Systemic exposure and urinary excretion of vanadium following perinatal subchronic exposure to vanadyl sulfate and sodium metavanadate via drinking water.

Vanadium is a ubiquitous environmental contaminant although there are limited data to assess potential adverse human health impact following oral exposure. In support of studies investigating the subchronic toxicity of vanadyl sulfate (V4+) and sodium metavanadate (V5+) following perinatal exposure via drinking water in male and female rats, we have determined the internal exposure and urinary excretion of total vanadium at the end of study. Water consumption decreased with increasing exposure concentration following exposure to both compounds. Plasma and urine vanadium concentration normalized to total vanadium consumed per day increased with the exposure concentration of vanadyl sulfate and sodium metavanadate suggesting absorption increased as the exposure concentration increased. Additionally, females had higher concentrations than males (in plasma only for vanadyl sulfate exposure). Animals exposed to sodium metavanadate had up to 3-fold higher vanadium concentration in plasma and urine compared to vanadyl sulfate exposed animals, when normalized to total vanadium consumed per day, demonstrating differential absorption, distribution, metabolism, and excretion properties between V5+ and V4+ compounds. These data will aid in the interpretation of animal toxicity data of V4+ and V5+ compounds and determine the relevance of animal toxicity findings to human exposures.

Immunotoxicity studies of sulfolane following developmental exposure in Hsd:Sprague Dawley SD rats and adult exposure in B6C3F1/N mice.

Sulfolane is a solvent used in the petrochemical industry and a groundwater contaminant in areas near refineries. The current studies were conducted to assess the impact of oral exposure to sulfolane on the immune system using two models: (1) a perinatal drinking water exposure to 0, 30, 100, 300, or 1000 mg/L from gestation day (GD) 6 until ∼13 weeks-of-age in Harlan Sprague Dawley rats; and, (2) a 90-day gavage exposure of adult female B6C3F1/N mice to 0, 1, 10, 30, 100, or 300 mg/kg/day. Immune parameters evaluated included measurement of antibody production against sheep red blood cells (SRBC) and keyhole limpet hemocyanin (KLH), ex vivo measurements of natural killer (NK) cell activity, cytotoxic T-cell (CTL) activity, and T-cell proliferation, as well as measures of splenic immune cell populations, hematological parameters, and histopathology of immune tissues. A decrease in ex vivo NK cell activity was observed in cells from female - but not male - F1 rats following developmental exposure. In adult female mice, splenic NK cell number was lower than the vehicle controls at doses ≥ 100 mg/kg; however, ex vivo NK cell activity was not affected by sulfolane treatment. In female mice, a decrease in the number of large unstained cells at doses ≥ 30 mg/kg was observed. In F1 rats, effects on white blood cells (WBC) were limited to a decreasing trend in leukocytes in females; no effects were observed in males. Under the conditions of this study, a no-observed-effect level (NOEL) of 3 mg/kg/day was identified based on reduced NK cell activity in female F1 rats. Overall, these findings suggest that oral exposure to sulfolane in rodents had minimal effects on the immune system.

14-Day Toxicity Studies of Tetravalent and Pentavalent Vanadium Compounds in Harlan Sprague Dawley Rats and B6C3F1/N Mice via Drinking Water Exposure.

