Article pubs.acs.org/est
Behavioral Intervention and Decreased Daily Melamine Exposure from Melamine Tableware Ming-Tsang Wu,*,†,∥,‡,§,# Chia-Fang Wu,† and Bai-Hsiun Chen‡,§,⊥ †
Department of Public Health, ‡Research Center of Environmental Medicine, and §Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan ∥ Department of Family Medicine and ⊥Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan # Center of Environmental and Occupational Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan S Supporting Information *
ABSTRACT: This study aims to examine whether behavior intervention can decrease total urinary melamine excretion. A total of 16 healthy subjects were recruited from two university buildings (eight subjects each). By using a stepped-wedge cluster randomized and controlled trial design, we randomly assigned eight subjects from the same building to the serial steps of either control−intervention−intervention or control−control−intervention. Each step lasted for 3 days. Subjects in the intervention step carried one bag containing stainless steel tableware as meal boxes and used them for each meal during the trial, whereas those in the control step carried one empty bag. The 24 h urine samples for 9 consecutive days were collected. In the control−intervention− intervention group, after excluding two subjects with missing data, the median absolute difference of the total 3 day melamine excretion between the seventh to the ninth day and from the first to the third day was −19.9 μg (a range from −160.6 to −7.2 μg, p = 0.028, n = 6). The median protection percent of the total 3 day melamine exposure (the amount from the seventh to the ninth day minus the amount from the first to the third day, divided by the amount from the first to the third day) was 68.4%, ranging from 41.8% to 91.8%. Regular use of stainless steel-made meals boxes can mitigate melamine exposure from melamine tableware.
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INTRODUCTION The 2008 melamine scandal in China caused more than 50 000 children to become hospitalized and at least six deaths due to kidney stones and other renal failures.1,2 In adults, low-dose melamine exposure can increase the risk of urolithiasis, suggesting the ubiquitous presence of melamine in the environment around the world, although that scandal has since wound down.3−5 A main source of melamine exposure in modern life is from the popular use of melamine tableware.6 Our previous crossover study reported that study subjects could excrete a substantial amount of melamine in their urine when they consumed hot soup using melamine tableware.7 However, to our knowledge, no experimental study had been conducted to provide evidence-based data on how to prevent melamine exposure from melamine tableware in daily life. Here, we conducted a cluster-randomized controlled trial (CRCT) by using the stepped-wedge trial design to examine whether the use of stainless steel meal boxes could decrease melamine exposure from the daily environment. Our primary hypothesis was that the continuous use of stainless steel meal boxes to contain and consume high-temperature soups or foods could decrease the total melamine excretion in the urine. The secondary hypothesis was that intervention could also decrease the mean urinary melamine levels by measuring the first onespot urine samples in the morning. © 2015 American Chemical Society
MATERIALS AND METHODS Observational Study. We first recruited 88 university student volunteers from two university buildings (Building A and B, 44 students each with the same sex proportion) to clarify their environmental melamine exposure from melamine tableware for the subsequent stepped-wedge CRCT study (Figure 1). The inclusion criteria were (1) aged between 18 and 30 years and (2) healthy students without cancer or chronic diseases such as hepatic or renal diseases, including renal stones, whereas the exclusion criteria were (1) positive family history of renal stones and (2) body weight less than 40 kg. The 88 eligible volunteers were asked to collect their first one-spot urine specimens for three consecutive mornings on September 23−25, 2014, for the measuring of urinary melamine levels. In addition, we also administered one short questionnaire to subjects to collect their demographic characteristics, including age, sex, body height, and body weight, and to determine how frequently they consumed hot soup or hot water by using melamine tableware 3 days prior to the collection of their first
Received: Revised: Accepted: Published: 9964
April 21, 2015 July 7, 2015 July 17, 2015 July 17, 2015 DOI: 10.1021/acs.est.5b01965 Environ. Sci. Technol. 2015, 49, 9964−9970
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Environmental Science & Technology
Figure 1. Study flowchart.
