Introduction

1.               The Scientific Advisory Committee on Nutrition (SACN) last considered maternal diet and nutrition in relation to offspring health, in its reports on ‘The influence of maternal, foetal and child nutrition on the development of chronic disease in later life’ (SACN, 2011) and on ‘Feeding in the first year of life’ (SACN, 2018). In the latter report, the impact of breastfeeding on maternal health was also considered. In 2019, SACN agreed to conduct a risk assessment on nutrition and maternal health focusing on maternal outcomes during pregnancy, childbirth and up to 24 months after delivery; this would include the effects of chemical contaminants and excess nutrients in the diet.

2.               SACN agreed that, where appropriate, other expert Committees would be consulted and asked to complete relevant risk assessments e.g., in the area of food safety advice. This subject was initially discussed during the Committee on the Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) horizon scanning item at their January 2020 meeting with a scoping paper being presented to the COT in July 2020. This included background information on a provisional list of chemicals proposed by SACN. It was noted that the provisional list of chemicals was subject to change following discussion by COT who would be guiding the toxicological risk assessment process: candidate chemicals or chemical classes can be added or removed as the COT considered appropriate. The list was brought back to the COT with additional information in September 2020. Following a discussion at the September 2020, COT agreed that papers on a number of compounds should be prioritised. The following paper provides the advice of the COT on whether exposure to citrinin would pose a risk to maternal health.

Background

3.               Citrinin (CIT) is a mycotoxin produced by several species of fungi of the genera Aspergillus, Penicillium and Monascus and is generally formed after harvest under storage conditions. It occurs mainly in grains but can also occur in other products of plant origin e.g. beans, fruits, fruit and vegetable juices, herbs and spices as well as in spoiled dairy products.

4.               Experimental data indicate that CIT residues may occur in edible tissues and eggs following oral exposure of animals with highly contaminated feed materials. (Abdelhamid and Dorra, 1990, Meerpoel et al., 2020a). CIT was not detected in edible animal products in the 2014 Total Diet Study (TDS) so the carryover of CIT from feed into animal products has not been considered further in this assessment (FSA, 2014).

5.              In addition, CIT is an undesirable contaminant in Monascus fermentation products such as red yeast rice (RYR) also known as red mould rice (RMR). RYR is used in Asian cuisine as a food colourant and flavour enhancer and is used in supplements claiming to decrease plasma triglyceride and cholesterol levels (Wei et al., 2003). In 2019, the maximum level (ML) for CIT in RYR preparation was reduced from 2000 µg/kg to 100 µg/kg in Commission Regulation (EC) No 1881/2006 (amendment: Commission Regulation (EU) 2019/1901). The majority of packaging of RYR supplements state that the product is either a) not suitable for children and/or women who are pregnant or breast feeding, or b) it is recommended these groups should consult a general practitioner (GP) prior to consumption. Due to the warnings on the packaging, RYR supplements have not been considered further in this assessment.

6.    CIT is acutely nephrotoxic in mice and rats, rabbits, pigs and poultry, causing swelling and eventual necrosis of the kidneys. CIT also affects liver function but to a lesser extent. Both in vitro and in vivo studies have provided clear evidence for reproductive and developmental toxicity of CIT (EFSA, 2012).

Previous assessments

EFSA 2012 opinion

7.    In 2012, the European Food Standards Agency (EFSA) assessed the risks to public and animal health related to the presence of CIT in food and feed. 

Toxicokinetic

8.    The available information on CIT shows it is eliminated predominantly by renal excretion; approximately 75 % of radiolabelled citrinin (14C-citrinin) given by intraperitoneal dose was recovered in urine (Reddy et al., 1982). Toxicokinetic studies with oral administration of CIT were not available.

Toxicity

9.    The acute lethal toxicity of CIT ranged from 19-134 mg/kg bw depending on species and route of administration (EFSA, 2012). The main changes in pathology were degeneration and necrosis of the kidneys in all species indicating nephrotoxicity. Repeat dosing studies confirmed the nephrotoxicity of CIT and highlighted the differences in susceptibility between species. Necropsy showed histopathological changes in the kidneys of all species tested (except hamsters), which were consistent with the acute signs observed. 

Genotoxicity and Carcinogenicity 

10.    EFSA concluded that the available data indicated that CIT is not mutagenic in conventional bacterial assays either with or without metabolic activation by S9 fraction (EFSA, 2012). Mutagenicity in the Ames test was only reported in one study when rat hepatocytes were used as the activating system (Sabater-Vilar et al., 1999). In mammalian cells in vitro, CIT did not induce DNA single-strand breaks, oxidative DNA damage or sister chromatid exchanges (SCE) but induced micronuclei, aneuploidy and chromosomal aberrations.

