The Speciation of Metals in Mammals Influences Their Toxicokinetics and Toxicodynamics and Therefore Human Health Risk Assessment

Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is reviewed to illustrate how the physicochemical characteristics of metals and their handling in the body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury, arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal speciation, uptake, and toxicity are evaluated. A classification system is presented to show that the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics. Essential metals, such as iron, are considered. These metals produce low oral toxicity under most exposure conditions but become toxic when biological processes that utilize or transport them are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because speciation can influence a metal\u27s fate and toxicity, different exposure standards should be established for different metal species. Many examples are provided which consider metal essentiality and toxicity and that illustrate how consideration of metal speciation can improve the risk assessment process. More examples are available at a website established as a repository for summaries of the literature on how the speciation of metals affects their toxicokinetics

Aluminum and Phosphorus Separation: Application to Preparation of Target from Brain Tissue for \u3csup\u3e26\u3c/sup\u3eAl Determination by Accelerator Mass Spectrometry

Acid digested brain containing 4 mg added 27Al was ashed at 1000°C to prepare an Al2O3 target for accelerator mass spectrometry (AMS) analysis of 26Al. A glass-like material usually resulted which was thought to be aluminum (Al) oxyphosphate. The separation of Al and phosphate was investigated. Al, but not phosphate, was bound by a cation exchange resin (AG 50-X8). Hydrofluoric acid eluted the Al from the resin. Removal of phosphate from acid digested brain by this method produced an amorphous material after ashing that was easier to recover from the porcelain crucible and had a higher AMS beam current. This procedure to separate Al from phosphate may have utility in other applications

Binding, Transcytosis and Biodistribution of Anti-PECAM-1 Iron Oxide Nanoparticles for Brain-Targeted Delivery

OBJECTIVE: Characterize the flux of platelet-endothelial cell adhesion molecule (PECAM-1) antibody-coated superparamagnetic iron oxide nanoparticles (IONPs) across the blood-brain barrier (BBB) and its biodistribution in vitro and in vivo. METHODS: Anti-PECAM-1 IONPs and IgG IONPs were prepared and characterized in house. The binding affinity of these nanoparticles was investigated using human cortical microvascular endothelial cells (hCMEC/D3). Flux assays were performed using a hCMEC/D3 BBB model. To test their immunospecificity index and biodistribution, nanoparticles were given to Sprague Dawley rats by intra-carotid infusion. The capillary depletion method was used to elucidate their distribution between the BBB and brain parenchyma. RESULTS: Anti-PECAM-1 IONPs were ~130 nm. The extent of nanoparticle antibody surface coverage was 63.6 ± 8.4%. Only 6.39 ± 1.22% of labeled antibody dissociated from IONPs in heparin-treated whole blood over 4 h. The binding affinity of PECAM-1 antibody (KD) was 32 nM with a maximal binding (Bmax) of 17 × 10(5) antibody molecules/cell. Anti-PECAM-1 IONP flux across a hCMEC/D3 monolayer was significantly higher than IgG IONP\u27s with 31% of anti-PECAM-1 IONPs in the receiving chamber after 6 h. Anti-PECAM-1 IONPs showed higher concentrations in lung and brain, but not liver or spleen, than IgG IONPs after infusion. The capillary depletion method showed that 17±12% of the anti-PECAM-1 IONPs crossed the BBB into the brain ten minutes after infusion. CONCLUSIONS: PECAM-1 antibody coating significantly increased IONP flux across the hCMEC/D3 monolayer. In vivo results showed that the PECAM-1 antibody enhanced BBB association and brain parenchymal accumulation of IONPs compared to IgG. This research demonstrates the benefit of anti-PECAM-1 IONPs for association and flux across the BBB into the brain in relation to its biodistribution in peripheral organs. The results provide insight into potential application and toxicity concerns of anti-PECAM-1 IONPs in the central nervous system

Manganese Distribution across the Blood-Brain Barrier. I. Evidence for Carrier-Mediated Influx of Managanese Citrate as well as Manganese and Manganese Transferrin

