Carcinogenicity study of 3-monochloropropane-1,2-diol in Sprague–Dawley rats
Introduction
3-Monochloropropane-1,2-diol (α-chlorohydrin, 3-MCPD) is a well-known contaminant, which has been detected in a wide range of foods and ingredients. It can be found in foods prepared by hydrochloric acid hydrolysis, such as acid-hydrolyzed vegetable protein. 3-MCPD has also been reported in flavor enhancer (Crews et al., 2002), some soy sources (Macarthur et al., 2000), roasted cereals, fermented sausages and toasted breads, as used in domestic cooking (Crews et al., 2001), and other ingredients, such as fat, salt, emulsifiers, sugar, and baking agents, which can lead to the formation of 3-MCPD (Breitling-Utzmann et al., 2005). The amount of 3-MCPD in foods, especially in acid-HVP, has markedly decreased from approximately 100 mg/kg to less than 1 mg/kg due to technological processes (FSA, 2001, FSA, 2005, Hamlet et al., 2002). Therefore, 3-MCPD is usually present in trace amounts (<1 mg/kg), but individual samples may contain high levels (up to a few hundreds mg/kg).
Several toxicological studies have shown that 3-MCPD induces infertility in rats (Jackson et al., 1977, Kwack et al., 2004) and causes suppression of the immune function (Lee et al., 2004, Lee et al., 2005). It does not produce neurotoxicity or neuromotor deficits in rats (Kim et al., 2004), but has been shown to cause small vacuolated lesions in the brainstem area of mice (Cavanagh et al., 1993). It has been found to be genotoxic in most in vitro assays (Silhankova et al., 1982, Stolzenberg and Hine, 1980, Zeiger et al., 1988), but in vivo assays produce negative results (El Ramy et al., 2007, Epstein et al., 1972, Frei and Wurgler, 1997, Robjohns et al., 2003). Based on the available results in 2001, the European Scientific Committee on Food (SCF) concluded that the genotoxic activity of 3-MCPD observed in vitro was not expressed in vivo (SCF, 2001). Four long-term bioassays on 3-MCPD have been conducted; two carcinogenicity studies that investigated both the subcutaneous and intra-peritoneal routes in Swiss mice (Van Duuren et al., 1974), as well as two dietary studies conducted on SD (Weisburger et al., 1981) and F344 rats, respectively (Sunahara et al., 1993). However, these studies (Van Duuren et al., 1974, Weisburger et al., 1981) were performed with inadequate protocols compared with the OECD Test Guideline 451 for ‘Carcinogenicity studies’ (OECD, 1981). In a chronic study on F344 rats, a high dose of 3-MCPD induced Leydig cell and mammary gland tumors in males and benign kidney tumors in both genders (Sunahara et al., 1993). However, the kidney tumors might be secondary to chronic progressive nephropathy, and the Leydig cell and mammary gland tumors due to species- and strain-specific mechanisms, including chronic changes associated with a hormonal imbalance (JECFA, 2002, Lynch et al., 1998). Therefore, additional experiments may be necessary to confirm the carcinogenicity and potential of hormonal imbalance. The purpose of this study was to clarify the possible involvement of the species- and strain-specific non-genotoxic carcinogenicity of 3-MCPD. Thus, the carcinogenicity of 3-MCPD when administered to SD rats in the drinking water was investigated according to the test guidelines from Korea Food and Drug Administration (KFDA) and the OECD Test Guideline 451 for ‘carcinogenicity study’ (OECD, 1981).
Section snippets
Test material
3-MCPD (Cas No. 96-24-02), 98% pure, was purchased from Sigma Aldrich Inc. (St. Louis, MO, USA). The structure and purity was verified prior to use, with its stability confirmed at all concentrations. The dose formulations were prepared every two weeks by dissolving 3-MCPD in deionized water and stored in glass vessels protected from the light at 4 °C. The solutions given to rats in the water bottles were replaced every three days. Periodic analyses of the dose formulations were conducted by
In-life observations
The survival rates of the rats administered 0, 25, 100 and 400 ppm 3-MCPD by the end of study were 28%, 34%, 18% and 26% for males and 30%, 44%, 22% and 32% for females, respectively. The survival of all the dosed groups was similar to that of the control (data not shown). The body weights of both sexes in the 400 ppm groups were significantly decreased throughout the study compared to those of the control (Fig. 1). The water consumptions of the male and female rats administered 400 ppm 3-MCPD
Discussion
In the current two-year carcinogenicity study, all surviving male rats were sacrificed at 100 weeks, as the survival of male control rats reached 28%. According to the OECD Test Guideline 451 for ‘Carcinogenicity studies’, termination of the study is acceptable when the numbers of survivors on the lower doses or in the control group reach 25%; if there is an apparent sex difference in the response, each sex should be considered separately. The overall survival of rats exposed to 3-MCPD for two
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgement
This research was supported by a Grant (05121KFDA455) from Korea Food and Drug Administration from 2002 to 2005.
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