Concentrations of vitamin A, E, thyroid and testosterone hormones in blood plasma and tissues from emaciated adult male Arctic foxes (Vulpes lagopus) dietary exposed to persistent organic pollutants (POPs).

The aim of the present study was to investigate the relationships and effects of oral POP exposure on retinol (vitamin A), α-tocopherol (vitamin E), thyroid hormones and testosterone in emaciated adult farmed Arctic foxes. Eight brother-pairs were exposed to either a diet containing naturally POP-contaminated minke whale blubber (Balaenoptera acutorostrata) (n=8), or a control diet containing pig (Sus scrofa) fat as the primary fat source (n=8) for 22 months. In the whale blubber containing feed the ∑POPs concentration was 802ng/g w.w. and it was 24ng/g w.w. in control feed. The liver mass was significantly higher and the ratio of FT4 (free thyroxine):FT3 (free triiodothyronine) was significantly lower in the POP exposed group as compared to the control group given feed with pig fat (both p<0.05). The exposed group revealed lower plasma and liver concentrations of α-tocopherol compared to the control group (both p<0.05). These results indicate that plasma FT4:FT3 ratio and plasma and liver α-tocopherol are valuable biomarker endpoints for chronic oral POP exposure in wild Arctic foxes. Based on this we suggest that plasma FT4:FT3 ratio and plasma and liver α-tocopherol are valuable biomarker endpoints for chronic POP exposure in wildlife Arctic foxes and that these perturbations may affect their health status.

A weight of evidence assessment approach for adverse outcome pathways.

The adverse outcome pathway (AOP) is a framework to mechanistically link molecular initiating events to adverse biological outcomes. From a regulatory perspective, it is of crucial importance to determine the confidence for the AOP in question as well as the quality of data available in supporting this evaluation. A weight of evidence approach has been proposed for this task, but many of the existing frameworks for weight of evidence evaluation are qualitative and there is not clear guidance regarding how weight of evidence should be calculated for an AOP. In this paper we advocate the use of a subject matter expertise driven approach for weight of evidence evaluation based on criteria and metrics related to data quality and the strength of causal linkages between key events. As a demonstration, we notionally determine weight of evidence scores for two AOPs: Non-competitive ionotropic GABA receptor antagonism leading to epileptic seizures, and Antagonist-binding and stabilization of a co-repressor to the peroxisome proliferator-activated receptor α (PPARα) signaling complex ultimately causing starvation-like weight loss.

Accumulation features of trace elements in mass-stranded harbor seals (Phoca vitulina) in the North Sea coast in 2002: the body distribution and association with growth and nutrition status.

Body distribution and growth- and nutritional status-dependent accumulation of 21 trace elements were investigated in harbor seals (Phoca vitulina) stranded in the North Sea coast in 2002. Higher concentrations and burdens of Mn, Se, Mo, Ag, Sn, Hg, and Bi in the liver, Cd in the kidney, As in the blubber, and Co, Sr, and Ba in the bone were observed. Significant positive correlations of hepatic Se, Mo, Ag, Cd, Sn, Hg, Tl, and Bi with standard body length were found, while significant negative relationships were detected for Mn, As, Rb, Sr, and Sb in the liver. Concentrations of Co, Se, Sr, Sn, Hg, and Bi in the liver, V, Sr, Ag, Sn, and Hg in the kidney, V, Mn, Co, Rb, Sr, Sn, Ba, and Pb in the blubber increased with decreasing blubber thickness of harbor seals, indicating enrichment of these elements in the target tissue by emaciation.

Pathological features in marine birds affected by the prestige's oil spill in the north of Spain.

A total of 2,465 seabirds, mainly common murres (Uria aalge), razorbills (Alca torda), and puffins (Fratercula arctica) that beached in the northwestern part of Spain after the "Prestige" oil spill on 19 November 2002 were examined by pathological methods. Birds were divided into three groups: dead birds with the body covered (group 1) or uncovered (group 2) by oil and birds recovered alive but which died after being treated at a rescue center (group 3). The main gross lesions were severe dehydration and emaciation. Microscopically, hemosiderin deposits, related to cachexia and/or hemolytic anemia, were observed in those birds harboring oil in the intestine. Severe aspergillosis and ulcers in the ventriculus were found only in group 3 birds, probably because of stress associated with attempted rehabilitation at the rescue center. The mild character of the pathological changes suggests that petroleum oil toxicosis causes multiple sublethal changes that have an effect on the ability of the birds to survive at sea, especially weak and young, inexperienced animals. Dehydration and exhaustion seem to be the most likely cause of death.

Pathology of domoic acid toxicity in California sea lions (Zalophus californianus).