11.    In vivo CIT induced chromosome abnormalities and hypodiploidy in the bone marrow of mice exposed at concentrations of 5-20 mg/kg bw for eight weeks, by oral administration (Jeswal, 1996).

12.    An 80-week feeding study exposed rats to CIT in the diet at initially about 70 mg/kg bw per day, the kidney was identified as the main target organ with reported incidences of adenomas (Arai and Hibino, 1983). EFSA concluded that given the observed high incidence of adenomas it cannot be excluded that carcinomas would have occurred if the exposure time had been increased to the full length of a carcinogenicity study (at least two years).

Immunotoxicity

13.    EFSA concluded that the data on immunotoxicity of CIT were incomplete and often non-specific and therefore did not allow for a conclusive evaluation.

Developmental and reproductive toxicity

14.    Data from in vitro and in vivo studies reported reproductive toxicity and teratogenic and embryotoxic effects of CIT (EFSA, 2012). However, in vivo studies also reported maternal toxicity, including nephrotoxicity, indicating that the reproductive, teratogenic and embryotoxic effects of CIT may be secondary to maternal toxicity.
 
15.    Kinetic investigations in pregnant rats provided no conclusive data about the percentage of CIT that crosses the placenta (Reddy et al., 1982b). EFSA could not determine the extent to which the offspring were exposed based on the available data.

16.               EFSA concluded that the derivation of a health-based guidance value (HBGV) would not be appropriate, given the available data on genotoxicity and the limitations and uncertainties in the current database.

17.               For compounds that are potentially genotoxic or carcinogenic EFSA recommends the use of the margin of exposure (MOE) approach. However, for CIT, EFSA did not consider an MOE approach appropriate due to the lack of human dietary exposure data. Instead, EFSA decided to characterise the risk of CIT and determine a level of no concern for nephrotoxicity in humans of 0.2 μg/kg bw per day. A level of no concern for nephrotoxicity is less secure than a HBGV and is a concentration at below which there is no appreciable concern for nephrotoxic effects. This level does not specifically address other end points.

18.               The level of no concern was based on a no observed effect level (NOAEL) of 20 μg/kg bw per day determined from a study in rats by Lee et al. (2010). In this study, CIT was given in the form of fermented RMR containing different concentrations of CIT (1, 2, 10, 20 and 200 mg/kg) and at the highest dose tested (equivalent to 20 µg CIT/kg bw per day) no toxicologically significant alterations were observed for any dose group. EFSA applied a default uncertainty factor (UF) of 100 for interspecies and interindividual variation.

19.               EFSA concluded that a concern for genotoxicity and carcinogenicity could not be excluded at the level of no concern for nephrotoxicity.

20.    A literature search was undertaken to gather any data published since the EFSA opinion on CIT in 2012. The following sections summarise the information retrieved from the years 2012-2024.  

Toxicokinetics

21.    A study in human volunteers demonstrated that ingested CIT undergoes conversion to dihydrocitrinone (DH-CIT) which is then excreted in the urine along with the remaining parent compound (Degen et al., 2018). A study in animals demonstrated differences in the toxicokinetic properties of CIT between pigs and chickens (Meerpoel et al., 2020b).

Toxicity

22.    An in vitro study in Chinese hamster lung fibroblast cells demonstrated that the toxic potency of the metabolite DH-CIT was less than CIT (Föllmann et al., 2014) while the interaction of DH-CIT with albumin did not show significant difference between species (Faisal et al., 2019). In the presence of albumin, the acute cytotoxic effects of both DH-CIT and CIT were significantly decreased on a Madin-Darby canine kidney (MDCK) cell line.

23.    A repeat dose study by Jagdale et al. (2020) (conducted according to OECD 407 guidelines) which treated rats daily by gavage with CIT (25 μg/kg bw or 100 μg/kg bw) for 28 days reported adverse histopathological changes in the kidney and the spleen at the higher dose. No significant histological changes were reported in animals dosed with 25 μg/kg bw. These findings are in support of the NOAEL of 20 μg/kg bw reported by EFSA.

24.    A 60-day study in rabbits suggested that at low concentrations, CIT (15 mg/kg feed) induced apoptosis in a time dependent manner and lipid peroxidation in the rabbit kidney, which according to the authors, appeared to play a major role in the pathogenesis of nephrotoxicity (Kumar et al. 2014; abstract only). 

Developmental and Reproductive toxicity

25.    Since the 2012 EFSA opinion, limited data has been published on the reproductive and developmental effects caused by CIT. The doses at which effects were reported in the published studies were in exceedance of EFSA’s level of no concern for nephrotoxicity.