one-spot urine specimen, defined as the “ever use” of melamine tableware. The study protocol was approved by the IRB at Kaohsiung Medical University Hospital, and all participants provided written informed consent. A total of 264 urine samples (88 students and three urine samples apiece) were measured for melamine using triplequadrupole liquid chromatography−tandem mass spectrometry (LC−MS/MS) by one laboratory technician who was blinded to the personal information and study design. The detailed analytical method has been described in detail elsewhere.3,4 The method of detection limit (MDL) was 0.4 ng/mL (ppb) in urine, with any measurement below MDL treated as 0.2 ng/mL. We found that melamine was detectable in 199 (75.4%) out of 264 urine samples (Table S1 in the Supporting Information). The urinary melamine levels were expressed as ng/mL and μg/mmol creatinine (Cr) without and with the correction of urinary creatinine, respectively.3,4 Stepped-Wedge CRCT Study. This study followed the guidelines of CONSORT for reporting CRCT.8 According to the questionnaire information from the observational study, we first selected study subjects who had ever consumed hot soup or hot water by using melamine tableware in the past 3 days (“ever use” of melamine tableware). We then listed their averaged 3 day concentrations of one-spot urinary melamine levels from the highest to the lowest in each building. We picked the subjects with the highest average urinary melamine levels (ng/mL) from those two buildings for the subsequent interventional study, if they agreed to participate, and equal sex ratios were present in those two buildings. A total of eight study subjects (four males and four females) from each building were chosen, and the stepped-wedge CRCT
design was applied. After all study subjects signed the consent forms, we randomly assigned one building to a series of control− intervention−intervention steps (Building B) and another building to a series of control−control−intervention steps (Building A) by computer. Each step lasted for 3 days, and the total experimental period was 9 days. Subjects in the intervention step carried one bag containing a combination of two stainless steel containers, one stainless steel spoon, and one pair of stainless steel chopsticks as meals boxes and used them for each meal during the trial (Figure S1 in the Supporting Information), whereas subjects in the control step only carried one empty bag without that stainless steel tableware, indicating that the tableware was provided by vendors, when dining out. We then collected the subjects’ 24 h urine samples for 9 consecutive days (starting from the first waking one-spot urine sample, indicated as the zeroth one-spot morning urine sample, on October 8, 2014, to the first waking one-spot urine sample on October 17, 2014, indicated as the ninth one-spot morning urine sample) for measuring the daily total melamine excretion amount and melamine levels in the first waking onespot urine samples daily (Figure S2 in the Supporting Information). For example, the first one-spot morning urine sample, collected in the morning of October 9, 2014, was vortexed; 1 ml was then aliquoted to another Eppendoff tube, and the rest of urine was mixed well with other urine samples (collected prior to the 24 h sample of urine from October 8, 2014) except for the zeroth one-spot morning urine sample. The total volume of this urine sample was used to represent 24 h urine excretion in the first day (Figure S2 in the Supporting Information). Both the first one-spot morning urine sample and the 24 h urine sample in the first day were measured for 9965
DOI: 10.1021/acs.est.5b01965 Environ. Sci. Technol. 2015, 49, 9964−9970
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Environmental Science & Technology melamine level by LC−MS/MS (Table S1 in the Supporting Information). A total melamine amount in the 24 h urine sample in the first day was calculated as: melamine level (μg/mL) of the 24‐hr urine sample in the first day ×total volume (mL) collected for 24 h in the first day =melamine amount (μg) in the first day
To calculate the total 3 day melamine excretion from the first to third day, we added melamine amount in the first day, second day, and third day together. Assurance of CRCT Protocol. To confirm that no melamine residues existed in the stainless steel containers, we randomly selected three such containers, filled them with hot water (95 °C) to approximately 80% full, left them for 30 min, and measured the melamine levels in the water. We found that all three measurements were below MDL. To check the adherence rate during the trial, we encouraged the study subjects to use their cellular phones to take pictures before eating their meals and e-mail them to us later (Figure S3 in the Supporting Information). We collected 95 pictures from Building A and 123 pictures from Building B, respectively, and found at an least 80% of adherence rate in each building during the trial (Table S2 in the Supporting Information). Statistical Analysis. For the observational study, a Wilcoxon rank-sum test was calculated to compare the differences of the mean urinary melamine levels in three one-spot urine samples between subjects with and without the consumption of hot soup or hot water by using melamine tableware 3 days prior to the collection of their first one-spot urine specimens. For the stepped-wedge CRCT study, we first examined the Spearman correlation between the melamine levels in the first one-spot urine samples in the mornings and the total melamine excretion in their previous 24 h urine samples. A Wilcoxon signed-rank test was then calculated to examine the absolute differences of the total 3 day melamine excretion and the mean 3 day melamine levels between steps (the first to the third day, the fourth to the sixth day, or the seventh to the ninth day) in the group of control−intervention−intervention or control−control− intervention, which were our primary and secondary outcomes. In addition, for each period of 3 days (the first to the third day, the fourth to the sixth day, or the seventh to the ninth day), a Wilcoxon rank-sum test was calculated to compare the absolute differences of the total 3 day melamine excretion between the two groups of control−intervention−intervention and control−control−intervention. All tests were performed by SAS 9.1 statistical software; p-values were two-sided at a significance level of 0.05.
