Vaginal microbiome Lactobacillus crispatus is heritable among European American women.

The diversity and dominant bacterial taxa in the vagina are reported to be influenced by multiple intrinsic and extrinsic factors, including but not limited to pregnancy, contraceptive use, pathogenic states, socioeconomic status, and ancestry. However, the extent to which host genetic factors influence variation in the vaginal microbiota is unclear. We used a biometrical genetic approach to determine whether host genetic factors contribute to inter-individual differences in taxa from a sample of 332 twins who self-identified as being of African (44 pairs) or European ancestry (122 pairs). Lactobacillus crispatus, a major determinant of vaginal health, was identified as heritable among European American women (narrow-sense heritability = 34.7%, P-value = 0.018). Heritability of L. crispatus is consistent with the reduced prevalence of adverse reproductive disorders, including bacterial vaginosis and preterm birth, among women of European ancestry.

Triclosan: a critical review of the experimental data and development of margins of safety for consumer products.

Triclosan (2,4,4'-trichloro-2'-hydroxy-diphenyl ether) is an antibacterial compound that has been used in consumer products for about 40 years. The tolerability and safety of triclosan has been evaluated in human volunteers with little indication of toxicity or sensitization. Although information in humans from chronic usage of personal care products is not available, triclosan has been extensively studied in laboratory animals. When evaluated in chronic oncogenicity studies in mice, rats, and hamsters, treatment-related tumors were found only in the liver of male and female mice. Application of the Human Relevance Framework suggested that these tumors arose by way of peroxisome proliferator-activated receptor alpha (PPARalpha) activation, a mode of action not considered to be relevant to humans. Consequently, a Benchmark Dose (BMDL(10)) of 47 mg/kg/day was developed based on kidney toxicity in the hamster. Estimates of the amount of intake from in the use of representative personal care products for men, women, and children were derived in two ways: (1) using known or assumed triclosan levels in various consumer products and assumed usage patterns (product-based estimates); and (2) using upper bound measured urinary triclosan levels from human volunteers (biomonitoring-based estimates) using data from the Centers for Disease Control and Prevention. For the product-based estimates, the margin of safety (MOS) for the combined exposure estimates of intake from the use of all triclosan-containing products considered were approximately 1000, 730, and 630 for men, women, and children, respectively. The MOS calculated from the biomonitoring-based estimated intakes were 5200, 6700, and 11,750 for men, women, and children, respectively. Based on these results, exposure to triclosan in consumer products is not expected to cause adverse health effects in children or adults who use these products as intended.

Expert panel report on a study of Splenda in male rats.

A recent study in rats investigated the retail sweetener product, Granulated SPLENDA No Calorie Sweetener (Splenda) (Abou-Donia et al., 2008. Splenda alters gut microflora and increases intestinal P-glycoprotein and cytochrome P-450 in male rats. J. Toxicol. Environ. Health A, 71, 1415-1429), which is composed of (by dry weight) maltodextrin ( approximately 99%) and sucralose ( approximately 1%). The investigators reported that Splenda increased body weight, decreased beneficial intestinal bacteria, and increased the expression of certain cytochrome P450 (CYP450) enzymes and the transporter protein, P-glycoprotein (P-gp), the latter of which was considered evidence that Splenda or sucralose might interfere with the absorption of nutrients and drugs. The investigators indicated that the reported changes were attributable to the sucralose present in the product tested. An Expert Panel conducted a rigorous evaluation of this study. In arriving at its conclusions, the Expert Panel considered the design and conduct of the study, its outcomes and the outcomes reported in other data available publicly. The Expert Panel found that the study was deficient in several critical areas and that its results cannot be interpreted as evidence that either Splenda, or sucralose, produced adverse effects in male rats, including effects on gastrointestinal microflora, body weight, CYP450 and P-gp activity, and nutrient and drug absorption. The study conclusions are not consistent with published literature and not supported by the data presented.

