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Title: Recent advances in the risk assessment of melamine and cyanuric acid in animal feed

Abstract

Melamine can be present at low levels in food and feed mostly from its legal use as a food contact material in laminates and plastics, as a trace contaminant in nitrogen supplements used in animal feeds, and as a metabolite of the pesticide cyromazine. The mechanism of toxicity of melamine involves dose-dependent formation of crystals with either endogenous uric acid or a structural analogue of melamine, cyanuric acid, in renal tubules resulting in potential acute kidney failure. Co-exposure to melamine and cyanuric acid in livestock, fish, pets and laboratory animals shows higher toxicity compared with melamine or cyanuric acid alone. Evidence for crystal formation between melamine and other structural analogs i.e. ammelide and ammeline is limited. Illegal pet food adulterations with melamine and cyanuric acid and adulteration of milk with melamine resulted in melamine–cyanuric acid crystals, kidney damage and deaths of cats and dogs and melamine–uric acid stones, hospitalisation and deaths of children in China respectively. Following these incidents, the tolerable daily intake for melamine was re-evaluated by the U.S. Food and Drug Administration, the World Health Organisation, and the Scientific Panel on Contaminants in the Food Chain of the European Food Safety Authority (EFSA). This review provides an overviewmore » of toxicology, the adulteration incidents and risk assessments for melamine and its structural analogues. Particular focus is given to the recent EFSA risk assessment addressing impacts on animal and human health of background levels of melamine and structural analogues in animal feed. Recent research and future directions are discussed. - Highlights: ► Melamine in food and feed. ► Forms crystals in kidney with uric acid or cyanuric acid. ► Toxicity higher with cyanuric acid. ► Recent EFSA risk assessment. ► Animal and human health.« less

Authors:
 [1];  [2];  [1];  [3];  [4];  [5];  [6];  [7];  [8];  [9]
  1. Unit on Contaminants, European Food Safety Authority, Largo N. Palli 5/A, 43121 Parma (Italy)
  2. NCTR, Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079 (United States)
  3. University of Utrecht (Netherlands)
  4. RIVM, Bilthoven (Netherlands)
  5. Norwegian Institute of Public Health, Oslo (Norway)
  6. Dietary and Chemical Monitoring, European Food Safety Authority, Largo N. Palli 5/A, 43121 Parma (Italy)
  7. FERA, York (United Kingdom)
  8. German Cancer Research Center, Heidelberg (Germany)
  9. Food Standard Agency, London (United Kingdom)
Publication Date:
OSTI Identifier:
22285348
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 270; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL FEEDS; CATS; CHILDREN; DOGS; DOMESTIC ANIMALS; FOOD CHAINS; LABORATORY ANIMALS; MELAMINE; MILK; PUBLIC HEALTH; RISK ASSESSMENT; TOXICITY; TUBULES; URIC ACID

