Biological fate of low-calorie sweeteners.

With continued efforts to find solutions to rising rates of obesity and diabetes, there is increased interest in the potential health benefits of the use of low- and no-calorie sweeteners (LNCSs). Concerns about safety often deter the use of LNCSs as a tool in helping control caloric intake, even though the safety of LNCS use has been affirmed by regulatory agencies worldwide. In many cases, an understanding of the biological fate of the different LNSCs can help health professionals to address safety concerns. The objectives of this review are to compare the similarities and differences in the chemistry, regulatory status, and biological fate (including absorption, distribution, metabolism, and excretion) of the commonly used LNCSs: acesulfame potassium, aspartame, saccharin, stevia leaf extract (steviol glycoside), and sucralose. Understanding the biological fate of the different LNCSs is helpful in evaluating whether reports of biological effects in animal studies or in humans are indicative of possible safety concerns. Illustrations of the usefulness of this information to address questions about LNCSs include discussion of systemic exposure to LNCSs, the use of sweetener combinations, and the potential for effects of LNCSs on the gut microflora.

Steviol glycoside safety: are highly purified steviol glycoside sweeteners food allergens?

Steviol glycoside sweeteners are extracted from the plant Stevia rebaudiana (Bertoni), a member of the Asteraceae (Compositae) family. Many plants from this family can induce hypersensitivity reactions via multiple routes of exposure (e.g., ragweed, goldenrod, chrysanthemum, echinacea, chamomile, lettuce, sunflower and chicory). Based on this common taxonomy, some popular media reports and resources have issued food warnings alleging the potential for stevia allergy. To determine if such allergy warnings are warranted on stevia-based sweeteners, a comprehensive literature search was conducted to identify all available data related to allergic responses following the consumption of stevia extracts or highly purified steviol glycosides. Hypersensitivity reactions to stevia in any form are rare. The few cases documented in the peer-reviewed literature were reported prior to the introduction of high-purity products to the market in 2008 when many global regulatory authorities began to affirm the safety of steviol glycosides. Neither stevia manufacturers nor food allergy networks have reported significant numbers of any adverse events related to ingestion of stevia-based sweeteners, and there have been no reports of stevia-related allergy in the literature since 2008. Therefore, there is little substantiated scientific evidence to support warning statements to consumers about allergy to highly purified stevia extracts.

High concentrations of hexavalent chromium in drinking water alter iron homeostasis in F344 rats and B6C3F1 mice.

Hexavalent chromium [Cr(VI)] induces hematological signs of microcytic anemia in rodents. Considering that Cr(VI) can oxidize ferrous (Fe(2+)) to ferric (Fe(3+)) iron, and that only the former is transported across the duodenum, we hypothesize that, at high concentrations, Cr(VI) oxidizes Fe(2+) in the lumen of the small intestine and perturbs iron absorption. Herein we report that 90-day exposure to Cr(VI) in drinking water resulted in dose-dependent decreases in Fe levels in the duodenum, liver, serum, and bone marrow. Toxicogenomic analyses from the duodenum indicate responses consistent with Fe deficiency, including significant induction of divalent metal transporter 1 (DMT1, Slc11a2) and transferrin receptor 1 (TFR1, Tfr1). In addition, at ⩾20mg Cr(VI)/L in drinking water, Cr RBC:plasma ratios in rats were increased and exceeded unity, indicating saturation of reductive capacity and intracellular absorption of Cr(VI) into red blood cells (RBCs). These effects occurred in both species but were generally more severe in rats. These data suggest that high concentrations of Cr(VI) in drinking limit Fe absorption and alter iron homeostasis. Furthermore, some effects observed at high doses in recent Cr(VI) chronic and subchronic bioassays may be explained, at least in part, by iron deficiency and disruption of homeostasis.

Development of a chronic noncancer oral reference dose and drinking water screening level for sulfolane using benchmark dose modeling.

Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000-36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference dose (RfD) based on benchmark dose modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark dose modeling were 0.01-0.04 mg kg(-1) per day, although modeling of developmental endpoints resulted in higher values, approximately 0.4 mg kg(-1) per day. The lowest, most conservative, RfD of 0.01 mg kg(-1) per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l(-1). It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane.

Using the correct regression analysis technique in method comparison studies.

Regression analysis frequently is used to evaluate a new clinical laboratory method. Results from the new method are compared to results from an existing more established method. If measurement error exists in the established method, then least squares may not be an appropriate statistical method to use for the regression analysis. An errors variable regression analysis model was used to evaluate data from five method comparison studies. Results were compared to least squares analyses performed on the same data. When significant measurement error existed in the "reference" method, the errors variable analysis provided a less biased estimate of the regression statistics, which differed markedly from the least squares results. Inappropriate use of least squares in method comparison studies can lead to erroneous conclusions about the relationship of a new analytical method to an existing method.

Serum 5'nucleotidase activity in rats: a method for automated analysis and criteria for interpretation.

A manual kit for determining serum 5'nucleotidase (5'NT, EC 3.1.3.5) activity was adapted for use with rat samples on a large discrete clinical chemistry analyzer. The precision of the method was good (within-run C.V. = 2.14%; between-run C.V. = 5.5%). A comparison of the new automated method with a manual and semi-automated method gave regression statistics of y = 1.18X -3.66 (Sy. x = 4.54), and y = 0.733X + 1.97 (Sy. x = 1.69), respectively. Temperature conversion factors provided by the kit manufacturer for human samples were determined to be inaccurate for converting results from rat samples. Analysis of components contributing to normal variation in rat serum 5'NT activity showed age and sex to be major factors. Increased serum 5'NT activity was observed in female rats when compared to male rats beginning at about 5 to 6 weeks of age. An analysis of variance of serum 5'NT, alkaline phosphatase, and GGT activities observed over a 9-week period in normal rats suggests several advantages for 5'NT as a predictor of biliary lesions in rats.