\r\n\tThe aim and objectives are to illustrate the current status of ethanol production from different feedstocks and the state of technologies involved in ethanol production from such different feedstock.
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\n
1. Introduction
\n
Surgical resection, radiation therapy, and chemotherapy are the three primary cancer treatment modalities. While chemotherapy is used in the treatment of almost all cancers, it has challenges and limitations. Most of the chemotherapeutic agents are highly cytotoxic to both cancer and normal tissues. Often chemotherapy is administered systemically, meaning it is not directed to the cancerous tissues. The drug uptake by normal tissues causes off target effects including severe toxicities to different organs such as heart, liver, or kidneys, immune system, and others. In quite a number of cases, the toxicity profile of the drug limits the maximum tolerated dose (MTD) that can be administered. It is well known that inadequate dose is a primary cause for tumor recurrence and development of drug resistance. Thus, typically the highest possible dose is given to a patient to maximize the amount taken up by the cancerous tissues. All these factors have led to the development of methods to direct the drug to the tumor tissue, including various nanoparticles such as liposomes.
\n
Liposome‐encapsulated drug has evolved as a very potent source of directing the drug to the site of tumor. There are several ways by which a drug can be targeted to the tumor using liposomes. Kunjachan et al. review the various methods by which liposomes can be used to target the tumors [1]. Standard chemotherapy involves the administration of free (i.e., unencapsulated) drug (Figure 1A). Encapsulating the drug within a liposomal formulation allows prolonged blood circulation with very limited tissue uptake. Liposomes and other nanoparticles are most often based on passive targeting (Figure 1B). That is, they rely on the enhanced permeability and retention (EPR) effect resulting from leaky tumor vessels combined with absent lymph drainage in most tumors [2]. As a result, liposomes preferentially accumulate within the tumor over typically 24–48 hours. Tumors can be actively targeted by adding antibodies to the liposome surface, which are specific to either the cancer cells themselves (Figure 1C), or specific to the endothelial cells of the tumor vasculature (Figure 1D). One limitation of this antibody‐based approach is that due to the heterogeneity of tumors, not all tumors or cancer cells have the unique antigen for the targeting antibody to bind. Another targeting method includes the use of an external trigger to release the drug either within the interstitium (i.e., after letting the liposomes accumulate via EPR effect) (Figure 1E1) or by releasing the drug within the vasculature of the tumor (Figure 1E2). The latter method requires liposomes specifically designed to respond to the specific trigger. Depending on the liposome, various external energy sources or biological signals may trigger drug release; these include heat, light, pH, and ultrasound, among others. In this chapter, we will focus on using heat as trigger, i.e., we will discuss in detail the evolution and current status of thermosensitive (or temperature sensitive) liposomes (TSLs).
\n
Figure 1.
Current drug targeting strategies. (A) Conventional therapy or free drug infusion. (B) Passive targeting by liposomes utilizing EPR effect. (C) Active targeting of liposomes labeled with tumor‐specific antibody. (D) Active targeting of liposomes with endothelial cell‐specific antibody. (E) Triggered drug release either (1) within the tumor interstitium or (2) intravascular release. TSL fall into this last category reproduced with permission from Ref. [1]. Copyright (2015) American Chemical Society.
\n
The strategy is that TSLs are administered systemically, followed by local hyperthermia (>40–42°C). The local hyperthermia triggers drug release within the targeted region, by which the drug becomes bioavailable and can exhibit the intended cytotoxic effect. Thus, the combination of TSL with a localized heating modality allows for localized drug delivery.
\n
Note, however, that TSLs may have additional clinical applications outside cancer therapy, as there are various other clinical indications where it is necessary to deliver a drug targeted to a specific region within the body.
\n
\n
\n
2. Background: evolution of thermosensitive liposomes (TSLs)
\n
Liposomes as carriers of therapeutic drugs have been long investigated as a tool for improving the therapeutic index (i.e., decreasing the toxicity associated with drug delivery, while improving delivery to tumor). In 1995, Doxil [3] became the first nanoliposomal drug to be approved by Food and Drug Administration (FDA). However, with liposomes, a major limitation was directing the liposomes to the tumor. Initial liposomal formulations such as Doxil depend on preferential passive liposome accumulation based on the enhanced permeability of the tumor blood vessels, together with the lack of lymph drainage (EPR effect). However, it takes a considerable time (about 1–2 days) for the liposomal drug to accumulate within tumor. Moreover, the drug accumulated within the tumor is not bioavailable as it is still encapsulated within the liposomes [4]. The result was that Doxil achieved reduced toxicity while efficacy was in general not better than unencapsulated drug.
\n
In 1978, Yatvin et al. [5] suggested for the first time the use of temperature sensitive liposomes (TSLs) (i.e., liposomes that release the encapsulated drug in response to heat) combined with hyperthermia for targeting the drug to tumors or local infections. The basic idea was to administer this liposomal drug systemically, and then expose only the tissue region where drug delivery is intended to hyperthermia. They proposed to use slightly higher temperature (42–44°C) than normal body temperature (37°C) to target drug delivery. This first TSL formulation used the two lipids dipalmitoyl phosphatidylcholine (DPPC) and distearoyl phosphatidylcholine (DSPC) to make liposomes sensitive to heat. DPPC and DSPC have “liquid‐crystalline transition temperatures (Tm)” of 41 and 54°C, respectively; here Tm is the temperature at which the lipids undergoe a transformation from a solid gel‐like structure (i.e., highly impermeable to hydrophilic substances) to a highly permeable liquid structure. These liposomes are now often termed as traditional thermosensitive liposomes (TTSLs) [6]. The reason that two lipids were used is because TSLs were too leaky when only a single lipid was used. Hence, a combination of DPPC and DSPC (ratio 3:1) was used, and these first TSLs encapsulated the antibiotic neomycin with the aim of treating bacterial infections.
\n
Use of TTSLs for cancer treatment was first tested by Weinstein et al. [7] in 1979 in mice‐carrying lung cancer. They showed that there was a fourfold increase in the amount of methotrexate delivered to heated tumors using the initial TTSL composition with slightly varied ratios (DPPC:DSPC = 7:3). A major limitation of this initial formulation was the quick elimination of the liposomes within 1 hour of the infusion.
\n
In the following decades, various modified compositions were proposed based on the original formulation above. The primary goal was to increase the liposome stability and reduce leakage of the contained drug when exposed to serum [8]. This search led to the incorporation of cholesterol to the composition of liposomes [8, 9]. Gaber et al. showed that by using cholesterol, the phase transition can be avoided as the lipids are in liquid‐ordered phase [10]. However, the incorporation of cholesterol delayed the complete release of the encapsulated drug doxorubicin to about 30 minutes at 42°C. Also around the same time, strategies were developed for circumventing the reticuloendothelial system and the immune system [11], which was addressed by the incorporation of polyethylene glycol (PEG) in the 1990s. Some studies showed that clearance of TSL was size dependent [12]. Larger liposomes were cleared quickly whereas smaller liposomes took a longer time to be cleared. However, small liposomes are less stable at normal body temperature (37°C). Hence, liposomes in the size range of 50–200 nm were recommended [12]. Around the same time mid‐1990s, Kono et al. [13, 14] proposed the incorporation of thermosensitive polymers into liposomes to make them temperature sensitive. TSLs carrying polymers such as poly (N‐isopropylacrylamide) were being evaluated [14]. However, a major setback for using these polymers was that they were not biodegradable. The next major breakthrough occurred in 2000 when Needham et al. [15] reported the successful incorporation of lysolipids and PEG into the liposomal lipid composition (DPPC:MPPC:DSPE‐PEG2000 in the ratio of 90:10:4). Lysolipids are derivatives of lipid in which acyl derivatives are removed by hydrolysis making them more hydrophilic. The incorporation of lysolipids caused the rapid release of the encapsulated doxorubicin at hyperthermia temperatures (42°C). These have been called as lysolipid temperature‐sensitive liposomes (LTSL). LTSL released much more rapidly (seconds) than prior formulations [16]. LTSLs were found to substantially improve delivery efficacy, with 3.5 times enhanced tumor drug delivery compared to TTSL, and ∼17 times higher than unencapsulated drug [17]. A formulation similar to the one proposed by Needham is so far the only TSL formulation that made it into human clinical trials. However, the plasma half‐life of LTSL is still not ideal with median initial plasma half‐life of about 1 hour in humans and 1.5 hours in dogs [18, 19].
\n
In 2004, Lindner et al. proposed a novel formulation based on the new lipid 1.2‐dipalmitoyl‐sn‐glycero‐3‐phosphoglyceroglycerol (DPPG2) with prolonged plasma half‐life and similarly short release rates as LTSL [20, 21]. Initial studies with DPPG2‐TSL filled with carboxyfluorescein (CF) demonstrated initial plasma half‐life 5 hours in rats [20]. More recent studies with doxorubicin‐filled DPPG2‐TSL in cats showed plasma half‐life of around 1 hour [22], similar to doxorubicin‐LTSL.
\n
As naturally occurring lipids were used for making TSL, they are usually considered safe.
\n
\n
2.1. Extravascular release versus intravascular triggered release
\n
Three key requirements must be fulfilled by TSLs to be effective:
\n
Encapsulation of therapeutically relevant drug payload with minimum leakage.
Avoidance of mononuclear phagocyte system (MPS) to prolonged circulation.
Release of the payload (encapsulated drug) at target location (e.g., tumor).
\n
The delivery strategy of initial liposome formulations (nonthermosensitive Stealth liposome, e.g., Doxil) was based on passive accumulation in tumor interstitial space (Figure 1B), followed by slow release within the interstitium (extravascular release). Since TSL release is actively triggered, TSL‐based delivery may be used based on either of two delivery approaches: extravascular and intravascular triggered release (indicated by (1) and (2) in Figure 1E), based on whether release occurs inside the vasculature/blood or in the tumor interstitium. For extravascular triggered release, the targeting is passive and mostly relies on the EPR effect. For intravascular triggered delivery, there is no explicit‐targeting mechanism, but rather targeting is based by location where heating is induced.
\n
Since extravascular triggered release requires passive accumulation of TSL in the tumor interstitium before trigger of release, there is a necessary time delay between TSL administration and hyperthermia (typically several hours). This also means that TSLs of adequate plasma stability are required, with a plasma half‐life exceeding many hours. Computer models suggest that the optimal release rate for extravascular triggered release is in the order of many minutes to hours [16, 23].
\n
For intravascular triggered release, hyperthermia occurs ideally immediately after, or even during TSL administration [24]. This is because any leakage of drug after delivery is detrimental during intravascular triggered delivery, as it reduces the amount available for release. Thus, plasma stability requirements are less stringent than for extravascular triggered delivery. Release occurs while TSLs transit the heated tumor region; this transit time is in the range of a few seconds for most tumors, and thus ideally TSL should release very rapidly (within seconds).
\n
Both intravascular and extravascular triggered approaches are the subject of ongoing preclinical studies as described in the previous section [25, 26]. It is interesting to note that, while the benefit of faster releasing TSL has been demonstrated in 2000 [17], it was only elucidated recently that intravascular triggered delivery was the dominant delivery mechanism, and responsible for improved delivery with fast‐release TSL [16, 27].
\n
Table 1 summarizes the differences between intravascular and extravascular triggered release.
\n
\n
\n
\n
\n
\n
\n\n
\n
Drug delivery system
\n
Tumor targeting
\n
Initiation of heating
\n
Typical TSL leakage rate
\n
Ideal TSL release rate
\n
\n\n\n
\n
Extravascular triggered TSL (TSL‐e)
\n
Passive (EPR)
\n
Hours after TSL infusion
\n
hours‐days
\n
hours
\n
\n
\n
Intravascular triggered TSL (TSL‐i)
\n
Active via heat source
\n
During, or immediately after TSL infusion
\n
minutes
\n
seconds
\n
\n\n
Table 1.
Comparison of TSL for intravascular and extravascular triggered release.
\n
Mathematical models are an effective tool to evaluate different TSL delivery strategies and drug transport kinetics. Such models have several advantages which include: ability to utilize a large body of physiological and physiochemical data, prediction of pharmacokinetics and target tissue dose, and extrapolation of results both across species and routes of administration [28, 29]. The latter point is of relevance since results from experimental animal studies often do not translate into human patients, and models can thus help explain such deviations [30].
\n
In 2012, extravascular and intravascular triggered release approaches were compared using a mathematical model [16]. Specifically, the following drug delivery strategies were compared based on the chemotherapy agent doxorubicin: (1) unencapsulated drug; (2) nonthermosensitive stealth liposomes; (3) intravascular triggered TSL (TSL‐i); and (4) extravascular triggered TSL (TSL‐e). The models predict that intravascular triggered release results in considerably higher drug uptake by cancer cells (i.e., efficacy) compared to the other delivery modalities (Figure 2). During intravascular triggered delivery, new TSLs enter the tumor vasculature and release drug as long as hyperthermia is present. The systemic blood volume thus serves as reservoir of nonbioavailable drug that becomes bioavailable when entering the target tissue region.
