Application of a key events dose-response analysis to nutrients: a case study with vitamin A (retinol).

The methodology used to establish tolerable upper intake levels (UL) for nutrients borrows heavily from risk assessment methods used by toxicologists. Empirical data are used to identify intake levels associated with adverse effects, and Uncertainty Factors (UF) are applied to establish ULs, which in turn inform public health decisions and standards. Use of UFs reflects lack of knowledge regarding the biological events that underlie response to the intake of a given nutrient, and also regarding the sources of variability in that response. In this paper, the Key Events Dose-Response Framework (KEDRF) is used to systematically consider the major biological steps that lead from the intake of the preformed vitamin A to excess systemic levels, and subsequently to increased risk of adverse effects. Each step is examined with regard to factors that influence whether there is progression toward the adverse effect of concern. The role of homeostatic mechanisms is discussed, along with the types of research needed to improve understanding of dose-response for vitamin A. This initial analysis illustrates the potential of the KEDRF as a useful analytical tool for integrating current knowledge regarding dose-response, generating questions that will focus future research efforts, and clarifying how improved knowledge and data could be used to reduce reliance on UFs.

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.

An evaluation of the maximized survey-derived daily intake (MSDI) as a practical method to estimate intake of flavouring substances.

Realistic estimates of intake are essential for risk assessments of flavouring agents, since substantial over or underestimations introduce inaccuracies into such evaluations. The objectives of this study were to examine the relationship between intakes estimated using methods based on the reported volume of production [e.g., maximized survey-derived daily intake (MSDI)] versus use-level data [e.g., possible average daily intake (PADI) and modified theoretical added maximum daily intake (mTAMDI)]. The impact of volatility, self-limiting organoleptic properties and whether 10% of the population are eaters, an assumption in the MSDI calculation, on intake estimates were investigated. Analyses on 221 flavouring substances showed that intake estimates derived from MSDI correlated with values determined from detailed 14-day menu-census data, PADI, and mTAMDI. Comparisons of menu-census intake data adjusted to account for factors such as volatile losses showed that MSDI estimates are realistic and sufficiently conservative, whereas mTAMDI results in substantial overestimates of intake. Very few flavours have less than 10% eaters, and in the worst case, this assumption underestimates percent eaters by a factor of about 4. This investigation supports the use of MSDI as a conservative yet practical method to estimate intake of flavouring substances.

Criteria for the safety evaluation of flavoring substances. The Expert Panel of the Flavor and Extract Manufacturers Association.

The current status of the GRAS evaluation program of flavoring substances operated by the Expert Panel of FEMA is discussed. The Panel maintains a rigorous rotating 10-year program of continuous review of scientific data related to the safety evaluation of flavoring substances. The Panel concluded a comprehensive review of the GRAS (GRASa) status of flavors in 1985 and began a second comprehensive review of the same substances and any recently GRAS materials in 1994. This second re-evaluation program of chemical groups of flavor ingredients, recognized as the GRAS reaffirmation (GRASr) program, is scheduled to be completed in 2005. The evaluation criteria used by the Panel during the GRASr program reflects the significant impact of advances in biochemistry, molecular biology and toxicology that have allowed for a more complete understanding of the molecular events associated with toxicity. The interpretation of novel data on the relationship of dose to metabolic fate, formation of protein and DNA adducts, enzyme induction, and the cascade of cellular events leading to toxicity provides a more comprehensive basis upon which to evaluate the safety of the intake of flavor ingredients under conditions of intended use. The interpretation of genotoxicity data is evaluated in the context of other data such as in vivo animal metabolism and lifetime animal feeding studies that are more closely related to actual human experience. Data are not viewed in isolation, but comprise one component that is factored into the Panel's overall safety assessment. The convergence of different methodologies that assess intake of flavoring substances provides a greater degree of confidence in the estimated intake of flavor ingredients. When these intakes are compared to dose levels that in some cases result in related chemical and biological effects and the subsequent toxicity, it is clear that exposure to these substances through flavor use presents no significant human health risk.

Soy isoflavones: a safety review.

Soy isoflavones have been a component of the diet of certain populations for centuries. The consumption of soy generally has been considered beneficial, with a potentially protective effect against a number of chronic diseases; because of their estrogenic activity, however, negative effects of isoflavones have been postulated. This review examines the literature associated with the safety of soy isoflavones, including dietary soy isoflavone exposure data of populations with high soy intakes, human studies in which soy protein or isoflavones were provided, and toxicologic studies investigating the potential genotoxicity, carcinogenicity, and reproductive and developmental toxicity of soy isoflavones. Whereas results in some studies are limited or conflicting, when viewed in its entirety, the current literature supports the safety of isoflavones as typically consumed in diets based on soy or containing soy products.

The FEMA GRAS assessment of cinnamyl derivatives used as flavor ingredients.

This publication is the seventh in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of cinnamyl derivatives as flavoring ingredients is evaluated.

Regulation of foods with health claims: a proposal.

Health claims linking foods and food components to disease are prohibited in Canada because of limitations of the Food and Drugs Act. Changes to the Act to permit such claims would require a Bill to Parliament, a lengthy and impractical solution. In this paper, an alternative approach is proposed, that is, to regulate "Foods with Health Claims" under a subsection of the Drug Regulations. Generic claims would be regulated in a similar manner to Class IV or minimum risk drugs, whereby monographs would be created for constituents for which claims are proposed. Product-specific claims would be individually evaluated. Each food bearing a claim would carry a Food Identification Number (FIN), provided by Health Canada through application. Details of procedures and conditions for the FIN process are suggested. The FIN plan would provide an expedient, balanced and accountable approach to allow health claims on food products in Canada.

