Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment

Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2‐year bioassay for TBBPA. The objective of the present study was to develop a cancer‐based and a non‐cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2‐year and 13‐week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg^?1 day^?1 based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg^?1 day^?1 based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E^?7 to 3.9 E^?6 mg kg^?1 day^?1 based on age‐adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E ^?7 to 8.4 E^?5 mg kg^?1 day^?1. Resulting margin of exposure (MOE) values were > 800 000 for non‐cancer endpoints and > 32 000 000 for cancer‐based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA. Copyright © 2015. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.     

West Nile Virus Infection Incidence Based on Donated Blood Samples and Neuroinvasive Disease Reports,Northern Texas,USA, 2012

During the 2012 outbreak of West Nile virus in the United States, approximately one third of the cases were in Texas. Of those, about half occurred in northern Texas. Models based on infected blood donors and persons with neuroinvasive disease showed, respectively, that ≈0.72% and 1.98% of persons in northern Texas became infected.     

Molecular analysis of R-factors from multiresistant nosocomial isolates

During an epidemic of infections at the Seattle Veterans Hospital, Washington, due to a multiresistant strain of Serratia marcencens, other enteric species were isolated that had antibiograms nearly identical to those of the epidemic S. marcescens. In 11 instances, these multiresistant species were isolated from specimens that also contained the epidemic serratia strain. All isolates of the epidemic serratia strain contained a conjugative 45-megadalton R-factor (pLST1000) coding for intermediate resistance to three amino-glycosides (minimal inhibitory concentrations, 4--8 micrograms/ml) and high-level resistance to ampicillin, carbenicillin, cephalothin, streptomycin, and sulfonamide. With the use of agarose gel electrophoresis and restriction endonuclease cleavage patterns after digestion with EcoRI, BamH1, and HindIII, it was determined that eight different enteric strains of six different species isolated from the patients contained an R-factor that was molecularly identical to the one isolated from the epidemic strain of S. marcescens. Thus, the epidemic of multiresistant infections at this hospital was caused both by the spread of an epidemic strain and an "epidemic plasmid." The molecular characteristics of pLST1000 appear to be different from previously described multiresistant plasmids.     

A new measure of health status for clinical trials in inflammatory bowel disease

We have developed a measure of subjective health status (quality of life) for patients with inflammatory bowel disease (IBD). Ninety-seven patients with IBD described problems they had experienced as a result of the disease; the 32 most frequent and important items were included in the Inflammatory Bowel Disease Questionnaire (IBDQ). Sixty-one IBD patients were evaluated twice. One month separated the evaluations, at which disease activity indices, the IBDQ, and a number of other questionnaires were administered. Reproducibility studies in 19 stable patients showed improvement in scores, but also a small within-person standard deviation. Responsiveness studies revealed large changes in scores in patients who had improved or deteriorated and suggested that the IBDQ was more responsive than a general health status measure. Responsiveness appeared greater in patients with ulcerative colitis than in those with Crohn's disease. Predicted and observed correlations between changes in IBDQ score and changes in other measures were similar. We conclude that although further testing is required, particularly in examining the relation between changes in the IBDQ and changes in the activity of Crohn's disease, the IBDQ shows promise as a measure of health status for clinical trials in IBD.     

Kidney and liver transplantation in HIV-infected patients: case presentations and review

Until recently, HIV-infected patients have been excluded from consideration for solid organ transplantation. The relatively high mortality rates among HIV-infected transplant recipients observed in the era prior to the use of highly active antiretroviral therapy (HAART), coupled with long waiting times for cadaveric organs, made it difficult to support organ transplantation in this patient group. However, in response to the marked reductions in morbidity and mortality associated with HIV infection, several transplant centers have developed pilot studies or revised their clinical criteria to allow transplantation in this group of patients. We describe two cases, one kidney and one liver transplant recipient, and review the major clinical and research issues related to this topic. Reports of transplantations in the pre-HAART era highlight two important findings. First, some HIV-infected transplant recipients did very well with long survival periods. However, overall progression to AIDS and death appeared accelerated. We recently reported on our preliminary experience with 45 selected transplant recipients in the HAART era. One-year patient survival rates were similar to unmatched survival data from the United Network for Organ Sharing (UNOS) database. Median CD4+ T-cell counts remained stable in the follow-up period compared to pretransplant. HIV-1 RNA nearly uniformly continued to be suppressed below the limits of detection. Preliminary data are promising and support the current efforts to evaluate patient and graft survival among HIV-infected transplant recipients and to explore the mechanisms underlying the many potential complications of transplantation in this population.     

Quality of life in patients with inflammatory bowel disease

To investigate the effect of inflammatory bowel disease (IBD) on the quality of life, we interviewed 43 patients with ulcerative colitis (UC) and 54 with Crohn's disease. Patients identified frequent and important problems in five areas. Primary bowel symptoms, systemic symptoms, and altered emotional function were common; functional and social impairment were less frequent. Systemic symptoms such as fatigue were more prevalent in patients with Crohn's disease. Apart from primary bowel complaints, patients seldom volunteered other facets of quality of life impairment; this was particularly true for impairment of emotional function. We conclude that despite troublesome intestinal and systemic symptoms, most patients with IBD avoid major disruption in work and personal lives. Physicians must inquire specifically about emotional problems relating to IBD; in particular, fear of surgery is important to address. Psychosocial interventions should be targeted to those patients with problems in this area.     

Amphotropic or Gibbon Ape Leukemia Virus Retrovirus Binding and Transduction Correlates with the Level of Receptor mRNA in Human Hematopoietic Cell Lines

ABSTRACT: The low level of amphotropic retrovirus mediated gene transfer into human hematopoietic stem cells (HSC) has been an impediment to gene therapy for hematopoietic diseases (1). We have previously shown that mouse and human HSC have low levels of the mRNA encoding PiT-2, the amphotropic retrovirus receptor. We hypothesized that the low level of PiT-2 mRNA was responsible for the low frequency of transduction of HSC by amphotropic retroviral vectors (2). In this study we compared the level of PiT-2 and PiT-1, the Gibbon Ape Leukemia Virus receptor (GaLV), in 5 human tissue culture cell lines. PiT-2 and PiT-1 mRNA levels were highest in K562 cells and lowest in HL60 cells. In hematopoietic cell lines, the level of PiT-2 or PiT-1 mRNA correlated directly with retrovirus binding and transduction with the appropriate (amphotropic or GaLV) retrovirus vector. The level of expression of PiT-2 and PiT-1 mRNA could be increased by treatment of HL60 cells with either PMA or Interleukin-1α. The increase in the level of PiT-2 and PiT-1 mRNA correlated with increased transduction with both amphotropic and GaLV retroviral vectors. We conclude that the improved transduction was a direct effect of the increased levels of receptor mRNA and unrelated to changes in the cell cycle status.