\n
Figure 2.
Doxorubicin concentrations (unencapsulated drug) in plasma, extravascular‐extracellular space (EES), and inside cells are plotted over time for different delivery systems: (A) free‐DOX (unencapsulated drug), (B) slow‐release TSL‐i‐DOX (release rate ∼min), (C) fast‐release TSL‐i‐DOX (release rate ∼seconds), and (D) TSL‐e‐DOX [7]. Hyperthermia for 30 minutes was applied immediately for TSL‐i, and after 24 hours for TSL‐e (to allow for TSL accumulation in EES). Reproduced from Ref. [16].
\n
\n
\n
2.2. Release kinetics
\n
As described above, the intravascular triggered delivery strategy is most effective when TSLs have very rapid release, within seconds. This is the reason why the later, fast‐release formulations that release within seconds greatly improved drug accumulation in tumors compared to early formulations that required many minutes to release (Figure 3). Unfortunately, plasma stability is directly tied to release during hyperthermia, i.e., typically the faster a liposome releases when heated, the more this liposome leaks at body temperature (Figure 3A) [26].
\n
Figure 3.
(A) Graph shows release rate during hyperthermia (40–41°C), as TSL stability at body temperature (37°C), comparing a slow‐release formulation and a newer fast‐release formulation (reproduced from Ref. [16]). (B) Graph shows a release rate within first few seconds between 39 and 45°C of a fast‐release formulation in fetal bovine serum (FBS) (unpublished data). TSLs were prepared according to Needham et al. [15] with slight modifications. (DPPC: MSPC: DSPE‐PEG2000 85.3:9.7:5), and loaded with Dox using a citrate‐based pH gradient.
\n
\n
\n
2.3. Intravital microscopy
\n
Intravital microscopy is an important technology that enables visualization of drug release and uptake at microscopic scales. This enables better understanding of how the drug is taken up by the tumor once it is released from the TSL. Using fluorescent compounds such as CF or doxorubicin, it is possible to observe the drug in different compartments (e.g., inside vasculature and cells). This imaging methodology requires visual access to tumors, which is typically provided by windows (Figure 4).
\n
Figure 4.
Window chamber in a mouse. Reproduced with permission from Ref. [32]. Copyright (2013) Nature Publishing.
\n
A detailed procedure of implantation of a window chamber was explained by Ritsma et al. [31]. A small viable piece of tumor (∼1–3 mm3) is transplanted into the fascia of the dorsal skin flap which is placed within a window chamber of the recipient mice [32]. To allow visualization during hyperthermia, the tumor needs to be heated. For this purpose, a special heating coil has been developed that allows the uniform heating of these window chambers carrying tumors. The imaging takes place while animals are under anesthesia, after TSLs have been administered. While tumors are exposed to hyperthermia, tumors are imaged using confocal fluorescence microscopes using appropriate excitation and emission filters depending on fluorescence properties of the molecule. Figure 5 demonstrates the uptake of doxorubicin released from the TSL within the blood during hyperthermia, and drug uptake by cancer cell nuclei.
\n
Figure 5.
Intravital fluorescence microscopy demonstrates intravascular triggered release. Images show labeled endothelial cells (green) and doxorubicin fluorescence (red). Tissue accumulation and cell uptake are demonstrated during hyperthermia‐induced release from TSL (30 minutes, 42°C), (A) after 5 minutes and (B) after 20 minutes (field of view (FOV) 500 × 500 μm). (C) Subcellular doxorubicin localization is observed at higher magnification (inlet). (D) Aggregate fluorescence within vessels, interstitium (EES), and intracellular regions extracted from image data in (A) and (B). These data demonstrate triggered initial intravascular release, followed by tissue uptake within EES and cells. Unpublished data courtesy of Dr. Timo ten Hagen.
\n
\n
\n
2.4. Targeted thermosensitive liposomes
\n
Various targeting moieties such as antibodies are nowadays widely used for targeted delivery of liposomes and other nanoparticles and have also been investigated for TSL. The idea of attaching an antibody to a TSL was reported by Sullivan and Huang [33] as early as 1985. Sullivan and Huang [33] used covalently attached antiH2Kk antibody to a palmitic acid derivative to make heat sensitive immunoliposomes (with DPPC) carrying carboxyfluorescein. They used a similar approach to successfully deliver uridine inhibitors to lymphoma cells in vitro. However, in vivo evaluation in mice carrying human ovarian cancers did not yield encouraging results. This was attributed to the leakiness of the liposomes, which used egg phosphatidylcholine, egg phosphatidylglycerol, cholesterol, and phosphatidylethanolamine in the ratio 38.1:4:32:1.9 [34].
\n
With the development of newer TSL formulations (e.g., LTSL), there has been an increased interest in conjugating targeting molecules to TSL, particularly to those carrying the chemotherapeutic drug doxorubicin. Antibodies, peptides, and aptamers have been successfully added to TSLs. Table 2 summarizes the targeting molecules that have been used.
107–111 pentapeptide of the parathyroid hormone‐related protein
\n
\n\n
Table 2.
Targeted thermosensitive liposomes.
\n
Antibodies targeting common receptors found in cancers such as human epidermal growth factor receptor 2 (HER‐2) [35] and epidermal growth factor receptor (EGFR) [36] have been conjugated to LTSL carrying doxorubicin that are being evaluated in animal models. Kullberg et al. [37] showed that adding listeriolysin O along with HER‐2 antibody enhanced cytoplasmic delivery of the cargo.
\n
Similarly, Na et al. added elastin‐like peptide (ELP), which significantly improved the drug uptake within cells [38].
\n
Moreover, peptides that target tumors have also been added to TSLs. Wang et al. added the tumor homing pentapeptide (Cys‐Arg‐Glu‐Lys‐Ala) (CREKA) to TSLs and evaluated their efficacy in MCF‐7 bearing nude mice [39]. Dicheva et al. [40] added a cyclic pentapeptide to TSL‐doxorubicin improving the drug uptake and delivery. Deng et al. [41] improved the antitumor efficacy by adding the iRGD peptide.
\n
Most recently, Zhang et al. [42] used an aptamer conjugated TSLs loaded with contrast agent that targeted the nucleoporin receptors. Besides displaying excellent biocompatibility, they showed promise in the early detection of cancers.
\n
In a somewhat different application, Lopez et al. developed a collagen‐based scaffold to which TSLs were covalently attached via targeting molecule to slowly release a peptide cargo with proosteogenic effect from the scaffold [43].
\n
\n
\n
\n
3. Payloads
\n
Ever since the initial studies where neomycin was encapsulated in TSL [5], several other drugs and reporter molecules have been encapsulated by various TSL formulations and evaluated. Several combinations have successfully made it to various stages of preclinical and clinical trials. A brief overview of the compounds that have been successfully encapsulated will be reviewed here.
\n
The fluorescent reporter carboxyfluorescein (CF) has been the molecule of choice for studying the release kinetics of TSLs. Starting from the initial studies until today, CF has been used in the study of various TSL combinations. Other fluorescent molecules such as calcein have also been used to study TSL release.
\n
Yatvin et al. encapsulated cisplatin (cis‐dichlorodiammineplatinum(II)) in 1981 [44] and evaluated against mice tumor sarcoma. This suggested that a whole array of different compounds could be encapsulated by TSLs. However, until the late 1980s, only water soluble compounds were being encapsulated into TSLs.
\n
Doxorubicin is an amphiphilic compound that was encapsulated into the TSL toward the end of 1980s. Doxorubicin is a highly cytotoxic chemotherapeutic drug belonging to the group of anthracyclines, with several off target effects such as cardiotoxicity and myelosuppression. Tomita et al. encapsulated doxorubicin in DPPC: cholesterol‐based TSL to improve stability [45]. Other formulations further attempted to improve TSL stability [10, 46]. Unezaki et al. reported the active loading of doxorubicin against a pH gradient into TSLs [47], which resulted in more than 90% encapsulation efficacy. The TSL composition developed by Needham et al. [15] is the formulation that progressed furthest toward clinical use, with ongoing clinical trials that will be discussed later. One of the significant developments that occurred more recently for TSL‐Dox was the incorporation of contrast agents. Several researchers encapsulated doxorubicin along with gadolinium‐based contrast agents [48–50]. This provided the ability of monitoring the release of a contrast agent from TSL and subsequent tissue uptake by magnetic resonance imaging (MRI), indicating the tissue regions where doxorubicin may be delivered to.
\n
Following doxorubicin, several groups encapsulated other drugs belonging to the same family of anthracycline drugs in TSL, including daunorubicin, idarubicin, and epirubicin. The initial studies with daunorubicin in the mid‐1990s in mice models of sarcoma were disappointing [51]. However, more recent studies with newer formulations of idarubicin‐TSL showed superior survival rate and tumor growth inhibition as compared to free idarubicin [52]. Similar results were demonstrated with epirubicin‐TSL in animals [53].
\n
The successful encapsulation of anthracyclines with high efficiency prompted the search for other molecules with high encapsulation efficiency. Liu et al. [54] reported that using metal ions such as Zn or Cu could lead to high efficacy in encapsulation of cisplatin. Moreover, the presence of metal bound liposomes increased the cytotoxicity.
\n
Apart from anthracyclines [65], the drugs bleomycin [55], melphalan [56], placitaxel [57], docetaxel [58], and gemcitabine [59] have been encapsulated into TSL and delivered to tumors, while reducing systemic drug toxicities.
\n
Another fluorescent compound that was successfully encapsulated in TSL is the cancer drug 5‐fluorouracil. Sabbagh et al. used a lipid combination containing DPPC, cholesterol, and PEG to encapsulate 5‐fluorouracil. They further found that complexing 5‐fluorouracil with copper‐polyethylenimine improved the stability of the liposomes with a higher encapsulation efficacy [60].
\n
Recently, vinorelbine was encapsulated into a TSL formulation [61]. Vinorelbine is a wide spectrum chemotherapeutic agent used in treatment of breast, lung, and liver cancers. However, free vinorelbine is associated with venous toxicity causing blisters when infused directly into the blood. The authors reported that combining vinorelbine‐TSL with hyperthermia resulted in enhanced antitumor activity. In another study, Wang et al. showed that [62] vinorelbine‐TSL in combination with radiofrequency ablation (RFA) improved the survival of micecarrying liver tumors.
\n
Another interesting recent application of TSL is the targeted delivery of the antibiotic ciprofloxacin to aid wound healing. Wardlow et al. [63] demonstrated the encapsulation of ciprofloxacin in TSL, and used these for delivery to hyperthermic areas using a rat model. They suggested that this formulation could be used for chronic wound healing. However, work still remains to evaluate these TSLs in an animal model of chronic would healing.
\n
Most recently, it was reported that chemotherapeutic drugs vincristine and doxorubicin were coloaded into TSL in combination. Li et al. showed that multiple drug loading could be achieved to exploit the synergy between drugs [64].
\n
It should be noted that each drug has to be individually tested, i.e., there is no single TSL formulation that would work for all drugs. In addition, the release rate and leakage will vary for different drugs, and it may not always be possible to achieve rapid release within seconds as is ideal for intravascular triggered release. Table 3 summarizes the drugs that have been encapsulated in a TSL formulation and the liposomal composition.
Thermosensitive liposomes composition and payloads.
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\n
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4. Heating modalities
\n
TSLs have been used successfully in combination with various heating modalities in both animal models and in human clinical trials. Some of these heating modalities include devices already in clinical use; others have only been used in animals. Ideally, only the targeted tissue region is exposed to temperatures within the range where TSL release (typically above ∼40°C). In addition, higher temperatures (>43–50°C) may result in reduced blood perfusion [66] and should be avoided since without perfusion TSLs are not transported to the target site. Thus, in an ideal case, the targeted tissue region should be exposed to a quite narrow temperature range (∼40–43°C). For larger tumors—particularly as can be the case in humans or large animals—achieving this temperature uniformity in large tissue volumes is challenging, and the hyperthermia device becomes an important element affecting TSL‐based drug delivery efficacy.
\n
Since deep‐seated tumors are typically identified based on medical imaging (e.g., computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound imaging), TSLs may be used for image‐guided drug delivery. Here, the intent is to deliver drug to a specific region of the body identified by medical imaging. Since TSLs are administered systemically, image‐guided drug delivery is realized by exposing the targeted tissue volume to hyperthermic temperatures by image‐guided heating devices. Thus, one important aspect that should guide the selection of the heating modality is ability to expose only the targeted tumor region to uniformly hyperthermic temperatures.
