authorized for use as an adhesive and a component of coatings
in food packaging to improve hardness, heat resistance, and stability
(Wagner, 2013). The food packaging materials analyzed in this study
were further divided into paper (n = 16) and plastic (n = 8) for com-
parison of concentrations. The concentrations of ∑melamine were
higher in paper packaging (median: 40.6 ng/g fw) than in plastic
packaging (18.1 ng/g fw), although the difference was not statistically
significant (p > 0.05). Our results suggest that food packaging can be a
source of melamine in foods, owing to the widespread use of melamine
in packaging materials. Several studies have reported migration of
melamine from melamine-based dinnerware under normal handling
conditions (Chien et al., 2011; Lund and Petersen, 2006; M.T. Wu et al.,
2015).
Disposition of melamine in animal tissues following administration
of melamine contaminated feed has been reported earlier (Chen et al.,
2010). The overall median concentrations of ∑melamine in animal feed
were 56.5 (13.9–294) ng/g fw. Cyanuric acid (median: 41.6 ng/g fw)
was the predominant compound found in animal feed, followed by
melamine (4.78 ng/g fw) and ammelide (4.22 ng/g fw). Accordingly,
the median concentrations of cyanuric acid (21.5 ng/g fw) in meat were
10-fold higher than those of melamine (1.77 ng/g fw). Cyanuric acid is
not approved by the USFDA as a non-protein source of nitrogen in

Fig. 1. Composition profiles of melamine and its derivatives in foodstuffs collected from Albany, New York, the United States. Mean concentrations were used to
calculate the composition profiles.

4
H. Zhu and K. Kannan
chicken and swine feeds (Karbiwnyk et al., 2009). It is not known
whether melamine or cyanuric acid was deliberately added as an ad-
ditive in feed; thus, further studies are needed on this regard. The
concentrations of Σmelamine varied widely within the category of
meat. The highest Σmelamine concentrations were found in chicken
(n = 10; median: 71.4 ng/g fw); which was followed, in decreasing
order, by turkey (n = 6; 37.4 ng/g fw), beef (n = 6; 15.5 ng/g fw), and
pork (n = 6; 3.38 ng/g fw). The median concentrations of Σmelamine in
pork meat were 20 times lower than those found in chicken. ∑melamine
concentrations were significantly higher in chicken feed (median:
111 ng/g fw) than in swine feed (28.7 ng/g fw) (p < 0.05), which can
explain the higher ∑melamine concentrations found in chicken meat
analyzed in this study.
Melamine and cyanuric acid also can be present at trace levels in
food/animal feed as degradation products of their precursors. For in-
stance, cyromazine is not only used for fly larvae control in manure and
floor areas of poultry farms but also authorized for use as an additive
(maximum: 4.5 mg/kg feed) in chicken feed in the US (USEPA, 2000).
The USEPA has reported that 10% of cyromazine is metabolized to
melamine in vivo (WHO, 2009a). Thus, elevated concentrations of
Σmelamine in chicken and turkey may be attributed to cyromazine
usage in poultry farming. Further, remarkable concentrations of mela-
mine (67.3, 27.9, and 21.0 ng/g fw in three samples) were found in
mushroom and carrot samples (vegetables category). Cyromazine is
also registered as an insecticide for fly control in mushroom production
(Shamshad et al., 2009). In addition, fertilizers have been reported as a
source of melamine and cyanuric acid in farm soils (Zhu et al., 2019b),
and the occurrence of these chemicals in vegetables suggests uptake by
plants (Ge et al., 2011; Qin et al., 2010). Trichloromelamine and di-
chloroisocyanurate are used in sanitizing solutions for disinfection of
water, food-processing equipment, utensils, and other food contact ar-
ticles in food-processing industries. Both chemicals can readily de-
compose to melamine and cyanuric acid in the environment (WHO,
2009a,b). Overall, the authorized uses of melamine precursors con-
tribute to the occurrence of these chemicals in foodstuffs.