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Figure 2. Comparison of the averaged melamine levels in urine from the 3 day one-spot urine samples in subjects with (n = 45) and without (n = 43) use of melamine tableware based on the questionnaire. (A) Without correction for creatinine (Cr); (B) with correction for Cr (Wilcoxon rank-sum test for p-value).
One male subject in Building A did not provide 24 h urine samples on day 4, whereas one male subject in Building B did not provide 24 h urine samples on days 3 and 7 (Figure S2). Due to the onset of menstruation, one female subject in Building B did not provide one-spot and 24 h urine samples after day 4. When examining the available urine samples for both the one-spot urine samples and the 24 h urine samples (n = 136), we found a high correlation for the one-spot urinary melamine concentration (μg/mmol Cr) with the total 24 h urinary melamine excretion (μg) (Spearman correlation coefficient r = 0.713) (Figure S4 in the Supporting Information). After excluding two subjects with missing data in the control− intervention−intervention group (n = 6), we found that the median absolute difference for the total 3 day melamine excretion between the seventh to the ninth day and the first to the third day was −19.9 μg (a range from −160.6 to −7.2 μg), which was significant (Wilcoxon signed-rank test, p = 0.028) (Table 2, Figure 3A, and Table S4 in the Supporting Information). The median protection percent of the total 3 day melamine exposure ([the amount in the seventh to the ninth day minus the amount in the first to the third day, divided by the amount in the first to the third day) was 68.4%, ranging from 41.8% to 91.8% (Figure 3B). However, we did not find a significant absolute
RESULTS
Observational Study. A total of 44 student participants (15 males and 29 females, aged 19 to 26 years) in each building participated (Table S3 in the Supporting Information). We found that about half of the 88 participants (45/88, 51.1%) had consumed hot soup or hot water by using melamine tableware in the previous 3 days before the collection of their one-spot urine samples. Compared to those without “ever use” of melamine tableware, participants with “ever use” of melamine tableware had significantly higher mean melamine levels in urine (Wilcoxon rank-sum test, p = 0.005 and 0.002 without and with correction for urinary creatinine) (Figure 2). Stepped-Wedge CRCT Study. The demographic characteristics were similar between the two groups (Table 1). 9966
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In addition, subjects regularly dining-out with the use of stainless steel meal boxes to contain hot foods had significantly lower levels of total melamine excretion in their urine. To our knowledge, this is the first study validating the idea that behavioral intervention by using proper and portable tableware could significantly decrease melamine exposure from melamine tableware. Melamine tableware consists of 70−75% melamine formaldehyde resin and 25−30% refined wood pulp; the remainder is tiny amounts of aluminum stearate and magnesium stearate. Many research groups have reported that melamine tableware can release a substantial amount of melamine chemicals into food when contacting hot food or acid.9−11 Our previous study also found that high melamine migration levels, ranging from 6.97 to 19.03 