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Patients with chronic pain disorders frequently show nondermatomal somatosensory deficits (NDSDs) that are considered to be functional. Typically, NDSDs show quadratomal or hemibody distribution ipsilateral to the areas of chronic pain. According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition and the International Classification of Diseases, 10th revision, such functional somatosensory deficits are classified in the chapter "conversion disorder." Many publications also used the term "hysterical sensory loss." However, doubts are increasing about this one-sided psychiatric view. We aimed to better characterize the biopsychosocial factors associated with NDSDs. Therefore, we compared 2 groups of inpatients with chronic pain disorder, of whom 90 suffered from NDSDs and 90 did not. The patients with NDSDs all showed widespread somatosensory deficits with hemibody distribution. On logistic regression analysis, history of a prior physical trauma was positively predictive for patients with NDSDs. Personality disorder and adverse childhood experiences were positively predictive for the control group with chronic pain disorders without NDSDs. The frequencies of comorbid depression and anxiety disorder did not differ statistically between groups. In conclusion, pain patients with NDSDs are, psychopathologically, by no means more noticeable personalities than patients with chronic pain disorder without NDSDs. Similar to complex regional pain syndromes, we assume a multifactorial etiology of NDSDs, including stress. Based on our observations, terms like "hysteric" should not be applied any longer to patients with NDSDs who suffer from chronic pain.

Patients with chronic pain disorders often show somatosensory disturbances that are considered to be functional. This paper aims at a more precise clinical description and at a documentation of functional neuroimaging correlates of this phenomenon. We examined 30 consecutive patients with unilaterally accentuated chronic pain not explained by persistent peripheral tissue damage and ipsilateral somatosensory disturbances including upper and lower extremities and trunk. The patients were assessed clinically and with conventional brain CT or MRI scan. In the last 11 patients functional neuroimaging was carried out (18-fluordeoxyglucose positron emission tomography=FDG-PET). Depressive symptoms were assessed with the Hamilton depression scale (HAMD-17) and pain intensity was rated with a visual analogue scale for pain (VAS). All patients suffered from mild to moderate depressive symptoms. All patients had experienced a prolonged antecedent phase of severe emotional distress; most of them remembered a "trigger episode of somatic pain" on the affected side. Somatosensory deficits were a replicable hyposensitivity to touch and heat perception of nondermatomal distribution. Conventional imaging procedures (brain CT or MRI scans) showed no structural changes. However, in 11 patients functional imaging with FDG-PET showed a significant hypometabolic pattern of changes in cortical and subcortical areas, mainly in the post-central gyrus, posterior insula, putamen, and anterior cingulate cortex. In summary, pain-related nondermatomal somatosensory deficits (NDSDs) are a phenomenon involving biological as well as psychosocial factors with replicable neuroperceptive clinical findings and a complex neurodysfunctional pattern in the FDG-PET.

OBJECTIVES: The purpose of this study is to evaluate (a) health-related quality of life (HRQL) after vertical banded gastroplasty (VBG) (Mason) and (b) predictors of HRQL. SUBJECTS: Eighty-two consecutive patients were assessed preoperatively and then after 6, 12 and 24 months. Patients filled out questionnaires for subjective appraisal of HRQL (physical well-being, mood, physical performance, perceived health, social support and coping/adjustment). RESULTS: The greatest improvement in weight and HRQL was seen within 6 months of surgery. Twenty-four months after VBG weight reduction (P

Animal research has indicated that the activity of the hypothalamic-pituitary-adrenal axis can be influenced by classical (Pavlovian) conditioning procedures. To test the hypothesis that alterations in plasma cortisol levels can be conditioned in humans, the present study used a prospective, randomized, double-blind, placebo-controlled design in which a distinctively flavored beverage was paired with p.o. administration of dexamethasone. Twenty-five healthy men were randomly assigned to one of two groups. During the conditioning phase of the study, subjects in the experimental group received three conditioning trials (pairings of a distinctively flavored beverage with a capsule containing 5 mg dexamethasone) separated by 1 wk recovery periods. Subjects in the control group were treated identically, except that the capsule contained a placebo. During the test phase, all subjects underwent a test day (reexposure to the distinctively flavored beverage before receiving a placebo capsule) and a comparison day (no exposure to the beverage or the capsule). Plasma cortisol was assessed repetitively before and after administration of the beverage and capsule, as were possible confounding factors, including: behavioral variables, psychological distress, aversive reactions to the beverage, and expectations of treatment. After reexposure to the beverage and administration of a placebo capsule (conditioned stimuli), the experimental group had significantly higher levels of plasma cortisol than the control group, after controlling for variability in baseline levels of cortisol (F(5,60)=3.09; P=0.015) that could not be explained by differences in other study variables. No differences in cortisol levels were found on the comparison day. These results support the study hypothesis that changes in plasma cortisol levels can be classically conditioned in humans by pairing a distinctive beverage with p.o. administration of dexamethasone.