Vitamin D mushrooms: comparison of the composition of button mushrooms (Agaricus bisporus) treated postharvest with UVB light or sunlight.

This study compared the compositional changes in mushrooms exposed to sunlight with those occurring after commercial ultraviolet (UV) light processing. Button mushrooms (75 kg) were processed in the presence or absence of UVB light; a third group was exposed to direct sunlight. Mushroom composition was evaluated using chemical analyses. Vitamin D concentrations were 5, 410, and 374 µg/100 g (dw) in control, UVB, and sunlight groups, respectively. On a dry weight basis, no significant changes in vitamin C, folate, vitamins B(6), vitamin B(5), riboflavin, niacin, amino acids, fatty acids, ergosterol, or agaritine were observed following UVB processing. Sunlight exposure resulted in a 26% loss of riboflavin, evidence of folate oxidation, and unexplained increases in ergosterol (9.5%). It was concluded that compositional effects of UVB light are limited to changes in vitamin D and show no detrimental changes relative to natural sunlight exposure and, therefore, provide important information relevant to the suitability and safety of UVB light technology for vitamin D enhanced mushrooms.

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.

The safety of whey protein concentrate derived from the milk of cows immunized against Clostridium difficile.

A whey protein concentrate prepared from the milk of cows that have been immunized against Clostridium difficile (C. difficile) and its toxins, toxin A and toxin B, is produced for use as a medical food for the dietary management of patients with C. difficile-associated diarrhea (CDAD) to prevent a relapse of the infection. The safety of anti-C. difficile whey protein concentrate (anti-CD WPC) is supported by analytical data comparing the composition of raw milk from immunized cows versus that from non-immunized cows, and the composition of anti-CD WPC versus that of regular whey protein concentrate. Additionally, a prospective clinical study was conducted in 77 patients with CDAD to demonstrate the safety of consuming anti-CD WPC to prevent relapse of the infection. This study, which included adverse event monitoring, physical examinations, and extensive hematological and biochemical assessments, showed that anti-CD WPC is safe to consume by patients with CDAD. The available analytical and clinical evidence demonstrate that anti-CD WPC is safe for use by individuals with CDAD, under the described conditions of use.

Setting tolerable upper intake levels for nutrients.

This paper is intended to present the background and general principles embodied in the model for the risk assessment of nutrients of the Food and Nutrition Board (FNB) of the Institute of Medicine, National Academies. Because no one had previously developed a comprehensive approach to the risk assessment of nutrients, the FNB Subcommittee on Upper Reference Levels of Nutrients first looked at various options that could be used to accomplish this task. During initial meetings, the committee considered a variety of options for setting tolerable upper intake levels and settled on the risk assessment approach described in this paper.

Use of hydrogen peroxide-based tooth whitening products and its relationship to oral cancer.

UNLABELLED: Tooth whitening products containing hydrogen peroxide or carbamide peroxide were evaluated in this review for potential oral cancer risk from their use. Hydrogen peroxide is genotoxic in vitro, but not in vivo. Hydrogen peroxide was not considered to pose a genotoxic risk to humans. The animal toxicology data relevant to the assessment of the carcinogenicity of hydrogen peroxide do not indicate that it has significant carcinogenic activity at any site, including the oral cavity. Hydrogen peroxide was found to enhance the carcinogenic effects of potent DNA reactive carcinogens in experimental animals. However, these experimental conditions are artificial as they are related to high exposures and are of no relevance to potential human exposures to low quantities of hydrogen peroxide from the use of tooth whitening products. Clinical data on hydrogen peroxide-containing tooth whitening products show no evidence for the development of preneoplastic or neoplastic oral lesions. Exposures to hydrogen peroxide received by the oral cavity are exceedingly low, of short duration (30-60 minutes), and could not plausibly enhance any carcinogenic risk associated with exposure of the oral cavity to chemicals in cigarette smoke or to alcohol, both known risk factors for the development of oral cancer. CLINICAL SIGNIFICANCE: Based on a comprehensive review of the available literature and research, the use of tooth whitening products containing hydrogen peroxide or carbamide peroxide does not appear to pose an increased risk of oral cancer in the general population, including those persons who are alcohol abusers and/or heavy cigarette smokers.

An evaluation of the possible carcinogenicity of bisphenol A to humans.

Bisphenol A (BPA) is a monomer component of polycarbonate plastics and epoxy resins. These resins are used in numerous consumer products, including food-contact plastics. There has been considerable scientific debate about the relevance to humans of reported estrogenic actions of BPA. Much less attention has been focused on the carcinogenic potential of BPA. The carcinogenic potential of BPA was assessed through a review of metabolic data, genetic toxicity studies, long-term toxicity/carcinogenicity studies, and estimates of consumer exposure. Following a weight-of-evidence approach as recommended by IARC and U.S. EPA, it was concluded that BPA is not likely to be carcinogenic to humans. The bases for this conclusion included: (a) the results of an NTP study which provided no substantive evidence to indicate that BPA is carcinogenic to rodents; (b) the lack of activity of BPA, at noncytotoxic concentrations, in standard in vitro genetic toxicity tests; (c) the lack of genotoxic activity of BPA in a GLP-compliant in vivo mouse micronucleus assay; and (d) the results of metabolism studies showing BPA is rapidly glucuronidated without evidence of formation of potentially reactive intermediates, except possibly at high doses that could saturate detoxication pathways. In addition, exposure assessment reveals that current use of BPA would result in only a trivial human exposure.

Aspartame: review of safety.

Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.