The Evaluation of Childhood Foods and Infant Formula Exposure to Furan, Chloropropanols and Acrylamide Contamination by Food Processing

This review attempted to evaluate the exposure of thermal processing contaminants such as furan, chloropropanols and acrylamide from infant formulas. Furan, chloropropanols and acrylamide exist at varying levels in several types of foods that are consumed in daily diet including infant formulas. The consumption of these foods leads to the exposure to the thermal processing contaminants. In this sense, it is apparent that humans face hidden danger through dietary exposure throughout their lives. Infants are considered as the age group that expose to the highest levels of these substances as a result of the fact that they have low body weight and con-sume infant formulas in their diets as alternative nutrition. The review emphasizes that the infant formulas are not innocent, on the contrary, they can be considered as safety critical for infants considering that infant formulas include furan, chloropropanols and acrylamide. Therefore, this review suggests that in this sense all share-holders’ (university, non-governmental organizations, public and private sector) acting in concert with each other is crucially important for the health of individuals and overall society.


Introduction
World Health Organization (WHO) and UNICEF advices that infants need to be exclusively breasted for the first 6 months and breastfeeding should last minimum 2 years. Nevertheless, around the world, the rate of breastfeeding in the first 6 months is still 38% and this percentage has not changed for about 20 years. It is known that breast milk significantly contributes to infants' physical and mental development and acts as a protector for infants against several diseases. Therefore, with the contributions of WHO and UNICEF, breast milk is being promoted in order to increase the rate of breastfeeding to 50% for the first 6 months until 2025 and studies are being carried out with regard to the importance of breast feeding in early periods of infancy [1,2].
Use of breast feeding as primary nutrition in early periods, namely in the first 6 months, of infancy is highly common around the world (Norway: 95%, Australia: 92%, Canada: 89%, United States: 77%) and the percentage increases gradually year by year. On the contrary, after 6 months is decreasing dramatically [3]. By all means, there are several factors affecting this case. Some of these factors are mothers' becoming a mother young, not having breastfeeding experience, concern of insufficient breast milk, desire to feed their babies with new tastes, active work life, long working hours and perceptions of mothers created by other individuals, mother's and baby's health condition, babies' becoming acquainted with pacifier and feeding bottle [4][5][6]. Besides these factors, depending on the development of the baby, mothers generally give their babies other nourishments as supplement to breast milk or use them as only source of nutrition for their babies. The top of these nourishments is infant formulas.
There are several firms operating globally in the sector of infant formulas which has become a massive market today. These firms invest in research-development activities, advertising activities and develop marketing strategies in order to gain advantage in the competition [7]. It is easy to find several follow-on milk, follow-on formulas and mixed formulas for the needs of 0-6 months-old and >6 monthsold babies, which are formulated either in powder or liquid form and enriched with various ingredients [8]. Infant formulas are often preferred in that they are accessible and easy to prepare; besides, they can be used by others when mother is not available for feeding. On the other hand, it is known that mothers are deeply anxious about the infant formulas although they try to make their best to choose the most appropriate formula for their babies based on their research on written and visual media, advices from others and past experiences [9,10].
On one hand, it is beyond argument that breast milk is the best choice for babies' nourishment, development and health; on the other hand, it is not always the one and only choice because of various reasons. Therefore, it needs to be ensured that the adverse effects of infant formulas, which are used as supplement to breast milk or used exclusively, on babies' health in the short-, medium-and long-term are eliminated and these formulas not to cause any health problems for babies. In this respect, certain legal regulations are designed for the production and marketing of infant formulas nationally and globally. However, in the literature, although infant formulas carry the risk with respect to furan, acrylamide, chloropropanols and polycyclic aromatic hydrocarbons, which are called thermal processing contaminants and have potential to cause various health problems for humans, this information has not been referred in the legal regulations. Considering that the contaminants in question are included in various foods that are frequently preferred in daily diets, individuals expose to these contaminants starting from very early periods of infancy and this exposure continues throughout their lives. To this end, the current review aims to evaluate the infant formulas with respect to certain thermal processing contaminants.

Thermal process contaminants
Besides bringing certain sensorial properties to foods, thermal process is a processing technique that eliminates or decreases the potential hazards originating from foods against consumers' health through making foods microbiologically more reliable. However, under certain conditions thermal processing applications cause certain toxic substances called "thermal processing contaminants" (heterocyclic aromatic amines, 5-hydroxymethylfurfural, polycyclic aromatic hydrocarbons, nitrosamines, furan, acrylamide, and chloropropanols) to emerge [11,12]. In the last 10 years, a great amount of research has focused on thermal processing contaminants and this topic is still current and important for consumers, health authorities and industries [13].

