An updated evaluation of potential health hazards associated with exposures to asbestos-containing drywall accessory products.

Following a previously published (2012) evaluation of the potential health hazards related to the use of asbestos-containing drywall accessory products, additional information regarding asbestos exposures during the use of accessory products, as well as studies of chrysotile asbestos risk as a function of exposure, have been published in the peer-reviewed literature. The purpose of this analysis is to update the original evaluation with this new information. It was previously estimated that a professional drywaller performing joint compound-associated tasks could have a lifetime cumulative chrysotile exposure of 12-26 f/cc-year. Using conservative assumptions regarding airborne asbestos levels during different drywalling tasks, task duration, and job tenure, we found that a range of 4.3-36.3 f/cc-year is a plausible estimate of a career drywaller's cumulative asbestos exposure from historical joint compound use. The estimated range for bystander exposures would be below (sometimes significantly below) this range depending on the frequency and duration of work near drywallers. Further, the estimated drywaller and bystander total fiber exposures were well below a recently published "no-observed adverse effect level, best estimate" for predominately chrysotile exposures of 89-168 f/cc-year for lung cancer and 208-415 f/cc-year for mesothelioma. We also determined that, even if the chrysotile or possibly talc ingredients in the drywall products had contained asbestiform tremolite, the cumulative tremolite exposures would have been well below a recently published tremolite no-effect level of 0.5-2.6 f/cc-year. Based on our calculations, typical drywall work using asbestos-containing drywall accessory products is not expected to increase the risk of asbestos-related lung cancer or mesothelioma. These conclusions are consistent with the lack of epidemiological evidence that drywall work resulted in an increased incidence of asbestos-related disease in the drywall trades.

Occupational exposures to cosmetic talc and risk of mesothelioma: an updated pooled cohort and statistical power analysis with consideration of latency period.

Objectives: We previously published a pooled statistical power analysis of mesothelioma incidence in the Italian, Norwegian, Austrian, and French cosmetic talc miner and miller cohorts. Soon thereafter, updates to the Italian and Norwegian cohorts were published, providing an additional 14,322 person-years of observation. In this study, we provide an updated power analysis using the newly available information. Methods: We pooled the current results regarding pleural cancer/mesothelioma mortality or incidence in four cosmetic talc miner and miller cohorts in Italy, Norway, Austria, and France. We used the expected numbers of cases as reported by the authors and the power analysis was based on an a priori one-sided significance level of 0.05 and Poisson distribution probabilities. Results: There was a pooled total of 113,344 person-years in the cohorts. Although 3.0 pleural cancers/mesotheliomas were expected, there were no reported pleural cancer or mesothelioma cases in any cohort. Our pooled analysis was associated with 79 and 62% power to detect a 3.0-fold and 2.5-fold or greater increase in pleural cancer/mesothelioma, respectively. These favorable power characteristics were effectively maintained when restricting the pooled cohort to workers with a latency period of 30 or more years (observation time from first employment). Conclusions: The epidemiological evidence from the cosmetic talc miner/miller cohort studies does not support the hypothesis that exposure to cosmetic talc is associated with the development of pleural cancer/mesothelioma.

Derivation of an occupational exposure limit for diacetyl using dose-response data from a chronic animal inhalation exposure study.

Occupational exposure limits (OELs) have been previously proposed for diacetyl; however, most of these values are based on worker cohort studies that are known to have several limitations and confounders. In this analysis, an 8 hour time-weighted average (TWA) OEL for diacetyl was derived based on data from a chronic, 2 year animal inhalation study recently released by the US National Toxicology Program. In that study, complete histopathology was conducted on male and female mice and rats exposed to 0, 12.5, 25 or 50 ppm diacetyl. Several responses in the lower respiratory tract of rats (the more sensitive species) were chosen as the critical endpoints of interest. Benchmark concentration (BMC) modeling of these endpoints was used to estimate BMC values associated with a 10% extra risk (BMC10 ) and the associated 95% lower confidence bound (BMCL10 ), which were subsequently converted to human equivalent concentrations (HECs) using a computational fluid dynamics-physiologically based pharmacokinetic (CFD-PBPK) model to account for interspecies dosimetry differences. A composite uncertainty factor of 8.0 was applied to the human equivalent concentration values to yield 8 hour TWA OEL values with a range of 0.16-0.70 ppm. The recommended 8 hour TWA OEL for diacetyl vapor of 0.2 ppm, based on minimal severity of bronchiolar epithelial hyperplasia in the rat, is practical and health-protective.

