Carcinogenic hazard assessment of cobalt-containing alloys in medical devices: Review of in vivo studies.

Cobalt (Co) alloys have been used for over seven decades in a wide range of medical devices, including, but not limited to, hip and knee implants, surgical tools, and vascular stents, due to their favorable biocompatibility, durability, and mechanical properties. A recent regulatory hazard classification review by the European Chemicals Agency (ECHA) resulted in the classification of metallic Co as a Class 1B Carcinogen (presumed to have carcinogenic potential for humans), primarily based on inhalation rodent carcinogenicity studies with pure metallic Co. The ECHA review did not specifically consider the carcinogenicity hazard potential of forms or routes of Co that are relevant for medical devices. The purpose of this review is to present a comprehensive assessment of the available in vivo preclinical data on the carcinogenic hazard potential of exposure to Co-containing alloys (CoCA) in medical devices by relevant routes. In vivo data were reviewed from 33 preclinical studies that examined the impact of Co exposure on local and systemic tumor incidence in rats, mice, guinea pigs, and hamsters. Across these studies, there was no significant increase of local or systemic tumors in studies relevant for medical devices. Taken together, the relevant in vivo data led to the conclusion that CoCA in medical devices are not a carcinogenic hazard in available in vivo models. While specific patient and implant factors cannot be fully replicated using in vivo models, the available in vivo preclinical data support that CoCA in medical devices are unlikely a carcinogenic hazard to patients.

Development and Assessment of Nano-Technologies for Cancer Treatment: Cytotoxicity and Hyperthermia Laboratory Studies.

Cancer treatment by magnetic hyperthermia offers numerous advantages, but for practical applications many variables still need to be adjusted before developing a controlled and reproducible cancer treatment that is bio-compatible (non-damaging) to healthy cells. In this work, Fe3O4 and CoFe2O4 were synthesized and systematically studied for the development of efficient therapeutic agents for applications in hyperthermia. The biocompatibility of the materials was further evaluated using HepG2 cells as biological model. Colorimetric and microscopic techniques were used to evaluate the interaction of magnetic nano-materials (MNMs) and HepG2 cells. Finally, the behavior of MNMs was evaluated under the influence of an alternating magnetic field (AMF), observing a more efficient temperature increment for CoFe2O4, a desirable behavior for biomedical applications since lower doses and shorter expositions to alternating magnetic field might be required.

Electrospinning synthesis and assessment of physicochemical properties and biocompatibility of cobalt nitrate fibers for wound healing applications.

The aim of this study was to develop polyurethane (PU) wound dressing incorporated with cobalt nitrate using electrospinning technique. The morphology analysis revealed that the developed composites exhibited reduced fiber and pore diameter than the pristine PU. The electrospun membranes exhibited average porosity in the range of 67% - 71%. Energy-dispersive X-ray spectra (EDS) showed the presence of cobalt in the PU matrix. The interaction of cobalt nitrate with PU matrix was evident in Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). The contact angle results indicated the improved wettability of the prepared PU/cobalt nitrate composites (82° ± 2) than the pure PU (100° ± 1). The incorporation of cobalt nitrate into the PU matrix enhanced the surface roughness and mechanical strength as evident in the atomic force microscopy (AFM) and tensile test analysis. The blood compatibility assays revealed the anticoagulant nature of the prepared composites by displaying prolonged blood clotting time than the PU control. Further, the developed composite exhibited less toxicity nature as revealed in the hemolysis and cytotoxicity studies. It was observed that the PU wound dressing added with cobalt nitrate fibers exhibited enhanced physicochemical, better blood compatibility parameters and enhanced fibroblast proliferation rates which may serve as a potential candidate for wound dressings.

Production responses and cost-benefit of long-acting pre-lambing anthelmintic treatment of yearling ewes in two commercial flocks in New Zealand.

AIMS: To investigate the production responses and cost-benefit of administering a controlled-release anthelmintic capsule (CRC) to pregnant yearling ewes prior to lambing. METHODS: Yearling ewes from two commercial sheep flocks (A, n=489; B, n=248) in the North Island of New Zealand were enrolled in the study. Prior to lambing, CRC containing albendazole and abamectin were administered to half the ewes while the other half remained untreated. Ewe liveweights and body condition scores were measured prior to lambing, at weaning and, for Flock B, prior to subsequent mating. Lambs were matched to dams shortly after birth and the weight and number of lamb weaned per ewe were determined. A cost-benefit analysis was undertaken for Flock B considering the increased weight of lamb weaned per ewe, and the weight of ewes at the next mating and the benefit in terms of lambs born. RESULTS: The mean weight at weaning of treated ewes was greater for treated than untreated ewes by 2.76 (95% CI 0.64-4.88) kg in Flock A (p<0.001) and 2.35 (95% CI -0.41-5.12) kg in Flock B (p=0.003); the weight of lamb weaned per ewe was greater for treated than untreated ewes by 1.43 (95% CI -0.71 to -3.49) kg in Flock A (p=0.041) and 3.97 (95% CI 1.59-6.37) kg in Flock B (p<0.001), and ewe liveweight prior to subsequent mating was greater for treated than untreated ewes in Flock B by 4.60 (95% CI 3.6-5.6) kg (p<0.001). There was no difference in the percentage of lambs reared to weaning between treated and untreated ewes in either flock (p>0.8). The overall cost-benefit of treatment for Flock B was NZ$9.44 per treated ewe. CONCLUSIONS AND CLINICAL RELEVANCE: Pre-lambing CRC administration to yearling ewes resulted in increased ewe weaning weights and weight of lamb weaned in both the flocks studied. There was an economic benefit in the one flock where this was assessed.

Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants Part II: Importance of physicochemical properties and dose in animal and in vitro studies as a basis for risk assessment.

The objective of the Part II analysis was to evaluate animal and in vitro toxicology studies of CoCr particles with respect to their physicochemistry and dose relevance to metal-on-metal (MoM) implant patients as derived from Part I. In the various toxicology studies, physicochemical characteristics were infrequently considered and administered doses were orders of magnitude higher than what occurs in patients. Co was consistently shown to rapidly release from CoCr particles for distribution and elimination from the body. CoCr micron sized particles appear more biopersistent in vivo resulting in inflammatory responses that are not seen with similar mass concentrations of nanoparticles. We conclude, that in an attempt to obtain data for a complete risk assessment, future studies need to focus on physicochemical characteristics of nano and micron sized particles and on doses and dose metrics relevant to those generated in patients or in properly conducted hip simulator studies.

Ecotoxicological assessment of cobalt used as supplement in the diet of common carp Cyprinus carpio.

Experiments were performed in the laboratory to determine if excess levels of Co used as dietary supplement (0.0, 0.05, 0.10 and 1.0%) to enhance growth of the fish Cyprinus carpio was safe for aquatic organisms. Lethal concentrations of Co for tadpole of toad Bufo melanostictus (96 h LC(50), 17.2 mg/L), oligochaet worm Branchiura sowerbyi (96 h LC(50), 179 mg/L) and crustacean zooplankton Diaptomus forbesi (96 h LC(50), 1.5 mg/L) were compared with the concentration of Co in the medium leached from the unused diets and faeces. The results indicated that the Co leached from diet containing 1.0% Co was ecotoxicologically unsafe for crustacean zooplankton.

An evaluation of plasma homocysteine in the assessment of vitamin B12 status of pasture-fed sheep.

AIM: To assess the diagnostic potential of concentrations of homocysteine (Hcy) in plasma in relation to those of methylmalonic acid (MMA) and vitamin B12, as predictors of responsiveness of young sheep to supplementation with vitamin B12. METHODS: Eighty-two ewes grazing ryegrass-white clover pasture were used, 39 of which had been supplemented with a Co bullet and 43 unsupplemented. Thirty days after commencement of parturition their lambs (n=53 and 59, respectively) were randomly allocated into one of two treatments, in a 2 x 2 factorial design. Half of the lambs from each group of ewes received an injection of vitamin B12, while the remainder were controls. The trial commenced 31 October 2001 (Day 0), and continued until 01 May 2002 (Day 182). All lambs were weighed, and blood samples taken from 16 identified animals from each treatment group, at approximately monthly intervals. Changes in concentrations of Hcy, vitamin B12 and MMA in plasma, and liveweight gain (LWG) of the treatment groups were evaluated during the suckling (Days 0-89) and post-weaning (Days 90-182) periods. RESULTS: Mean LWG was 40% greater in supplemented than unsupplemented lambs. The concentrations of vitamin B12 and MMA in plasma in the unsupplemented lambs were in the deficient reference ranges of <170 pmol/L and >16 mumol/L, respectively. Mean monthly concentrations of Hcy in plasma ranged from 1.5 to 4.5 mumol/L but showed no pattern of response to vitamin B12 deficiency or supplementation. CONCLUSIONS: Measurement of the concentration of Hcy in plasma as a metabolic indicator of reduced methylation capability of sheep on typical pastures in New Zealand appeared to have little value in detection of vitamin B12 responsiveness, and was less sensitive than the concentration of the vitamin itself or the indicator of adenosyl-cobalamin deficiency, MMA, in plasma. The possibility that concentrations of Hcy in plasma remain low due to re-methylation of Hcy to methionine via the alternative betaine-choline rather than the vitamin B12-dependent methyl-tetrahydrofolate metabolic pathway is rejected, but the possibility is raised that high rates of trans-sulphuration of Hcy to cysteine in the gastrointestinal tract of grazing sheep could be responsible. CLINICAL RELEVANCE: The propionate-succinate pathway appears to be the first rate-limiting pathway in vitamin B12 deficiency, and the product of disruption of this pathway, increased MMA, is the most reliable indicator of metabolic abnormality in predicting responsiveness to supplementation.

