Human exposure model-II : user's guide.

Mode of access: Internet.

Environmental carcinogens and human cancer : estimation of exposure to carcinogens in the ambient air /

Sponsored by Health Effects Research Laboratory, Research Triangle Park, N.C.

An SAB report : human exposure assessment : a guide to risk ranking, risk reduction, and research planning /

"EPA-SAB-IAQC-95-005."

Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects

Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 mug/g and 3.8 mug/g creatinine and these subjects faced 10-15% increase in the probability of having abnormal urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (chi(2) = 22, P < 0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r = 0.48 P < 0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r = 0.46 to 0.54. P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary CA excretion accounted for 25% of the total variation in urine 7-OHC excretion (P < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Intervention Trial to Assess Arsenic Exposure from Food Crops in Bangladesh

The authors assessed the contribution of food irrigated with arsenic-contaminated water to human exposure to arsenic in Bangladesh. An intervention trial was conducted in a village in the Jessore District of Bangladesh, where irrigation water had been field-tested in March 2000 and was found to contain arsenic with concentrations ranging from 100 to 500 mu g/l. In May 2000, a random sample of 63 households was selected from the village, and I eligible person from each household was recruited to the study and randomized to an intervention or control group. The intervention group received food purchased from a village where irrigation water was found to contain 100 mu g/l arsenic. Pre- and postintervention urine samples were collected for urinary arsenic speciation assays. Preintervention, the mean urinary total arsenic concentrations were 139.25 mu g/l and 129.15 mu g/l for the intervention and control groups, respectively. These concentrations did not change significantly following intervention. Arsenic concentrations in samples of selected raw and cooked foods from the low-contamination area did not contain less arsenic than samples from the high-contamination area. Further studies to investigate the arsenic content of food grown in areas with high and low arsenic contamination of irrigation water are recommended.

Cytotoxic T-lymphocyte epitope vaccination protects against human metapneumovirus infection and disease in mice

Human metapneumovirus (hMPV) has emerged as an important human respiratory pathogen causing upper and lower respiratory tract infections in young children and older adults. In addition, hMPV infection is associated with asthma exacerbation in young children. Recent epidemiological evidence indicates that hMPV may cocircullate with human respiratory syncytial virus (hRSV) and mediate clinical disease similar to that seen with hRSV. Therefore, a vaccine for hMPV is highly desirable. In the present study, we used predictive bioinformatics, peptide immunization, and functional T-cell assays to define hMPV cytotoxic T-lymphocyte (CTL) epitopes recognized by mouse T cells restricted through several major histocompatibility complex class I alleles, including HILA-A*0201. We demonstrate that peptide immunization with hMPV CTL epitopes reduces viral load and immunopathollogy in the lungs of hMPV-challenged mice and enhances the expression of Th1-type cytokines (gamma interferon and interleukin-12 [IL-12]) in lungs and regional lymph nodes. In addition, we show that levels of Th2-type cytolkines (IL-10 and IL-4) are significantly lower in hMPV CTL epitope-vaccinated mice challenged with hMPV. These results demonstrate for the first time the efficacy of an hMPV CTL epitope vaccine in the control of hMPV infection in a murine model.

Attentional changes in pre-stimulus oscillatory activity within early visual cortex are predictive of human visual performance

Physiological and neuroimaging studies provide evidence to suggest that attentional mechanisms operating within the fronto-parietal network may exert top–down control on early visual areas, priming them for forthcoming sensory events. The believed consequence of such priming is enhanced task performance. Using the technique of magnetoencephalography (MEG), we investigated this possibility by examining whether attention-driven changes in cortical activity are correlated with performance on a line-orientation judgment task. We observed that, approximately 200 ms after a covert attentional shift towards the impending visual stimulus, the level of phase-resetting (transient neural coherence) within the calcarine significantly increased for 2–10 Hz activity. This was followed by a suppression of alpha activity (near 10 Hz) which persisted until the onset of the stimulus. The levels of phase-resetting, alpha suppression and subsequent behavioral performance varied between subjects in a systematic fashion. The magnitudes of phase-resetting and alpha-band power were negatively correlated, with high levels of coherence associated with high levels of performance. We propose that top–down attentional control mechanisms exert their initial effects within the calcarine through a phase-resetting within the 2–10 Hz band, which in turn triggers a suppression of alpha activity, priming early visual areas for incoming information and enhancing behavioral performance.

The role of tissue transglutaminase in 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in differentiated human SH-SY5Y neuroblastoma cells

Tissue transglutaminase (TG2) can induce post-translational modification of proteins, resulting in protein cross-linking or incorporation of polyamines into substrates, and can also function as a signal transducing G protein. The role of TG2 in the formation of insoluble cross-links has led to its implication in some neurodegenerative conditions. Exposure of pre-differentiated SH-SY5Y cells to the Parkinsonian neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) resulted in significant dose-dependent reductions in TG2 protein levels, measured by probing Western blots with a TG2-specific antibody. Transglutaminase (TG) transamidating activity, on the other hand, monitored by incorporation of a polyamine pseudo-substrate into cellular proteins, was increased. Inhibitors of TG (putrescine) and TG2 (R283) exacerbated MPP+ toxicity, suggesting that activation of TG2 may promote a survival response in this toxicity paradigm.

A study of the calcium-induced morphological transistions of human erythrocytes

An examination was made of the morphological transitions induced in human erythrocytes by the elevation of cytosolic calcium, and of the biochemical mechanisms responsible. The loss of the discocyte morphology and the sequential progression of cells through the echinocyte stages 1, 2, 3 and sphereo-echinocyte was found to occur in both a calcium concentration- and a time-dependent manner. SDS-PAGE analysis of cytoskeletal proteins prepared from intact cells loaded with 150uM or 1mM calcium revealed the partial proteolytic loss of proteins 2.1, 2.2 and 4.1. The rate of proteolysis was not paralleled by that of echinocytosis, making a causative relationship unlikely. Cytoskeletal integrity did appear to influence shape reversal from the echinocyte to the discocyte morphology after removal of the calcium and ionophore A23187. The loss of 80% protein 4.1, 40% 2.1 and 30% 2.2 was associated with, although not necessarily the sole cause, of irreversible sphereo-echinocytosis. Pre-treatment of cells with wheat germ agglutinin preserved the discocyte morphology despite continued cytoskeletal proteolysis during calcium-loading. All observations were made on cells incubated either in the presence or absence of glycolytic substrates, effectively altering cell metabolic status. This influenced the rate of progression of cells through the echinocyte stages, the rate of proteolysis of cytoskeletal proteins, and the extent and kinetics of shape reversal from cells transformed to the sphereo-echinocyte morphology. The stage 1 to discocyte transition was the rate limiting step of this shape recovery. In contrast the rate of loss of the discocyte morphology was independent of cell metabolic status during exposure to calcium, as was the extent of restoration of the discocyte morphology from cells transformed to stage 1 echinocytes. An hypothesis is presented that echinocytosis is a discontinuous process with discrete steps initiated by different biochemical mechanisms varying in their dependence on metabolic energy.