Manganese (Mn) is an essential element and a neurotoxicant. Regulation of Mn movement across the blood–brain barrier (BBB) contributes to whether the brain Mn concentration is functional or toxic. In plasma, Mn associates with water, small molecular weight ligands and proteins. Mn speciation may influence the kinetics of its movement through the BBB. In the present work, the brain influx rates of 54Mn2+, 54Mn citrate and 54Mn transferrin (54Mn Tf) were determined using the in situ brain perfusion technique. The influx rates were compared to their predicted diffusion rates, which were determined from their octanol/aqueous partitioning coefficients and molecular weights. The in situ brain perfusion fluid contained 54Mn2+, 54Mn citrate or 54Mn Tf and a vascular volume/extracellular space marker, 14C-sucrose, which did not appreciably cross the BBB during these short experiments (15–180 s). The influx transfer coefficient (Kin) was determined from four perfusion durations for each Mn species in nine brain regions and the lateral ventricular choroid plexus. The brain Kin was (5–13)×10−5, (3–51)×10−5, and (2–13)×10−5 ml/s/g for 54Mn2+, 54Mn citrate, and 54Mn Tf, respectively. Brain Kin values for any one of the three Mn species generally did not significantly differ among the nine brain regions and the choroid plexus. However, the brain Kin for Mn citrate was greater than Mn2+ and Mn Tf Kin values in a number of brain regions. When compared to calculated diffusion rates, brain Kin values suggest carrier-mediated brain influx of 54Mn2+, 54Mn citrate and 54Mn Tf. 55Mn citrate inhibited 54Mn citrate uptake, and 55Mn2+ inhibited 54Mn2+ uptake, supporting the conclusion of carrier-mediated brain Mn influx. The greater Kin values for Mn citrate than Mn2+ and its presence as a major non-protein-bound Mn species in blood plasma suggest Mn citrate may be a major Mn species entering the brain

Distribution and Movements of the Teshekpuk Caribou Herd 1990–2005: Prior to Oil and Gas Development