Four subjects working in sharpening and grinding operations of hard metal tools were examined. Only 1 worker, a 37-year-old female exposed for 7 years to hard metal dusts, developed hard metal pneumoconiosis, which rapidly progressed to death. Cytology of the bronchoalveolar lavage (BAL) showed a high number of eosinophils, more than 30% of the cell population. Biopsy of the lung revealed interstitial fibrosis with hyperplasia of the pneumocytes of the second type and inflammatory cellular infiltration of the interstitium. High tungsten (W) and tantalum concentrations were determined in the admission BAL and in the biopsy 4 months later by neutron activation analysis while cobalt (Co) levels were near to normal values. The content of Co and W in blood and urine and particularly in pubic hair and toe nails of the patients was significantly higher than the normal values. This suggests that these biological specimens could be used as indicators of chronic exposure to hard metal dusts.

Electrothermal atomic absorption spectrophotometry (ETAAS), inductively coupled plasma mass spectrometry (ICP-MS) and neutron activation analysis (NAA) were used for the quantitative determination of 13 trace elements in urine and seven trace elements in whole blood of healthy unexposed British subjects living in three regions of the United Kingdom. Careful control of pre-analytical and analytical factors have enabled the results obtained from more than 200 individuals to be used in proposing reference intervals for the following elements; Al, As, Cd, Co, Cr, Cu, Hg, Mn, Mo, Ni, Pb, Se, Tl in urine, and Cd, Cr, Hg, Mn, Pb, Se and Tl in blood.

An evaluation of published values for 'normal' concentrations of vanadium levels in human blood, serum, and urine have been determined in order to identify the reasons for existing large variations of these values. The published data were scrutinized according to criteria on sampling and analysis developed for the TRACY (EUREKA; ENVIRON1) project which aims at establishing reference values for persons without occupational exposure to metals. Of the sampling factors, living in environmentally polluted areas, contamination-free sampling and sample handling were found to be highly important. Expert experience is needed for the accurate vanadium determination in these fluids using well defined radiochemical neutron activation analysis (RNAA) or NAA with pre-irradiation separation or graphite furnace atomic absorption spectrometry (GF-AAS). RNAA is superior for this purpose. Lack of suitable reference materials is a severe handicap in assessing accuracy of vanadium determinations at low levels. Although no reference values for vanadium are established, it appears that values, around 1 nmol l-1 for blood and serum and around 10 nmol l-1 or slightly lower for urine may be considered tentative normal values.

The movement of Co and the other components of the hard metal in the body fluids, their solubility, their links to the cells and proteins of the body, and their clearance are largely unknown. The first aim of this work is to evaluate whether Neutron Activation Analysis (NAA), a new analytical technique based on the radiochemical separation of samples irradiated in a Nuclear Reactor, may be suitable for studying the movement of elements in tissues or body fluids of workers over time. We have investigated seven hard metal workers, all employed in the grinding process, with NAA studies (single study in two, follow-up in five) of 29 elements on lung tissue, BAL fluid, blood, urine, pubic hair, toenails and sperm. In three, the diagnosis of hard metal pneumoconiosis was easy; in the other four, due to evident bilateral hilar lymphadenopathy, it was difficult to distinguish between pneumoconiosis and sarcoidosis stage II, and the final diagnosis, after pulmonary biopsy, was hard metal pneumoconiosis in three, and sarcoidosis in one. In spite of high potential, NAA gives a number of unexpected results, with apparent controversies and no clear relationship in the evolution of levels of Co, W and Ta: there is no simple explanation for such apparent inconsistencies at present, so that the study of the movement of elements in body fluid sometimes appears disappointing with this technique. Other observations were noted from the data available: 1) the concentration of elements (Co, Ta, W) in lung tissue is far higher than in BAL fluid, but the factor is so variable that BAL fluid cannot be taken as representative of the concentration of elements in lung tissue. 2) High concentrations in tissues or body fluids are indicative for exposure, but not for disease. In the light of available data, there are no levels above which development of disease is inevitable. 3) When the problem is to distinguish between sarcoidosis and pneumoconiosis in exposed subjects, the concentration of elements is of no value, and the pulmonary biopsy is still necessary. However a NAA study may be helpful to confirm the presence of the offending agent, and to avoid pulmonary biopsy in cases where the occupational history is unclear.