\n
\n
4.1. Animal hyperthermia systems
\n
\n
4.1.1. Water bath
\n
Water bath as a heat source has been used extensively in preclinical studies, especially involving small animals. Usually the animal is anesthetized, hair removed if necessary and the region surrounding the tumor is immersed in a water bath, which is preheated to the required temperature (usually >40°C). It is essential to make sure that the skin distant from the targeted tumor is not exposed to the heat from the water bath. For example, some researchers used a water bath cover made of material that does not conduct heat, with the other parts of the body covered by a polystyrene cover [50]. Other studies used a plastic syringe to hold the leg of mice in place to expose only the tumor to heated water while protecting the other leg from heat [32]. Ultrasound gel or vaseline has also been applied to protect the tissues surrounding the tumor from heat exposure.
\n
\n
\n
4.1.2. Light sources
\n
Various light sources have been employed to induce hyperthermia, usually for surface heating of subcutaneous tumors. Several groups used a cold lamp, which emits visible light (350–700 nm wavelength) [50, 59]. By adjusting the power of the lamp, a target temperature of ∼41–43°C was achieved. White cotton wool was placed around the area surrounding the tumor to avoid heating and drug delivery.
\n
Near infrared (NIR) lasers (∼800–1000 nm wavelength) have also been used as a heating sources in nanoparticle‐based drug delivery systems, which can penetrate tissue to depths in the range of ∼0.5 cm [51, 67, 68]. The diameter of the laser spot can be adjusted by optical lenses to correspond to the targeted area.
\n
\n
\n
4.1.3. Microwave hyperthermia
\n
Microwave devices have a long history for use in hyperthermia studies [69] and have been used in combination with TSLs, for example by the first in vivo TSL study by Weinstein et al. in 1979 [7]. They used a system specifically designed to expose subcutaneous rodent tumors to hyperthermia through microwave antennas placed on the skin. Three other studies also used surface microwave applicators: one trial in dogs [19], one in cats [22], and a phase I trial in humans for breast cancer; the latter two used a FDA‐approved microwave hyperthermia system [70]. While there are also interstitial microwave antennas for heating deep tissue regions [69], to our knowledge these have not yet been used in combination with TSL.
\n
\n
\n
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4.2. Clinically used hyperthermia and thermal ablation devices
\n
\n
4.2.1. Radiofrequency ablation
\n
Thermal tumor ablation is a heat‐based cancer therapy, where the cancer is killed by heat alone, by heating above ∼50°C. Most widely used is radiofrequency ablation (RFA), where radiofrequency electric current is applied to tissue via electrode inserted into the tumor under image guidance [71]. The electric current results in localized tissue heating (Figure 6). In the clinic, RFA is used guided by medical imaging techniques such as MRI, ultrasound, or CT, and is currently in use for liver, lung, kidney, and other types of cancer.
\n
Figure 6.
Overview of liver radiofrequency tumor ablation procedure as clinically performed. An RFA electrode is inserted into the tumor under imaging guidance, and the tumor is killed by heat. Tumor recurrences following ablation occur primarily in the margin of the ablation zone, where inadequate temperatures were obtained (<50°C). The combination with TSL delivers drug at high dose to this ablation margin, potentially reducing recurrences. Adapted from Ref. [72].
\n
Since local tumor recurrence often occurs at the margin of the tissue regions killed by heat, TSLs have been combined with RFA to preferentially deliver chemotherapy to these margins that are exposed to sublethal, hyperthermic temperatures (Figure 7). This combination is also being examined in clinical trials for treatment of primary liver cancer.
\n
Figure 7.
Combination of tumor ablation with TSL. (a) Two‐dimensional (2‐D) computer simulation of temperature (left), and of drug delivery (right), showing drug uptake in the margin of the ablation zone. Results are based on a prior computer model [73]. (b) Results of a recent porcine animal study (normal liver) demonstrating visible ablation zone, and (c) drug delivery in the margin of the ablation zone visualized by fluorescence imaging (unpublished results), qualitatively similar to computer model prediction in (a).
\n
There are other technologies for tumor ablation similar to RFA used clinically, such as microwave ablation and laser. While these could also be combined with TSL, studies on such combinations are not yet available.
\n
\n
\n
4.2.2. High‐intensity focused ultrasound (HIFU)
\n
High‐intensity focused ultrasound (HIFU) in combination with magnetic resonance imaging (MRgHIFU) is in clinical use for treatment of tumors by heating them to >50°C (i.e., thermal ablation). HIFU employs focusing of ultrasound emitted from external ultrasound transducers into deep tissue regions, resulting in highly localized tissue heating (∼mm range diameter of focal spot). The focal spot can be electronically steered, allowing precise spatial targeting with mm accuracy. A technique named magnetic resonance (MR) thermometry allows real‐time noninvasive imaging of tissue temperature and is ideally suited to monitor and control HIFU heating (Figure 8A) [73]. MRgHIFU thus allows noninvasive targeted heating of deep tissue regions while monitoring and controlling desired temperature, thus being ideally suited for TSL‐based drug delivery (Figure 8B) [74–76]
\n
Figure 8.
(A) Temperature map during MRgHIFU‐hyperthermia measured via MR thermometry, overlaid on preprocedural proton density‐weighted image of rabbit thigh muscle. The targeted tissue region is heated to ∼40–42°C after administration of TSL‐Dox. (B) Doxorubicin distribution visualized via fluorescence microscopy in extracted tissue sample demonstrating localized, image‐guided drug delivery. Figure adapted from Ref. [75].
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\n
\n
\n
\n
5. Clinical trials
\n
TSL formulations have been evaluated in both veterinary trials as well as in human clinical trials as cancer therapy. TSL formulations using doxorubicin have been evaluated in the veterinary clinic for various cancers. A TSL‐doxorubicin formulation (ThermoDox® by Celsion), which is based on the LTSL formulation by Needham et al., has been actively evaluated in the treatment of hepatocellular carcinoma and recurrent breast wall cancers. These clinical trials are briefly discussed below.
\n
\n
5.1. Animal trials
\n
A phase I clinical trial was conducted in companion dogs with solid tumors (carcinomas and sarcomas). Of the 20 dogs that were enrolled in the study, from those that were treated at least twice with TSL‐Dox, 12 dogs had stable disease and 6 had partial response. The toxicities observed were manageable [19].
\n
Similarly, TSL‐doxorubicin was evaluated in a pilot trial in the veterinary clinic for the treatment of feline soft tissue sarcoma [22]. Eleven cats with advanced sarcoma were divided into three treatment groups with increasing dosage of TSL‐doxorubicin. Up to six treatments were delivered every alternate week with a radiofrequency applicator. Two cats in the highest dosage group showed partial response. Dosage was well tolerated in all the cats showing potential for larger studies.
\n
\n
\n
5.2. Human trials
\n
There have been several human clinical trials with TSL‐Dox, all with the formulation ThermoDox® (Celsion Corp.), which is based on the LTSL formulation [15].
\n
The furthest progress has been combining TSL with radiofrequency ablation (RFA) in primary liver cancer (i.e., hepatocellular carcinoma). The motivation was delivery of high doses of doxorubicin to the margin of the zone killed by heat, as shown in Figure 6. As there was a significant proportion of patients that had local tumor recurrence just outside the ablation zone, there was a strong premise for this approach. Wood et al. [18] reported results at the conclusion of a phase I study involving RFA and TSL‐Dox in liver cancer patients. This safety trial showed that TSL‐Dox was well tolerated with manageable side effects up to a maximum tolerated dose (MTD) of 50 mg/m2 (this is in the same range as the MTD for unencapsulated doxorubicin). With the successful completion of this phase I trial, TSL‐doxorubicin in combination with RFA was fast tracked to a phase III trial for primary/metastatic liver tumors in the “HEAT trial” (NCT00617981) [77], which unfortunately failed. There have been several possible explanations that have been attributed to this failure, which have been described in detail by Dou et al. [78]. However, a retrospective analysis showed that TSL‐Dox in combination with RFA performed better in those patients where the RFA duration was at least 45 minutes [79], which was supported by further animal studies [80]. As a result, a follow‐up phase III trial (“OPTIMA trial,” NCT0211265) was initiated where required RFA duration was increased, and this trial is ongoing.
\n
Another trial recently initiated in England also focuses on liver cancer (both primary and metastatic cancer) and combines TSL‐Dox with HIFU (“TARDOX trial,” NCT02181075).
\n
In addition, there have been a few phase I and phase I/II trials where TSL‐Dox was combined with microwave hyperthermia for recurrent chest breast wall cancer (“DIGNITY trial,” NCT00826085). Zagar et al. reported the results of a phase I study using TSL‐Dox in recurrent breast wall cancer [70]. Patients who had exhausted all other therapies were enrolled in this trial. Almost 17% of the enrolled patients showed complete remission and another 31% showed partial response. Based on the promising results of these prior phase I/II trials, a follow‐up trial has been initiated in Europe (“EURO‐DIGNITY,” NCT02850419).
\n
Finally, a phase I study has been recently announced in the United States, where TSL‐Dox will be combined with MRgHIFU for treating childhood sarcomas (NCT02536183). Thus, at least four different ongoing clinical trials are in various stages of recruiting patients.
\n
A phase I study of lyso‐thermosensitive liposomal doxorubicin and MR‐HIFU for pediatric refractory solid tumors (NCT02536183).
Targeted chemotherapy using focused ultrasound for liver tumors (TARDOX) (NCT02181075).
Study of ThermoDox with standardized radiofrequency ablation (RFA) for treatment of hepatocellular carcinoma (HCC) (OPTIMA) (NCT0211265).
Heat‐activated target therapy of local‐regional relapse in breast cancer patients (EURO‐DIGNITY) (NCT02850419).
\n
\n
\n
\n
6. Conclusion
\n
While TSLs have been first proposed almost 40 years ago, only within the last decade have first results from clinical trials in humans become available. Animal studies have shown that in ideal conditions, up to 20–30 times of bioavailable drug can be delivered to the tumor tissue (measured within a few hours of infusion) as compared to administration of the same dosage of free drug. TSL benefit from reduced off‐target toxicity effects, similar to nontemperature sensitive liposomes already in clinical use. The efficacy of TSL depends both on the specific liposomal formulation (e.g., release rate, plasma stability), the encapsulated drug, and on the specific heating modality. Several such heating modalities are clinically available, with MRgHIFU being one of the most attractive methods. HIFU is noninvasive, allows exquisite spatial control of heating with mm accuracy, and combined with MR‐thermometry tissue temperature can be monitored and controlled in real time.
\n
Contrary to most other nanoparticle approaches, TSLs can be employed for image‐guided drug delivery where the goal is to deliver drug to a region identified by medical imaging. Such an approach may find additional clinical applications apart from cancer. One limitation of many current TSL formulations is the still relatively short plasma half‐life (∼1 hour), which limits the duration available for delivery, reduces the quantity of encapsulated drug available for release, and also negatively impacts systemic toxicities.
\n
In summary, TSLs represent a highly promising drug delivery approach that has the potential for considerable clinical impact in the near future.