Lack of oral embryotoxicity/teratogenicity with D-ribose in Wistar rats.

The present oral embryotoxicity/teratogenicity study of d-Ribose (DR) was conducted in female rats; 28 rats/group were exposed via the diet to 0, 5, 10, or 20% DR (0.0, 4.25, 7.94, 9.91g/kg body weight/day), from day 0 of gestation until Caesarian section and maternal sacrifice on day 21. All animals survived to the end of the study. Fecundity index, gestation index, pre-implantation loss, post-implantation loss, and sex ratio were all unaffected by treatment with DR. External observations of fetuses and placentas were unremarkable across the study groups. Mean fetal and placental weights, across all viable fetuses, did not differ significantly between treated and control groups. Observations of visceral malformations, anomalies, and variations were unremarkable and did not differ between treated and control groups. In summary, administration of DR to pregnant rats at concentrations up to 20% of the diet resulted in no significant adverse effects on the developing embryo/fetus at doses that were not otherwise a severe metabolic stress on the dam. A No Observed Adverse Effect Level (NOAEL) for teratogenicity could be seen at a concentration of 5% DR in the diet, corresponding to an average daily intake of DR of between 3.64 and 4.61g/kg body weight/day.

Sub-chronic (13-week) oral toxicity study with D-ribose in Wistar rats.

The present study evaluated the toxicity from sub-chronic administration of D-ribose (DR) to male and female albino Wistar rats. Groups of 20 male and 20 female rats were exposed via the diet to 0%, 5%, 10%, or 20% DR, seven days per week (mean daily intake of 0.0, 3.6, 7.6, and 15.0 g/kg body weight/day in males and 0.0, 4.4, 8.5, and 15.7 g/kg body weight/day in females), for 13 consecutive weeks. Mean feed consumption and feed conversion efficiency values were comparable across all study groups; however, and mean body weights of all treated animals were decreased relative to those of controls. Absolute cecal weights were increased in the mid- and high-dose animals, and the relative weights were increased in all treated animals. Analysis of microscopic histopathology revealed no evidence of changes that could be attributed to the DR treatment. It is scientifically reasonable to conclude that the present study supports a concentration of 5% DR in the diet, corresponding to an average daily intake of DR of 3.6 and 4.4 g/kg body weight/day in male and female rats, respectively, as being the absolute no observed adverse effect level (NOAEL) for this substance.

Tiered toxicity testing: evaluation of toxicity-based decision triggers for human health hazard characterization.

A set of biologically-based toxicity testing decision triggers was developed and analyzed within a tiered testing and decision-making framework for evaluating potential human health hazards and risks associated with chemical exposures. The proposed three-tiered toxicity testing approach starts from a base set of toxicity studies (acute toxicity, in vitro genetic toxicity, in vitro cytogenetics, repeat dose/subchronic toxicity, developmental toxicity, reproductive toxicity) and then uses the toxicity triggers to identify which specific additional tests are needed to adequately characterize a substance's hazard potential. The toxicity triggers were initially evaluated using published information for eight chemicals, representing diverse classes. A retrospective validation study was then conducted using seven chemicals which had completed the USEPA's Voluntary Children's Chemical Evaluation Program (VCCEP). The toxicity triggers were shown to identify appropriate higher tier tests and to be reasonably predictive of the results expected in higher tiered tests. Employing these toxicity triggers within a tiered testing framework could lead to a reduction in the number of laboratory animals without diminishing the degree of scientific certainty necessary for hazard evaluations. The toxicity triggers appear to be suitable for identifying which specific endpoints and tests warrant further evaluation, and which do not, and for documenting the scientific basis for such decisions.

Framework for use of toxicity screening tools in context-based decision-making.