1 The fate of a soluble form of titanium (Ti) was studied in rats injected intraperitoneally with 1 ?g of Ti per rat as [44Ti]ammonium oxalotitanate (IV).2 After 16 h the Ti concentration in all tissues tested was of the order of 0.5 ng/g wet weight. After 19 days the Ti concentration increased in most tissues, especially in spleen, femur and kidney. By this time 55 ng had been excreted both via urine and faeces and the Ti concentration in blood plasma (mainly associated with plasma proteins) was three times lower than at 16 h postinjection.3 Chromatographic separation of the day 19 liver cytosol showed the ability of biological macromolecules to incorporate Ti compounds.4 Ti-labelled 'titanic acid' and 'titanium phosphate' showed low solubility which was, however, higher in human serum than in water and sodium chloride solution. The chromatographic profiles of plasma from incubated human blood in vitro with [44Ti]titanium oxalate showed the capacity of plasma proteins to complex Ti compounds. The results indicated that the long retention of Ti in the body may be due to its ability to form biocomplexes with cellular constituents.

(1981). Poisoning by Triphenyltin Acetate. Report of Two Cases and Determination of Tin in Blood and Urine by Neutron Activation Analysis. Clinical Toxicology: Vol. 18, No. 11, pp. 1343-1353.

The chronic exposure of man to increasing amounts of heavy metals as a consequence of environmental pollution, requires accurate knowledge of how much the homeostatic control of trace elements can stand increased exposure to abnormal amounts of metal pollutants without alteration of the biochemical functions. This topic includes the study of the accumulation of metal pollutants in the body with the identification of metal biocomplexes under long term-low level exposure (LLE) conditions. Extremely sensitive analytical techniques are required for experimentation at the heavy metal levels which are typical of a polluted environment in order to assess the limits of physiological homeostatic controls. The possiblity of applying nuclear and radiochemical techniques, such as neutron activation analysis, multiple tracing, high resolution gamma-ray spectrometry and Cerenkov counting, coupled with biochemical techniques, such as gel filtration, ion-exchange chromatography, polyacrylamide gel electrophoresis and differential centrifugation, has been demonstrated in various typical applications in metallobiochemistry. The subject of the first part of this paper is the development and improvement of the techniques, dealing with potential metal binding components, such as metalloenzymes and nucleic acids chosen as models. The developments refer to: preparation of labelled metal pollutants with very high specific activity to label in vivo nanogram or subnanogram amounts of pollutant metals; neutron activation analysis of enzymes and nucleic acids with the aim of analyzing concentrations of many metal pollutants in the identified metal binding components of the microsamples; radiochemical methods including radiobiochemical techniques for multielement tracer experiments and for studying the interaction of heavy metas and metal binding components; development of complementary counting techniques. The in vivo applications are centered on biochemical studies on cadmium, in particular on the long term-low exposure experiment, which is under investigation at present, with the identification of both critical organs of accumulation and of the cadmium binding components. Results are given for biochemical mechanisms involving cadmium such as the stimulation of the "de novo" biosynthesis of rat liver and intestine cadmium binding proteins (CdBP) and on the systematic study of the interaction of metal pollutants and rat liver cadmium binding proteins itself. Preliminary data are also given for short term experiments dealing with the identification of cellular metal binding components for V, Se, Cd and Pb.

