Safety assessments for stevia
Non-nutritive sweeteners (NNS) have been suggested for use in connection with improving oral health, diabetes care, general reductions in caloric intake, and as anti-hypertensive agents etc.
Over the years, many NNS (e.g. cyclamate, aspartame) have also been associated with public concern over safety. Sugar substitutes, low calorie sweeteners or NNS are defined as chemical additives that give a sweet taste to foods without contributing significant calories or promoting tooth decay. The first NNS were introduced in late nineteenth century (saccharine). Most NNS exhibit 100-200 times the sweetening action shown by sucrose.
Seven NNS are now approved for use in the US and many other jurisdictions1. Within the EU, you will find 15 NNS designated as the “900 series”, i.e. food additives with E-numbers between 950 and 967. The overall aim of this assignment is to apply the principles of toxicology to risks and safety issues related to sweeteners. For this case study we use the sweetener, stevia.
Critically evaluate the range of new evidence provided by petitioners in or after 2008 to support safety claims for the non-nutritive sweetener stevia. In your answer consider the following points:
- History of use
- Technical data and product specifications )
- Biological data related to ADME
- Toxicological data related setting ADI
- Pre 2008 objections to safety petitions
Considering the emerging trends of obesity and metabolic diseases and their evidenced associations with sugar consumption, have resulted in the manufacturing of a variety of non-nutritive sweeteners, of which, stevia has been advocated to be beneficial. Stevia is a natural sugar substitute sourced from the leaves of Stevia rebaudiana, with active sweetening compounds of rebaudioside and stevioside, 150 times strong than traditional sugar (EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2010). The following paragraphs of this report will shed light on the history of stevia usage, the technical information and specifications underlying products, its biological and toxicological data and objections pertaining to its safety petitions.
Discussion: History of Use
The usage of stevia as a traditional sweetener has been associated with a number of indigenous communities in Brazil and Paraguay for the sweetening of local concoctions and beverages (Chesterton and Yang 2016). The plant’s characteristic as a sweetener first found discovery by Moises Santiago, a botanist from Switzerland. From 1931 onwards, after isolation of its sweetening glycosides by chemists in France, stevia began to gain popularity as a potential natural sugar substitute (Sharma et al. 2016). The 1990s witnessed stevia being banned and not receiving adequate approval for commercial usage by the United States Food and Drug Administration (USDA) and European Food Safety Authority (EFSA). Upon receiving a petition from the Whole Earth Sweetener Company, the FDA released a notice of ‘no objection’ on Truvia – a sweetener product based on rebaudioside. However, due to incomplete data on toxicological evidence, stevia was unsuccessful in being recognized as ‘Generally Recognized as Safe” (GRAS). At present from 2017, stevia is permitted to be used as an ingredient in food items which are manufactured and retailed in the United States (Parris, Shock and Qian 2016).
Technical Data and Product Specifications
The technical data provided by the three petitioners in the GRAS claim of stevia as mentioned in the scientific opinion on safety produced by the EFSA, outline that products containing stevia must comply to recommendations outlined by the Joint FAO/WHO (World Health Organization) Expert Committee on Food Additives (JECFA) (EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) 2010). As per the JECFA guidelines, the steviol glycosides used for sweetening must possess a level of purity which must be at least 95% of the total amount of the seven glycosides stevioside, dulcoside, rebaudioside A, rebaudioside B, rebaudioside C, steviolbioside and rubusoside (Elnaga et al. 2016). Such standards of purity and safety assays continue to be adhered to and claimed by petitioners till date, as noted in the GRAS petition by ‘Cargill’. Considering this specification, as noted by the petition of 2008, food manufacturers are required to specify the technical data of their products, observed to be composed of rebaudioside A and stevioside, small amounts of the above mentioned glycosides all amounting to 95% (Food and Drug Administration 2018). However, considering this recommendation, it can be observed that recent petitions seek to outline details of a highly purified product as observed from the >95% purity assay in petition by ‘Tate & Lyle’ in 2017 (Food and Drug Administration 2017).