3.3. Human dietary exposure
In addition to the six categories of foods analyzed in this study,
melamine and cyanuric acid concentrations, reported for dairy products
from Albany, New York (Zhu and Kannan, 2018b), were included in
dietary intake calculation. Dietary intake of ammeline and ammelide
was not calculated due to their low detection frequencies and con-
centrations in foods.
Among the five age groups, the highest median EDI values for
melamine and cyanuric acid were found for toddlers (72.7 and 347 ng/
kg bw/day, respectively), followed by children (36.1 and 187 ng/
kg bw/day), infants (29.3 and 122 ng/kg bw/day), teenagers (18.4 and
103 ng/kg bw/day), and adults (13.4 and 75.4 ng/kg bw/day) in that
decreasing order (Table 2). The variation in daily intake rates among
the age groups was due to different consumption rates and patterns of
Table 2
Estimated daily intakes (EDIs; ng/kg bw/day) and hazard quotients (HQs) of melamine and cyanuric acid for various age groups in the United States. Contributions
from dairy products were including from the results of our previous study (Zhu and Kannan, 2018b). HQs were based on the tolerable daily intakes of 63,000 and
1,500,000 ng/kg bw/day for melamine and cyanuric acid as reported by the USFDA and WHO, respectively.
Age group Melamine
EDI HQs
Average Worst-case Average
−4
Infants (< 1 yr) 29.3 327 4.65 × 10
Toddlers (1 to < 6 yrs) 72.7 529 1.15 × 10−3
Children (7 to < 11 yrs) 36.1 295 5.74 × 10−4
Teenagers (12 to < 21 yrs) 18.4 168 2.92 × 10−4
Adults (21 yrs and older) 13.4 156 2.12 × 10−4
5
Environment International 130 (2019) 104950
foods. For the high-exposure scenario, the EDIs of melamine and cya-
nuric acid were as high as 529 and 2630 ng/kg bw/day, respectively.
The EDIs of cyanuric acid were 3–5 times higher than those of mela-
mine.
The reported median EDI of melamine and cyanuric acid for adults
via the seven food categories was 1070 and 1680 ng/kg bw/day, re-
spectively, across 17 European countries in 2010 (EFSA, 2010), which
were 1–2 orders of magnitude higher than that found in our study. This
indicates a reduction in the dietary exposure of melamine and cyanuric
acid in recent years. On the basis of external exposure and reverse
dosimetry (based on urinary concentrations), the EDIs of melamine and
cyanuric acid in humans were calculated to be 0.80–1130 (mean: 65.5)
and 31.8–4130 (mean: 315) ng/kg bw/day, respectively (Zhu and
Kannan, 2018a). In comparison to the values calculated through reverse
dosimetry, the EDIs of melamine and cyanuric acid by US adults
through diet explain ~20% of the total intakes. This suggests that, in
addition to foodstuffs, other sources of human exposure to melamine
and cyanuric acid exist. Other potential sources of melamine and cya-
nuric acid exposure include indoor dust ingestion (7.50 and 1.81 ng/
kg bw/day, respectively) (Zhu and Kannan, 2018c), inhalation (C.F. Wu
et al., 2015), and melamine-based dinnerware (M.T. Wu et al., 2015).
Further studies are needed to fully assess exposure of the US population
to melamine and cyanuric acid, especially considering the increase in
the prevalence of chronic kidney diseases in children and adults.
The contribution of each food category to the overall dietary ex-
posure to melamine and cyanuric acid is described in Fig. 2. Dairy
products were the major contributors to melamine exposure in the US
(median EDI: 3.81–42.6 ng/kg bw/day), followed by cereal products
(3.14–10.2 ng/kg bw/day), meat (2.12–7.03 ng/kg bw/day), vegetables
(1.84–5.02 ng/kg bw/day), beverages (0.65–5.06 ng/kg bw/day),
cooking oil (0.66–5.06 ng/kg bw/day), and fish and seafood
(0.04–0.25 ng/kg bw/day). For cyanuric acid, dairy products (median
EDI: 15.0–168 ng/kg bw/day), cereal products (23.4–76.0 ng/kg bw/
day) and meat (25.8–85.4 ng/kg bw/day) accounted for > 90% of the
total dietary exposure. In general, dietary exposure to melamine and
cyanuric acid via fish and seafood consumption is minimal. It should be
noted that the small sample size analyzed in this study may have
tempered dietary intake estimates, and, thus, our estimates should be
considered as an approximate value. Further, several categories of food
items were not included in the analysis (e.g., sweets, eggs, breast milk,
tap water).