Four caribou (Rangifer tarandus grantii) herds calve on the North Slope of Alaska, three of which have been exposed to little or no resource development. We present 15 years of baseline data on the distribution and movements of 72 satellite-collared and 10 GPS-collared caribou from the Teshekpuk caribou herd (TCH) that have had little to no exposure to oil and gas activities. Fixed-kernel home range analyses of collared caribou revealed that calving grounds were concentrated (i.e., 50% kernel utilization distribution) along the northeastern, eastern, and southeastern shores of Teshekpuk Lake. During the postcalving period, 51% and 35% of caribou moved through two constricted zones to the east and west of Teshekpuk Lake, respectively, and accessed insect-relief habitat along the Beaufort Sea coast. During late summer and early fall, TCH caribou were concentrated to the southeast and southwest of Teshekpuk Lake. Although 65% of the Teshekpuk caribou wintered in two areas on the central coastal plain around the village of Atqasuk and south of Teshekpuk Lake, other TCH animals wintered in a great variety of places, including the Seward Peninsula, the eastern and southern Brooks Range, and the Arctic National Wildlife Refuge. We detected an apparent emigration rate of 6.9%. One male and five female TCH caribou joined the breeding populations of the Western Arctic and Central Arctic herds. TCH caribou traveled an average distance of 2348 ± 190 km annually. Movement rates were at a maximum in midsummer, lowest in winter, and intermediate during spring and fall migrations. Restrictions on oil and gas leasing and surface occupancy have been in place to protect calving, migratory corridors, and insect-relief habitat for the TCH, but these protections are likely to be removed. These data will provide a good baseline that can be used to compare predevelopment distribution and movement patterns of TCH caribou to distribution and movement patterns during and after petroleum development.Quatre hardes de caribous (Rangifer tarandus grantii) vêlent sur la côte nord de l’Alaska, dont trois de ces hardes ont été exposées à peu ou pas d’aménagement des ressources. Nous présentons des données de base échelonnées sur 15 ans relativement à la répartition et aux déplacements de 72 caribous dotés d’un collier émetteur par satellite et de 10 caribous munis d’un collier émetteur GPS de la harde de caribous de Teshekpuk (HCT), caribous qui ont été peu ou pas du tout frottés aux activités pétrolières et gazières. L’analyse du noyau fixe des domaines vitaux des caribous à collier a révélé que les lieux de vêlage étaient concentrés (c’est-à-dire 50 % de la répartition de l’utilisation du noyau) le long des côtes nord-est, est et sud-est du lac Teshekpuk. Après la période de vêlage, 51 pour cent et 35 pour cent des caribous se déplaçaient au sein de deux zones de constriction à l’est et à l’ouest du lac Teshekpuk, respectivement, et accédaient un habitat où se trouvait moins d’insectes sur la côte de la mer de Beaufort. Vers la fin de l’été et le début de l’automne, les caribous de la HCT étaient concentrés au sud-est et au sud-ouest du lac Teshekpuk. Bien que 65 pour cent des caribous de Teshekpuk passaient l’hiver dans deux régions de la plaine côtière centrale autour du village d’Atqasuk et au sud du lac Teshekpuk, les autres bêtes de la HCT passaient l’hiver dans divers endroits, dont la péninsule de Seward, les versants est et sud des montagnes de Brooks et la Réserve faunique nationale de l’Arctique. Nous avons détecté un taux d’émigration apparent de 6,9 pour cent. Un caribou mâle et cinq caribous femelles de la HCT ont rejoint les populations de reproduction des hardes de l’ouest et du centre de l’Arctique. En moyenne, le caribou de la HCT parcourait une distance de 2348 ± 190 km annuellement. Les taux de déplacement étaient à leur point le plus élevé au milieu de l’été, tandis qu’ils étaient à leur niveau le plus bas l’hiver et à un niveau intermédiaire pendant les migrations du printemps et de l’automne. Il existe des restrictions en matière de location et d’occupation en surface pour le pétrole et le gaz afin de protéger le vêlage, les corridors de migration et les habitats à faible taux d’insectes pour la HCT, mais il est vraisemblable que ces restrictions soient éliminées. Ces données fourniront une bonne base pour comparer la répartition et les déplacements du caribou de la HCT avant la mise en valeur des ressources à la répartition et aux déplacements du caribou de la HCT pendant et après la mise en valeur pétrolière

Use of satellite telemetry data, GIS, and HTML to create an interactive display of caribou movements

The use of animation clearly reveals the large annual variation in wintering areas and large differences in daily movement rates for this herd. This interactive display can be adapted for school groups, subsistence hunters, the general public, or scientists

Use of satellite telemetry to evaluate movements of caribou within subsistence hunting areas in northern Alaska

Caribou from the Teshekpuk Herd (TH) are an important subsistence resource for residents of Inupiaq villages in northern Alaska. In recent years the use of satellite telemetry has increased the understanding of the herd's annual movements and interactions with other herds. Most caribou of the TH are within the National Petroleum Reserve—Alaska (NPRA) throughout the year. The northeastern portion of NPRA has undergone two lease sales for oil and gas exploration, and lease sales are tentatively scheduled for the central/northwest portion of the NPRA in 2004. During 1990—1999, the movements of 27 caribou from the TH were tracked using satellite collars. We evaluated the proportion of time caribou were available to Inupiaq hunters by incorporating maps depicting subsistence-use areas for each of seven Inupiaq villages, and then examining seasonal and annual movements of caribou relative to those areas. By combining caribou locations with subsistence hunting areas, we were able to explore spatial and temporal patterns in caribou availability to subsistence hunters. This information is useful for managers to set appropriate hunting regulations and for devising sensible alternatives and mitigation of likely petroleum development in NPRA

Cerium dioxide, a Jekyll and Hyde nanomaterial, can increase basal and decrease elevated inflammation and oxidative stress