Over 100 free-ranging adult California sea lions (Zalophus californianus) and one Northern fur seal (Callorhinus ursinus), predominantly adult females, were intoxicated by domoic acid (DA) during three harmful algal blooms between 1998 and 2000 in central and northern California coastal waters. The vector prey item was Northern anchovy (Engraulis mordax) and the primary DA-producing algal diatom was Psuedonitzschia australis. Postmortem examination revealed gross and histologic findings that were distinctive and aided in diagnosis. A total of 109 sea lions were examined, dying between 1 day and 10 months after admission to a marine mammal rehabilitation center. Persistent seizures with obtundation were the main clinical findings. Frequent gross findings in animals dying acutely consisted of piriform lobe malacia, myocardial pallor, bronchopneumonia, and complications related to pregnancy. Gross findings in animals dying months after intoxication included bilateral hippocampal atrophy. Histologic observations implicated limbic system seizure injury consistent with excitotoxin exposure. Peracutely, there was microvesicular hydropic degeneration within the neuropil of the hippocampus, amygdala, pyriform lobe, and other limbic structures. Acutely, there was ischemic neuronal necrosis, particularly apparent in the granular cells of the dentate gyrus and the pyramidal cells within the hippocampus cornu ammonis (CA) sectors CA4, CA3, and CA1. Dentate granular cell necrosis has not been reported in human or experimental animal DA toxicity and may be unique to sea lions. Chronically, there was gliosis, mild nonsuppurative inflammation, and loss of laminar organization in affected areas.

28-day repeated oral toxicity study of a hypolipidemic agent, NK-104 in rats.

NK-104, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, was administered orally to Wistar rats at a dose of 2, 10, 50 or 100 mg/kg for 28 days consecutively, and the toxicity of NK-104 and its recovery with 2 weeks cessation of drug treatment were examined. As major clinical signs, loose stool, diarrhea, crouching and emaciation were observed in both sexes at 50 or 100 mg/kg, and all females at 100 mg/kg died or became moribund due to severe emaciation before the completion of treatment. The suppression of body weight gain or decrease in body weight was observed in the female dose group at 50 mg/kg and both sexes at 100 mg/kg. Decreased food intake was observed in both sexes at 100 mg/kg. Moreover, an increase in cholinesterase (Ch.E) in the male dose groups at 50 and 100 mg/kg and an increase in glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) in the female dose group at 50 mg/kg were observed in blood chemistry testing. Macroscopic examination showed thickening of the forestomach mucosa in the groups of 10 mg/kg or more. Microscopic examination revealed hyperkeratosis and hypertrophy of the spinous layer associated with both cell infiltration of the mucosal propria and submucosal edema. In addition, skeletal muscle lesions including atrophy, vacuolation and focal necrosis were observed in the female dose groups at 50 and 100 mg/kg. The above-mentioned microscopic changes were not observed on cessation of drug treatment. The non-toxic dose level of NK-104 in the 28-day repeated oral toxicity study using rats was determined to be 2 mg/kg.

Effect of topical application of 13-cis retinoic acid on skin of hairless rats and hairless mice.

The potential effectiveness of topical 13-cis retinoic acid (13-cis RA) as a sebosuppressive agent was evaluated in hairless ("fuzzy") rats and hairless mice. At nontoxic dosages (i.e., concentrations which induced no weight loss), topical 13-cis RA had no detectable sebosuppressive effects in either of these species. In hairless rats, the topical application of 0.2% 13-cis RA induced more severe symptoms of toxicity than was induced by the administration of equivalent amounts of the drug by either oral or subcutaneous routes. Due to variability in species sensitivity to 13-cis RA, the potential effectiveness of the topical use of this retinoid can probably only be evaluated in human volunteers.

Toxicological studies on Amfenac sodium (AHR-5850) (I) Acute toxicities in mice and rats.

Acute toxicities of Amfenac sodium (AHR-5850), new nonsteroidal anti-inflammatory agent, were studied in mice and rats. Each value of LD50 by oral, sc, im, iv and ip administration with this compound was 1190, 580, 540, 550 and 790 mg/kg for male mice and 1450, 625, 610, 630 and 710 mg/kg for female mice, respectively. Rats showed higher lethality than mice. There was no significant difference of sex in the values of LD50 for mice and rats. Movement and respiration rate followed by gastrointestinal ulcer, secondary peritonitis and systemic emaciation. These results suggest that the death is caused by secondary peritonitis and systemic emaciation due to gastrointestinal ulcer.

Triamcinolone-induced wasting disease in young mice.

Young mice were treated for up to 8 weeks with daily graded doses of triamcinolone diacetate. The body weights of treated, placebo and nontreated animals were measured daily throughout the experimental period, calculated and analysed. By the first injections, significant decrease was noted in the body weight of all experimental mice regardless of their sex or initial bodyweight. The latter was followed by a so-called 'steady state' which longed for approximately 4 weeks. Marked deterioration and mortality also occurred but became severe from the fifth week of triamcinolone administration. Possible explanations for the above findings are discussed.