A new case of rare-earth (RE) pneumoconiosis is described. The subject had worked as a photoengraver for 13 years and had not been exposed for 17 years. Chest X-ray showed a diffuse nodular pattern (q 2/3-ILO/1980). The patient was asymptomatic despite a restrictive spirometric impairment. The diagnosis derived from the finding, in the bronchoalveolar lavage fluid, of abnormal levels of La, Ce, Nd, Sm, Tb, Yb, and Lu. The presence of these elements was demonstrated by two methods: the neutron activation analysis and (as regards Ce alone) the X-ray energy spectrometry of mineral particles observed with electron microscope. Abnormal levels of rare earths were demonstrated also in the nails, suggesting an absorption of the RE from the lung.

51Cr-labelled Cr3+ and CrO2-4 solutions were administered intratracheally to male rats in doses of 0.1 and 10 μg of Cr per rat to evidentiate metabolic differences especially in the lung and in the mechanisms of excretion. Twenty four hours after administration the highest 51 Cr amount was present in the lungs for both valency states, being in the Cr (III)-treated group, however, about two times higher. In all other tissues tested the values in the Cr (VI)-treated animals were much higher. Intracellularly, in the Cr (III)-treated group more than 40% of the total lung homogenate was found in the nuclear fraction and only 10% in the cytosol. In the Cr (VI)-treated group 25% was present in the nuclei and more than 50% in the cytosol. Gel filtration 24 h after intratracheal injection showed that in both cytosols chromium was eluted in three peaks including a low-molecular-weight component. Quantitatively, however, the ratios between the 51Cr associated with the three peaks were significantly different between the Cr (III)- and the Cr (VI)-treated animals. This suggests that binding of chromium to low-molecular-weight components should be involved in the passage of this element from the lung to the other tissues. Excretion studies for 7 days showed that after this time the Cr (III)-treated animals excreted about 4% of the dose via urine and more than 36% via faeces, whereas in the Cr (VI)-treated rats the 51Cr was eliminated nearly equally between urine and faeces.

The study of possible relationships between iron and vanadium metabolism (E. Sabbioni and E. Marafante, Proc. XIth Int. Conf. Biochem., 13-5-R122, Toronto, Canada) was extended to the vanadium in the biochemical mechanisms which involve the exchange of iron between transferrin and ferritin. The transfer of vanadium between transferrin and ferritin was investigated using 48V radiotracer and gel filtration technique. 48V labeled human transferrin and horse spleen ferritin, 48V plasma from rats injected with 48VO2+, unlabelled rat liver cytosol, and plasma were used as sources of the two proteins for their incubation under different conditions. The results show that the equilibrium: V - transferrin in equilibrium V - ferritin occurs in vitro at physiological pH under the conditions of this experiment. No transfer of vanadium between the two proteins, however, occurs when they are incubated simply in a buffer at pH = 7.4. The maximum transfer was observed when transferrin and ferritin were mixed in their natural environments such as plasma and liver cytosol. This suggests that the exchange of the vanadium between the two proteins is affected by biochemical factors which are present in the body. A brief evaluation of the significance on the very low amounts of the element exchanged between the two proteins is also presented.

In vivo experiments using 203Pb and radioactively labelled precursors such as [14C] arginine and [3H] tryptophan were performed to identify lead binding components in rat liver. The distribution of lead in 9 tissues and the intracellular distribution in liver and kidney was also investigated. Male rats were injected intravenously with 18 μg of 203Pb/rat and the 203Pb radioactivity was measured in whole tissues as well as in nuclei, mitochondria, lysosomes, microsomes and soluble fractions obtained by centrifugation of liver and kidney homogenates. The subcellular fractions from liver were purified and fractionated into macromolecular components by ultracentrifugation, gel filtration, ion exchange chromatography and solvent extraction. Nuclei were fractionated into membranes, chromatin proteins (histone and residual non-histone proteins) and DNA. Most of the lead was detected in the nuclear membrane fraction bound exclusively to membrane proteins and absent in phospholipids. The intranuclear lead was associated with histone fractions and other basic or very weakly acid proteins as indicated by the incorporation of [14C] arginine and [3H] tryptophan. Lead was present in the chromatographically purified DNA fraction but whether lead was really bound to the nucleic acid was not determined. Mitochondria were fractionated into heavy, soluble and light subfractions representing the inner membranes, the intramitochondrial matrix and the outer membranes respectively. These subfractions contained appreciable quantities of lead. No appreciable lead was present in lipids of the mitochondrial membranes. Significant quantities of lead were associated with the endoplasmic reticulum. Fractionation of microsomes into rough and smooth membranes showed that lead was almost exclusively bound to membranes of rough-surfaced microsomes associated with the heavy rough membrane subfraction. No significant lead was present in the free polysome subfraction or in lipids from the endoplasmic reticulum. More than one lead binding site was identified in the soluble fraction, the high molecular weight components representing the most important lead binding site.