One of the principal applications of toxicology data is to inform risk assessments and support risk management decisions that are protective of human health. Ideally, a risk assessor would have available all of the relevant information on (a) the toxicity profile of the agent of interest; (b) its interactions with living systems; and (c) the known or projected exposure scenarios: to whom, how much, by which route(s), and how often. In practice, however, complete information is seldom available. Nonetheless, decisions still must be made. Screening-level assays and tools can provide support for many aspects of the risk assessment process, as long as the limitations of the tools are understood and to the extent that the added uncertainty the tools introduce into the process can be characterized and managed. Use of these tools for decision-making may be an end in itself for risk assessment and decision-making or a preliminary step to more extensive data collection and evaluation before assessments are undertaken or completed and risk management decisions made. This paper describes a framework for the application of screening tools for human health decision-making, although with some modest modification, it could be made applicable to environmental settings as well. The framework consists of problem formulation, development of a screening strategy based on an assessment of critical data needs, and a data analysis phase that employs weight-of-evidence criteria and uncertainty analyses, and leads to context-based decisions. Criteria for determining the appropriate screening tool(s) have been identified. The choice and use of the tool(s) will depend on the question and the level of uncertainty that may be appropriate for the context in which the decision is being made. The framework is iterative, in that users may refine the question(s) as they proceed. Several case studies illustrate how the framework may be used effectively to address specific questions for any endpoint of toxicity.

An analysis of factors that influence personal exposure to nitrogen oxides in residents of Richmond, Virginia.

Nitrogen oxides (NO(x)) are ubiquitous pollutants in outdoor and indoor air. However, epidemiologic studies that evaluate health effects associated with NO(x) commonly rely upon outdoor concentrations of NO(x), nitrogen dioxide (NO(2)), or residence characteristics as surrogates for personal exposure. In this study, personal exposures (48 h) and corresponding indoor and outdoor concentrations of nitric oxide (NO), NO(2), and NO(x) were measured (July-September) in 39 adults and 9 children from 23 households in Richmond, Virginia, using Ogawa passive NO(x) monitors. Demographic, time-activity patterns, and household data were collected by questionnaire and used to develop exposure prediction models. Adults had higher NO(2), NO, and NO(x) exposures (means: 16, 63, and 79 ppb, respectively) than children (13, 49, and 62 ppb). Measurements taken in bedrooms (18, 57, and 75 ppb) and living rooms (19, 65, and 84 ppb) surpassed measurements taken outdoors (15, 21, and 36 ppb). In indoor locations, NO(x) concentrations were influenced largely by NO, and consequently, personal exposure prediction models for NO(x) were reflective of models for NO. Statistical models that best predicted personal exposures included indoor measurements; outdoor measurements contributed relatively little to personal exposure. Close to 70% of the variation in personal NO(2) and NO(x) exposure was explained by two variable models (bedroom NO(2) and time spent in other indoor locations; bedroom NO(x) and time spent in kitchen). Given appropriate resources, measurement error in epidemiologic studies can be reduced significantly with the use of personal exposure measurements or prediction models developed from indoor measurements and survey data.

Toxicological and metabolic investigations of the safety of N-alpha-lauroyl-L-arginine ethyl ester monohydrochloride (LAE).

Studies were conducted to assess the safety of N-alpha-lauroyl-L-arginine ethyl ester monohydrochloride, (LAE), a novel food preservative, or Mirenat-N (a 25% solution of LAE in propylene glycol). Short term studies demonstrated low acute toxicity. LAE was shown to have mild dermal irritation effects but neither LAE nor Mirenat-N are skin sensitizers. LAE was demonstrated to be a severe eye irritant. In two 13-week feeding studies in rats, systemic NOAELs were established for LAE at 15,000 ppm and for Mirenat-N at 50,000 ppm. There were no signs of neurotoxicity with LAE after 13-weeks at dietary levels as high as 50,000 ppm. Embryo-fetal studies with LAE in rats and rabbits showed no developmental effects at oral gavage doses up to 2000 and 1000 mg/kg/day for rats and rabbits, respectively. NOAELs for systemic maternal effects (reduced food intake and body weights in rabbits) were 2000 mg/kg/day for rats and 300 mg/kg/day for rabbits. In a battery of 5 in vitro genotoxicity tests with LAE or Mirenat-N, neither material was observed to have genotoxic (clastogenic or mutagenic) activity. Metabolism studies with LAE show that it is rapidly metabolized to the amino acid arginine by hydrolysis of the ethyl ester and lauroyl amide functions. The arginine subsequently enters the naturally occurring urea cycle where it is further metabolized to ornithine and urea and eventually to CO(2) through normal mammalian biochemical pathways. The other product of LAE cleavage is lauric acid, which is a human dietary component found in many plant sources, and as such, would enter into normal fatty acid metabolism.

