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Tooth whitening products (TWP) containing hydrogen peroxide (HPO) or carbamide peroxide (CPO) were evaluated in relation to potential oral cancer risk from their use. HPO is genotoxic in vitro, but such activity is not expressed in vivo. The genotoxic risk of HPO exposure of the oral mucosa encountered from TWP use is likely therefore to be vanishingly small. Available animal data on the carcinogenicity of HPO are of limited relevance to risk assessment of oral hazard of HPO exposure from TWP, and where relevant, do not indicate that there is an increased oral cancer risk for people using TWP. Clinical data on HPO-containing TWP only show evidence of mild, transient gingival irritation and tooth sensitivity, with no evidence for the development of preneoplastic or neoplastic oral lesions. Exposures to HPO received by the oral cavity, including areas commonly associated with oral cancer, are exceedingly low and do not plausibly pose a risk for the promotion of initiated cells or for induction of co-carcinogenic effects in conjunction with cigarette smoke or alcohol. The use of TWP was concluded not to pose an increased risk for oral cancer in alcohol abusers and/or heavy cigarette smokers. Furthermore, TWP were concluded to be safe for use by all members of the population, including potential accidental use by children.

Oral rinse and toothpaste products (Viadent) containing Sanguinaria extract have been shown through extensive clinical trials to be effective against plaque build-up and gingivitis. To establish safety, a comprehensive research program was conducted, including a series of clinical studies and a number of animal studies to evaluate acute, subchronic, and chronic toxicity, and the potential for irritation of mucosal tissues. In 1990 and 1993, an Expert Panel reported on reviews of these data and concluded that Viadent products are safe for their intended use. Despite the large database of information to support the safety of Viadent products, Damm et al. (1999) recently raised the possibility that their usage may be causally associated with development of oral leukoplakia. However, a critique of this recent report shows that it does not fulfil criteria for establishing causation. In particular, the study does not show that exposure to Viadent preceded the onset of leukoplakia, it does not demonstrate dose-response or biological plausibility, and it suffers from selection and information bias and from potential confounding. Furthermore, upon critical evaluation, the Damm et al. (1999) report on a case-series is inconsistent with the weight of available clinical evidence showing that Sanguinaria extract-containing oral health care products cause no cytotoxic or significant irritant effects in the oral mucosa in human studies of up to 6 months duration. The animal data similarly do not support a causal association between Viadent usage and oral leukoplakia in humans. These data demonstrate that Sanguinaria extract and whole Viadent formulations are without significant irritation potential and have no effects on the oral mucosa, even in studies with life-long dietary exposure to Sanguinaria extract. The mutagenicity and genotoxicity data do not indicate that Sanguinaria extract or its components are genotoxic in vivo. The results of 2 GLP-compliant rat oncogenicity studies provide no evidence of any carcinogenic effect of Sanguinaria extract. In conclusion, the available clinical and animal data provide no support for and in fact argue strongly against the hypothesis that the use of Viadent toothpaste and/or oral rinse products may be causally associated with the development of leukoplakia in humans.