Magnetic resonance‐guided high‐intensity focused ultrasound
MSPC
Myristoyl lyso glycero phosphocholine
MTD
Maximum tolerated dose
PEG
Poly ethylene glycol
RFA
Radiofrequency ablation
TSL
Thermosensitive liposomes
TTSL
Traditional thermosensitive liposomes
\n',keywords:"liposomes, thermosensitive liposomes, triggered release, hyperthermia, drug targeting, drug delivery",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/55377.pdf",chapterXML:"https://mts.intechopen.com/source/xml/55377.xml",downloadPdfUrl:"/chapter/pdf-download/55377",previewPdfUrl:"/chapter/pdf-preview/55377",totalDownloads:1192,totalViews:584,totalCrossrefCites:3,totalDimensionsCites:8,hasAltmetrics:0,dateSubmitted:"November 18th 2016",dateReviewed:"February 27th 2017",datePrePublished:null,datePublished:"October 25th 2017",dateFinished:null,readingETA:"0",abstract:"Thermosensitive liposomes (TSLs) are a drug delivery system for targeted delivery that release the encapsulated drug when heated to fever temperatures (∼40–42°C). Combined with localized hyperthermia, TSLs allow precise drug delivery to a targeted region. While mostly investigated as cancer therapy, other applications including treatment of local infections and wound healing have been explored. Over the last ∼40 years, numerous TSL formulations and payloads have been investigated. As with other nanoparticles, the addition of targeting molecules to TSL has been examined to improve targeted delivery. TSL release kinetics and plasma stability are two important factors that affect efficacy, and new formulations often aim to further improve on these properties. The possibility of encapsulating a magnetic resonance (MR) contrast agent that is released together with the encapsulated drug allows for visualization of drug delivery with MR imaging. Various heating modalities have been examined in combination with TSL. Since the goal is to expose a defined tissue region to uniform temperatures within the range where TSLs release (typically ∼40–43°C), the choice of an appropriate heating modality has considerable impact on treatment efficacy. Several ongoing clinical trials with TSL as cancer therapy suggest the potential for clinical impact in the near future.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/55377",risUrl:"/chapter/ris/55377",book:{slug:"liposomes"},signatures:"Anjan Motamarry, Davud Asemani and Dieter Haemmerich",authors:[{id:"201952",title:"Prof.",name:"Dieter",middleName:null,surname:"Haemmerich",fullName:"Dieter Haemmerich",slug:"dieter-haemmerich",email:"haemmer@musc.edu",position:null,institution:{name:"Medical University of South Carolina",institutionURL:null,country:{name:"United States of America"}}},{id:"207116",title:"Mr.",name:"Anjan",middleName:null,surname:"Motamarry",fullName:"Anjan Motamarry",slug:"anjan-motamarry",email:"Motamarr@musc.edu",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Background: evolution of thermosensitive liposomes (TSLs)",level:"1"},{id:"sec_2_2",title:"2.1. Extravascular release versus intravascular triggered release",level:"2"},{id:"sec_3_2",title:"2.2. Release kinetics",level:"2"},{id:"sec_4_2",title:"2.3. Intravital microscopy",level:"2"},{id:"sec_5_2",title:"2.4. Targeted thermosensitive liposomes",level:"2"},{id:"sec_7",title:"3. Payloads",level:"1"},{id:"sec_8",title:"4. Heating modalities",level:"1"},{id:"sec_8_2",title:"4.1. Animal hyperthermia systems",level:"2"},{id:"sec_8_3",title:"4.1.1. Water bath",level:"3"},{id:"sec_9_3",title:"4.1.2. Light sources",level:"3"},{id:"sec_10_3",title:"4.1.3. Microwave hyperthermia",level:"3"},{id:"sec_12_2",title:"4.2. Clinically used hyperthermia and thermal ablation devices",level:"2"},{id:"sec_12_3",title:"4.2.1. Radiofrequency ablation",level:"3"},{id:"sec_13_3",title:"4.2.2. High‐intensity focused ultrasound (HIFU)",level:"3"},{id:"sec_16",title:"5. Clinical trials",level:"1"},{id:"sec_16_2",title:"5.1. Animal trials",level:"2"},{id:"sec_17_2",title:"5.2. Human trials",level:"2"},{id:"sec_19",title:"6. Conclusion",level:"1"},{id:"sec_22",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'Kunjachan S, Ehling J, Storm G, Kiessling F, Lammers T. Noninvasive imaging of nanomedicines and nanotheranostics: Principles, progress, and prospects. Chemical Reviews. 2015;115:10907–10937. DOI: 10.1021/cr500314d\n'},{id:"B2",body:'Maeda H. The enhanced permeability and retention (epr) effect in tumor vasculature: The key role of tumor‐selective macromolecular drug targeting. Advances in Enzyme Regulation. 2001;41:189–207\n'},{id:"B3",body:'Barenholz Y. Doxil(r)—the first fda‐approved nano‐drug: Lessons learned. Journal of Controlled Release. 2012;160:117–134. DOI: 10.1016/j.jconrel.2012.03.020\n'},{id:"B4",body:'Park K. Facing the truth about nanotechnology in drug delivery. ACS Nano. 2013;7:7442–7447. DOI: 10.1021/nn404501g\n'},{id:"B5",body:'Yatvin MB, Weinstein JN, Dennis WH, Blumenthal R. 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Enhanced specificity and drug delivery in tumors by crgd‐anchoring thermosensitive liposomes. Pharmaceutical Research. 2015;32:3862–3876. DOI: 10.1007/s11095‐015‐1746‐7\n'},{id:"B41",body:'Deng Z, Xiao Y, Pan M, Li F, Duan W, Meng L, Liu X, Yan F, Zheng H. Hyperthermia‐triggered drug delivery from irgd‐modified temperature‐sensitive liposomes enhances the anti‐tumor efficacy using high intensity focused ultrasound. Journal of Controlled Release. 2016;243:333–341. DOI: 10.1016/j.jconrel.2016.10.030\n'},{id:"B42",body:'Zhang K, Liu M, Tong X, Sun N, Zhou L, Cao Y, Wang J, Zhang H, Pei R. Aptamer‐modified temperature‐sensitive liposomal contrast agent for magnetic resonance imaging. Biomacromolecules. 2015;16:2618–2623. DOI: 10.1021/acs.biomac.5b00250\n'},{id:"B43",body:'Lopez‐Noriega A, Ruiz‐Hernandez E, Quinlan E, Storm G, Hennink WE, O’Brien FJ. Thermally triggered release of a pro‐osteogenic peptide from a functionalized collagen‐based scaffold using thermosensitive liposomes. 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Hyperthermia potentiates antitumor effect of thermosensitive‐liposome‐encapsulated melphalan and radiation in murine melanoma. Tumour Biology. 1997;18:250–260\n'},{id:"B57",body:'Wang ZY, Zhang H, Yang Y, Xie XY, Yang YF, Li Z, Li Y, Gong W, Yu FL, Yang Z, Li MY, Mei XG. Preparation, characterization, and efficacy of thermosensitive liposomes containing paclitaxel. Drug Delivery. 2016;23:1222–1231. DOI: 10.3109/10717544.2015.1122674\n'},{id:"B58",body:'Zhang H, Gong W, Wang ZY, Yuan SJ, Xie XY, Yang YF, Yang Y, Wang SS, Yang DX, Xuan ZX, Mei XG. Preparation, characterization, and pharmacodynamics of thermosensitive liposomes containing docetaxel. Journal of Pharmaceutical Sciences. 2014;103:2177–2183. DOI: 10.1002/jps.24019\n'},{id:"B59",body:'Limmer S, Hahn J, Schmidt R, Wachholz K, Zengerle A, Lechner K, Eibl H, Issels RD, Hossann M, Lindner LH. Gemcitabine treatment of rat soft tissue sarcoma with phosphatidyldiglycerol‐based thermosensitive liposomes. Pharmaceutical Research. 2014;31:2276–2286. DOI: 10.1007/s11095‐014‐1322‐6\n'},{id:"B60",body:'Al Sabbagh C, Tsapis N, Novell A, Calleja‐Gonzalez P, Escoffre JM, Bouakaz A, Chacun H, Denis S, Vergnaud J, Gueutin C, Fattal E. Formulation and pharmacokinetics of thermosensitive stealth(r) liposomes encapsulating 5‐fluorouracil. Pharmaceutical Research. 2015;32:1585–1603. DOI: 10.1007/s11095‐014‐1559‐0\n'},{id:"B61",body:'Zhang H, Wang ZY, Gong W, Li ZP, Mei XG, Lv WL. Development and characteristics of temperature‐sensitive liposomes for vinorelbine bitartrate. International Journal of Pharmaceutics. 2011;414:56–62. DOI: 10.1016/j.ijpharm.2011.05.013\n'},{id:"B62",body:'Wang S, Mei XG, Goldberg SN, Ahmed M, Lee JC, Gong W, Han HB, Yan K, Yang W. Does thermosensitive liposomal vinorelbine improve end‐point survival after percutaneous radiofrequency ablation of liver tumors in a mouse model? Radiology. 2016;279:762–772. DOI: 10.1148/radiol.2015150787\n'},{id:"B63",body:'Wardlow R, Bing C, VanOsdol J, Maples D, Ladouceur‐Wodzak M, Harbeson M, Nofiele J, Staruch R, Ramachandran A, Malayer J, Chopra R, Ranjan A. Targeted antibiotic delivery using low temperature‐sensitive liposomes and magnetic resonance‐guided high‐intensity focused ultrasound hyperthermia. International Journal of Hyperthermia. 2016;32:254–264. DOI: 10.3109/02656736.2015.1134818\n'},{id:"B64",body:'Li M, Li Z, Yang Y, Wang Z, Yang Z, Li B, Xie X, Song J, Zhang H, Li Y, Gao G, Yang J, Mei X, Gong W. Thermo‐sensitive liposome co‐loaded of vincristine and doxorubicin based on their similar physicochemical properties had synergism on tumor treatment. Pharmaceutical Research. 2016;33:1881–1898. DOI: 10.1007/s11095‐016‐1924‐2\n'},{id:"B65",body:'AllenTM, Martin FJ. Advantages of liposomal delivery systems for anthracyclines. Seminars in Oncology. 2004;31:5–15\n'},{id:"B66",body:'Rossmann C, Haemmerich D. Review of temperature dependence of thermal properties, dielectric properties, and perfusion of biological tissues at hyperthermic and ablation temperatures. Critical Reviews in Biomedical Engineering. 2014;42:467–492\n'},{id:"B67",body:'You J, Shao R, Wei X, Gupta S, Li C. Near‐infrared light triggers release of paclitaxel from biodegradable microspheres: Photothermal effect and enhanced antitumor activity. Small. 2010;6:1022–1031. DOI: 10.1002/smll.201000028\n'},{id:"B68",body:'You J, Zhang P, Hu F, Du Y, Yuan H, Zhu J, Wang Z, Zhou J, Li C. Near‐infrared light‐sensitive liposomes for the enhanced photothermal tumor treatment by the combination with chemotherapy. Pharmaceutical Research. 2014;31:554–565. DOI: 10.1007/s11095‐013‐1180‐7\n'},{id:"B69",body:'Ryan TP, Brace CL. Interstitial microwave treatment for cancer: Historical basis and current techniques in antenna design and performance. International Journal of Hyperthermia. 2017;33:3–14. DOI: 10.1080/02656736.2016.1214884\n'},{id:"B70",body:'Zagar TM, Vujaskovic Z, Formenti S, Rugo H, Muggia F, O’Connor B, Myerson R, Stauffer P, Hsu IC, Diederich C, Straube W, Boss MK, Boico A, Craciunescu O, Maccarini P, Needham D, Borys N, Blackwell KL, Dewhirst MW. Two phase I dose‐escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (ltld) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer. International Journal of Hyperthermia. 2014;30:285–294. DOI: 10.3109/02656736.2014.936049\n'},{id:"B71",body:'Rossmann C, Rattay F, Haemmerich D. Platform for patient‐specific finite‐element modeling and application for radiofrequency ablation. 2012;1:0. DOI:10.1615/VisualizImageProcComputatBiomed.2012004898\n'},{id:"B72",body:'GasselhuberA, Dreher MR, Negussie A, Wood BJ, Rattay F, Haemmerich D. Mathematical spatio‐temporal model of drug delivery from low temperature sensitive liposomes during radiofrequency tumour ablation. International Journal of Hyperthermia. 2010;26:499–513. DOI: 10.3109/02656731003623590\n'},{id:"B73",body:'Rieke V, Butts Pauly K. Mr thermometry. Journal of Magnetic Resonance Imaging. 2008; 27:376–390. DOI: 10.1002/jmri.21265\n'},{id:"B74",body:'Gasselhuber A, Dreher MR, Partanen A, Yarmolenko PS, Woods D, Wood BJ, Haemmerich D. Targeted drug delivery by high intensity focused ultrasound mediated hyperthermia combined with temperature‐sensitive liposomes: Computational modeling and preliminary in vivo validation. International Journal of Hyperthermia. 2012;28:337–348. DOI: 10.3109/02656736.2012.677930\n'},{id:"B75",body:'StaruchRM, Hynynen K, Chopra R. Hyperthermia‐mediated doxorubicin release from thermosensitive liposomes using mr‐hifu: Therapeutic effect in rabbit vx2 tumours. International Journal of Hyperthermia. 2015;31:118–133. DOI: 10.3109/02656736.2014.992483\n'},{id:"B76",body:'Grull H, Langereis S. Hyperthermia‐triggered drug delivery from temperature‐sensitive liposomes using mri‐guided high intensity focused ultrasound. Journal of Controlled Release. 2012;161:317–327. DOI: 10.1016/j.jconrel.2012.04.041\n'},{id:"B77",body:'Celsion’s phase iii thermodox(r) heat study recommended for continuation by data monitoring committee. 2017. Available from: http://investor.celsion.com/releasedetail.cfm?releaseid=469443 (Accessed: February 2, 2017)\n'},{id:"B78",body:'Dou Y, Hynynen K, Allen C. To heat or not to heat: Challenges with clinical translation of thermosensitive liposomes. Journal of Controlled Release. 2017;249:63–73. DOI: 10.1016/j.jconrel.2017.01.025\n'},{id:"B79",body:'Lencioni R, Tak W.‐Y, Chen M. H, Finn R. S, Sherman M, Makris L, O’Neal M, Simonich W, Haemmerich D, Reed R, Borys N, Poon R. T. P, Abou‐Alfa G. K: Standardized radiofrequency ablation (srfa) ≥ 45 minutes (m) plus lyso‐thermosensitive liposomal doxorubicin (ltld) for solitary hepatocellular carcinoma (hcc) lesions 3–7 cm: A retrospective analysis of phase iii heat study. Journal of Clinical Oncology. 2014; 32:e15143–e15143. DOI:10.1200/jco.2014.32.15_suppl.e15143\n'},{id:"B80",body:'Swenson CE, Haemmerich D, Maul DH, Knox B, Ehrhart N, Reed RA. Increased duration of heating boosts local drug deposition during radiofrequency ablation in combination with thermally sensitive liposomes (thermodox) in a porcine model. PLoS One. 2015;10:e0139752. DOI: 10.1371/journal.pone.0139752\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Anjan Motamarry",address:null,affiliation:'
Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