μg/mL, could be measured from all five tested melamine-made cups containing 20 mL 3% acetic acid in a water bath of 90 °C for 30 min.6 The migration of the melamine amount is dependent on different temperatures, contact times, simulant, and the prices of tableware. In a subsequent crossover study, we also found that subjects consuming hot noodle soup served in melamine bowls (compared to those consuming soup served in ceramic bowls) excreted much more melamine (approximately 7 μg in difference) in urine.7 After the 2008 melamine scandal in China, wherein melamine caused kidney-related diseases and failure in children,12 several research groups surveyed urinary melamine levels in the general population who had not accidentally consumed toxic milk products before to examine whether melamine was ubiquitously present in the environment. In 2012, Panuwet et al. reported that 76% of 492 urine samples from the general U.S. population had detectable melamine levels (MDL = 0.66 ng/mL), and the geometric mean concentration and the highest measures were 2.37 and 161.0 ng/mL, respectively, although the age distribution was unknown.5 This study also found that melamine was detectable in about two-thirds of 264 urine samples, similar to the report from the study of Panuwet et al., and the geometric mean concentration and the highest measures were 6.52 and 218.9 ng/mL (Table S3 in the Supporting Information). Our recent data of 87 urine samples from 22 children, aged 6−10 years, and 70 urine samples from their parents in one Taiwanese community revealed that only two urine samples did
Table 1. Demographic Characteristics and BaselineAveraged 3 Day Urinary Melamine Levels in 16 Student Participants control−control− intervention group (Building A) N sex male female age (years) body height (cm) body weight (kg) BMI (kg/cm2) melamine (ng/mL)1 melamine (μg/mmol Cr)1
8
control−intervention− intervention group (Building B) 8
4 4
4 4 mean ± SD (median, range) 20.9 ± 1.7 21.6 ± 1.7 (20.0, 20.0 to 25.0) (21.0, 20.0 to 25.0) 166.5 ± 10.2 166.8 ± 7.6 (164.0, 153.0 to 181.0) (165.0, 157.0 to 178.0) 57.4 ± 10.9 60.3 ± 10.8 (55.0, 44.0 to 75.0) (56.5, 52.0 to 85.0) 20.6 ± 2.3 21.9 ± 5.1 (19.9, 18.2 to 25.6) (20.6, 18.0 to 34.0) 19.4 ± 12.7 29.1 ± 35.2 (13.1, 6.3 to 41.3) (18.8, 0.2 to 112.3) 1.4 ± 0.8 2.0 ± 1.8 (1.3, 0.5 to 2.6) (1.8, 0.01 to 6.0)
Abbreviations: BMI, body mass index; Cr, creatinine; SD, standard deviation. 1Averaged melamine levels of three one-spot urinary specimens from the observational study.
difference in the total 3 day melamine excretion between the fourth to the sixth day and the first to the third day in the control−intervention−intervention group (n = 6), as well as the seventh to the ninth day and the fourth to the sixth day in control−control-intervention group (n = 7) (Wilcoxon signedrank test, p = 0.600 and 0.237, respectively). When combining these two (n = 13), we also noted no significantly absolute difference (a median of −5.1 μg, a range from −65.3 to 60.3 μg, p = 0.650). By using the averaged melamine levels from the 3 day or 4 day one-spot urinary samples, we found similar results (Table 2).
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DISCUSSION This study found that participants previously consuming hot soup or hot water by using melamine tableware had significantly higher melamine levels in urine than those not.
