Currently, due to the large number of reports regarding the harmfulness of food additives, more and more consumers follow the so-called “clean label” trend, i.e., prefer and choose the least-processed food products. One of the compounds known as a preservative with a high safety profile is sodium benzoate. While some studies show that it can be used to treat conditions such as depression, pain, schizophrenia, autism spectrum disorders, and neurodegenerative diseases, others report its harmfulness. For example, it was found to cause mutagenic effects, generate oxidative stress, disrupt hormones, and reduce fertility. Due to such disparate results, the purpose of this study is to comprehensively discuss the safety profile of sodium benzoate and its potential use in neurodegenerative diseases, especially in autism spectrum disorder (ASD), schizophrenia, major depressive disorder (MDD), and pain relief.
Due to its properties, sodium benzoate is used to preserve food products with an acidic pH, such as fruit pulp and purees, jams, pickles, pickled herring and mackerel, margarine, olives, beer, fruit yogurts, canned vegetables, and salads [ 11 ]. Most often, sodium benzoate is added to carbonated drinks, sauces, mayonnaises, margarines, tomato paste, and fruit preserves. In turn, in its natural form, it is present in, among other things, cinnamon, mushrooms, cranberries, blueberries, and cloves. Therefore, sodium benzoate is classified as a compound with a broad safety profile. It is also approved for therapeutic use in the form of two drugs: Ammonul/Ucephan and Buphenyl [ 12 , 13 ]. The indications for their use are urea cycle disorders, as well as hyperammonemia. Moreover, some studies report that not only is sodium benzoate an excellent preservative, but it may also have potential therapeutic uses in the treatment of diseases such as major depressive disorder (MDD), schizophrenia, autism spectrum disorder (ASD), and neurodegenerative diseases. Officially, sodium benzoate is regarded as not harmful—only when consumed in large amounts can it cause allergic reactions or contribute to the exacerbation of disease symptoms in aspirin-induced asthma (with hypersensitivity to aspirin and other non-steroidal anti-inflammatory drugs) [ 14 , 15 , 16 ]. However, in recent years, some reports have provided for its adverse health effects. Interestingly, various and often contradictory results of scientific research prove that sodium benzoate has unfavorable or, on the contrary, beneficial effects on the body (especially in the treatment of certain diseases) by engaging in the same mechanisms of action. Due to the controversial and often contradictory results of reports and studies, the aim of this study is to assess on the one hand the adverse effects of sodium benzoate and on the other its potential use in the selected diseases related to the nervous system.
Sodium benzoate does not accumulate in the body. Benzoate is conjugated with glycine to form hippurate in the liver and kidney in a reaction occurring in the mitochondrial matrix [ 8 ]. Upon entering the matrix, the compound is converted to benzoyl-coenzyme A (CoA) (ligase) and then to hippurate (glycine N-acyltransferase), which leaves the mitochondrion. It is excreted primarily through the urinary system. The administration of sodium benzoate causes a strong but transient increase in anthranilic acid (involved in tryptophan metabolism) and acetylglycine. The benzoate is one of the cinnamon metabolites [ 9 , 10 ]. Cinnamon contains cinnamaldehyde, which is converts to cinnamic acid in the liver and is then β-oxidized to benzoate (sodium salt or benzoyl-CoA). It is easily absorbed from the gastrointestinal tract and metabolized in the liver into hypuronic acid. In this form, it is excreted from the body with urine usually within 6 h of ingestion.
Sodium benzoate (according to the European nomenclature E211) is a salt of benzoic acid and is well soluble in water, tasteless, and odorless, and due to its antifungal and antibacterial properties, it is a preservative added to food in strictly defined doses. It inhibits the growth of bacteria, yeast, and mold [ 6 ]. Sodium benzoate was approved as the first of all food preservatives by the Food and Drug Administration (FDA). The permissible limit of its consumption is 0–5 mg/kg of body weight. It also has a GRAS (generally regarded as safe) status according to the FDA [ 7 ]. Sodium benzoate is considered safe for human health if it is consumed in amounts of less than 5 mg/kg of body weight per day. At this level, the Acceptable Daily Intake (ADI) was established. It determines the dose of a given substance that can be consumed by a person daily throughout his or her life without suffering any health damage.
Due to the advancing chemicalization of food in recent years, an increasing number of consumers have declared their interest in such food features as sensation, health, and, above all, safety [ 1 , 2 , 3 , 4 , 5 ]. For fear of the adverse effects of chemicals added to food in order to improve its taste and appearance or extend its shelf life, the choice of the least-processed products that do not contain additives, including preservatives, has become more and more popular, thus creating the trend of the so-called “clean label”.