Citation Formats

Dorne, Jean Lou, E-mail: jean-lou.dorne@efsa.europa.eu, Doerge, Daniel R., Vandenbroeck, Marc, Fink-Gremmels, Johanna, Mennes, Wim, Knutsen, Helle K., Vernazza, Francesco, Castle, Laurence, Edler, Lutz, and Benford, Diane. Recent advances in the risk assessment of melamine and cyanuric acid in animal feed. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2012.01.012.
Dorne, Jean Lou, E-mail: jean-lou.dorne@efsa.europa.eu, Doerge, Daniel R., Vandenbroeck, Marc, Fink-Gremmels, Johanna, Mennes, Wim, Knutsen, Helle K., Vernazza, Francesco, Castle, Laurence, Edler, Lutz, & Benford, Diane. Recent advances in the risk assessment of melamine and cyanuric acid in animal feed. United States. doi:10.1016/J.TAAP.2012.01.012.
Dorne, Jean Lou, E-mail: jean-lou.dorne@efsa.europa.eu, Doerge, Daniel R., Vandenbroeck, Marc, Fink-Gremmels, Johanna, Mennes, Wim, Knutsen, Helle K., Vernazza, Francesco, Castle, Laurence, Edler, Lutz, and Benford, Diane. 2013. "Recent advances in the risk assessment of melamine and cyanuric acid in animal feed". United States. doi:10.1016/J.TAAP.2012.01.012.
@article{osti_22285348,
title = {Recent advances in the risk assessment of melamine and cyanuric acid in animal feed},
author = {Dorne, Jean Lou, E-mail: jean-lou.dorne@efsa.europa.eu and Doerge, Daniel R. and Vandenbroeck, Marc and Fink-Gremmels, Johanna and Mennes, Wim and Knutsen, Helle K. and Vernazza, Francesco and Castle, Laurence and Edler, Lutz and Benford, Diane},
abstractNote = {Melamine can be present at low levels in food and feed mostly from its legal use as a food contact material in laminates and plastics, as a trace contaminant in nitrogen supplements used in animal feeds, and as a metabolite of the pesticide cyromazine. The mechanism of toxicity of melamine involves dose-dependent formation of crystals with either endogenous uric acid or a structural analogue of melamine, cyanuric acid, in renal tubules resulting in potential acute kidney failure. Co-exposure to melamine and cyanuric acid in livestock, fish, pets and laboratory animals shows higher toxicity compared with melamine or cyanuric acid alone. Evidence for crystal formation between melamine and other structural analogs i.e. ammelide and ammeline is limited. Illegal pet food adulterations with melamine and cyanuric acid and adulteration of milk with melamine resulted in melamine–cyanuric acid crystals, kidney damage and deaths of cats and dogs and melamine–uric acid stones, hospitalisation and deaths of children in China respectively. Following these incidents, the tolerable daily intake for melamine was re-evaluated by the U.S. Food and Drug Administration, the World Health Organisation, and the Scientific Panel on Contaminants in the Food Chain of the European Food Safety Authority (EFSA). This review provides an overview of toxicology, the adulteration incidents and risk assessments for melamine and its structural analogues. Particular focus is given to the recent EFSA risk assessment addressing impacts on animal and human health of background levels of melamine and structural analogues in animal feed. Recent research and future directions are discussed. - Highlights: ► Melamine in food and feed. ► Forms crystals in kidney with uric acid or cyanuric acid. ► Toxicity higher with cyanuric acid. ► Recent EFSA risk assessment. ► Animal and human health.},
doi = {10.1016/J.TAAP.2012.01.012},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 270,
place = {United States},
year = 2013,
month = 8
}
  • The adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of cats and dogs in the USA and other countries. In a previous 7-day dietary study in F344 rats, we established a no-observed-adverse-effect level (NOAEL) for a co-exposure to melamine and cyanuric acid of 8.6 mg/kg bw/day of each compound, and a benchmark dose lower confidence limit (BMDL) of 8.4–10.9 mg/kg bw/day of each compound. To ascertain the role played by the duration of exposure, we treated F344 rats for 28 days. Groups of male and female rats weremore » fed diet containing 0 (control), 30, 60, 120, 180, 240, or 360 ppm of both melamine and cyanuric acid. The lowest dose that produced histopathological alterations in the kidney was 120 ppm, versus 229 ppm in the 7-day study. Wet-mount analysis of kidney sections demonstrated the formation of melamine cyanurate spherulites in one male and two female rats at the 60 ppm dose and in one female rat at the 30 ppm dose, establishing a NOAEL of 2.1 mg/kg bw/day for males and < 2.6 mg/kg bw/day for females, and BMDL values as low as 1.6 mg/kg bw/day for both sexes. These data demonstrate that the length of exposure is an important component in the threshold of toxicity from a co-exposure to these compounds and suggest that the current risk assessments based on exposures to melamine alone may not reflect sufficiently the risk of a co-exposure to melamine and cyanuric acid. -- Highlights: ► A 28-day dietary co-exposure to melamine and cyanuric acid was conducted in F344 rats. ► The NOAELs were 2.1 mg/kg bw/day for males and < 2.6 mg/kg bw/day for females. ► BMDL values as low as 1.6 mg/kg bw/day for both sexes were determined. ► The length of exposure plays an important role in the threshold of toxicity. ► Current assessments may underestimate the risk of melamine and cyanuric acid.« less
  • Melamine and cyanuric acid, two compounds connected to tainted pet food, have been analyzed using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry. (M+H)+ ions were observed for melamine, ammelide, and ammeline under positive ion conditions with sinapinic acid as the matrix. With alpha-cyano-4-hydroxy-cinnamic acid as the matrix, a matrix-melamine complex was observed. (M-H)- was observed for cyanuric acid with sinapinic acid as the matrix.
  • Single-crystal samples of the 1:1 adduct between cyanuric acid and melamine (CA {center_dot} M), an outstanding case of noncovalent synthesis, have been studied by Raman spectroscopy and synchrotron X-ray diffraction in a diamond anvil cell up to pressures of 15 GPa. The abrupt changes in Raman spectra around 4.4 GPa have provided convincing evidence for pressure-induced structural phase transition. This phase transition was confirmed by angle dispersive X-ray diffraction (ADXRD) experiments to be a space group change from C2/m to its subgroup P2{sub 1}/m. On release of pressure, the observed transition was irreversible, and the new high-pressure phase was fullymore » preserved at ambient conditions. We propose that this phase transition was due to supramolecular rearrangements brought about by changes in the hydrogen bonding networks.« less
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