26.     A repeated oral dose toxicity study in female mice was carried out by exposing the animals to 1.25, 7.5, 15 and 30 ppm CIT for 70-90 days in drinking water (Hayashi et al., 2012). CIT did not produce any noticeable toxicity at any of the dose levels, except for an increase of both absolute and relative ovary weights accompanied by large follicles at ≥ 15 ppm (authors estimated this was equivalent to 2.25 mg/kg body weight/day).

27.     In a one generation study by Singh et al. (2016, abstract only) male and female rats were administered 1, 3 and 5 ppm CIT in feed for 10 weeks before mating. The offspring were also fed CIT at the same doses until the age of six weeks. The authors concluded that the effects of CIT could be observed until the F1 generation in a dose-dependent manner and that apoptosis and oxidative stress played a role in CIT toxicity. CIT toxicity however did not lead to apoptosis and oxidative stress in male gonads until the F1 generation. As only the abstract was available it is not clear how the authors reached their conclusions.

28.    Sharma et al. (2012) administered CIT (10 mg/kg feed) to pregnant rats from gestational day (GD) 6-20, showing a significant increase in the percentage of apoptotic cells in kidneys of dams and foetuses.
29.    Newly fertilised zebrafish eggs were exposed to concentrations of 0.78-50 μМ CIT before individuals reached free-feeding stage. (Csenki et al., 2021). This is whilst the zebrafish are still embryos prior to reaching the juvenile stage of development Results showed no mortalities but exposure to 50 μM CIT led to pericardial oedema, blood accumulation, incorrect heart looping, and reduced the size of cardiac chambers.

Genotoxicity

30.     In vitro assays showed CIT to induce a dose dependent increase in micronuclei (MN) frequencies, chromosomal aberrations and sister chromatid exchanges (Anninou, 2014; Föllmann, 2014; Tsai, 2023: abstract only).

31.    A series of in vivo studies by Kuroda (2013) in rats administered CIT by gavage at 20-40 mg/kg bw for a maximum of 28 days showed no evidence that chromosomal abnormalities, or genotoxic mechanisms were involved in CIT-induced renal carcinogenesis.

Carcinogenicity 

32.    Tsai et al. (2023) concluded that CIT exposure activated cancer and cell cycle-related signalling pathways when human embryonic kidney 293 (HEK293) cells were treated for 3 and 30 days (Tsai, 2023; abstract only). 

33.    In vivo CIT showed evidence of promoting cell cycle progression when rats were administrated 20 and 40 mg/kg bw day CIT for 28 days (Kuroda et al., 2013). The maximum dose of 40 mg/kg was decreased to 30 mg/kg from day four due to decreases in body weight. Regenerative tubules were observed in the kidney cortex of rats treated with CIT in the high dose group and the labelling index of proliferating cell nuclear antigen (PCNA)-positive cells was significantly increased at all doses. The mRNA expression analysis showed increases in Ccna2, Ccnb1, Ccne1, and its transcription factor E2f1 following treatment with all doses of CIT.

Immunogenicity

34.    Limited data was available on the immunotoxicity of CIT since the EFSA opinion in 2012.

35.    In in vitro mammalian cell assays CIT was reported to show evidence of immunomodulatory and immunotoxic effects (Sugiyama et al., 2013: abstract only; Islam et al., 2012; Xu et al., 2022).

36.     In vivo, mice treated with CIT (1, 5, or 10 mg/kg bw) showed reduced levels of serum immunoglobulin M (IgM) and changes in the regulation of the different immune cell populations in the spleen, mesenteric lymph nodes and small intestine. The authors concluded that CIT has multiple immune modulatory effects in mice that may alter normal functions of immune system (Islam et al., 2012).

37.    CIT and DH-CIT have been reported in urine from different human cohorts from Belgium, Czech Republic, Portugal, Germany, Haiti, Bangladesh, Nigeria, Turkey, and Tunisia (Narváez et al., 2021). CIT has been detected in the breast milk and urine of mothers and the urine of exclusively breastfed infants (Ezekiel et al., 2022).

38.    Three biomonitoring studies were carried out to measure the concentration of CIT and DH-CIT in pregnant women, infants and children in Bangladesh (Ali and Degen, 2020; Kyei et al., 2023, 2022). CIT was detected in 61% of the urine samples collected from pregnant women and dietary exposure to CIT, based on urinary levels, was estimated to exceed the level of no concern for nephrotoxicity set by EFSA (2012) in 16% of pregnant women. No evidence was found for an association between higher maternal daily intakes of CIT, and duration of pregnancy, birth weight, birth length, and head circumference at birth.

39.    Overall, the new data published since the 2012 EFSA opinion supports previous findings or adds to the overall knowledge base of CIT. CIT is acutely nephrotoxic, and both in vitro and in vivo studies have provided clear evidence for reproductive and developmental toxicity. CIT’s potential genotoxicity remains uncertain. 

