Melamine

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

other: Review, with the ultimate aim to determine the threshold of melamine intake at which a urolithiasis risk can be expected.

Adequacy of study:

key study

Study period:

<=2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Review of existing publications.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Urolithiasis in children and exposure to melamine: A review of the epidemiological literature

Author:

Swaen GMH

Year:

2019

Bibliographic source:

Toxicology Research and Application. Volume 3: 1–10. 2019

Materials and methods

Study type:

other: Review of epidemiological publications

Endpoint addressed:

other: Urolithiasis

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

A literature search on epidemiology studies with connection to melamine exposure was conducted and the obtained results were assessed. The ultimate aim was to determine the threshold of melamine intake at which a urolithiasis risk can be expected.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Melamine

EC Number:

203-615-4

EC Name:

Melamine

Cas Number:

108-78-1

Molecular formula:

C3H6N6

IUPAC Name:

1,3,5-triazine-2,4,6-triamine

Test material form:

solid: particulate/powder

Method

Type of population:

general

Ethical approval:

not applicable

Details on study design:

A literature search on epidemiology studies with connection to melamine exposure was conducted and the obtained results were assessed.
To find relevant epidemiology studies on melamine exposure and human health, several literature searches were made in PubMed up to August 2018, with combinations of “melamine” AND “exposure” and “melamine” AND “urolithiasis” and melamine AND “kidney.”

Results and discussion

Results:

In total, 667 journal articles were found and the abstracts were reviewed to determine whether the journal article was an epidemiology study. Reference lists of journal articles on epidemiology studies were further searched for relevant publications. In total, 36 epidemiology studies on ME intake and urolithiasis were identified; 26 studies were conducted in Mainland China, 6 in Hong Kong, and 4 in Taiwan; 5 studies were prospective cohort studies of ME-exposed children, 3 were case–control studies, 14 were cross-sectional studies, 8 were prospective follow-up studies on pediatric urolithiasis cases (prognostic studies), and 6 were case series. Three of the 36 were on adults.
In newborns and children under the age of 2, urolithiasis is rarely diagnosed. Urolithiasis prevalence rates between 0.03% and 0.6% have been reported in Hong Kong and of 0.8% in Turkey with its hot and arid climate. In a screening survey in children living in Mainland China, the prevalence of urolithiasis was reported to be 0.41% in non-ME-exposed children and 2.51% in children with intake of ME-tainted formula.
Several epidemiologic studies provided data on the dose–response relationship between daily ME intake and urolithiasis prevalence or data relevant to it. Some of these, including Li, applied flawed methodologies. However, some epidemiologic studies provide several anchoring points for the dose–response relationship between daily ME intake and urolithiasis:

1. The urolithiasis incident was restricted to Mainland China, but there was concern that it had spilled over to Hong Kong,which triggered several investigations there. These Hong Kong studies (Lam HS et al. 2013; Lau YL et al. 2013) found no urolithiasis and concluded the prevailing ME intake had not caused any health effects. Daily ME intake in Hong Kong was reported to be between 0.01 mg/kg/day and 0.21 mg/kg/day. This range therefore must be considered as being an exposure level below the No Observed Adverse Effect Level (NOAEL), how far it is below the NOAEL cannot be determined from these data.

2. The only epidemiology study (Li G et al. 2010) conducted in Mainland China for which the data were analyzed in a dose–response format is unreliable and has serious methodological shortcomings and should not be used for standard setting or for the derivation of dose–response descriptors.

3. Sun et al. 2010 compared ME intake between 79 urolithiasis cases and 103 non-urolithiasis cases. Mean estimated daily ME intake in the cases was 5.17 mg/kg/day as compared to 2.38 mg/kg/day in the controls with a standard deviation of 3.39 mg/ kg/day, suggesting that the latter dose is not associated with urolithiasis risk.

4. In Taiwan, Wang et al. 2009 conducted a case–control study of urolithiasis and estimated ME intake. They reported no increase in urolithiasis in the group, with estimated daily intake of food products containing ME between 0.05 ppm and 2.5 ppm.

Applicant's summary and conclusion

Conclusions:

There are no other publications or reports in the open scientific literature that melamine intake can induce urolithiasis in humans other than those from the food tampering incident in Mainland China and the spillover to Taiwan.
All observations described demonstrate that at low melamine intake, the incidence of urolithiasis is not above the background incidence as reported in nonexposed populations. In the epidemiology studies on children with melamine intake and urolithiasis, there is no reliable indication that there is a urolithiasis risk below or in the range of 2.38 mg/kg/day and a standard deviation of 3.39 mg/kg/day.
None of the epidemiologic studies with sound methodology provide evidence that at or below this level a risk of increased urolithiasis exists and consequently they provide no evidence that the WHOestimated TDI of 0.2 mg/kg bw/d is unsafe.

Executive summary:

A literature search on epidemiology studies with connection to melamine exposure was conducted and the obtained results were assessed.

There are no other publications or reports in the open scientific literature that melamine intake can induce urolithiasis in humans other than those from the food tampering incident in Mainland China and the spillover to Taiwan. There is no evidence that melamine intake other than this incident has led to urolithiasis in humans.

All observations described demonstrate that at low melamine intake, the incidence of urolithiasis is not above the background incidence as reported in nonexposed populations. In the epidemiology studies on children with melamine intake and urolithiasis included in this review, there is no reliable indication that there is a urolithiasis risk below or in the range of 2.38 mg/kg/day and a standard deviation of 3.39 mg/kg/day.

The highest daily melamine intake with no increase in urolithiasis reported in the reliable studies has been reported by Sun et al. 2010 which was 2.38 mg/kg/day in the controls free of urolithiasis, with a standard deviation of 3.39 mg/kg/day. None of the epidemiologic studies with sound methodology provide evidence that at or below this level a risk of increased urolithiasis exists and consequently they provide no evidence that the WHOestimated TDI of 0.2 mg/kg bw/d is unsafe.