The term chlorinated chemicals is used to describe diverse groups of chemicals of varying chemical structure, including those used in water disinfection, as well as numerous aliphatic, aromatic, and polycyclic chlorinated substances. This report elaborates a number of scientific principles that govern the evaluation of the potential for chlorinated organic chemicals to cause adverse effects on the environment and to human health. The purpose of the report is to demonstrate the importance of applying these scientific principles in the evaluation of potential adverse effects of chlorinated organic chemicals. The four major principles upon which such a scientific analysis must be based are: (1) the fate and biological activity of a compound are determined by the chemical properties of the compound; (2) compounds do not show adverse effects below certain threshold concentrations, and the magnitude of response is related to dose; (3) inherent metabolic processes allow organisms to accommodate low doses of chlorinated organic chemicals; (4) observations associated with the presence of a certain compound must be biologically plausible effects, based on the specificity of the compound's activity in experimental systems. With respect to the first of these principles, there is abundant scientific evidence that the physical and chemical properties of chlorinated organic chemicals govern their bioaccumulative potential, toxicological properties, and thus their potential behavior and effects in the environment. Chemicals that have low solubility in water are highly lipophilic and have low vapor pressure, tend to accumulate in biological systems, and degrade slowly in the environment. Chlorinated organic chemicals that possess these characteristics include those having a carbon ring structure and multiple chlorine substitution. Other chlorinated organic chemicals with lesser degrees of chlorine substitution, such as 2,4-dichlorophenoxyacetic acid (2,4-D), trichlorophenol, chloroform, and dichloroethane, do not share the physical and chemical properties of the high molecular weight, cyclic, polychlorinated compounds and, as such, do not have the same potential to bioaccumulate. These differences among chlorinated organic chemicals with respect to their physical and chemical properties and behavior in the environment preclude the generalization that all organic chemicals containing chlorine behave similarly in the environment and act as persistent, bioaccumulative chemicals. The reactivity of chlorinated organic chemicals and hence their potential to produce biological effects depends on their specific molecular features. The substitution of chlorine into an organic molecule may increase or may reduce its biological activity.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.

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.

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.

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.

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.

The IARC Monographs (Vols 1–70) were studied to determine the time of onset of treatment-related tumorigenicity in long-term rodent studies for chemicals classified by IARC as having sufficient evidence of carcinogenicity in animals. The analysis excluded studies on metals and their salts, studies on particulates, studies by parenteral routes of administration that resulted in tumours only at the site of exposure, and studies that did not approximate to the current standard long-term rodent carcinogenicity bioassay, for instance transplacental or multigeneration studies, initiator-promoter studies, lung tumour assays in Strain A mice and studies in newborn animals. Data from a total of 210 chemicals revealed that, overall, evidence of treatment-related tumorigenicity was first apparent within 12 months for 66% of the chemicals and for only 7% were studies of longer than 18 months necessary. All IARC Group 1 chemicals were detected in animals within 18 months, and most within 12 months. Most of the tumour types that required more than 18 months for detection were of dubious relevance to human risk assessment. Termination of rodent carcinogenicity studies at 18 months or earlier would greatly reduce the complications that arise in interpreting the findings in aged animals which often have defective hepatic or renal function and would also markedly reduce the time required for histopathological examination of dozens of tissues taken from the approximately 500 animals routinely employed in these studies.

For decades, it has been known that a number of different factors (e.g., species, metabolism, age, animal husbandry, diet) may exhibit a significant modulating effect on the process of carcinogenesis. Often, however, these modulators have been largely uncontrolled and thus have made uncertain the results of many carcinogenicity bioassays. Fortunately, current research into molecular carcinogenesis is beginning to provide methods, not only to understand the molecular basis of known modulators of carcinogenesis, previously described only in empirical terms, but also to allow genetic modulation of carcinogenesis in experimental systems. An expanding body of knowledge regarding the role of oncogenes and tumor suppressor genes in neoplastic events is leading to a better understanding of carcinogenic mechanisms and points to the use of transgenic animal species in carcinogenicity bioassays. The transgenic animal provides methods to examine the molecular basis of carcinogenesis in experimental systems in addition to enhancing the sensitivity of carcinogen identification and the biological specificity of chemical risk extrapolation.

Carcinogenicity is a major consideration in the assessment of risks due to environmental chemicals. The carcinogen bioassay therefore is a very important component of the battery of toxicological tests used in hazard evaluation. The strengths and limitations of this bioassay are discussed with emphasis upon the unresolved practical considerations, the interpretation of negative results, the significance of tumors induced in the presence of a high background incidence of naturally occurring tumors, and the difficulties in transspecies extrapolation. These factors, in combination with consideration of the biological mechanisms of chemical cancer induction, will be valuable in assessing the potential risk to man posed by individual chemicals.