It is believed that benzoate can be transformed by decarboxylation into toxic benzene, especially in combination with vitamin C, and then become a compound of high toxicity, mutagenicity, and teratogenicity [17]. There are also reports that sodium benzoate has a weak genotoxic effect. Moreover, it was shown to increase the DNA damage in human lymphocytes in vitro. The compound did not affect the rate of replication, but it did reduce the mitotic rate [18]. Mutagenic and genotoxic effects were also demonstrated in another study on human lymphocytes [19]. This compound caused micronucleus formation and chromosome breakage. In addition, the research shows that sodium benzoate generates oxidative stress and has an adverse effect on the immune system, liver, kidneys, and fertility.
Oxidative stress, but also the inflammatory process, play an important role in the pathomechanisms of many diseases. Oxidative stress is associated with an imbalance between the production of reactive oxygen species (ROS) and the amount of antioxidants or radical scavengers [20]. The excess of oxygen free radicals leads to the activation of transcription factors such as NF-κB, AP-1, and HIF-1α, as well as pro-inflammatory genes, leading in turn to the induction of proteins, cell adhesion molecules (CAM), monocyte chemoattractant protein (MCP-1), tumor necrosis (TNF-α), interleukin (IL) -1, and transforming growth factor (TGF-β). ROS may also affect tyrosine kinases, including Src, Ras, phosphoinoside 3-kinase (PI3K), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK) or p38MAPK, c-Jun-N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK) by inducing inflammatory processes and aging mechanisms. On the other hand, the ongoing inflammatory process leads to an increase in oxidative stress, which in turn creates a vicious circle [21]. Moreover, according to the free radical theory of aging, the accumulation of oxidative damage leads to the loss of cell functionality, which in turn leads to cell death [22]. It has therefore been suggested that oxidative stress and related inflammatory processes are related to age-related diseases. Increased levels of oxidative stress and inflammatory processes are observed, inter alia, in neurodegenerative diseases, cancer, diseases of the bile ducts and kidneys, diabetes, and cardiovascular diseases [23]. The effect of sodium benzoate (6.25, 12.5, 25, 50, and 100 μg/mL) on the increasing oxidative stress was observed in erythrocytes in an in vitro study [24]. After the treatment of cells with benzoate, there was observed increased lipid peroxidation, as well as decreased levels of antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione S-transferase. In another study, its effect on the induction of apoptosis was observed [25]. In addition, inhibition of antioxidant enzymes, decreased levels of glutathione (GSH), increased levels of nitric oxide (NO), and inflammation (increased in IL-6 and TNF α) were noted. The effects of sodium benzoate on oxidative stress have been also examined on male rats at different doses and for different periods of time [26]. In some of the study groups, decreased levels of GSH and malondialdehyde (MDA) were observed. Sodium benzoate also affected sodium and potassium levels (elevation). The effect of benzoate on oxidative stress was associated with an oxidative damage increase. This effect was confirmed in another study [27]. Sodium benzoate was administered to rats for 30 days at different doses (70, 200, 400, and 700 mg/kg b.w.) [28]. In this study, the dose of 70 mg/kg was found to be safe; however, at higher doses, the compound decreased the antioxidant enzymes activity.
The effect of benzoate on B and T lymphocyte reactivity was also investigated [29]. The highest non-cytotoxic dose of the compound (1000 mg/mL), determined by the MTT assay was chosen for the study. This dose decreased the functional activity of both classes of lymphophytes. Additionally, sodium benzoate affected the cell cycle by stopping the cells in the G1 phase. It also inhibited T lymphocyte proliferation against allogeneic MHC antigens and affected cytokine levels. There was a decrease in CD8 expression for T lymphocytes and CD19 for B lymphocytes and in the expression of activation markers such as CD95 (both classes of lymphocytes), CD28 (T lymphocytes), and CD40 (B lymphocytes). In vivo studies showed that administrating sodium benzoate (200, 400, and 700 mg /kg b.w) to rats for 30 days increased the level of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) and decreased the body weight of the animals [28].