BACKGROUND: The National Toxicology Program (NTP) performed short-term toxicity studies of tetra- and pentavalent vanadium compounds, vanadyl sulfate and sodium metavanadate, respectively. Due to widespread human exposure and a lack of chronic toxicity data, there is concern for human health following oral exposure to soluble vanadium compounds. OBJECTIVES: To compare the potency and toxicological profile of vanadyl sulfate and sodium metavanadate using a short-term in vivo toxicity assay. METHODS: Adult male and female Harlan Sprague Dawley (HSD) rats and B6C3F1/N mice, 5 per group, were exposed to vanadyl sulfate or sodium metavanadate, via drinking water, at concentrations of 0, 125, 250, 500, 1000 or 2000 mg/L for 14 days. Water consumption, body weights and clinical observations were recorded throughout the study; organ weights were collected at study termination. RESULTS: Lower water consumption, up to -80% at 2000 mg/L, was observed at most exposure concentrations for animals exposed to either vanadyl sulfate or sodium metavanadate and was accompanied by decreased body weights at the highest concentrations for both compounds. Animals in the 1000 and 2000 mg/L sodium metavanadate groups were removed early due to overt toxicity. Thinness was observed in high-dose animals exposed to either compound, while lethargy and abnormal gait were only observed in vanadate-exposed animals. CONCLUSIONS: Based on clinical observations and overt toxicity, sodium metavanadate appears to be more toxic than vanadyl sulfate. Differential toxicity cannot be explained by differences in total vanadium intake, based on water consumption, and may be due to differences in disposition or mechanism of toxicity.

Toxicological evaluation of smokeless tobacco: 2-year chronic toxicity and carcinogenicity feeding study in Wistar Han rats.

UNLABELLED: A comprehensive 2-year oral chronic toxicity/carcinogenicity study was conducted with smokeless tobacco using modern toxicological test methods and well-accepted standards. The study included a 1-year interim subgroup to assess toxicity at that intermediate time point. Test groups consisted of a tobacco blend (B) used in snus, and an aqueous tobacco extract of that tobacco blend (E) administered at 0.2, 2, or 5 mg nicotine/kg body weight/day via dosed feed to male and female Wistar Han rats. The dosages were selected to simulate potential exposure in humans ingesting smokeless tobacco or an aqueous extract of smokeless tobacco (the latter intended to simulate a snus extract, to enable bridging these data to snus epidemiology data). The following endpoints were evaluated: clinical observations, body weights, feed consumption (FC), ophthalmic exams, toxicokinetics, clinical pathology, gross pathology, and histopathology. During the 2-year study, clear treatment-related, dose-responsive effects included: (1) increases in plasma nicotine and cotinine (indicating that animals were appropriately exposed to levels relevant to human exposure) and (2) decreases in body weights with some alterations in FC. At the 2-year time point, two tumor types (in the highest B doses) displayed statistically significantly increased incidence trends vs. CONTROLS: (1) uterine carcinoma in females and (2) epididymal mesothelioma in males. Three tumor types displayed statistically significantly decreased incidence trends: (1) mammary gland adenomas in females, (2) skin basal cell carcinomas in females, and (3) thyroid follicular cell adenomas in males. These increases (and decreases) in tumor trends were interpreted as not being treatment-related because: (1) there were no preneoplastic or related non-neoplastic histopathological findings in the treated rats at the 1-year or 2-year time points to suggest that any of these neoplastic findings were treatment-related and (2) the tumor morphologies and incidences were generally within the expected range of historical controls for Wistar Han rats. Findings from this study indicate that chronic exposure of male and female Wistar Han rats to either a tobacco blend used in snus, or a tobacco extract of that blend does not lead to increased toxicity or carcinogenicity, based on the specified outcomes measured.

Toxic effects of dietary methylmercury on immune function and hematology in American kestrels (Falco sparverius).