In vivo experiments with 48V and 59Fe radiotracers were performed to study the association of V with Fe proteins. Each male rat was injected ip with 10 micrograms 48VO2+ and then with 1 microgram 59Fe3+ to label Fe-containing proteins. The radioactivities incorporated were measured in plasma transferrin, red blood cell hemoglobin, liver ferritin, partially purified heart myoglobin, and liver mitochondrial and microsomal cytochromes b and c and ferriporphyrin. Liver ferritin can bind V in vivo similarly to plasma transferrin, as shown by gel filtration and immunoprecipitation. Negligible amounts of 48 V were incorporated into hemoglobin, partially purified myoglobin, and cytochromes b and c. These findings suggest that the nonenzymatic Fe-containing proteins may be involved in the V metabolism.

Rats treated intravenously with 51Cr-labelled sodium chromate, 0.1 or 100 microgram Cr/rat, excreted more 51Cr into bile in a 2-hr period than did the animals given equal amounts of chromium in the trivalent state. Distinct patterns of hepatic intracellular distribution of the radiotracer were also observed. In the Cr-VI rats over 50% of the liver chromium was present in the supernatant fraction whereas in the Cr-III rats almost all the liver radioactivity was localized in the cell organelles. Fractionation of bile on Sephadex G-75 demonstrated binding of chromium to low-molecular weight substances. It is suggested that complexes of chromium with low-molecular weight components of liver cytosol are involved in the passage of this element from the liver to bile. A low cytosolic content of diffusable Cr-complexes associated with the incorporation of a large fraction of liver chromium in cell organelles may be a factor contributing to the low rates of 51Cr biliary excretion in the animals given Cr-III. 24 hr after the injection of 51Cr to bile duct-ligated rats appreciable levels of radiotracer were found in the gastrointestinal tract. The animals given Cr-VI exhibited significantly higher values of chromium content in the gut than those treated with Cr-III.

A case of rare-earth (RE) pneumoconiosis is described and discussed. A man working in a lithographic laboratory as a photoengraver, and exposed to the smoke of cored carbon arc lamps over a period of 46 years developed an interstitial pneumoconiosis. Neutron activation analysis (NAA) of eight rare-earths (La, Ce, Nd, Sm, Eu, Tb, Yb and Lu) in lung and lymph node biopsies showed an abnormally high amount of these elements in comparison to the corresponding values of 11 autopsied for unexposed subjects. The estimated radiological dose due to the inhalation of natural thorium, as calculated from NAA of thorium in the biopsies, tends to exclude the effect of ionizing radiation in the pathogenesis of lung fibrosis. Effects of other potential pathogenetic agents such as coal or heavy metal dusts, other than RE, irritative agents such as nitrous and hydrofluoric vapours originated during the photoengraving process, are also discussed. The findings strongly suggest that a relationship exists between the pneumoconiosis diagnosed and the occupational exposure to rare-earth dusts calling attention to proposals for maximum permissible concentration limits of occupational exposure to RE in air.

The simultaneous determination of heavy metals in microsamples of chromatographically isolated cadmium-binding protein (Cd-BP) from rat liver was performed by neutron activation analysis. The results suggested that metals other than those already reported (Cd, Zn, Cu, and Hg) can bind the protein. These observations were confirmed by in vivo radiotracer experiments by injecting i.p. 21 labelled metal ions in cadmium-treated rats. Of the metals tested, 109Cd, 65Zn, 64Cu, 203Hg, 106Ag and 113Sn were found incorporated in the Cd-BP. The incorporation of 35S-cysteine, used as an indicator of Cd-BP biosynthesis, was increased in rats exposed to cadmium as compared to untreated animals. In order to establish the influence of other metal ions on the biosynthesis of Cd-BP and the incorporation of cadmium in the protein, in vivo experiments were carried out by i.p. injection of 109Cd and 35S-cysteine. In the presence of 42 metal ions no influence was observed on the incorporation of the two radioisotopes in the Cd-BP. These observations tend to support the hypothesis that cadmium can act as a highly specific inducer of Cd-BP and that this protein might be involved in the metabolism of several heavy metals.