Safety aspects regarding the consumption of high-dose dietary diacylglycerol oil in men and women in a double-blind controlled trial in comparison with consumption of a triacylglycerol control oil.

With the approval for use in foods in Japan and the United States, the use of diacylglycerol (DAG) oil in fat-based products may become extensive due to equivalent physicochemical properties to conventional triacylglycerol (TAG) oil. The objective of the present study was to compare the effects of high-dose consumption of DAG oil in humans with that of TAG oil. In a double-blind controlled parallel trial, moderately lean men (n=42) and women (n=39) consumed either DAG or TAG at a dose of approximately 0.5 g/kg body weight/day as part of their diet for 12 weeks. All subjects completing the study tolerated the test oils well and showed no overt effects. Total caloric and fat intake remained constant and showed no significant differences between the groups. There was no significant difference in the occurrence of clinical signs and physical complaints related to test oil consumption. Although some statistically significant effects were reported in hematological and serum chemistry parameters in both DAG and TAG groups, none of these reported changes were considered biologically significant. Overall, this 12-week clinical study revealed no significant or treatment-related adverse effects of DAG oil consumed at a dose of 0.5 g/kg of body weight/day as part of the diet.

Spontaneous renal tubular hyperplastic and neoplastic lesions in three Sprague-Dawley rats from a 90-day toxicity study.

Multiple renal tubular cell adenomas and atypical tubular hyperplasia were diagnosed in 2 high-dose and 1 mid-dose female Sprague-Dawley (Crl:CD (SD)IGS BR) rats from a 90-day toxicity study of an amino acid found in green tea. The tumors were bilateral multicentric adenomas accompanied by atypical foci of renal tubular hyperplasia in both kidneys of the 3 animals. Toxic tubular changes that typically accompany renal carcinogenesis were not seen in any of the other animals of the study, suggesting rather, an underlying germline mutation of a tumor suppressor gene in these three rats. The histological appearance of these tumors and short latency was reminiscent of the spontaneous lesions reported to arise in Sprague-Dawley rats in the Nihon rat model. Nihon rats develop kidney tumors as a result of a spontaneous mutation in the rat homologue of the Birt-Hogg-Dubé gene (Bhd). Frozen samples of liver from two tumor-bearing rats were assayed for germline alterations in the Bhd gene. The entire coding region (exons 3-13) of the Bhd gene was sequenced, and a guanine (nt106G) to adenine (nt106A) polymorphism was detected resulting in a glycine to arginine (G36R) substitution in both tumor-bearing animals. In the study animals, the frequency of the A-allele (adenine) was determined to be 27% (19/70). Interestingly, rats obtained from two other sources (n = 17) only carried the nt106G-allele, consistent with the published rat sequence for this gene. Genetic fingerprinting of microsatellite loci indicated that the rats had a shared genetic background. Laser capture microdissection (LCM) of the tumor cells demonstrated a loss of heterozygosity in the Bhd gene in neoplastic cells of one of the two animals. Taken together, these data suggest that the tumors observed in these animals arose spontaneously as a result of a shared genetic susceptibility leading to the development of renal tubular neoplasms.