It was hypothesized that the catalyst nanoceria can increase oxidative stress/inflammation from the basal state and reduce it from the elevated state . Nanoceria are cleared by macrophages. To test the hypothesis, M0 (non-polarized), M1- (classically activated, pro-inflammatory), and M2-like (alternatively activated, regulatory phenotype) RAW 264.7 macrophages were nanoceria exposed. Responses were quantified by arginase activity, IL-1ß level, cell oxygen consumption rate (OCR), the glycolysis stress test (GST), morphology determined by light microscopy, macrophage phenotype marker expression and morphology using a novel three dimensional immunohistochemical method, and RT-qPCR. Nanoceria blocked arginase and IL-1ß effects, increased M0 cell OCR and GST toward the M2 phenotype and altered multiple M1- and M2-like cell endpoints toward the M0 level. M1-like cells had greater volume and less circularity/roundness, and the M2-like cells had greater volume than M0 macrophages. Nanoceria converted M1- and M2-like cells toward M0 morphology. The results are overall consistent with the hypothesis

Disease-Toxicant Interactions in Manganese Exposed Huntington Disease Mice: Early Changes in Striatal Neuron Morphology and Dopamine Metabolism

YAC128 Huntington's disease (HD) transgenic mice accumulate less manganese (Mn) in the striatum relative to wild-type (WT) littermates. We hypothesized that Mn and mutant Huntingtin (HTT) would exhibit gene-environment interactions at the level of neurochemistry and neuronal morphology. Twelve-week-old WT and YAC128 mice were exposed to MnCl2-4H2O (50 mg/kg) on days 0, 3 and 6. Striatal medium spiny neuron (MSN) morphology, as well as levels of dopamine (DA) and its metabolites (which are known to be sensitive to Mn-exposure), were analyzed at 13 weeks (7 days from initial exposure) and 16 weeks (28 days from initial exposure). No genotype-dependent differences in MSN morphology were apparent at 13 weeks. But at 16 weeks, a genotype effect was observed in YAC128 mice, manifested by an absence of the wild-type age-dependent increase in dendritic length and branching complexity. In addition, genotype-exposure interaction effects were observed for dendritic complexity measures as a function of distance from the soma, where only YAC128 mice were sensitive to Mn exposure. Furthermore, striatal DA levels were unaltered at 13 weeks by genotype or Mn exposure, but at 16 weeks, both Mn exposure and the HD genotype were associated with quantitatively similar reductions in DA and its metabolites. Interestingly, Mn exposure of YAC128 mice did not further decrease DA or its metabolites versus YAC128 vehicle exposed or Mn exposed WT mice. Taken together, these results demonstrate Mn-HD disease-toxicant interactions at the onset of striatal dendritic neuropathology in YAC128 mice. Our results identify the earliest pathological change in striatum of YAC128 mice as being between 13 to 16 weeks. Finally, we show that mutant HTT suppresses some Mn-dependent changes, such as decreased DA levels, while it exacerbates others, such as dendritic pathology

Cocaine, d -amphetamine, and pentobarbital effects on responding maintained by food or cocaine in rhesus monkeys

The effects of IM injections of cocaine, d -amphetamine, and pentobarbital were studied in rhesus monkeys whose lever-press responding was maintained under a second-order fixed-interval, fixed ratio schedule of reinforcement. Within each session, fixed-interval components, ending with the IV injection of 30 μg/kg cocaine (one group of monkeys) or the delivery of a 300 mg food pellet (second group of monkeys), alternated with fixed-interval components ending without an injection of cocaine or the delivery of food (extinction). Drug pretreatments generally caused comparable dose-related decreases in the overall rates of responding reinforced either by cocaine or by food. Response rates during extinction usually increased and then decreased as the dose of each drug increased. An analysis of the drug effects on response rates in different temporal segments of the fixed intervals showed that in both the reinforcement and extinction components, the normally low control rates of responding which occurred earlier in the intervals were usually increased, while higher control rates which occurred later in the intervals were increased less or decreased. Thus, the effects of these drugs were relatively independent of the reinforcing event (food or cocaine) and tended to depend more on the ongoing rate of responding under these conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46409/1/213_2004_Article_BF00427508.pd