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Review",slug:"modification-of-fatty-acid-composition-in-meat-through-diet-effect-on-lipid-peroxidation-and-relatio",signatures:"Gema Nieto and Gaspar Ros",authors:[{id:"141016",title:"Dr.",name:"Gema",middleName:null,surname:"Nieto",fullName:"Gema Nieto",slug:"gema-nieto"},{id:"141332",title:"Prof.",name:"Gaspar",middleName:null,surname:"Ros",fullName:"Gaspar Ros",slug:"gaspar-ros"}]},{id:"38458",title:"Lipid Peroxidation After Ionizing Irradiation Leads to Apoptosis and Autophagy",slug:"lipid-peroxidation-after-ionizing-irradiation-leads-to-apoptosis-and-autophagy",signatures:"Juliann G. Kiang, Risaku Fukumoto and Nikolai V. Gorbunov",authors:[{id:"157452",title:"Dr.",name:"Juliann",middleName:null,surname:"Kiang",fullName:"Juliann Kiang",slug:"juliann-kiang"},{id:"158709",title:"Dr.",name:"Risaku",middleName:null,surname:"Fukumoto",fullName:"Risaku Fukumoto",slug:"risaku-fukumoto"},{id:"158710",title:"Dr.",name:"Nikolai",middleName:null,surname:"Gorbunov",fullName:"Nikolai Gorbunov",slug:"nikolai-gorbunov"}]},{id:"38467",title:"Tissue Occurrence of Carbonyl Products of Lipid Peroxidation and Their Role in Inflammatory Disease",slug:"tissue-occurrence-of-carbonyl-products-of-lipid-peroxidation-and-their-role-in-inflammatory-disease",signatures:"Maria Armida Rossi",authors:[{id:"148504",title:"Prof.",name:"Maria",middleName:null,surname:"Rossi",fullName:"Maria Rossi",slug:"maria-rossi"}]},{id:"38465",title:"The Role of Physical Exercise on Lipid Peroxidation in Diabetic Complications",slug:"the-role-of-physical-exercise-on-lipid-peroxidation-in-diabetic-complications",signatures:"Yaşar Gül Özkaya",authors:[{id:"142843",title:"Dr.",name:"Y. Gul",middleName:null,surname:"Ozkaya",fullName:"Y. Gul Ozkaya",slug:"y.-gul-ozkaya"}]},{id:"38466",title:"Reactive Oxygen Species Act as Signaling Molecules in Liver Carcinogenesis",slug:"reactive-oxygen-species-act-as-signaling-molecules-in-liver-carcinogenesis",signatures:"María Cristina Carrillo, María de Luján Alvarez, Juan Pablo Parody, Ariel Darío Quiroga and María Paula Ceballos",authors:[{id:"142215",title:"PhD.",name:"Maria Cristina",middleName:null,surname:"Carrillo",fullName:"Maria Cristina Carrillo",slug:"maria-cristina-carrillo"},{id:"142855",title:"Dr.",name:"Maria De Luján",middleName:null,surname:"Alvarez",fullName:"Maria De Luján Alvarez",slug:"maria-de-lujan-alvarez"},{id:"142858",title:"BSc.",name:"Juan Pablo",middleName:null,surname:"Parody",fullName:"Juan Pablo Parody",slug:"juan-pablo-parody"},{id:"142859",title:"Dr.",name:"Ariel Darío",middleName:null,surname:"Quiroga",fullName:"Ariel Darío Quiroga",slug:"ariel-dario-quiroga"},{id:"142861",title:"BSc.",name:"Maria Paula",middleName:null,surname:"Ceballos",fullName:"Maria Paula Ceballos",slug:"maria-paula-ceballos"}]},{id:"38459",title:"Lipid Peroxidation and Antioxidants in Arterial Hypertension",slug:"lipid-peroxidation-and-antioxidants-in-arterial-hypertension",signatures:"Teresa Sousa, Joana Afonso, António Albino-Teixeira and Félix Carvalho",authors:[{id:"131252",title:"Prof.",name:"Félix",middleName:null,surname:"Carvalho",fullName:"Félix Carvalho",slug:"felix-carvalho"},{id:"140800",title:"Prof.",name:"António",middleName:null,surname:"Albino-Teixeira",fullName:"António Albino-Teixeira",slug:"antonio-albino-teixeira"},{id:"142410",title:"Prof.",name:"Teresa",middleName:null,surname:"Sousa",fullName:"Teresa Sousa",slug:"teresa-sousa"},{id:"142411",title:"MSc.",name:"Joana",middleName:null,surname:"Afonso",fullName:"Joana Afonso",slug:"joana-afonso"}]},{id:"38476",title:"Lipid Peroxidation and Reperfusion Injury in Hypertrophied Hearts",slug:"lipid-peroxidation-and-reperfusion-injury-in-hypertrophied-hearts",signatures:"Juliana C. 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Konieczko",authors:[{id:"141806",title:"Dr.",name:"Mary",middleName:null,surname:"Vagula",fullName:"Mary Vagula",slug:"mary-vagula"},{id:"150947",title:"Prof.",name:"Elisa",middleName:null,surname:"Konieczko",fullName:"Elisa Konieczko",slug:"elisa-konieczko"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"66635",title:"Food Additives in Food Products: A Case Study",doi:"10.5772/intechopen.85723",slug:"food-additives-in-food-products-a-case-study",body:'\n
\n
1. Introduction
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The history of food additives goes back to ancient times. As great civilisations developed, populations grew and so did the demand for food. In ancient Egypt, where the climate was not conducive to food storage, especially due to the heat, people started looking for ways to extend the usability life of products. Common practices included the addition of salt, drying in the sun, curing/corning, meat and fish smoking, pickling, and burning sulphur during vegetable preservation. The earliest preservatives included sulphur dioxide (E220), acetic acid (E260), and sodium nitrite (E250), while turmeric (E100) and carmine (E120) were among the first colours. Food preservation was also of immense importance during numerous armed conflicts. Both during the Napoleonic wars in Europe and during the American Civil War, seafarers and soldiers needed food. Limited access to fresh food at the front motivated the armed forces to transport their food with them. This is when cans were introduced for food preservation purposes. In the subsequent centuries, ammonium bicarbonate (E503ii), also known as salt of hartshorn, used as a rising agent for baked goods, and sodium hydroxide solution (E524), used in the production of salty sticks, rose to prominence [1, 2].
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The nineteenth century saw considerable advancements in the fields of chemistry, biology, and medicine. A name that needs to be mentioned here is Louis Pasteur, a French scientist, who studied microbiology, among other things. He was the first to prove that microorganisms were responsible for food spoilage. At the same time, new chemical compounds were discovered that were able to inhibit the growth of microbes. Some substances, such as picric acid, hydrofluoric acid, and their salts, often had disastrous consequences when added to food. Insufficient knowledge of toxicology resulted in consumer poisonings and even deaths [1, 3]. At that time, food preservation was the number one priority, which was achieved, for instance, by using salicylic acid, formic acid (E236), benzoic acid (E210), boric acid (E284), propionic acid (E280), sorbic acid (E200) and its potassium salt (E202), and esters of p-hydroxybenzoic acid. Later, food concerns also focused on improving the organoleptic properties of their products and started to enhance food with colours, flavours, and sweeteners, without first researching their effects on human health. For example, such practices involved the use of synthetic colours used in fabric dyeing. This desire to make money on beautiful-looking products led to adulterating food with copper and iron salts, which have a negative impact on the human body. It was as late as in 1907 that the United States studied 90 of the synthetic colours used at that time for food dyeing and found only 7 to be acceptable for further use. Detailed studies and strict regulations on the use of food additives were created almost a century later [1, 4].
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Globally, food safety is ensured by the World Health Organization (WHO) and the Food and Agriculture Organization (FAO). In 1962, these organisations established a special agenda—the Codex Alimentarius Commission. The Commission has prepared and updated the Codex Alimentarius, which is not a legal Act per se, but provides a reference for standards on raw materials and food products, acceptable contamination levels, hygienic processing, research methods, and food additives for almost all countries worldwide [5]. In the European Union, the body responsible for improving human health protection and food safety risk mitigation, as well as for taking care of purchaser interests, is the European Food Safety Authority (EFSA). It is a scientific agency established in 2002 pursuant to the Regulation of the European Parliament and of the Council of 28 January 2002. European legislation is based on the Codex Alimentarius but conducts its own complementary research. Therefore, the list of food additives permitted by the European Union is different from the American one [5].
\n
The primary legal Act governing food in Poland is the Food and Nutrition Safety Act of 25 August 2006 (as amended). It specifies the requirements applicable to food and nutrition, concerning product labelling, hygienic conditions throughout the production process, and product replacement rules, as well as requirements concerning the use of food additives. The key document that pertains specifically to food additives is the Regulation of the European Parliament and of the Council of 16 December 2008 on food additives. The EU-approved list of food additives is presented in the Commission Regulation (EU) of 11 November 2011 [4, 5].
\n
A food additive (additional substance) is any substance that is not a food in itself or an ingredient in food, but when added to a product for processing purposes, it becomes part of the food [5]. The following are not considered to be food additives: ingredients in food or chemicals to be used in other products, i.e. in particular sweeteners, such as monosaccharides, disaccharides, and oligosaccharides; substances with flavouring, dyeing, and sapid properties (such as dried fruit); glazing and coating substances, which are not intended to be consumed; and chewing gum bases, dextrin, modified starch, ammonium chloride, edible gelatine, milk protein and gluten, blood plasma, casein, and inulin. The law forbids the use of food additives in unprocessed food, honey, non-emulsified oils and fats of an animal or vegetable origin, butter, milk, fermented milk products (unflavoured, with living bacteria cultures), natural mineral and spring water, unflavoured leaf tea, coffee, sugar, dry pasta, and unflavoured buttermilk [5]. Any marketed additive must comply with the requirements of the European Food Safety Authority, i.e. it has to be technologically justified. It must not put consumers’ life or health at risk; its use should not mislead the purchaser; its acceptable daily intake (ADI), or quantum satis, the smallest amount which is needed to achieve a specific processing objective for the substance, must be calculable; and, last but not least, such an additive must not adulterate the product it is to be added to. Producers are also required to include information on any food additives on product labelling [6, 7].
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EU legislation has approved approximately 330 food additives for use. The primary objectives behind the use of additives are to extend the shelf life and freshness of products, prevent product quality impairment, make the product more attractive to customers, achieve the desired texture, ensure specific product functionality, facilitate production processes, reduce production costs, and enrich the nutritional value of products. In order to harmonise, effectively identify any additives, and ensure smooth exchange of goods, each food additive has its own, standardised, code. This code is consistent with the International Numbering System (INS) and comprises the letter “E” and three or four digits. There are several food additive classifications. One is based on the regulation and differentiates between colours (approx. 40), sweeteners (approx. 16), and other additives (approx. 277) [8, 9].
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Additional substances can also be categorised on the basis of code numbers:
Colours—E100–E199
Preservatives and acidity regulators—E200–E299
Antioxidants and synergists—E300–E399
Stabilising, thickening, emulsifying, coating, and bulking substances—E400–E499
Other substances—E500 and above
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Food additives can also be divided into four major groups, based on their processing purpose. These are substances that prevent food spoilage, those which improve sensory features, firming additives and excipients. The most numerous group among additives that slow down food spoilage are preservatives. These are either natural or synthetic chemical compounds added to food to restrict as much as possible the biological processes that take place in the product, e.g. the development of microflora and pathogenic microbes, and the effects of enzymes that affect food freshness and quality. In food products, preservatives change the permeability of cytoplasmic membranes or cell walls, damage the genetic system, and deactivate some enzymes. Food is preserved using antiseptics or antibiotics. The former are synthetically produced simple compounds that often have natural correlates, and they make up no more than 0.2% of the product. Antibiotics, or substances produced by microorganisms, are used in very small, yet effective, doses. The effectiveness of preservatives depends primarily on their effect on a specific type of microorganism, which is why it is vital to select the appropriate preservative based on the microbes found in the product (bacteria, mould, or yeast). Other factors that determine the effectiveness of preservatives include the pH value (a low pH is desirable), temperature, the addition of other substances, and the chemical composition of the product. Preservatives constitute an alternative to physical and biological product freshness stabilisation methods, such as drying, pickling, sterilising, freezing, cooling, and thickening. Consumer objections concerning the widespread use of chemical preservatives and their effects on human health have motivated producers to develop new food preservation procedures. These include radiation, packaging, and storing products in a modified atmosphere, using aseptic technology. Products that are most commonly preserved include ready-made dishes and sauces, meat and fish products, fizzy drinks, and ready-made deserts [9, 10].
