The use of botanicals and dietary supplements derived from natural substances as an adjunct to an improved quality of life or for their purported medical benefits has become increasingly common in the United States. This review addresses the safety assessment and regulation of food products containing these substances by the U.S. Food and Drug Administration (FDA). The issue of safety is particularly critical given how little information is available on the toxicity of some of these products. The first section uses case studies for stevia and green tea extracts as examples of how FDA evaluates the safety of botanical and herbal products submitted for consideration as Generally Recognized as Safe under the Federal Food, Drug, and Cosmetics Act. The 1994 Dietary Supplement Health Education Act (DSHEA) created a regulatory framework for dietary supplements. The article also discusses the regulation of this class of dietary supplements under DSHEA and addresses the FDA experience in analyzing the safety of natural ingredients described in pre-market safety submissions. Lastly, we discuss an ongoing interagency collaboration to conduct safety testing of nominated dietary supplements.

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is the redox regulator of multiple stress-inducible transcription factors, such as NF-κB, and the major 5'-endonuclease in base excision repair (BER). We utilized mice containing heterozygous gene-targeted deletion of APE1/Ref-1 (Apex +/-) to determine the impact of APE1/Ref-1 haploinsufficiency on the processing of oxidative DNA damage induced by 2-nitropropane (2-NP) in the liver tissue of mice. APE1/Ref-1 haploinsufficiency results in a significant decline in NF-κB DNA binding activity in response to oxidative stress in liver. In addition, loss of APE1/Ref-1 increases the apoptotic response to oxidative stress where a significant increase in GADD45g expression, p53 protein stability and caspase activity are observed. Oxidative stress displays a differential impact on monofunctional (UDG) and bifunctional (OGG1) DNA glycosylase initiated BER in liver of Apex +/-mice. APE1/Ref-1 haploinsufficiency results in a significant decline in the repair of oxidized bases (e.g., 8-OHdG), while removal of uracil is increased in liver nuclear extracts of mice using an in vitro BER assay. Apex +/-mice exposed to 2-NP displayed a significant decline in 3'-OH-containing single-strand breaks and an increase in aldehydic lesions in their liver DNA suggesting an accumulation of repair intermediates of failed bifunctional DNA glycosylase initiated BER.

This study uses a base excision repair (BER)-deficient model, the DNA polymerase B heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged B-pol +/À mice express 50% less B-pol transcripts and protein (P < 0.05) than aged B-pol +/+ mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in B-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged B-pol +/À mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of B-pol +/À mice exhibited lymphoid hyperplasia, whereas none of the B-pol +/+ exhibited this phenotype. B-pol +/À mice were also more likely to develop adenocarcinoma (2.7-fold increase; P < 0.05) and more likely to develop multiple tumors, as 20% of the B-pol +/À animals died bearing multiple tumors compared with only 5% of the B-pol +/+ animals (P < 0.05). In spite of accelerated tumor development, no gross effect of B-pol heterozygosity was seen with respect to life span. However, the survival curves for the B-pol +/+ and B-pol +/À mice are not identical. A maximum likelihood estimation analysis showed a modest but significant (P < 0.05) acceleration of the age-dependent mortality rate in B-pol +/À mice. Thus, the B-pol +/À mouse represents a model in which mortality rate and tumor development are accelerated and provides evidence supporting the role of genomic maintenance in both aging and carcinogenesis. (Cancer Res 2006; 66(15): 7460-5)

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Background It is well-recognized that consumers face many challenges in understanding and applying nutritional guidance for low-calorie sweeteners (LCS). Thus, this research aims to (1) assess how benchmarks for safe levels of consumption of LCS are utilized by researchers, and (2) understand how varying use of such benchmarks may contribute to challenges in understanding and applying nutritional guidance for LCS consumption. Methods A systematic mapping exercise was employed to characterize when and how acceptable daily intake (ADI) values are used as health-based benchmarks in nutrition research studies that consider the safety of LCS. Results Based on results from charting 121 studies, our findings demonstrate that comparisons of LCS intake to an ADI derived by an authoritative body have been made in a diverse set of published literature, varying widely in their objectives, approaches, and populations of interest. The majority of studies compared the ADI to intake in a population under study; these represent the type of comparison that is most consistent with the intent of the ADI. Other applications of the ADI included use as a benchmark in experimental studies, risk-benefit analyses, and metabolism studies. Conclusion Although most instances of ADI use were reasonable within the context of the individual studies’ objectives, the diversity in use by original-study authors amplifies the continued need for development of “best practices” regarding the use and interpretation of the ADIs in current research. Using comparisons to the ADI can be a helpful way to provide context to research findings. However, in doing so, it is important that researchers utilize the value in a manner specific with its intent, as the ADI is a metric that represents an estimate of the amount of a substance that can be consumed daily over a lifetime without presenting an appreciable risk to health.