Significant differences in biological data of stevia glycosides as per absorption, distribution, metabolism and excretion were not prevalent in any of the petitions during 2008 or after. Glycosides from stevia do not undergo complete absorption from the digestive tract. Upon consumption, stevia surpasses the upper gastrointestinal tract organs which includes the stomach and small intestines, completely unabsorbed (EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) 2010). Colonic digestion occurs after steviol glycosides reach the colon where colonic bacteria perform micronbial fermentation resulting in the removal of all glycoside units except for steviol. The produced steviol theundergoes intestinal absorption, hepatic modification and excretion in the form of steviol glucuronide. It for this absence of absorption which denotes stevia is non-calorific properties allowing it to lend desirable amounts of sweetness without the fear of excessive calorie consumption as compared to sugar. However, there continues to be a lack of evidence pertaining to the above information using human trials with a majority observed in animal based studies (Mukhtar et al. 2016).
ADME Table for Stevia (As designed by the Author)
Stevia remains unabsorbed till Colon.
Undergoes no distribution till Colon
Undergoes Colonic Bacteria Fermentation –Steviol produced
Steviol absorbed, modified in the liver to be excreted as steviol glucuronide
Present petition as well as the notable 2008 petition concerning GRAS approval of stevia, highlight a lack of sufficient studies concerning the toxicity of stevia compounds with the utilization of human subjects or trials. Existing literature outline extensive data on animal trials concerning the toxicological levels of stevia. The compound stevioside was reported to possess a high value of LD50, that is 0.5 g/kg body weight in rats, mice and dogs. Additional studies have indicated that stevioside, formulated at purity levels of 93 to 95% have been found to be orally safe in mice, hamsters and rats when fed at extremely high quantities of 15 gm/kg body weight (Abbas Momtazi-Borojeni et al. 2017). Previous animal based studies prior to the 2008 GRAS petitions, have highlighted that the No Adverse Effect Level (NOAEL) for stevioside is 970mg/kg body weight per day after which JECFA postulated an Acceptable Daily Intake (ADI) of 2 mg/kg body weight for steviol glycosides. Succeeding the same, further standards on ADI has been formulated by additional organizations, that is by the Food Standards Australia New Zealand (FSANZ), resulting in an ADI value of 4 mg/ per kg body weight taking insights again from the animal trials conducted previously. Hence, GRAS petition notices as well as established intake standards continue to consider the ADIs postulated by the JECFA and FSANZ resulting in a final ADI for steviol to be 4 to 10 mg and for rebaudioside A to be 12 to 30 mg/ per kg body weight (Food and Drug Administration 2019). Based on these values, the consumption of stevia can be considered as safe since it is highly unlikely that that an average adult will be able to exceed the above mentioned ADI standards. However, the safety surrounding stevia continue to be questioned due to the lack of sufficient quality, validity or adequacy on research utilizing human subjects pertaining to its toxicological values, as discussed in the succeeding sections (Zhang et al. 2017).
Objections to Safety Specifications
One of the primary objections to the use of stevia by the FDA prior to the petitions presented in 2008, include the lack of sufficient data on the toxicological characteristics of stevia as well as biological data surrounding is ADME. Indeed, petitions as well as JECFA recommendations have based their claims on ADI and toxicology as per the previously conducted animal studies (Žlabur et al. 2015). There lies a dearth of evidence on trials recruiting human subjects, including studies on absorption which have primarily utilized stimulated environments employing derived digestive enzymes. Similar objections were raised by the European Commission taking insights from previous studies hence resulting in the banning of stevia from markets in the European Union (Samuel et al. 2018). Further aggravating stevia’s tumultuous history with global approval was due to studies in 1991 claiming that compounds in the sweetener posed the potential to cause cancer. It was only after counter evidence in the year 1995, which led the FDA to permit the usage of stevia, not as a sweetener but as a food supplement (Pérez et al. 2016).