Understanding outcomes and toxicological aspects of second generation metal-on-metal hip implants: a state-of-the-art review.

Hip implants have improved the mobility and quality of life in millions of individuals. This review presents the evolution of scientific knowledge regarding the history and understanding of systemic and local metal toxicological concerns of hip implants designs utilizing metal-on-metal (MoM) bearing surfaces used in hip resurfacing arthroplasty (HRA) and total hip arthroplasty (THA). This analysis addresses: (1) the history of the development of MoM hip implants; (2) the clinical and toxicological rationale for introducing second-generation MoM implants in the early 2000s as an alternative to metal-on-polyethylene bearings; (3) the subsequent history regarding success and failure of second-generation MoM devices; (4) a detailed review of the history of MoM toxicology, including carcinogenic potential, metal blood levels, hypersensitivity, and release of wear particles; and (5) a review of local tissue effects and MoM patient management. We have included an analysis of MoM THA and HRA survivorship trends aggregated from over 200 studies. By around 2008, HRA continued to be a challenging procedure with variable success rates, and concurrently, some THA devices began to experience higher than expected revision rates based on annual registry reports. The unexpected THA outcomes and continued challenges with HRA devices prompted many surgeons to question the role of toxicological effects in device performance. Regarding hypersensitivity, while conversion to metal sensitized status in some MoM patients occurs based on the skin patch or lymphocyte transformation testing, there is no evidence of a causal relationship between positive test results and device failure. The weight of evidence indicates that nanoparticles released from MoM implants are cleared from the local synovial space under normal wear conditions. The available data indicate that there are no discernible increases in local or systemic tumors following CoCr alloy implantation. Systemic health effects are rarely reported in MoM implant patients and are unlikely when blood concentrations are below 300 µg/L except when patients have specific risk factors. Over time, patient management evolved to include assays aimed at predicting implant function (blood monitoring) and soft tissue reactions (MRI and ultrasound imaging). Validation of these biomarkers as a diagnostic tool for implant function, patient pain, and, ultimately, implant survival, remains lacking. After the introduction of these biomarkers, differences in implant revision decisions emerged based on imaging abnormalities, increased serum metal ion levels, and overall clinical presentation. Discrepancies in patient management algorithms and the lack of consensus in local biological effects terminology have contributed to variability in reporting incidence, etiology, and dose effects on local tissue responses in MoM implants. This variability has contributed to a debate regarding the benefit or risk of revising asymptomatic patients. Therefore, while toxicological assessments of normal functioning MoM implants indicate that MoM implants are relatively safe because of low wear and clearance of metal, more analysis of revision data is needed in order to best inform patient management decisions, particularly for asymptomatic patients, as well as patients with minor symptoms under consideration for conservative pain management treatments.

Cosmetic talc as a risk factor for pleural mesothelioma: a weight of evidence evaluation of the epidemiology.

OBJECTIVE: Due to some historical (and inaccurate) reports that asbestos might be present in some cosmetic talc products, questions are occasionally raised regarding the potential pleural mesothelioma risks associated with cosmetic talc products. Our objective was to determine the incidence of pleural mesothelioma of individuals exposed to cosmetic talc. MATERIALS AND METHODS: We conducted a systematic review of the epidemiological literature for cosmetic talc miners and millers and found three occupational cohort studies that evaluated pleural mesothelioma incidence in workers in Italy, Norway, France, and Austria. We conducted a second literature review to evaluate the incidence and mortality of pleural mesothelioma among patients who received talc pleurodesis treatments before 1965 and found retrospective clinical studies including over 300 patients with follow-up ranging from 14 to 40 years. RESULTS: There were no mesotheliomas reported in any of the cosmetic talc miner and miller cohorts. A pooled analysis of data from the cohort mortality studies indicated that four mesothelioma deaths would have been expected from the 90,022 person-years of observation, and this was associated with 84% and 67% statistical power to observe a 3-fold or 2.5-fold increase in pleural mesothelioma mortality, respectively. None of the patients who received talc pleurodesis treatments developed mesothelioma. CONCLUSION: We conclude that there is no epidemiological evidence to support the hypothesis that exposure to cosmetic talc is associated with the development of pleural mesothelioma.

A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay.