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Other substances used as preservatives are acids and acidity regulators. These substances lower the pH level and slow down the growth of enzymes, which hampers the development of microbes. They are used mainly in the production of marinades. For a specific acid or acidity regulator to fulfil its role as a preservative, it needs to be added in highly concentrated form, but acetic acid, for instance, can irritate mucous membranes when its concentration exceeds 3%. Acids and acidity regulators are also used to enhance flavour (usually in fruit or vegetable products, or beverages, to bring out their sour taste) or to facilitate gelatinisation and frothing during food processing [11, 12].
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Not only microorganisms but also oxygen is responsible for food spoilage. Products such as oils, fats, and dry goods (flour, semolina) oxidise when they come into contact with atmospheric oxygen. Fat oxidisation (rancidification) occurs in oils, lard, flour, and milk powder. The browning of fruit, vegetables, and meat, on the other hand, is the result of non-fat substance oxidisation. These oxidisation processes can be slowed down or eliminated completely using antioxidants. There are natural and synthetic antioxidants and synergists. Synthetic antioxidants are primarily esters (BHA, BHT, propyl gallate). These are used to stabilise fats used to fry, e.g. crisps and chips. The most common natural antioxidants are tocopherols, i.e. vitamin E. Other antioxidants include phenolic compounds, such as flavonoids and phenolic acids. Synthetic antioxidants are more potent and resistant to processing. Synergists are substances that support and extend the functioning of antioxidants. They can form complexes with heavy metal ions, which retard the oxidisation process. The most frequently used synergists are EDTA, citric acid, and ascorbic acid. Antioxidants do not pose a risk to human health. In fact, they can be beneficial. Antioxidants prevent unfavourable interactions between free radicals and tissue and slow down ageing processes and the development of some diseases [12, 13].
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In order to extend the freshness of consumer goods, products are also packaged in a modified atmosphere. As part of this process, the oxygen content inside the packaging is reduced and replaced with other gases, such as nitrogen, argon, helium, and hydrogen. Furthermore, products in the form of aerosol sprays, such as whipped cream, have nitrous oxide, butane, or propane added to them. All these gases are also food additives with their own E codes [5, 11].
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The organoleptic properties of consumer goods are very important to consumers. Visual appeal is considered to be as important as taste or smell. This is where food colours come into play. These are used to add colour to transparent products (e.g. some beverages), intensify or bring out product colour (beverages, sweets), preserve or reproduce colours that have faded as a result of processing, ensure that all product batches have a specific colour, and provide the products that are diluted after purchase with strong colour. In order to add colour to a product, manufacturers use natural, nature-identical, synthetic, and inorganic colours. Natural colours are produced from edible plant parts (fruits, flowers, roots, leaves) and from animal raw materials, such as blood, chitinous exoskeletons of insects, and muscle tissue. New technologies have also made it possible to obtain colours from algae, fungi, and mould. Natural colouring substances include carotenoids that provide a spectrum of yellow and orange colours (carrot, citrus fruit skin), flavonoids that give products blue and navy-blue colours (grapes, currants, chokeberry, elder), betalains that give products a red colour (beetroot, capsicum), and chlorophyll that lends green colours (salad, parsley), as well as riboflavin (vitamin B2), curcumin, and caramel. Natural colours are desirable for consumers, as they do not show any negative effects on health. However, a significant drawback to using natural colours is that they are very sensitive to environmental factors, such as pH, ambient temperature, oxygen content, or sun exposure, which is why they are not durable when it comes to processing and storage. Moreover, the cost of obtaining such colouring substances is rather high. The list of additives contains 17 natural colours, and their market share in 2012 was approx. 31% and was subject to an upward trend [6, 8].
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Synthetic food colours are very competitive compared to natural ones. They offer a wide spectrum of colours, including those that are not available in nature, provide strong colouring, and are resistant to environmental factors, so they do not fade during processing. Furthermore, they are not expensive to produce, which contributes to low end-product prices. Synthetic colours can be divided into organic and inorganic, with organic constituting the considerable majority in terms of food colouring. In the past, chemical colours were made of coal, while now crude oil is used for this purpose. EU law approves 15 synthetic colours, including the so-called Southampton colours. A study conducted in 2007 in the United Kingdom (in Southampton, hence the name) showed the particularly negative effects of six colours on children’s health [10]. Specifically, tartrazine (E102), quinoline yellow (E104), sunset yellow (E110), azorubine (E122), cochineal red (E124), and Allura red AC (E129) were found to cause hyperactivity. As a result, since 2010, manufacturers which add at least one of their products have been required to provide label information about their negative effects on concentration and brain functioning in children. Acceptable daily doses of these colours have also been reassessed and updated. Moreover, research conducted on lab animals has shown that the long-term use of synthetic colours, and especially the three that account for 90% of the use of all synthetic colours (Allura red, tartrazine, and sunset yellow), can cause cancer, allergies, and chromosome mutations. Products that are most often synthetically coloured include candy, wine gums, ready-made desserts, and refreshing beverages [8, 10].
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During consumption, one can experience product taste, smell, and consistency. These three sensations are referred to as palatability and are caused by flavours. Taste is experienced by taste buds located in the tongue. Adult individuals have approximately 10,000 such receptors. There are four primary tastes, namely, salty, sweet, bitter, and sour. There is also an additional type, referred to as umami, which is Japanese for “savoury, meaty”. This taste experience is provided by monosodium glutamate. Smell is experienced through volatile compounds that go directly through the nasal or oral cavity and throat to smell receptors. Taste and smell provide a ready source of information on whether the product is fresh, whether it has specific characteristics, and whether it has been adulterated. Flavours are mixtures of many compounds, in which the specific characteristic smell is produced by a single compound or several indispensable compounds. These are added to enhance the taste or smell of the product or to give something the flavour or aroma that has been lost during product processing [6, 7, 11]. There are natural, nature-identical, and synthetic flavours. Natural flavours are obtained from parts of fruits and vegetables, spices, and their flavouring compounds, such as lactones (found in fruits and nuts), terpenes (in essential oils, found in almost every plant), and carbonyl compounds (fermented dairy products). Nature-identical flavours are compounds originally found in a given raw material that can be recreated in the lab. Synthetic flavours are compounds that have been chemically created and produced and do not have their equivalent in nature. Similarly to natural colours, natural flavours are easily degraded during processing, and their extraction is costly, which is why the food industry generally uses synthetic substances to provide products with specific taste and odour. Moreover, synthetic compounds are capable of giving products much stronger flavours than natural ones [6, 7, 13].
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A separate group that enhances the sensory properties of food are sweeteners. Formerly, in order to make products sweet, manufacturers used sucrose, commonly known just as sugar, obtained from sugar beet or sugarcane. Now large-scale methods are commonly used, such as chemical production and the extraction of intensively sweetening substances, known as sweeteners, from specific plants. What is characteristic about such substances is that they are much more potent as sweeteners compared to sucrose, and, at the same time, their calorific value is close to zero. Natural sweeteners include glucose-fructose syrup (or syrup based on one of those sugars), thaumatin, neohesperidin DC, stevia, and xylitol. Synthetic sweeteners include acesulfame K, aspartame (and the salts of these two compounds), sucralose, cyclamates, saccharin, and neotame. Sweeteners are used in the production of beverages, juices, dairy products, spirits, sweets, marmalade, and chewing gum [14, 15]. In contrast to sucrose, the majority of synthetic sweeteners do not increase blood sugar level and do not cause tooth decay. These substances are attractive for producers because the cost of their production is low, and even small amounts of such compounds are able to ensure the desired sweetness of the product, so these are economical to use. In addition, most sweetener additives remain functional during processing, although some compounds are not resistant to high temperatures. A study conducted in 2010 on lab animals raises some concerns when it comes to sweetener safety in relation to human health [20]. Its findings showed that regular consumption of sweeteners in large quantities caused obesity and neoplasms in animals. Sweetener additives in consumer goods have been considered safe for humans [10]. Each such additive has a specific ADI value and amount (in milligrammes) that can be added to 1 kg (or 1 dm3) of product [13, 14, 15].
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The additives that are vital in terms of processing are firming additives. They create or stabilise the desirable product structure and consistency. Firming agents include gelling, thickening, emulsifying, bulking, binding, and rising agents, humectants, and modified starches. The highest status among these substances is enjoyed by hydrocolloids. Hydrocolloids, known as gums, are polysaccharides of plant, animal, or microbiological origin. There are natural (guar gum, agar, curdlan), chemically and physically modified (modified starches), and synthetic gums. With their macromolecular structure, they are able to bind water, improve solution viscosity, and create gels and spongiform masses. Hydrocolloids are used as gelling (e.g. in the production of jelly, desserts, pudding, and fruit-flavoured starch jelly), thickening (ready-made sauces, vegetable products), water-binding (powdered products to be consumed with water, frozen food), and emulsifying agents (to create oil-in-water-type emulsions). They also act as emulsion stabilisers. Hydrocolloids are considered safe for human health, although some of them can cause allergies. Consumed in large quantities, they can have laxative effects [12].
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What is also important in creating product structure are emulsifiers and the emulsification method. Emulsifiers are compounds which facilitate emulsification. There are water-in-oil (margarine) and oil-in-water (mayonnaise) type of emulsions. Emulsifiers position themselves at the interface between two different phases to stabilise the emulsion. There are natural emulgents, with lecithin as the most common, and synthetic emulgents (glycerol and its esters) [1]. Product consistency and texture are also adjusted using modified starches. Such starches are usually obtained from potatoes or corn (also genetically modified one) with chemically altered composition. Similarly to hydrocolloids, such substances can bind water and produce gels and are also resistant to high temperatures [11, 12]. Modified starches are added to ready-made sauces and dishes (such as frozen pizza), frozen goods, bread, and desserts (also powdered) to thicken and maintain product consistency after thermal processing. In order to enhance starch properties, phosphates are often added during starch modification. The human body needs phosphorus, but its excess can negatively affect the bones, kidneys, and the circulatory system [7, 11, 12].
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Nowadays, consumer goods are widely available, and consumers are provided with a broad range of products to choose from. The continuously growing number of world population (approximately 7 billion in 2011) has made supply on the food market exceed demand. This situation is characteristic of countries with a high GDP. Food producers examine consumer behaviour patterns to see what encourages them to make a purchase, and also the purchase itself and its consequences, and then analyse these processes to launch a new product or a substitute for an already existing one. To sum up, the market has provided more food products than consumers are able to purchase, which results in unimaginable food wastage. Each year, approximately 100 million tonnes of food goes to waste in Europe. This quantity does not include agricultural and food waste or fish discards [13].
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2. Materials and methods
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The methodology of this study was based on the information contained on the labels. The chemical composition of the investigated food products was presented. Interview with the store’s seller concerned the popularity and frequency of sales listed in the product tables. It should be noted that the examined store is representative when it comes to this type of stores in the majority of small towns in south-eastern Poland.
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This study was based on data on the most frequently chosen consumer goods in a store in a small town in Poland. The town is located in a commune that has 5300 residents. Data were obtained by monitoring the sales over the course of 12 months. These products are presented in Tables 2, 3, 4, 5, 6 and classified into the following categories: (i) meat and fish; (ii) beverages; (iii) condiments; (iv) ready-made sauces, soups, and dishes; and (v) sweets and desserts. The main classification criterion was segregation into primary food groups. The chemical composition of each product, as listed on the packaging, was included in a table and then assessed against the presence of any food additives. Sixteen most common additives were selected in all the investigated products; only chemical compounds that were found in at least four food products were taken into consideration. The most common food additives were highlighted in Holt in the “product composition” column and presented in Table 1, together with their E codes. Then, based on the literature, the study described the most common additional substances.
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Name
\n
Symbol
\n
Number of products
\n
\n\n\n
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Citric acid
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E330
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15
\n
\n
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Monosodium glutamate
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E621
\n
10
\n
\n
\n
Guar gum
\n
E412
\n
8
\n
\n
\n
Sodium nitrite
\n
E250
\n
7
\n
\n
\n
Disodium 5′-ribonucleotides
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E635
\n
6
\n
\n
\n
Sodium erythorbate
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E316
\n
5
\n
\n
\n
Glucose-fructose syrup
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Not considered an additive
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5
\n
\n
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Soy lecithin
\n
Not considered an additive
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5
\n
\n
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Maltodextrin
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Not considered an additive
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5
\n
\n
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Triphosphates
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E451
\n
4
\n
\n
\n
Xanthan gum
\n
E415
\n
4
\n
\n
\n
Carrageenan
\n
E407
\n
4
\n
\n
\n
Tocopherols
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E306
\n
4
\n
\n
\n
Glucose syrup
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Not considered an additive
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4
\n
\n
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Sodium benzoate
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E211
\n
4
\n
\n
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Ammonia caramel
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E150c
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4
\n
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Table 1.