Hence, to conclude, stevia continues to remain a controversial product considering the inadequate research pertaining to its usage coupled with the existence of conflicting historical evidence associated with its safety. Recalling the emerging trends of metabolic disorders with an increasing global consumption of sugar, the need of the hour is to formulate alternative suagr sweeteners. Further research is required to fully establish stevia’s efficacy which may pave the way for greater global acceptance.
Abbas Momtazi-Borojeni, A., Esmaeili, S.A., Abdollahi, E. and Sahebkar, A., 2017. A review on the pharmacology and toxicology of steviol glycosides extracted from Stevia rebaudiana. Current pharmaceutical design, 23(11), pp.1616-1622.
Chesterton, B.M. and Yang, T., 2016. The Global origins of a” Paraguayan” sweetener: ka’a He’e and stevia in the twentieth century. Journal of World History, 27(2), pp.255-279.
EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2010. Scientific opinion on the safety of steviol glycosides for the proposed uses as a food additive. EFSA Journal, 8(4), p.1537.
Elnaga, N.A., Massoud, M.I., Yousef, M.I. and Mohamed, H.H., 2016. Effect of stevia sweetener consumption as non-caloric sweetening on body weight gain and biochemical’s parameters in overweight female rats. Annals of Agricultural Sciences, 61(1), pp.155-163.
Food and Drug Administration (2017). GRAS NOTICE FOR HIGH-PURITY REBAUDIOSIDE M. [online] Fda.gov. Available at: https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/UCM626070.pdf [Accessed 28 Mar. 2019].
Food and Drug Administration (2018). GRAS NOTICE FOR STEVIA LEAF EXTRACTS. [online] Fda.gov. Available at: https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/UCM626071.pdf [Accessed 28 Mar. 2019].
Food and Drug Administration (2019). GRAS NOTICE FOR REBAUDIOSIDE A (REB A). [online] Wayback.archive-it.org. Available at: https://wayback.archive-it.org/7993/20171031055327/https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/UCM264109.pdf [Accessed 28 Mar. 2019].
Mukhtar, M., Tiong, C.S., Bukhari, S.I., Abdullah, A.H. and Ming, L.C., 2016. Safety and efficacy of health supplement (Stevia rebaudiana). Archives of Pharmacy Practice, 7(5), p.16.
Parris, C.A., Shock, C.C. and Qian, M., 2016. Dry leaf and steviol glycoside productivity of Stevia rebaudiana in the Western United States. HortScience, 51(10), pp.1220-1227.
Pérez, E., González, C., Vaillant, F. and Lares, M., 2016. Stevia derivative and its potential uses in diabetic-directed foods. Review. Journal of Nutrients, 3(1), pp.1-20.
Samuel, P., Ayoob, K.T., Magnuson, B.A., Wölwer-Rieck, U., Jeppesen, P.B., Rogers, P.J., Rowland, I. and Mathews, R., 2018. Stevia leaf to Stevia sweetener: Exploring its science, benefits, and future potential. The Journal of nutrition, 148(7), pp.1186S-1205S.
Sharma, S., Walia, S., Singh, B. and Kumar, R., 2016. Comprehensive review on agro technologies of low?calorie natural sweetener stevia (Stevia rebaudiana Bertoni): a boon to diabetic patients. Journal of the Science of Food and Agriculture, 96(6), pp.1867-1879.
Zhang, Q., Yang, H., Li, Y., Liu, H. and Jia, X., 2017. Toxicological evaluation of ethanolic extract from Stevia rebaudiana Bertoni leaves: Genotoxicity and subchronic oral toxicity. Regulatory Toxicology and Pharmacology, 86, pp.253-259.
Žlabur, J.Š., Vo?a, S., Dobri?evi?, N., Brn?i?, M., Dujmi?, F. and Brn?i?, S.R., 2015. Optimization of ultrasound assisted extraction of functional ingredients from Stevia rebaudiana Bertoni leaves. International Agrophysics, 29(2), pp.231-237.
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