A teratogenic study on sodium benzoate was reported in a zebrafish model [30]. At low doses (1–1000 ppm), the embryos exhibited a 100% survival rate, but higher doses caused deformation of the larvae. Another study based on the same model also showed that embryo survival depended on the time and dose [31]. The larvae were also characterized by reduced locomotor activity and decreased expression of tyrosine hydroxylase and dopamine transporter. In another study, it was reported that the effect of benzoate may be cumulative when it affects hormones [26]. It is possible that such an effect is also noted for other parameters. Moreover, some experiments were conducted on pregnant female rats administered with sodium benzoate (0.5, 1, and 1.5 mg/mL) [32]. This compound had little effect on maternal weight gain, but no toxic effects were observed. Perinatal mortality was significantly increased in the 1% and 1.5% benzoate dose groups. However, no fetal malformations or weight loss were observed. Benzoate also showed genotoxic effects on liver tissue in both fetuses and mothers. In contrast, in another study, sodium benzoate (doses 9.3 and 18.6 mmol/kg b.w.) decreased the fetal weight of rats and increased their mortality [33]. In addition, one more study found fetal deformities after prior treatment of pregnant females with benzoate (280 and 560 mg/kg b.w.) [34]. Among them, the following were observed: skin hemorrhages, craniofacial deformities, limb defects, spine defects, and neural tube defects. Developmental defects in mouse fetuses were also reported in a study where potassium benzoate was administered (280 and 560 mg/kg b.w.) [35]. Eye development defects, such as deformed lenses and also retinal folds with undeveloped layers accompanying hemorrhages, were observed in these fetuses. Another study also confirms its harmful effects on the fetus (280 and 560 mg/kk b.w.) [36]. Contrasting results regarding the teratogenicity of benzoate were observed in chickens (5–200 mg/kg b.w.) [37]. This compound did not adversely affect neural tube development in these embryos. However, its use should be limited, especially in pregnant women, due to its potential teratogenic properties.
It should be noted that benzoate was shown to affect the sperm motility (1 mg/kg b.w./day) [25]. It caused changes in the reproductive organs and affected the levels of sex hormones. Moreover, in another study, sodium benzoate affected the male reproductive system. The compound caused a 50% reduction in sperm count compared to the control group, as well as increased oxidative stress [38]. Another study also reported testicular dysfunction in rats after the administration of sodium benzoate at 100 mg/kg of body weight for 28 days [39]. This was associated with impaired semen quality and endocrine function of the testes and changes in their structure. In another in vivo study, the compound (0.01 mg/kb b.w.) also affected sex hormone levels (follicle-stimulating hormone (FSH), luteinizing hormone (LH), and free testosterone) [40]. A similar observation was related to the decrease in FSH, LH, and testosterone levels (sodium benzoate: 280 mg/kg/day) [41]. Additionally, a decrease in thyroxine and triiodothyronine and an increase in thyrotropin were observed. In contrast, another study reported a decrease in both thyroxine and thyrotropin (the dose of sodium benzoate was 50–200 mg/kg/day) [42].
The sodium benzoate in animals affected the lipid profile and liver and kidney parameters. Moreover, there were observed histopathological and dose-dependent changes in the biochemical markers of liver damage (150–700 mg /kg b.w) [28,43]. It affected the histology of the kidney and liver. In addition, it was found that sodium benzoate may rather affect the kidneys than the liver [44]. This compound (100 mg/kg bw) was added to drinking water for 15 weeks. Similar to the previous study, the rats showed histological changes, including necrosis and atrophy of glomeruli and tubules, as well as increased urea and creatinine and decreased antioxidant defense. Another in vivo study confirmed its negative effects on the liver, as evidenced by an increase in the serum liver enzymes (alkaline phosphatase, aspartate aminotransferase (AST)) (the doses of sodium benzoate were 30, 60, 120 mg/kg b.w./day) [45]. In a rat model of schizophrenia, benozesan also affected liver parameters, i.e., alanine transaminase and AST increased and total protein and albumin decreased [40]. Furthermore, the toxic effects of benzoate (sodium benzoate administered 2.40% (for rats) and 3.00% (for mice) of sodium benzoate) on the liver were observed in F344 rats and B6C3F1 mice [46]. In the test animals, changes in the liver parameters, i.e., albumin, total protein, γ-glutamyltranspeptidase, and elevated serum phospholipids and cholesterol were observed. Sodium benzoate also caused an increase in the absolute liver weight in both animal species and in the absolute kidney weight of the rats. As in the previous studies, histological changes were observed. Negative effects on the liver and kidney were also confirmed in other experiments [47,48,49].
Attention-deficit hyperactivity disorder (ADHD) is mainly associated with symptoms of hyperactivity, inattention, and impulsivity [50]. Beverages containing benzoate preservatives in their composition were given (45 mg/day) to 3-year-old children, who then experienced an increase in hyperactivity [51]. These behaviors were reduced after the withdrawal. Another study showed a similar effect of sodium benzoate in 8-, 9-, and 3-year-old children [52]. Furthermore, a survey was conducted among college students that examined the association between the consumption of sodium benzoate-rich beverages and symptoms associated with ADHD [53]. Thus, it was shown that the consumption of such beverages was associated with a higher prevalence of symptoms of ADHD. However, it should be noted that due to the nature of this study (i.e., a survey), the feelings of the respondents were subjective.