40.    The COT agrees with EFSA that a HBGV cannot be set and that it was appropriate to use a level of no concern for nephrotoxicity to characterise the risk of CIT to consumers. The doses administered in the available reproductive and developmental studies were higher than the level of no concern for nephrotoxicity, and so this level would be adequately protective for maternal, reproductive and developmental toxic effects.

41.               Exposure to CIT was determined for women of child-bearing age (16-49 years), using consumption data from the National Diet and Nutrition Survey (NDNS) and occurrence data from the 2014 Total Diet Study (TDS) (Bates et al., 2014, 2016, 2020; Roberts et al., 2018, FSA, 2014).

42.               Occurrence data from all food samples analysed for CIT were below the limit of quantification (LOQ) and the exposures calculated are based on the lower bound (LB) and upper bound (UB) values. As the LB is zero for a commodity, it cannot be determined whether a commodity makes a contribution to the overall exposure.

43.               Mean total exposure to CIT for women of child-bearing age ranged from 0-17 ng/kg bw/day, whilst exposure in high consumers (97.5^th percentile) ranged from 0-43 ng/kg bw/day. The food groups with the highest UB values were tea with a mean value of 6.2 ng/kg bw/day and a 97.5^th percentile value of 23 ng/kg bw/day; instant coffee with a mean value of 2.6 and 97.5^th percentile value of 17 ng/kg bw/day; wine with a mean value of 1.0 ng/kg bw/day, and 97.5^th percentile value of 6.5 ng/kg bw/day.

44.               The carryover of CIT into animal products was not included in the exposure assessment but would not be expected to significantly add to the exposure under normal, non-experimental, circumstances.

45.               CIT is nephrotoxic, causing swelling and eventual necrosis of the kidneys, and in some studies was also reported to affect liver function.  Exposure to CIT has also been associated with reproductive toxicity and teratogenic and embryotoxic effects.

46.               Based on the data available, including data published since the EFSAs opinion, the COT did not think it appropriate to set a HBGV but continued to use EFSA’s approach, applying a level of no concern for nephrotoxicity in humans of 0.2 μg/kg bw per day.

47.               While a number of studies reported developmental and reproductive toxicity of CIT it is not clear whether these effects might be secondary to maternal toxicity. A study reported by EFSA in 2012 failed to determine the amount of CIT that would cross the placenta, and no metabolites of CIT were detected in the foetus. However, as the doses administered in the available reproductive and developmental studies were higher than the level of no concern for nephrotoxicity, the COT considered the level of no concern for nephrotoxicity to be adequately protective for maternal, reproductive and developmental toxic effects.

48.               In 2012, EFSA did not consider there to be enough data to conclude on the immunotoxic effects of CIT. While some additional data has been published since EFSA’s opinion, the database is still very limited, and a conclusive assessment cannot be carried out.

49.               The available data demonstrates that citrinin does not cause gene mutations but may have a thresholded effect on microtubules and/or spindle assembly. However, due to the limitations in the database a risk of genotoxicity and carcinogenicity cannot be excluded.

50.               Mean and 97.5^th percentile total estimated exposures for CIT were 0-17 and 0- 43 ng/kg bw respectively and are below the level of no concern for nephrotoxicity set by EFSA. Hence, the estimated exposures are not of toxicological concern for nephrotoxicity and reproductive and developmental effects, but carcinogenicity and genotoxicity cannot be excluded.

51.               It should be noted that the TDS data used to calculate exposure are from 2014 and changes in the prevalence of citrinin may have occurred since then. Dietary patterns may also have changed, for example the increased consumption of plant-based drinks, and vegan/vegetarian diets, which may not be fully represented in the data.

52.               The current assessment was based on consumption data from the NDNS for women of maternal/childbearing age and therefore may not be representative of maternal diet. In addition, the NHS recommends that those who are pregnant or planning to become pregnant should not drink alcohol. The inclusion of the UB values for wine, beer, alcopops and cocktails in the assessment may therefore lead to an over estimation of exposure when considering pregnant women.

53.               Based on the data available the COT concluded that a HBGV could not be set and agreed with the continued use of EFSA’s previous approach, using a level of no concern for nephrotoxicity. The COT also considered this level to be adequately protective for maternal, reproductive and developmental effects. However, due to the limitations in the database a risk of genotoxicity and carcinogenicity cannot be excluded.

54.                Estimated exposures are not of toxicological concern for nephrotoxicity and reproductive and developmental effects. In addition, CIT was not detected above the LOQ in any of the food groups further supporting that exposure to CIT is low and not of concern to UK consumers.

COT Secretariat

October 2024

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