Ian C. Munro

An overview of the safety of sucralose

Sucralose is a non-nutritive sweetener used in a broad range of foods and beverages and is the non-nutritive sweetener in retail SPLENDA Sweetening Products, composed of sucralose and common food ingredients. A review of the extensive body of evidence that supports the safety of sucralose is provided. The results of an independent review of a new study investigating the safety of a sucralose-mixture retail product, Granulated SPLENDA No Calorie Sweetener, are also discussed. The collective evidence supports the conclusion that the ingredient, sucralose, is safe for use in food and that the sucralose-mixture product, Granulated SPLENDA No Calorie Sweetener, is also safe for its intended use.

Carcinogenicity of Monochloro-1,2-Propanediol (α-Chlorohydrin, 3-MCPD)

3-Monochloro-1,2-propanediol (3-MCPD) is a by-product found in trace amounts, generally less than 1 mg/kg (<1 ppm), in hydrolyzed vegetable protein produced through acid hydrolysis. In a chronic study with F344 rats, high doses of 3-MCPD produced benign renal tumors in both sexes and Leydig-cell and mammary tumors in males. 3-MCPD is genotoxic in vitro, but there is no evidence of genotoxicity in vivo. There is some question about the mechanism responsible for the carcinogenicity of 3-MCPD in certain species. Here we present a critical review of the toxicological, metabolic, and mechanistic data on 3-MCPD. On the basis of this review, the tumors reported in F344 rats are concluded to have developed as a result of nongenotoxic mechanisms and are considered not to be relevant to humans exposed to trace amounts of 3-MCPD. This conclusion was based on the lack of carcinogenicity of 3-MCPD in mice or Sprague-Dawley rats; the benign nature of the tumors involved; the dependence of the Leydig-cell and mammary tumors on species-and strain-dependent mechanisms involving chronic changes in hormone balance; the association of the renal tumors with chronic nephropathy and nephrotoxicity; and differences between bacterial and mammalian systems in the metabolism of 3-MCPD that likely account for its genotoxic activity in certain in vitro test systems. At trace levels in foods, 3 MCPD is considered not to pose a carcinogenic risk to humans.

Review of the regulation and safety assessment of food substances in various countries and jurisdictions

This review compares the regulations, definitions and approval processes for substances intentionally added to or unintentionally present in human food in the following specific countries/jurisdictions: Argentina, Australia, Brazil, Canada, China, the European Union, Japan, Mexico, New Zealand, and the United States. This includes direct food additives, food ingredients, flavouring agents, food enzymes and/or processing aids, food contact materials, novel foods, and nanoscale materials for food applications. The regulatory authority of each target jurisdiction/country uses its own regulatory framework and although the definitions, regulations and approval processes may vary among all target countries, in general there are many similarities. In all cases, the main purpose of each authority is to establish a regulatory framework and maintain/enforce regulations to ensure that food consumed and sold within its respective countries is safe. There is a move towards harmonisation of food regulations, as illustrated by Australia and New Zealand and by Mercosur. The European Union has also established regulations, which are applicable for all member states, to establish a common authorisation procedure for direct food additives, flavourings and enzymes. Although the path for approval of different categories of food additives varies from jurisdiction to jurisdiction, there are many commonalities in terms of the data requirements and considerations for assessment of the safety of use of food additives, including the use of positive lists of approved substances, pre-market approval, and a separation between science and policy decisions. The principles applied are largely reflective of the early work by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) committees and JECFA assessments of the safety of food additives for human and animal foods.

Technological challenges of addressing new and more complex migrating products from novel food packaging materials.

The risk assessment of migration products resulting from packaging material has and continues to pose a difficult challenge. In most jurisdictions, there are regulatory requirements for the approval or notification of food contact substances that will be used in packaging. These processes generally require risk assessment to ensure safety concerns are addressed. The science of assessing food contact materials was instrumental in the development of the concept of Threshold of Regulation and the Threshold of Toxicological Concern procedures. While the risk assessment process is in place, the technology of food packaging continues to evolve to include new initiatives, such as the inclusion of antimicrobial substances or enzyme systems to prevent spoilage, use of plastic packaging intended to remain on foods as they are being cooked, to the introduction of more rigid, stable and reusable materials, and active packaging to extend the shelf-life of food. Each new technology brings with it the potential for exposure to new and possibly novel substances as a result of migration, interaction with other chemical packaging components, or, in the case of plastics now used in direct cooking of products, degradation products formed during heating. Furthermore, the presence of trace levels of certain chemicals from packaging that were once accepted as being of low risk based on traditional toxicology studies are being challenged on the basis of reports of adverse effects, particularly with respect to endocrine disruption, alleged to occur at very low doses. A recent example is the case of bisphenol A. The way forward to assess new packaging technologies and reports of very low dose effects in non-standard studies of food contact substances is likely to remain controversial. However, the risk assessment paradigm is sufficiently robust and flexible to be adapted to meet these challenges. The use of the Threshold of Regulation and the Threshold of Toxicological Concern concepts may play a critical role in the risk assessment of new food packaging technologies in the future.

Stevioside and related compounds: therapeutic benefits beyond sweetness.

The recent review by Chatsudthipong and Muanprasat (2009) of the toxicity, clinical, metabolism, and biochemical data available on stevioside and related compounds, including stevia, rebaudioside A, and steviol contains a number of important omissions and shortcomings. The article discussed these compounds in relation to perceived pharmacological activity, their potential use as therapeutic agents, and human safety. Unfortunately, the authors failed to differentiate between studies using uncharacterized stevioside/ steviol glycoside preparations and those conducted with purified preparations of stevioside/steviol glycosides and steviol. Secondly, the authors fail to note that in vitro and intravenous dosing studies are of no relevance to the exposure of steviol glycosides consumed orally from food matrices. Third, a number of critical animal toxicology and human clinical studies are either missing or mentioned only briefly. Finally, the authors do not include the latest positions of regulatory authorities regarding human safety. Each of these study shortcomings are briefly described below. It is well established that some stevia extracts are crude mixtures that contain multiple components of the stevia leaf, including those components that do not provide a sweet taste. These mixtures also vary considerably in quality, purity, and composition. Therefore, it is not surprising that sometimes these crude and uncharacterized materials may contain substances that possess some degree of pharmacologic activity but any such effects cannot be attributed specifically to the steviol glycosides. In contrast to studies conducted with less pure steviol glycoside preparations, studies conducted with purified preparations do not indicate any evidence of pharmacological effects. The authors consistently cite pharmacological, toxicological, and biochemical effects from in vitro studies or from studies in which animals were dosed intravenously (e.g., Melis, 1992a,b,c). Steviol glycosides are hydrolyzed completely by the gut microflora to steviol prior to absorption, with no systemic absorption of the glycone form following oral exposure. Therefore, the results of in vitro and intravenous, intraperitoneal, or subcutaneous dosing studies of the glycone form are not relevant to the safety of steviol glycosides consumed orally. The opinion of the authors that remaining uncertainties exist regarding the safety of steviol glycosides andmust be resolved may be explained in part by their failure to identify, review and/or discuss of key publications relating to the metabolism that safety of stevioside and/or rebaudioside A. Of particular note is the absence of, or lack of substantive discussion of the results of a Good Laboratory Practices (GLP)-compliant 2-generation reproductive toxicity study conducted with rebaudioside A in rats (Curry, Roberts, & Brown, 2008), a teratogenicity study on stevioside (Usami, Sakemo, Kawashima, Tsuda, & Ohno, 1995), two subchronic toxicity studies of purified rebaudioside A (Curry & Roberts, 2008; Nikiforov & Eapen, 2008), a