Fifty-nine adult male American kestrels (Falco sparverius) were assigned to one of three diet formulations including 0 (control), 0.6, and 3.9 µg/g (dry wt) methylmercury (MeHg). Kestrels received their diets daily for 13 weeks to assess the effects of dietary MeHg on immunocompetence. Immunotoxic endpoints included assessment of cell-mediated immunity (CMI) using the phytohemagglutinin (PHA) skin-swelling assay and primary and secondary antibody-mediated immune responses (IR) via the sheep red blood cell (SRBC) hemagglutination assay. Select hematology and histology parameters were evaluated to corroborate the results of functional assays and to assess immunosuppression of T and B cell-dependent components in spleen tissue. Kestrels in the 0.6 and 3.9 µg/g MeHg groups exhibited suppression of CMI, including lower PHA stimulation indexes (p = 0.019) and a 42 to 45% depletion of T cell-dependent splenic lymphoid tissue (p = 0.006). Kestrels in the 0.6 µg/g group exhibited suppression of the primary IR to SRBCs (p = 0.014). MeHg did not have a noticeable effect on the secondary IR (p = 0.166). Elevation of absolute heterophil counts (p < 0.001), the heterophil to lymphocyte ratio (p < 0.001), and total white blood cell counts (p = 0.003) was apparent in the 3.9 µg/g group at week 12. Heterophilia, or the excess of heterophils in peripheral blood above normal ranges, was apparent in seven of 17 (41%) kestrels in the 3.9 µg/g group and was indicative of an acute inflammatory response or physiological stress. This study revealed that adult kestrels were more sensitive to immunotoxic effects of MeHg at environmentally relevant dietary concentrations than they were to reproductive effects as previously reported.

Toxic effects of dietary methylmercury on immune system development in nestling American kestrels (Falco sparverius).

This study evaluated the effects of dietary methylmercury (MeHg) on immune system development in captive-reared nestling American kestrels (Falco sparverius) to determine whether T cell-mediated and antibody-mediated adaptive immunity are targets for MeHg toxicity at environmentally relevant concentrations. Nestlings received various diets, including 0 (control), 0.6, and 3.9 µg/g (dry wt) MeHg for up to 18 d posthatch. Immunotoxicity endpoints included cell-mediated immunity (CMI) using the phytohemagglutinin (PHA) skin-swelling assay and antibody-mediated immune response via the sheep red blood cell (SRBC) hemagglutination assay. T cell- and B cell-dependent histological parameters in the spleen, thymus, and bursa of Fabricius were correlated with the functional assays. For nestlings in the 0.6 and 3.9 µg/g MeHg groups, CMI was suppressed by 73 and 62%, respectively, at 11 d of age. Results of this functional assay were correlated with T cell-dependent components of the spleen and thymus. Dose-dependent lymphoid depletion in spleen tissue directly affected the proliferation of T-lymphocyte populations, insofar as lower stimulation indexes from the PHA assay occurred in nestlings with lower proportions of splenic white pulp and higher THg concentrations. Nestlings in the 3.9 µg/g group also exhibited lymphoid depletion and a lack of macrophage activity in the thymus. Methylmercury did not have a noticeable effect on antibody-mediated immune function or B cell-dependent histological correlates. We conclude that T cell-mediated immunosuppression is the primary target of MeHg toward adaptive immunity in developing kestrels. This study provides evidence that environmentally relevant concentrations of MeHg may compromise immunocompetence in a developing terrestrial predator and raises concern regarding the long-term health effects of kestrels that were exposed to dietary MeHg during early avian development.

Survey of parasites and bacterial pathogens from free-living waterfowl in zoological settings.

To determine if free-living waterfowl residing in a zoological setting pose health risks for its animal collections, visitors, and employees, 450 fecal samples were collected and cultured for the presence of Campylobacter jejuni, Escherichia coli, Salmonella spp., and Pasteurella multocida. A survey of endoparasites infecting the waterfowl was also conducted. Sixty-seven percent, 42%, and 1.7% of the samples tested positive for E. coli, C. jejuni, and Salmonella spp., respectively. No P. multocida was isolated from the sampled population. Antimicrobial susceptibility testing for the bacterial isolates demonstrated that a majority of the isolates were susceptible to the antibiotics tested. A survey for parasites revealed 16% of the samples had coccidia oocytes; 8% of the sample had spirurid ova; and 17% of the sample had strongylate-type nematode ova. Ascaris spp. ova, Capillaria spp. ova, oxyurid ova, and mites were also noted in some fecal samples.