The association of sodium benzoate with ADHD symptoms may be supported by the reports regarding its effects on the HPA axis [26]. In some subtypes of disease, there is hyperactivity of this axis [54,55]. In addition, it has been mentioned previously that benzoate consumption may be associated with increased allergy tendencies [56]. This is another feature that links sodium benzoate to ADHD. Allergy prevalence is shown to be associated with the occurrence of this [57,58]. In some studies, sodium benzoate was adversely affected by oxidative stress and inflammation, as described above. It is therefore highly probable that the consumption of benzoate-rich beverages is associated with the occurrence of ADHD. In such patients, antioxidant defense is impaired, and inflammatory parameters are increased [59,60]. They also develop a decrease in cholesterol in the LDL fraction [61]. As mentioned above, sodium benzoate lowers the cholesterol [62], and such a property might also exacerbate the ADHD symptoms. Furthermore, it was shown that the cerebellar dysfunction may play an important role in the pathogenesis of ADHD [63]. It is noteworthy that sodium benzoate decreased the volume of the hemispheres, cortex, and intracerebral nuclei and the number of cells in the cortex in rats [64]. In ADHD patients, sodium benzoate may have some harmful effects. Consumption of benzoate-rich products should also be avoided among these patients.
The effect of benzoate (oral provocation with 20 mg of sodium benzoate) on gastric mucosa was studied in a clinical trial [65]. It was shown that it increased the release of allergic mediators, i.e., histamine and prostaglandins, from the mucosa compared to the control group. The same study suggested that benzoate-related allergic reactions may be mediated by prostacyclins and histamine.
Although there are no studies that clearly confirm the harmfulness of these additives, it has been proven that when used as a preservative, sodium benzoate can react with vitamin C and thus form carcinogenic benzene [17]. In practice, this combination is often used in colorful, sweetened drinks. In many studies, elevated levels of benzene were reported in carbonated beverages, fruit juices, and other products where benzoate was present in combination with vitamin C [66,67,68,69]. It has been shown that the hydroxyl radical, formed by the metal-catalyzed reduction in O2 and H2O2 by ascorbic acid, can attack benzoic acid to form benzene [70]. However, it is worth noting that heat and light can increase the rate of benzene formation [71]. In one in vivo study, ascorobic acid exacerbated the deleterious effects of sodium benzoate on fertility [39]. Among other things, it potentiated damage to testicular tissue structure and deterioration of semen quality induced by benzoate.
Wistar (healthy) rats received sodium benzoate in different concentrations in water (from 0.5–2%) [72]. This compound was shown to increase anxiety-like, depressive, and antisocial behaviors. Similar results were observed in another study where rats were given benzoate at a dose of 200 mg/kg/day [73]. Animals treated with these compounds experienced an increase in anxiety-like behaviors and impaired motor skills. The researchers suggest that this may be related to decreased levels of glycine in the body (it is consumed as a result of benzoate detoxification) and disruption of processes affected by this amino acid or disruption of zinc levels.
In another study performed on rats treated with sodium benzoate, an increase in body weight and food intake and a decrease in memory scores and anxiogenic effects were reported [74]. In addition, an increase in brain MDA, acetylcholinesterase (AChE), and caspase 3 and a decrease in TNF-α and IL-10 were observed. There was also an increase in SOD levels at 125 mg/kg and 250 mg/kg and a decrease in SOD at 500 mg/kg. Thus, it has been shown that benzoate enhances inflammatory response and has proapoptotic effects.
Sodium benzoate was also tested in a zebrafish (larva) model [75]. The compound-induced developmental defects in them and also contributed to increased oxidative stress and the development of anxiety-like behaviors. The developmental defects that were most commonly observed were yolk sac edema, pericardial edema, and tail-bending. In addition, it should be noted that larval mortality was observed even at lower than acceptable concentrations (<1000 ppm).
In another study, sodium benzoate (0.56, 1.125, and 2.25 mg/mL) was administered to healthy mice in different concentrations for 4 weeks [76]. It was shown that in healthy animals, benzoate induced impaired memory and motor coordination compared to the control group. Benzoate decreased GSH levels and increased MDA levels in the brain. The compound did not affect acetylcholinesterase (AChE) levels.
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