Immunization with native and cobalt 60-irradiated Crotalus durissus terrificus venom in swiss mice: assessment of the neutralizing potency of antisera

ELISA was used to evaluate, follow, and compare the humoral immune response of Swiss mice during hyperimmunization with natural and Cobalt 60-irradiated (60Co) Crotalus durissus terrificus venom. Potency and neutralization were evaluated by in vitro challenges. After hyperimmunization, immunity was observed by “in vivo” challenge and the side effects were assessed. The animals immunization with one LD50 of the venom was on days one, 15, 21, 30, and 45, when blood samples were collected; the challenges occurred on the 60th day. Results showed that ELISA was efficient in evaluating, following, and comparing mouse immune response during hyperimmunization. Serum titers produced with natural venom were similar to those produced with irradiated venom. Immunogenic capacity was maintained after 60Co irradiation. Serum produced from Crotalus durissus terrificus irradiated venom showed higher potency and neutralization capacity than that from natural venom. All antibodies were able to neutralize five LD50 from these venoms. Clinical alterations were minimum during hyperimmunization with irradiated venom

A combined cobalt and C-14 2-deoxyglucose approach to antiepileptic drug assessment.

The cobalt model of epilepsy, in combination with the C-14 2-deoxyglucose (2-DG) autoradiographic technique, was used to assess the effects of phenytoin (PHT) and ethosuximide (ESM), two antiepileptic drugs, and ketamine (KET), a drug with anticonvulsant properties, on brain activity. Nine days after the unilateral insertion of a cobalt rod into visual cortex, the nondrugged control rats showed the usual hypermetabolic regions of putative epileptogenic tissue both adjacent to the necrotic cortical cobalt rod implant zone and more distally in the connecting thalamus. PHT and ESM, given a single injections immediately before the 2-DG uptake and clearing period, diminished glucose uptake in the cobalt-induced hypermetabolic "patches" as well as in normal tissue. However, both drugs decreased 2-DG uptake more in the thalamic patches, than in the less hypermetabolic cortical patches, where the drug-induced depression in glucose metabolism was the same as for normal tissue. These findings suggest that PHT and ESM, regardless of their actions on cell receptors and membrane conductances, are ultimately of therapeutic value because more active nervous tissue (such as epileptic tissue) is more vulnerable to the depressing effects of these drugs than is less active tissue. KET, in contrast to PHT and ESM, did not depress metabolic activity throughout the brain generally and even clearly increased it in limbic system structures. Also in contrast to PHT and SEM, KET diminished activity in the cobalt-induced patches without reducing it in the normal tissue of the homotopic control regions. The more selective depressing action of KET, an N-methyl-D-aspartate (NMDA) antagonist, may be related to the role NMDA receptors play in supporting strong nervous activity. The discussion emphasizes the usefulness of a combined cobalt/2-DG approach to antiepileptic drug assessment.

An assessment of the efficacy and safety of selenium and cobalt included in an anthelmintic for sheep.

A trial was devised to assess whether the administration of selenium and cobalt together with the anthelmintic mebendazole (Ovitelmin S&C) was safe and could improve the supplies of selenium and cobalt for adult sheep fed a whole grain diet, low in both elements, which produced a steady decrease in blood glutathione peroxidase (GSHPx) and plasma vitamin B12 concentrations. Ovitelmin S&C, when given orally in a single dose as a suspension containing 0.34 mg selenium/ml, and 0.44 mg cobalt/ml (to provide 0.11 mg selenium and 0.15 mg cobalt/kg liveweight) significantly increased the GSHPx activity in blood. After a second dose given 28 days later the rate of change increased from 2.5 to 3.5 u/g haemoglobin/day. The responses in GSHPx were similar for a preparation which contained twice the concentration of selenium. Ovitelmin S&C increased the concentration of vitamin B12 in the plasma by about 1000 pg/ml for four to seven days after each dose and the increases were similar to those observed in sheep treated with an Ovitelmin preparation containing 45 times more cobalt (providing 6.7 mg cobalt/kg liveweight). After 63 days, liver vitamin B12 concentrations were 43 per cent higher in the cobalt treated than in the untreated groups (P less than 0.01) with no differences among the groups given cobalt. Neither adverse reactions nor signs of toxicity followed the administration of Ovitelmin S&C or Ovitelmin containing the higher concentrations of selenium and cobalt.