Table 2. Total 3 Day Melamine Excretion and Averaged 3 Day Melamine Levels Categorized by Groups median (range) of total 3 day melamine excretion (μg)
control−intervention− intervention (n = 6) control−control− intervention (n = 7) median (range) of averaged 3 day melamine levels (μg/mmol Cr)
baseline1
intervention/ control
control/control the first to third day
the fourth to sixth day
28.1 (14.5 to 184.3) 15.1 (5.5 to 74.8)
intervention/ intervention
p-value2
0.028
45.5 (2.7 to 134.0)
0.600
9.6 (2.7 to 23.7)
13.3 (4.3 to 78.9)
−7.9 (−28.2 to 63.9)3
0.499
13.6 (3.0 to 29.3)
−1.5 (−50.5 to 2.7)4
0.237
intervention/ intervention
difference
p-value2
mean seventh to ninth day − mean zeroth to third day -0.35 (−5.88 to 0.24)6
0.028
-0.58 (−5.40 to −0.20)6
0.012
1.5 (0.01, 6.0) 0.87 (0.55 to 6.23) 1.45 (0.37 to 5.58)
intervention/ control mean fourth to sixth day 1.43 (0.13 to 5.06) 0.82 (0.34 to 9.78)
difference
the seventh to ninth day
difference total seventh to ninth day − total first to third day -19.9 (−160.6 to −7.2)4
control/control
1.3 (0.5, 2.6)
p-value2
total fourth to sixth day − total first to third day 1.1 (−56.4 to 60.3)3
mean zeroth to third day control−intervention− intervention (n = 7) control−control− intervention (n = 8)
difference
p-value2
mean fourth to sixth day − mean zeroth to third day −0.41 (−1.64 to 1.90)5
mean seventh to ninth day 1.000
−0.19 (−3.93 to 4.19)5
0.575
0.44 (0.08 to 2.06) 0.68 (0.07 to 1.40)
1
Data of averaged 3 day melamine levels from three one-spot urine samples in the observational study. 2Wilcoxon signed-rank test. 3Wilcoxon ranksum test, p = 0.668. 4Wilcoxon rank-sum test, p = 0.086. 5Wilcoxon rank-sum test, p = 1.000. 6Wilcoxon rank-sum test, p = 0.418. 9967
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Figure 3. Difference of 3 day summations of urinary melamine excretion between the steps by two different interventional groups. (A) Absolute difference and (B) protection percent; − indicates median and * indicates Wilcoxon signed-rank test p-value of 0.028.
not have detectable melamine at MDL of 0.8 ng/mL.13 From those 22 studied children with two one-spot urine samples collected on two different days, we found that the geometric mean concentration and the highest melamine concentrations were 8.89 and 85.0 ng/mL in the first one-spot urine samples and 7.28 and 61.5 ng/mL in the second onespot urine samples. For their parents, the geometric mean concentration and the highest melamine concentrations were 6.13 and 41.5 ng/mL in their fathers’ combined 34 one-spot urine samples and 5.59 and 38.6 ng/mL in their mothers’ combined 36 one-spot urine samples.13 The aforementioned results indicated that both of the different ethnic populations are continuously exposed to melamine from the general
environment, even after the end of the 2008 melamine scandal. Panuwet et al. suggested that the low-level exposure to melamine in the U.S. population was probably from the degradation of the pesticide cyromazine to form melamine.5 However, in this study, along with our previous ones, we reported that environmental melamine exposure from melamine tableware cannot be ignored.6,7 Thus, the findings of this study have significant impact in the primary prevention of melamine exposure. Why was the decrease of 3 day total melamine excretion only present after the double-cycle, instead of the single-cycle, 3 day intervention in both groups? (Figure 3) Our previous study has suggested that the estimated half-life of urinary melamine 9968
DOI: 10.1021/acs.est.5b01965 Environ. Sci. Technol. 2015, 49, 9964−9970
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Environmental Science & Technology elimination was at least 6 h,7 so the significance of the decrease immediately after the implementation of the intervention was not reached probably due to the residual effect before the intervention. This study also found that the strength of the correlation between the one-spot urine sample and the 24 h total urinary melamine excretion in the stepped-wedge CRCT study was relatively high. Our previous study has reported that the melamine concentration of the one-spot overnight urine sample in the morning of the second day in subjects aged 6−10 yrs was highly correlated with the previous 8 and 24 h total melamine excretions in urine (r = 0.936, p < 0.001, n = 21 and r = 0.616, p < 0.001, n = 21, respectively).13 The two studies suggest that the melamine concentration in one-spot urine can predict the previous 24 h total melamine excretion in both adults and children. Currently, it is not clear whether low amounts of melamine intake are safe in humans, and furthermore, whether long-term low melamine exposure may confer a healthy risk to humans.2,14 The tolerable daily intakes (TDI) originally recommended by the World Health Organization (WHO) and the U.S. Food and Drug Administration (FDA) were all revised to 0.2 mg/kg of body weight per day and 0.063 mg/kg of body weight per