The most common food additives and ingredients.
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3. Results and discussion
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Table 1 shows 16 of the most popular substances found in food. The majority of these substances are food additives; four other substances are not considered in the European Union as food additives. The additives that are the most frequently found in the food products examined in this study are citric acid (E330), monosodium glutamate (E621), and guar gum (E412). In Ref. [16] it is reported that the most popular preservatives found in food are the mixture of sodium benzoate and potassium sorbate, or potassium sorbate (E202) and sodium benzoate (E211) used separately, and also ulphur dioxide (E220). Data presented in Table 1 shows that, compared to citric acid, another preservative, sodium benzoate, is used rarer. No potassium sorbate was found in any of the products examined in this study. In Ref. [13] it can be concluded that the most commonly used preservatives and antioxidants are sorbic acid and its salts (E200-203), benzoic acid and its salts (E210-213), sulfur dioxide (E220), sodium nitrite (E250), lactic acid (E270), citric acid (E330) and tocopherols (E306). The majority of the additives listed in Ref. [13] can be found in Table 1.
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Table 2 shows 10 meat and fish products and their composition, as specified on the label. Each of the investigated items contained at least 1 of the 16 most common food additives (Table 1). As much as 50% of meat and fish products contained four or more of such additives. The highest number of additives (seven) was found in “Z doliny Karol” mortadella. “Masarnia u Józefa” crispy ham and “Lipsko” Śląska sausage contained six different food additives. Seventy percent of the examined products had had sodium nitrite (E250) added. This means that this preservative is frequently added to meat products, as confirmed in Ref. [9]. Other widespread preservatives mentioned in Ref. [9] include lactic acid (E270), sodium benzoate (E211), sorbic acid (E200), and sulphur dioxide (E220). In Ref. [9] it also mentions other additives frequently added to meat and fish products; these include carrageenan, gum arabic, and xanthan gum. In this study, 50% of the examined items contain one or two gums, and carrageenan is present in only three in ten products. A study in Ref. [17] demonstrates that fish products are the second leading food (after edible fats) in terms of preservative content.
Food additives and ingredients in the studied meat and fish products.
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Table 3 shows ten non-alcoholic beverages, six of which contain at least one common food additive (Table 1). Foreign substances that are most frequently found in this food group are citric acid (E330), sodium benzoate (E211), and glucose-fructose syrup. A study in Refs. [18, 19] shows that the most popular sweeteners in non-alcoholic beverages are glucose, fructose, and glucose-fructose syrups. As shown on product label, 100% juice by brands such as “Hortex” and “Tymbark”, as well as “Cisowianka” and “Kubuś” mineral waters, is additive free. Pursuant to the Regulation of the European Parliament and of the Council (EC) of 16 December 2008, no food additives may be used in mineral and spring bottled water. The beverage to contain the largest number of additive substances was white orangeade by “Hellena”.
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\n\n
\n
Product
\n
Ingredients
\n
Product
\n
Ingredients
\n
\n\n\n
\n
Woda mineralna gazowana (carbonated mineral water) Cisownianka 1.5 L
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Natural mineral water, unsaturated with carbon dioxide, moderately mineralised
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Woda mineralna niegazowana (non-carbonated mineral water) Kubuś water 0.5 L
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Water, cane sugar, apple juice from concentrated apple juice, lemon juice from concentrated lemon juice, flavouring
Sok multiwitamina (multivitamin juice) 100% 1 L Tymbark
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Juices from concentrated apple juice 60% and orange juice 22%, carrot juice from concentrated juice 12%, purées from banana 3%, peach, guava, papaya, juices from concentrated pineapple juice 2%, mango juice 0.5%, passion fruit juice 0.1%, lychee juice 0.05%, cactus fig juice, kiwi fruit juice and lime juice, vitamins A, C, E, B6, and B12, thiamine, riboflavin, niacin, biotin, folic acid, pantothenic acid
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Tymbark 2 L jabłko-pomarańcza (apple-orange)
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Water, orange juice from concentrated juice 19%, glucose-fructose syrup, sugar, peach juice from concentrated juice 1%, lemon concentrate, flavourings, ascorbic acid, carotenes
Food ingredients in the studied non-alcoholic beverages.
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Table 4 shows 12 food items, such as ketchup, mustard, herbs and spices, and tomato concentrates, together with their composition. Only four products in this group contain a food additive, of which three are preserved using citric acid (E330). In this group of products, the products to contain the most common additive substances were the ketchup and the Kucharek seasoning by “Prymat”. Pursuant to the Regulation of the European Parliament and of the Council (EC) of 16 December 2008, tomato products (such as concentrates) must not contain food colours. They may, however, contain other additives. The ketchup has no colours, but contains other food additives. Studies in Ref. [17] demonstrate that mayonnaises and mustards are the fourth most often preserved product group, with ready-made concentrates ranking seventh. One of the two mustards examined in this paper contained a preservative, and two of the presented tomato concentrates had not had any food additives added to them.
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\n\n
\n
Product
\n
Ingredients
\n
Product
\n
Ingredients
\n
\n\n\n
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Koncentrat pomidorowy (tomato concentrate) Aro 190 g
Salt, died vegetables, monosodium glutamate, disodium 5′-ribonucleotides, sugar, starch, black pepper, riboflavin
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Table 4.
Food ingredients in the studied condiments.
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Table 5 shows 12 products categorised into ready-made dishes, soups and sauces, and their chemical composition. Each of these products contains at least one common additive. Citric acid (E330) was added to nearly 67% of the products in this category. Only five in twelve items (including four instant soups and stock cubes) contain the three most popular food additive substances (Table 1). A study in Ref. [13] shows that the most common additives in ready-made dishes are citric acid (E330), sunset yellow (E110), guar gum (E412), disodium guanylate (E627), disodium inosinate (E631), and monosodium glutamate (E621).
Food ingredients and additives in the studied ready-made dishes, soups, and sauces.
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Table 6 shows 10 food items classified as sweets and desserts. As many as nine products in this group contained at least one of the most common food additives (Table 1). Glucose-fructose or glucose syrups were found in six of the examined items. A study in Ref. [19] shows that sweets often include the so-called Southampton colours, such as quinoline yellow and tartrazine. However, the study reports that the amounts of these substances added to sweets are much lower than the maximum values allowed by the applicable law.
Food additives and ingredients in the studied sweets.
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Citric acid (E330) is a natural compound found in citrus fruits. It is also the by-product of digestive processes in the human body. However, on the industrial scale, the substance is produced using the Aspergillus niger mould. Citric acid is used in food as an acidity regulator, preservative, and flavour enhancer. Outside the food industry, the acid is added to cleaning agents and acts as a decalcifying agent. Citric acid in food is a safe additive and is added to food on the quantum satis basis; nevertheless its widespread use constitutes a risk. This substance is found in many food products, such as beverages, juices, lemonades, sweets, ice creams, canned goods, and even bread, so customers consume it in large quantities everyday [20]. When consumed frequently in excess, citric acid can lead to enamel degradation and teeth deterioration. This additive also supports the absorption of heavy metals, which, in turn, might lead to brain impairment. It can also affect the kidneys and liver [13, 15].
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Monosodium glutamate (E621) is the most widespread flavour enhancer. It is even considered to be one of the five basic tastes (umami). Glutamic acid and its (magnesium, potassium, and calcium) salts lend a meaty flavour to products. The substance was first extracted from algae by a Japanese scientist, but now it is generally produced by biotechnological means using microorganisms that can be genetically modified [6]. Another commonly used flavour enhancer is chemically produced disodium 5′-ribonucleotides (E635). These additives can be found in ready-made dishes, sauces, meat and fish products, instant soups, crisps, and cakes. These flavour enhancers are the not inert in relation to the neurological system [16]. This can affect brain cells and lead to headaches, heart palpitations, excessive sweating, listlessness, nausea, and skin lesions. Such anomalies, which could have been caused by the excessive consumption of products rich in glutamates, are referred to as the Chinese restaurant syndrome [20]. Flavour enhancers can also serve a positive function by increasing appetite in the sick or the elderly [20]. Other additional substances commonly found in foodstuffs are polysaccharides:
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Guar gum (E412) and xanthan gum (E415). These are referred to as hydrocolloids, i.e. substances that bind water, are easily soluble in both cold and warm water, and improve mixture viscosity. Guar gum is a polysaccharide obtained from guar, a leguminous plant grown in India and Pakistan [14]. Xanthan gum is a polysaccharide of microbiological origin. On the industrial scale, it is obtained as a result of Xanthomonas campestris bacteria fermenting the sugar contained in corn (often genetically modified). Both these additives are approved for use in all food products as thickening, firming, and stabilising agents, on the quantum satis basis. Guar gum and xanthan gum can be found mainly in bread, cakes, ready-made sauces and dishes, and powdered food, where they ensure the appropriate consistency. Moreover, they prevent the crystallisation of water in ice cream and frozen food and the separation of fluids in dairy products and juices. The human body is not capable of digesting, breaking down, or absorbing these gums. These substances swell in the intestines, which can cause flatulence and stomach ache. In addition, guar gum can cause allergies [13, 14, 15].
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A commonly found preservative is sodium nitrite (E250). It is a salty and white or yellowish crystalline powder, obtained by the chemical processing of nitric acid or some lyes and gases [9]. This additive is generally used in the meat industry to inhibit botulinum toxin and Staphylococcus aureus bacteria, slow down fat rancidification, maintain the pink red colour of meat, and provide meat with a specific flavour. It does not, however, prevent the growth of yeast or mould. Sodium nitrite is toxic, oxidising, and dangerous to the environment, so it must not be added to food in its pure form. This additive is used in very small doses (0.5–0.6%) in the form of a mixture with domestic salt [9] in amounts up to 150 mL per L or mg kg−1. When consumed in large quantities, nitrites can cause cyanosis, whose symptoms include blue coloration of the skin, lips, and mucous membranes. During digestion, nitrites are transformed into carcinogenic nitrosamines. Moreover, they are particularly dangerous for children, since they stop erythrocytes from binding oxygen, which can lead to death by suffocation [11].
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A common ingredient in food is maltodextrin, which in the European Union is not considered as a food additive, but as an ingredient. Therefore, within the community, maltodextrin has no E code, while in Sweden it is considered an additive and identified as E1400 [18]. Maltodextrin is a disaccharide obtained from corn starch, but it is not sweet in taste. Nevertheless, it provides greater sweetness than normal sugar or grape sugar (the glycaemic index of maltodextrin is 120, that of normal sugar is 70, and that of grape sugar is 100). It is used as a thickening agent, stabiliser, bulking agent, and even as a fat substitute in low-calorie products. It is added to products for athletes and children, to instant soups, sweets, and meat products [10]. Maltodextrin does not affect the natural product taste or flavour, while it provides human body with carbohydrates and energy. Due to the fact that glucose particles in maltodextrin are broken down only in the intestines, it can also support metabolism. A negative aspect of its use is tooth decay [10, 18].
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What frequently occurs in consumer goods is glucose-fructose syrup. Similarly to maltodextrin, it is not considered to be a food additive, but, due to its widespread application, it is important to mention it here. Glucose-fructose syrup, also known as high-fructose corn syrup (HFCS), replaces traditional sugar in many products, such as beverages, sweets, jams, fruit products, and liqueurs, and in the United States and Canada is the dominant sweetener [19]. Sucrose is a disaccharide composed of glucose and fructose, which are joined with alpha-1,4-glycosidic bond, and HFCS contains free fructose and free glucose in specific proportions. The name of this substance depends on the proportion of its ingredients. When the syrup contains more fructose, it is referred to as fructose-glucose syrup [12]. It is obtained mainly from corn starch as a result of acid or enzymatic hydrolysis. Glucose-fructose syrup is much sweeter and cheaper than traditional sugar, it does not crystallise, and it has a liquid form, which makes it functional during processing. Nevertheless, there are some disturbing aspects of using this substance. During the consumption of products with glucose-fructose syrup, the body receives unnatural amounts of fructose, which is broken down in the liver in a manner similar to alcohol. Therefore, its excessive amounts can cause fatty liver and overburden this organ. This has even been named “non-alcoholic fatty liver disease”. In addition, heavy consumption of monosaccharides has been found to contribute to obesity, which, in turn, can cause high blood pressure and diabetes. Fructose affects the lipid metabolism and disrupts the perception of hunger and satiety. Labels do not provide the exact HFCS content, but it is estimated that the consumption of a single product with this substance satisfies the acceptable daily monosaccharide intake [5, 6, 11, 13].