Furan
Furan is colorless, highly volatile and flammable compound with a boiling point close to room temperature (≈31°C). It is soluble in most of the organic solvents such as alcohol and acetone. Furan with a molecular formula of C 4 H 4 O and CAS number of 110-00-9 is a heterocyclic and aromatic compound [14].
Formation of furan in foods is the result of various mechanisms. It has been documented that besides the presence of reducing sugar or amino acids, thermal degradation or Maillard reaction, ascorbic acid, thermal oxidation, oxidized polyunsaturated lipids, serine and cysteine without other sources [15,16].
In the risk assessment undertaken by U.S. National Institutes of Health (NIH) and Joint FAO/WHO Expert Committee on Food Additives (JECFA) depending on the studies on laboratory animals, furan was reported to be a strong carcinogenic compound that affected several organs [17,18]. It has been identified as "possibly carcinogen to humans" (Group 2B) by International Agency for Research on Cancer (IARC) [19].
In this respect, Table 2 displays the results of dietary exposure of furan in individuals from diverse group of ages reported by EFSA.
It has not been ascertained that whether chloropropanol is a carcinogenic compound. On the other hand, it is disturbing that some free chloropropanol forms in foodstuffs are potentially toxic. The JECFA reported that 1,3-DCP is a genotoxic carcinogen, however, there is not enough evidence for the toxicologic evaluation of 2-MCPD [36,37]. In this respect, Lee Table 2.
Dietary exposure of furan [27]. et al. suggested that 3-MCPD carries unignorable risks for human health with regard to its potential hazard [39]. In some other studies 1,3-DCP and 3-MCPD are defined as possible human carcinogens (group 2B) and similarly glycidol is referred as a probable human carcinogen (group 2A) [40][41][42]. One of the most comprehensive studies on the toxicologic evaluation of chloropropanols revealed that whereas the carcinogenic effect of 1,3-DCP was highly evident, for the reason that the level of its presence in foodstuffs was considerably low, 1,3-DCP did not carry a risk for human health. This comprehensive study emphasized the insufficiency of the research on the level of the presence of 2-MCPD and 2,3-DCP in foodstuffs and the toxicologic evaluation of these substances. However, current evidence suggests that these compounds can be considered within low risk group for human health for the reason that the level of the presence of these compounds in foodstuffs is low [43]. EFSA determined the tolerable daily intake (TDI) for 3-MCPD as 0.8 μg/kg bw per day, whereas JECFA suggested the provisional maximum tolerable daily intake (PMTDI) of 4 μg/kg bw/day [44,45]. Recent studies revealed that chloropropanols was found in several foodstuffs at different levels particularly in soy sauces, meat and meat products, fish and sea foods, cereals, snacks, bread, biscuits, crisps, chips, baby foods and infant formulas as well [46,47]. Table 3 shows the levels of chloropropanols in foodstuffs reported in the comprehensive study by EFSA.
Considering the other studies on infant formulas and chloropropanols, Zelinková et al.  [49][50][51]. Table 4 displays the results suggested by EFSA regarding the dietary exposure of chloropropanols for the individuals from different age groups.
EFSA revealed that the food group that contributes 50% and higher levels of 3-MCPD, 2-MCPD and glycidol exposure for infants is infant formulas and follow-on formulas, which are followed by vegetable fats and oils, besides cookies. The levels of 3-MCPD, 2-MCPD and glycidol considering the exposure from only infant formulas were calculated as 2.4, 0.7-1.3, and 1.8-2.1 μg/kg bw per day, respectively [48]. JECFA estimated the average exposure to glycidol equivalents for babies between 0.1 and 3.6 μg/kg bw/day. However, the exposure level of 3-MCPD equivalents can increase to 10 μg/kg bw/day on average for the babies that are fed by infant formulas in the early periods of their lives [45]. Spungen et al. estimated the exposure of 3-MCPD equivalents for 0-1, 2-3 and 5-6 months old babies as 10,

Acrylamide
Acrylamide (AA), which was identified for the first time as a chemical compound in 1893 in Germany, is a chemical agent used extensively in such sectors as dams, tunnels, water treatment, paper and textile [54]. The presence of AA in foods for the first time was identified in 2002 by a group of researchers in Sweden [55]. Acrylamide formation in foods is explained through several mechanisms. The most important of all these mechanisms is especially Maillard reaction, which is performed in thermal processing with the presence of asparagines amino acid and reducing sugar [56]. It has been revealed that, apart from this mechanism, acrolein, B-alanine, aspartic acid, pyruvic acid and carnosine cause AA formation through various reactions [57].
In the experimental studies carried out with animals, a positive dose-response relationship between AA and the cancer in multi-organs and tissues was found [58,59]. In epidemiological studies conducted with humans, it was suggested that AA could seriously affect fetal development [60] and neurological changes [61]. On the other hand, there is not a clear consensus on the relationship between AA and cancer yet. Whereas, some studies reveal that AA increases the risk of contracting ovarian cancer [62], lung cancer [63] and the cancers related to digestive and respiratory systems [64], some other studies determine that AA has no positive relationship with several types of cancer [65][66][67]. However, IARC classifies AA as a probable human carcinogen (group 2A) [68].
EFSA reported the results of the study that show AA levels in several foodstuffs in 2015 ( Table 5).
In the other studies on infant formulas, different acrylamide levels were reported; Fohgelberg et al. found 3.5-223 μg/kg and Elias et al. found <LOD (limit of detection)-353 μg/kg [70,71]. Likewise,  [72]. Considering the other studies on AA exposure, Health Canada estimated the AA exposure for <1 years and 1-3 years old babies as