The median dietary exposure doses of melamine and cyanuric acid
estimated in our study were 3–5 orders of magnitude lower than the
current reference dose. Among the five age groups, the HQ for mela-
mine (HQ: 1.15 × 10−3) and cyanuric acid (2.31 × 10−4) was the
highest for toddlers, and the lowest HQs were found for adults (mela-
mine HQ: 2.12 × 10−4 and cyanuric acid HQ: 5.03 × 10−5). On the
basis of the TDI value of 3150 ng/kg bw/day for melamine re-
commended by Choi et al. (2010), the highest melamine HQ in the
high-exposure scenario reached a value of 0.17. These results suggest
that the current level of melamine or cyanuric acid exposure does not
Cyanuric acid
EDI HQs
Worst-case Average Worst-case Average Worst-case
−3 −5
5.20 × 10 122 893 8.16 × 10 5.95 × 10−4
8.39 × 10−3 347 2630 2.31 × 10−4 1.75 × 10−3
4.68 × 10−3 187 1413 1.25 × 10−4 9.42 × 10−4
2.67 × 10−3 103 786 6.86 × 10−5 5.24 × 10−4
2.48 × 10−3 75.4 600 5.03 × 10−5 4.00 × 10−4
H. Zhu and K. Kannan
Fig. 2. Contribution of various food groups to estimated daily dietary intakes of melamine (A) and cyanuric acid (B) for different age groups (yrs = years) in the
United States. Estimated daily intakes of melamine and cyanuric acid via dairy products consumption were from our previous study (Zhu and Kannan, 2018b).
pose a significant health risk.
4. Conclusions
Very few studies have reported human dietary exposure to ∑mela-
mine. Our results document the continuing occurrence of melamine and
its derivatives in food samples from the US. The current concentrations
of melamine and cyanuric acid in foods were 1–2 orders of magnitude
lower than the concentrations reported in the period 2007–2008, fol-
lowing the melamine food scandals. The predominance of cyanuric acid
in the majority of foodstuffs suggests the need for further studies to
elucidate sources of this compound. Melamine concentrations in food
packaging were an order of magnitude higher than those in foodstuffs,
indicating that packaging can be a source of melamine in foodstuffs.
Significantly higher cyanuric acid concentrations in chicken feed than
in swine feed explain high concentrations of this chemical found in
chicken meat. Among the seven food categories analyzed, dairy pro-
ducts (49%), cereal products (17%), meat (12%), and vegetables (9.3%)
account for, on average, three-quarters of the total dietary exposure to
melamine in the US general population. Dairy products (39%), meat
(30%) and cereal products (26%) are the major dietary sources of cy-
anuric acid in the US population. Considering the small sample size and
uncertainties associated with exposure and risk calculations, the results
should be interpreted with caution.
Declaration of Competing Interest
The authors declare no competing financial interest.
Appendix A. Supplementary data
Details regarding instrumental analysis, tables containing list of
foodstuffs and food packaging materials analyzed, as well as target
chemical concentrations (Tables S1 and S2), multiple reaction mon-
itoring transitions and method detection limits of MS/MS method
(Table S3) as well as matrix spike recoveries (Table S4) of target che-
micals, per capita daily intake rates of foodstuffs (Table S5) used in the
estimation of daily dietary intakes of melamine and cyanuric acid for
various age groups (Table S6). Figure showing pathways of melamine
hydrolysis (Fig. S1). Supplementary data to this article can be found
online at https://doi.org/10.1016/j.envint.2019.104950.
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