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Another frequently added substance is sodium erythorbate (E316). This synthetic compound is used as an antioxidant and stabiliser in meat and fish products and is useful for ham and sausage pickling [13]. It has similar properties to ascorbic acid, but it is not effective as vitamin C. Sodium erythorbate is considered to be noninvasive in the human body [12, 13].
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The most widespread natural emulsifier is soy lecithin. Etymologically, the word “lecithin” can be traced back to lekythos, Greek for egg yolk, but this compound is actually found in any plant or animal cell. Lecithin is produced from eggs, sunflower and rapeseed oils, and soybeans [11, 12, 13]. This additive is identified as E322 and is used for the production of mayonnaise, ice creams, margarine, ready-made desserts, sauces, and instant soups. Products with added lecithin dissolve in water more easily. EU law does not impose any limits on the use of E322. Only in products for children, lecithin content must not exceed 1 g per L.
\n
Triphosphates (E451), as well as diphosphates and polyphosphates, are used as preservatives, flavour enhancers, stabilisers, and rising and water-binding agents. Triphosphates are produced chemically and have a broad application. They are added to sauces, meats and meat products, desserts, bread, pâtés, fish products, ice creams, and non-alcoholic beverages [21]. The human body needs phosphorus in specific amounts, but the widespread use of phosphoric acids and phosphates in food makes people likely to consume this element in excess. When consumed regularly, increased doses of phosphates can lead to osteoporosis or contribute to kidney dysfunction and affect the circulatory system [13, 21]. A popular hydrocolloid found in food is carrageenan (E407). This substance is extracted from Eucheuma, a tribe of red algae. Carrageenan is highly soluble in water and is used as a bulking agent in dietary products, and it is also added to beverages, ice creams, sauces, marmalades, and powdered milk [6, 7]. Carrageenan can be used on the quantum satis basis. Usually, it is combined with other hydrocolloids. This additive is not digestible by the human body. There are certain objections concerning the consumption of carrageenan, e.g. it can cause intestinal cancer and stomach ulcers [11, 12, 13].
\n
Tocopherols (E306) are commonly known as vitamin E, insoluble in water and soluble in fats. It is used as a preservative, stabiliser, and potent antioxidant in such products as oils, margarines, desserts, meat products, and alcoholic beverages. Tocopherols are produced synthetically or obtained from plant oils, but natural vitamin E is twice as easily absorbed by the human body [21].
\n
Common preservatives include benzoic acid and its salts, of which the most frequently used is sodium benzoate (E211). Negligible amounts of these substances are naturally found in berries, mushrooms, and fermented milk-based drinks. On an industrial scale, it is produced synthetically from toluene obtained from crude oil [3, 12]. What is characteristic of sodium benzoate is that it slows down the growth of mould and yeast, but does not prevent the growth of bacteria, which is why it is often used with other preservatives, such as sulphur dioxide (E220). It is commonly used in products with acidic pH, such as marinades, fruit juices, and products with mayonnaise, such as vegetable salads. Sodium benzoate can cause allergies [6, 13]. Our own study (see “Results and discussion”) showed that ammonia caramel (E150c) and sulphite ammonia caramel (E150d) are fairly common colours. It adds brown to black colours to products. Under natural conditions, this substance is created when sugar is heated. As a food additive, it is produced chemically using ammonia, as well as phosphates, sulphates, and sulphites (sulphite ammonia caramel is produced) [19]. This substance is approved for use under EU law [5]; however, there are studies that have confirmed that it negatively affects human health. It has been proven that this colour can cause hyperactivity and liver, thyroid, and lung neoplasms and also impair immunity. Ammonia caramel is used to dye non-alcoholic beverages, such as cola and marmalades [10, 11].
\n
The external aspect that is most crucial for buyers when it comes to food selection is its freshness. Buyers assess the best before date against the possibility of consuming the food quickly or storing it for future use. Another determinant is the value of the item. Any consumer will pay attention to the price of the product they buy. Another factor is the product ingredients specified on the packaging. Buyers have been observed to have developed a habit of reading labels before buying anything. Some customers also pay attention to the country of origin or brand [22]. Men and women who are determined to stay fit will also consider nutritional value. The factors that are not considered that are relevant include net product weight, information about any genetically modified raw material content, and notices about any implemented quality management systems. Moreover, consumers are likely to be affected by marketing devices, such as advertisements or special offers, used by producers. A temporary reduction in price, or the opportunity to buy two items for the price of one, encourages customers to make a purchase [3, 4]. What is also vital is whether the food is functional. Many people live at a fast pace, work a lot, or get stuck in traffic jams, and the lack of free time pushes them to buy ready-made dishes to be heated up at home or food that can be prepared in an instant [4, 13, 22].
\n
Nowadays, food additives are very widespread in the everyday human diet, but not all of them are synthetic and invasive to human health. Products which must not contain foreign substances do not contain food additives. The explorations undertaken by this and other studies confirm the widespread use of the investigated additives, except for citric acid, which is less popular an additive than sodium benzoate and potassium sorbate. This study shows that when adopting a healthy lifestyle, consumers can choose from a range of food and pharmaceutical products that either contain a limited amount of unconventional substances or do not contain such substances at all.
\n
\n\n',keywords:"food additives, preservatives, sweeteners, colours",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/66635.pdf",chapterXML:"https://mts.intechopen.com/source/xml/66635.xml",downloadPdfUrl:"/chapter/pdf-download/66635",previewPdfUrl:"/chapter/pdf-preview/66635",totalDownloads:1006,totalViews:0,totalCrossrefCites:1,dateSubmitted:"September 4th 2018",dateReviewed:"March 8th 2019",datePrePublished:"April 9th 2019",datePublished:"October 9th 2019",dateFinished:null,readingETA:"0",abstract:"Socioeconomic progress, diseases, and the constantly changing pace of life and lifestyles of consumers worldwide require food to be improved and tailored to meet the needs of purchasers. The produced food is functional, convenient, and enriched. This is achieved, i.e. with food additives. Nowadays, food additives are very widespread in the human diet, but not all of them are synthetic and invasive on human health. All food additives, and their application and dosage, are subject to strict regulations. The purpose of this work was to investigate which food additives are the most common in our everyday diet and how they affect our health.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/66635",risUrl:"/chapter/ris/66635",signatures:"Aleksandra Badora, Karolina Bawolska, Jolanta Kozłowska-Strawska and Jolanta Domańska",book:{id:"7943",title:"Nutrition in Health and Disease",subtitle:"Our Challenges Now and Forthcoming Time",fullTitle:"Nutrition in Health and Disease - Our Challenges Now and Forthcoming Time",slug:"nutrition-in-health-and-disease-our-challenges-now-and-forthcoming-time",publishedDate:"October 9th 2019",bookSignature:"Gyula Mózsik and Mária Figler",coverURL:"https://cdn.intechopen.com/books/images_new/7943.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"182561",title:"Dr.",name:"Aleksadra",middleName:null,surname:"Badora",fullName:"Aleksadra Badora",slug:"aleksadra-badora",email:"aleksandra.badora@up.lublin.pl",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Materials and methods",level:"1"},{id:"sec_3",title:"3. Results and discussion",level:"1"}],chapterReferences:[{id:"B1",body:'Toussaint-Samat MA. History of Food. Oxford, United Kingdom: Wiley-Blackwell; 2009. ISBN: 978 1-405-18119-8\n'},{id:"B2",body:'Couture L. The history of canned food. Johnson and Wales University School of Arts and Science. Academic Symposium of Underground Scholarship; 2010\n'},{id:"B3",body:'Gram L, Ravn L, Rasch M, Bruhn JB, Christensen AB, Givskov M. Food spoilage—Interactions between food spoilage bacteria. International Journal of Food Microbiology. 2002;78(1-2):79-97. PMID: 12222639\n'},{id:"B4",body:'Publikacja Komisji Europejskiej. Zrozumieć politykę UE—Bezpieczeństwo Żywności (Understanding EU policy—Food Safety). Urząd Publikacji Unii Europejskiej; 2014 (in Polish)\n'},{id:"B5",body:'Rozporządzenie Parlamentu Europejskiego i Rady (WE) z dnia 16 grudnia 2008 r. w sprawie dodatków do żywności [The Regulation of the European Parliament and of the Council (EC) of 16 December 2008 on food additives]. Dz. Urz. L 354 (in Polish)\n'},{id:"B6",body:'Sharma S. Food preservatives and their harmful effects. International Journal of Scientific and Research Publications. 2015;4(5):1-2. ISSN 2250-3153\n'},{id:"B7",body:'Abdulmumeen HA. Food: Its preservatives, additives and applications. International Journal of Chemical and Biochemical Sciences. 2012;1:36-45. DOI: 10.13140/2.1.1623.5208\n'},{id:"B8",body:'Kobylewski S, Jacobson MF. Food Dyes, A Rainbow of Risks. Washington: Centre for Science in the Public Interest; 2010. Available from: https://cspinet.org/resource/food-dyes-rainbow-risks\n\n'},{id:"B9",body:'Uchman W. Substancje dodatkowe w przetwórstwie mięsa [Additives in Meat Processing]. Poznań: Wydawnictwo Uniwersytetu Przyrodniczego w Poznaniu; 2008 (in Polish)\n'},{id:"B10",body:'McCam D, Barrett A, Cooper A, Crumpler D, Dalen L, Grinshaw K, et al. Food additives and hyperactive behavior in 3-years-old and 8/9-years-old children in the community, a randomized, double-blind, placebo-controlled trial. The Lancet. 2007;370:1560-1567. DOI: 10.1016/S0140-6736(07)61306-3\n'},{id:"B11",body:'Belitz H. Food Chemistry. Berlin: Springer Berlin Heidelbeg; 2009. DOI: 10.1007/978-3-540-69934-7\n'},{id:"B12",body:'Wüstenberg T. General overview of food hydrocolloids in cellulose and cellulose derivatives in the food industry. Fundamentals and Applications. 2014;16:986-994. DOI: 10.1002/9783527682935.ch01\n'},{id:"B13",body:'Report of European Food Safety Authority. Scientific opinion on the safety and efficacy of citric acid when used as a technological additive (acidity regulator). EFSA Journal. 2015;13(2):4010. Available from: www.efsa.europa.eu/efsajourna\n\n'},{id:"B14",body:'Tripathy S, Das MK. Guar gum: Present status and applications. Journal of Pharmaceutical and Scientific Innovation. 2013;7(2):24-28. DOI: 10.7897/2277-4572.02447\n'},{id:"B15",body:'Sengar GI, Sharma HK. Food caramels: A review. Journal on Food Science and Technology. 2014;51(9):1686-1696. DOI: 10.1007/s13197-012-0633-z\n'},{id:"B16",body:'Husarova V, Ostatnikowa D. Monosodium glutamate toxic effects and their implications for human intake. JMED Research. 2013:2013:1-12. DOI: 10.5171/2013.608765\n'},{id:"B17",body:'Ratusz K, Maszewska M. Ocena występowania konserwantów w żywności na rynku warszawskim [The Assessment of Preservative Occurrence in Food in Warsaw]. Bromatologia i Chemia Toksykologiczna. 2013;3(45):917-922 (in Polish). Available from: https://docplayer.pl/13226410-Ocena-wystepowania-konserwantow-w-zywnosci-na-rynku-warszawskim.html\n\n'},{id:"B18",body:'Chronakis J. On the molecular characteristics, compositional properties and structural—Functional mechanism of maltodextrins. Critical Review in Food Science and Nutrition. 2010;38(7):599-637. Available from: http://www.tandfonline.com/page/terms-and-conditions\n\n'},{id:"B19",body:'Jacobson MF. Carcinogenicity and regulation of caramel colorings. International Journal of Occupational and Environmental Health. 2011;18(3):254-259. DOI: 10.1179/1077352512Z.00000000034\n'},{id:"B20",body:'Gahalawat S, Singh M, Farswan A. Chinese restaurant syndrome by MSG: A Myth or Reality. Guru Dron. Journal of Pharmacy Research. 2014;2(2):38-41. Available from: http://www.sbspgi.edu.in/downloads/SSR_NAAC.pdf\n\n'},{id:"B21",body:'Zielińska A, Nowak I. Tokoferole i tokotrienole jako witamina E [Tocopherols and tocotrienols as vitamin E]. Chemik. 2014;7(68):585-591 (in Polish)\n'},{id:"B22",body:'Rudawska E, Perenc J. Tendencje zachowań konsumenckich na regionalnym rynku [Consumer behaviour trends on the regional market]. Szczecin: Wydawnictwo Naukowe Uniwersytetu Szczecińskiego; 2010 (in Polish). ISSN 1640-6818\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Aleksandra Badora",address:"aleksandra.badora@up.lublin.pl",affiliation:'
Department of Agricultural and Environmental Chemistry, The University of Life Sciences in Lublin, Lublin, Poland
Department of Agricultural and Environmental Chemistry, The University of Life Sciences in Lublin, Lublin, Poland
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