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.     

Skin involvement in juvenile dermatomyositis is associated with loss of end row nailfold capillary loops

OBJECTIVE: To determine associations of dermatological findings in children with juvenile dermatomyositis (JDM) with specific nailfold capillary (NFC) structural abnormalities. METHODS: Sixty newly diagnosed, previously untreated children who met the Bohan-Peter criteria for definite JDM were seen between 1993 and 2002. They were classified by duration of untreated disease and by a disease activity score (DAS) composed of separate subscores for dermatological (DAS skin) and musculoskeletal (DAS muscle) findings. Routine NFC measurements yielded the number of end row loops, arboreal (bushy), and dilated capillary loops. Laboratory testing included muscle enzymes, von Willebrand Factor Antigen, and neopterin. RESULTS: DAS skin, but not DAS muscle, was associated with NFC end row capillary loss (rs = -0.394, p = 0.008). End row capillary loss (reflecting avascularity), arboreal (bushy), and dilated capillary loops (reflecting change in vascular morphology) were each associated with longer untreated symptom duration (rs = -0.401, rs = 0.534, rs = 0.371). CONCLUSION: End row capillary loss measured by NFC was associated with the dermatological, but not musculoskeletal manifestations of JDM, suggesting that damage to skin and muscle may each have distinct disease pathophysiology. In JDM, skin involvement indicates a vasculopathy that progresses with increasing duration of untreated disease and is not revealed by standard serological laboratory tests. We propose that the cutaneous manifestations of JDM are associated with vascular disease and warrant aggressive therapy.     

In vivo metabolism of the designer anabolic steroid hemapolin in the thoroughbred horse

Hemapolin (2α,3α‐epithio‐17α‐methyl‐5α‐androstan‐17β‐ol) is a designer steroid that is an ingredient in several “dietary” and “nutritional” supplements available online. As an unusual chemical modification to the steroid A‐ring could allow this compound to pass through antidoping screens undetected, the metabolism of hemapolin was investigated by an in vivo equine drug administration study coupled with GC‐MS analysis. Following administration of synthetically prepared hemapolin to a thoroughbred horse, madol (17α‐methyl‐5α‐androst‐2‐en‐17β‐ol), reduced and dihydroxylated madol (17α‐methyl‐5α‐androstane‐2β,3α,17β‐triol), and the isomeric enone metabolites 17β‐hydroxy‐17α‐methyl‐5α‐androst‐3‐en‐2‐one and 17β‐hydroxy‐17α‐methyl‐5α‐androst‐2‐en‐4‐one, were detected and confirmed in equine urine extracts by comparison with a library of synthetically derived reference materials. A number of additional madol derivatives derived from hydroxylation, dihydroxylation, and trihydroxylation were also detected but not fully identified by this approach. A yeast cell‐based androgen receptor bioassay of available reference materials showed that hemapolin and many of the metabolites identified by this study were potent activators of the equine androgen receptor. This study reveals the metabolites resulting from the equine administration of the androgen hemapolin that can be incorporated into routine GC‐MS antidoping screening and confirmation protocols to detect the illicit use of this agent in equine sports.     

Immune and Inflammatory Determinants Underlying Alzheimer’s Disease Pathology

Journal of Neuroimmune Pharmacology - This study examines the link between peripheral immune changes in perpetuation of the Alzheimer’s disease (AD) neuropathology and cognitive deficits. Our...     

Functional MT + lesion impairs contralateral motion processing

Human motion processing region MT + is retinotopically organized with perception of and attention to motion in the right visual field preferentially associated with left MT + activity and vice versa. However, the degree to which MT + is crucial for motion processing is uncertain. We report an epilepsy patient with visual symptoms early in his seizure evolution and a left temporal-occipital seizure onset electrographically in whom we hypothesized a functional left MT + lesion. The patient was impaired in his right but not left visual field on a hemifield motion attention task and demonstrated worse performance on a hemifield picture identification task when pictures implying motion were presented in the right as opposed to the left visual field. Functional MRI (fMRI) during a full-field motion detection task activated right MT + but failed to activate left MT + despite activating both left and right MT + in each of 10 controls. Furthermore, fMRI during a hemifield motion attention task also showed a lack of left MT + attention effects in the patient. Together these results suggest that MT + is necessary for normal motion processing.