Acrylamide, furan and chloropropanol exposure caused by breast milk
It is estimated that babies are exposed to contaminants coming from breast milk from the first seconds of their lives. This exposure varies depending on the impact of many factors such as the age of the mother, dietary habits, living space, and environmental contaminants etc. on the compounds in breast milk. Therefore, breast milk is globally monitored as a biomarker for exposure and sheds light on exposure evaluation studies [74,75].
The mean of the dietary AA exposure [69].
to the fetus through blood and it can reach μg/L in breast milk. They state that acrylamide exposure caused by breast milk continues until the end of breastfeeding, and therefore nursing mothers should avoid foods containing acrylamide until uncertainties about acrylamide are eliminated [76]. Fohgelberg et al. stated that traces of acrylamide were detected in all breast milk samples, the acrylamide level was determined as 0.51 μg/kg only in one sample while the acrylamide levels in the other 18 samples were under the limit of quantification (0.5 μg/kg). The mean acrylamide level in breast milk was assumed to be 0.25 μg/kg in the study and the mean acrylamide exposure was estimated as 0.04 μg/kg bw per day (the mean body weight is calculated as 5.5 kg) for infants that are fed only with breast milk during the early breastfeeding period. The results revealed the importance of breastfeeding as a way of preventing the baby from being exposed to acrylamide as the level of acrylamide in breast milk is very low [70]. The source and possible consequences of 3-MCPD in breast milk have not been entirely explored yet. However, it has been stated that dietary habits of mothers are an important factor for presence of 3-MCPD in breast milk [34,77]. Zelinkova et al. determined the 3-MCPD level between 11 and 76 μg/kg and the mean amount as 35.5 μg/kg in 12 breast milk samples. They determined the 3-MCPD exposure caused by breast milk in babies (breastfed for up to 4 months) as 26,625 μg/day (average daily intake of mother's milk by the baby is about 750 mL) and 8.19 μg/kg bw per day [77]. Jędrkiewicz et al. stated that 2-MCPD and 3-MCPD reached 2.2 mg/kg in breast milk and therefore it was highly difficult for babies to avoid chloropropanols [78].
Polychlorinated dibenzofurans (PCDFs), which are another contaminant in breast milk, have been examined in studies together with polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDDs). A lot of studies can be found in the literature on this subject compared to acrylamide and chloropropanols. As breast milk is the first and most important way of conveying PCBs and PCDD/Fs to babies, WHO has been conducting global studies on dioxin detection in breast milk since 1987 [79]. Costopoulou 3.94, 5.57 and 6.14 pg/g fat WHO-TEQ ) [80]. WHO has estimated the range of tolerable daily dose as 1-4 pg TEQ/kg bs per day for babies exposed to dioxin contaminants such as PCDD/Fs and PCBs [81]. Focant et al. calculated the average concentration for total TEQ (PCDD/Fs and PCBs) as 17.81 pg/g and the daily intake of PCDD/Fs and PCBs as 62.3 TEQ/kg bw per day [82]. In a study they conducted in China (Guangdong Province), Huang et al. predicted the mean EDI level of PCDD/PCBs resulting from breast milk as 54.3 pg TEQ/kg bw per day [83].

Conclusion
The current review evaluated infant formulas that have an important place in the diets of babies, with respect to the thermal processing contaminants; furan, chloropropanols and acrylamide, which have become one of the foci of researchers. When the results of the studies regarding the exposure of these contaminants are evaluated, it is suggested that babies are in the risk group, who are highly exposed to these contaminants because of their low body weight compared to other individuals, besides; there are no alternative foods to infant formulas in their daily diet. In the light of the evidence revealed by the previous studies, the current review proposes that regarding the furan, chloropropanols and acrylamide, infant formulas can be a concern for baby health. Nevertheless, the review further suggests that it is important to decrease the level of thermal processing contaminants or specify certain upper limits and determine these regulations by law for the individual health and the health of the overall society. Furthermore, the current review emphasized that infant formulas are not alternatives to breast milk and educating mothers in this respect is critically important for the health of next generations. One last thing to emphasize is the need to raise the awareness of breastfeeding mothers in avoiding the consumption of foods that have a rich content in terms of the abovementioned contaminants.
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