Comparative metabolism of 2-monochloropropane-1,3-diol (2-MCPD) and 3-monochloropropane-1,2-diol (3-MCPD) in rats and humans

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Fatty acid esters of 2-monochloropropane-1,3-diol (2-MCPD) and 3-monochloropropane-1,2-diol (3-MCPD) are common heat-induced food contaminants, which are hydrolyzed efficiently in the gastrointestinal tract to release 2/3-MCPD. In repeated dose studies in rats, the most prominent non-neoplastic effects of 3-MCPD exposure were observed in kidney (nephropathy and hypertrophy), testes (atrophy and arteritis) and mammary gland (glandular hyperplasia). In addition, 3-MCPD increased incidences of renal tubular adenoma and carcinoma, hyperplasia and adenomas of the Leydig cells and of the mammary gland in 2-year bioassays in rats. There is no data on 2-MCPD-induced carcinogenic effects in animals and on 2/3-MCPD carcinogenic effects in humans. The International Agency for Research on Cancer (IARC) has classified 3-MCPD as possibly carcinogenic to humans.The concepts of the molecular mechanisms explaining the toxicity and carcinogenicity of 2/3-MCPD in rats are limited. A better understanding depends on the available information on the metabolism of both compounds, which may also help to clarify the relevance of some of the toxic effects observed in rats for human health. The current proposal aims at the comparative elucidation of the metabolism of 2/3-MCPD in rats and humans. The animal model allows generating sufficient amounts for a systematic characterization of metabolites. The rats will receive single oral doses of 2- or 3-MCPD and also of [13C3]2-MCPD or [13C3]3-MCPD. The urinary metabolites will be separated by preparative chromatography and characterized by mass spectrometry (MS) and 13C-nuclear magnetic resonance (NMR) spectroscopy. The data on the compounds resulting from rat metabolism will be the basis for the characterization of 2/3-MCPD metabolites excreted in human urine samples, collected in a controlled exposure study (conducted previously) with hazelnut oil containing relatively high amounts bound 2-MCPD (24.2 mg/kg) and 3-MCPD (54.5 mg/kg). The information of the 2/3-MCPD metabolism is a good basis for the choice of human biomarkers of exposure for both substances. We propose to develop analytical techniques for the quantification of metabolites of 2/3-MCPD in 24-h urine, which meet the requirements on sensitivity and specificity. The selected biomarkers will be used to estimate the external 2/3-MCPD exposure of study participants with distinct dietary habits (omnivores, vegans and raw food eaters; sample collection finished in 2020). In summary, the data provided on 2/3-MCPD metabolism will help to understand the toxic effects in rats and, possibly, the relevance for humans, and will support determining the human exposure in individuals and future recommendations on risk management.