day, respectively, due to its uncertainties.15 However, some recent studies further recommended that a lower TDI of melamine to 0.0081 mg/kg of body weight per day should be considered in humans, especially in susceptible populations such as children.16,17 Several updated studies also show that some children who suffered from melamine-associated renal stones had a daily melamine exposure even lower than the WHO- or FDA-recommended TDI.18,19 The lowest estimated exposure of melamine is 0.01 mg/kg of body weight per day for those children with melamine-associated renal stones. Choi et al. completed one in vivo study and recommended a much lower TDI to 0.00315 mg/kg/day for melamine.20 Thus, these studies recommended that even low amounts of melamine exposure may still be a risk factor of urolithiasis or renal damage in humans.16,18−20 The main reason for using CRCT in this study is to prevent potential “contamination” within the building and decrease the possible spillover of the treatment effect from one group to another.8 The CRCT study cannot be conducted as a complete double-blinded one; however, the technician who analyzed the urinary melamine levels was unaware of the trial group, and the study subjects did not have foreknowledge about the main purpose of this study. Thus, this study further took the advantage of the “waiting list” strategy by using stepped-wedge design to decrease the impact of nonblinded and ethical issues.21 The main limitation of the stepped-wedge CRCT study is the relatively small sample size. Due to this, the gender effect cannot be examined either. Another limitation is that some subjects did not send the pictures by e-mail when they were dining out (Table S2 in the Supporting Information), although we did find good compliance if they did send them. This potential bias may cause cross-contamination and probably dilute the significance. This is a “real-world” experimental study that cannot avoid the fact that some vendors may provide melamine-free tableware (e.g., ceramic tableware) for the control steps. However, this bias is likely to underestimate our findings. One other limitation is the possibility of other unknown sources of melamine exposure (e.g., food sources), which may explain the findings of our wide interventional effect, ranging from 41.8% to 91.8%. We found that the use of nonbreakable melamine tableware is common in our daily life, and regular dining out using
stainless steel meal boxes to contain high-temperature foods can mitigate melamine exposure from melamine tableware, with this decrease ranging between 41.8% and 91.8% from the baseline. This study demonstrates how to primarily prevent against environmental melamine exposure from melamine tableware in the short term, although the clinical significance of the levels of decrease of melamine in the human body has yet to be established. Future study is necessary to examine the long-term beneficial effect of this behavior intervention.
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ASSOCIATED CONTENT
S Supporting Information *
Figures depicting the interventional and control steps, the protocol of the urinary sample series collection, representative trial pictures, and the correlation of one-spot urinary concentration with total 24 h urinary melamine excretion. Tables showing data for the number of urine samples, adherence rate based on the total pictures e-mailed, demographic characteristics of participants, and raw data for urinary melamine amount and level. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.est.5b01965.
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AUTHOR INFORMATION
Corresponding Author
*Phone: 886-7-312-1101-2141 ext. 55; Fax: 886-7-3221806; E-mail:
[email protected] or
[email protected]. Author Contributions
M.T.W. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design, acquisition of data, obtaining of funding, and study supervision were performed by M.T.W. Analysis and interpretation of data were performed by C.F.W. and B.H.C. Drafting of the manuscript and statistical analysis were formed by C.F.W. and M.T.W. Administrative, technical, and material support was performed by B.H.W. and M.T.W. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Mr. Steve Tredrea to assisting in editing the manuscript. This work was supported by Kaohsiung Medical University (KMU-DT103004), Kaohsiung Medical University Hospital (KMUH103-3R67, KMUH101-1I04), the Taiwan Ministry of Science and Technology (NSC 101-2314-B-037037-MY3), and Taiwan’s National Health Research Institutes (NHRI-EX104-10209PI), none of which had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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REFERENCES
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DOI: 10.1021/acs.est.5b01965 Environ. Sci. Technol. 2015, 49, 9964−9970
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DOI: 10.1021/acs.est.5b01965 Environ. Sci. Technol. 2015, 49, 9964−9970