A male subject exposed for many years to rare earth (RE)-containing fumes and dusts emitted from carbon arc lamps in photoengraving laboratories was investigated to rule out RE pneumoconiosis. While chest x-ray films showed a severe pulmonary fibrosis, clinical analysis showed obvious high RE concentrations in the pulmonary and lymph node biopsy specimens compared with the corresponding tissues of 11 unexposed subjects. In addition to other elements, levels of thorium (Th), which is generally present as an impurity of RE compounds, were also determined to estimate the radiation dose which may be involved in inducing pneumoconiosis. The results show that the levels of Th are more than two orders of magnitude lower than the maximum permissible concentration for occupational exposure to natural 232Th, suggesting that the long-term accumulation of RE in the lungs played a role in the pathogenesis of the observed pulmonary fibrosis of the worker.

The biliary excretion of vanadium was studied in bile duct cannulated rats at various times after the iv administration of a single dose of 48V-labelled pentavalent vanadium. The tissue disposition, hepatic intracellular distribution and binding of 48V to plasma, bile and liver components were also investigated. During the first 6 hours after the injection of V, 0.9 to 30 microgram/kg, less than 2 per cent of the dose was excreted into the bile and up to 20 per cent of vanadium was eliminated in urine. The bile flow was markedly decreased in rats cannulated 24 hours after the injection of V, 30 microgram/kg, while higher doses produced signs of severe toxicity immediately after the administration. Evidence was also obtained that a concentration gradient triggers the passage of vanadium from plasma to the liver, where only a fractional amount becomes available from canalicular excretion, due to the extensive binding of the metal to organelles and other tissue ligands.

Multielemental analysis, using neutron activation, was carried out on the urine, whole blood, pubic hair and toenails of thirty subjects occupationally exposed to hard metal dusts. A high concentration of Co, W and Cr was observed in all samples analysed. The concentrations determined, when subjected to statistical analysis using pattern recognition techniques (e.g. cluster analysis), indicated a positive correlation, at p = 0.001, for the pair (Co, W) in urine and blood, as well as a possible influence of Cr on this pair.

Rabbits were treated with single doses of 50 micrograms AsO2-/kg b.w. by IP injection. At 48 h, 83.0 +/- 2.1% of arsenic is excreted via the urine. Also in blood the clearance of arsenic is rapid. Liver, kidney, and lung, among the tissues tested, show the highest concentration of arsenic at 5, 16, and 48 h after injection. Arsenic was found to be present at subcellular levels mainly in the nuclear and soluble fractions of the above-mentioned tissues. Chromatographic studies performed by gel filtration have shown that in plasma and in lung cytosol, arsenic is present, associated mainly to low molecular weight components, whereas in liver and kidney cytosol it is prevalently recovered in the fractions corresponding to the high molecular weight components. This different interaction of arsenic with molecular components was shown to influence the metabolic fate of this compound in the rabbit.

The retention, subcellular distribution in the liver, kidneys and lungs and binding of vanadium in the rat were investigated at 3 h, 1 d and 12 d after intratracheal instillation of 200 ng/kg body weight of 48V-labelled pentavalent and tetravalent vanadium. The metabolic patterns of both chemical forms of vanadium were similar. The lungs, liver, kidneys, bone, testes and spleen are the target tissues at risk, vanadium being removed from them with time at different rates. Pulmonary vanadium clearance was initially rapid - 80-85% of the 48V was removed within 3 h. At 12 d about 2% of the element was still present in the lung. Intracellularly, the major part of liver, kidney and lung vanadium was present in the nuclear fraction (30-40% of the homogenate), followed by cytosol and mitochondrial fractions. Gel filtration chromatography of the lung cytosol showed two biochemical pools of vanadium: the first corresponding to protein bound vanadium, which may be involved in the long-term accumulation of the element in the lung, the second pool representing a diffusible vanadium form. The retention of the tetravalent and pentavalent vanadium forms was also investigated 1 d after oral administration. No obvious differences were observed in the distribution pattern of 48V in the tissues, the retention factor being higher by two orders of magnitude in comparison with the intratracheally instilled animals. These findings suggest that the metabolic pathways of tetravalent and pentavalent vanadium are independent of the route of vanadium exposure.