The objective of this preliminary study was to evaluate the threshold for immune stimulation in mice following local exposure to metal particles and ions representative of normal-functioning cobalt-chromium (CoCr) metal-on-metal (MoM) hip implants. The popliteal lymph node assay (PLNA) was used in this study to assess immune responses in BALB/c mice following treatment with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3 and NiCl2), or Cr2O3 particles together with metal salts using single-dose exposures representing approximately 10days (0.000114mg), 19years (0.0800mg), and 40years (0.171mg) of normal implant wear. The immune response elicited following treatment with Cr2O3 particles together with metal salts was also assessed at four additional doses equivalent to approximately 1.5months (0.0005mg), 0.6years (0.0025mg), 2.3years (0.01mg), and 9.3years (0.04mg) of normal implant wear. Mice were injected subcutaneously (50µL) into the right hind foot with the test article, or with the relevant vehicle control. The proliferative response of the draining lymph node cells (LNC) was measured four days after treatment, and stimulation indices (SI) were derived relative to vehicle controls. The PLNA was negative (SI<3) for all Cr2O3 particle doses, and was also negative at the lowest dose of the metal salt mixture, and the lowest four doses of the Cr2O3 particles with metal salt mixture. The PLNA was positive (SI>3) at the highest two doses of the metal salt mixture and the highest three doses of the Cr2O3 particles with the metal salt mixture. The provisional NOAEL and LOAEL values identified in this study for immune activation corresponds to Co and Cr concentrations in the synovial fluid approximately 500 and 2000 times higher than that reported for normal-functioning MoM hip implants, respectively. Overall, these results indicate that normal wear conditions are unlikely to result in immune stimulation in individuals not previously sensitized to metals.

An updated evaluation of reported no-observed adverse effect levels for chrysotile asbestos for lung cancer and mesothelioma.

Although consumption of chrysotile asbestos has decreased since the 1970s, the latency period of asbestos-related cancers is thought to be at least 20-30 years, and therefore the potential health risks associated with historical exposures is still actively researched. This analysis represents an update to a previous paper in which we evaluated the exposure-response relationships for lung cancer and mesothelioma in chrysotile-exposed cohorts. Here, we review several recently published studies as well as updated information from previous studies. For each of the 14 studies considered, we identified the "no-observed adverse effect level" (NOAEL) for lung cancer and/or mesothelioma. NOAEL values for lung cancer ranged from 1.1 to <20 f/cc-years to 1600-3200 f/cc-years, and for mesothelioma ranged from 100-400 f/cc-years to 800-1599 f/cc-years. The range of "best estimate" NOAELs was estimated to be 89-168 f/cc-years for lung cancer and 208-415 f/cc-years for mesothelioma. None of the six cohorts of cement or friction product manufacturing workers exhibited an increased lung cancer risk at any exposure level, while all of the five studies of textile workers reported an increased risk at one or more exposure levels. This is likely because friction and cement workers were exposed to much shorter chrysotile fibers. Of the seven cases of peritoneal mesothelioma reported in the included studies, none were observed in the analyses of cement or friction product manufacturing workers in the absence of crocidolite exposure. These findings will help characterize potential worker and consumer health risks associated with historical and current chrysotile exposures.

Best-practices approach to determination of blood alcohol concentration (BAC) at specific time points: Combination of ante-mortem alcohol pharmacokinetic modeling and post-mortem alcohol generation and transport considerations.

Alcohol concentrations in biological matrices offer information regarding an individual's intoxication level at a given time. In forensic cases, the alcohol concentration in the blood (BAC) at the time of death is sometimes used interchangeably with the BAC measured post-mortem, without consideration for alcohol concentration changes in the body after death. However, post-mortem factors must be taken into account for accurate forensic determination of BAC prior to death to avoid incorrect conclusions. The main objective of this work was to describe best practices for relating ante-mortem and post-mortem alcohol concentrations, using a combination of modeling, empirical data and other qualitative considerations. The Widmark modeling approach is a best practices method for superimposing multiple alcohol doses ingested at various times with alcohol elimination rate adjustments based on individual body factors. We combined the selected ante-mortem model with a suggestion for an approach used to roughly estimate changes in BAC post-mortem, and then analyzed the available data on post-mortem alcohol production in human bodies and potential markers for alcohol production through decomposition and putrefaction. Hypothetical cases provide best practice approaches as an example for determining alcohol concentration in biological matrices ante-mortem, as well as potential issues encountered with quantitative post-mortem approaches. This study provides information for standardizing BAC determination in forensic toxicology, while minimizing real world case uncertainties.

An assessment of formaldehyde emissions from laminate flooring manufactured in China.

Formaldehyde emissions from two laminate flooring products, labeled as California Air Resources Board (CARB) compliant, were evaluated. Passive 24-hr samples (n = 79) and real-time measurements were collected following installation and removal of the products in two rooms of similar size. Mean formaldehyde concentrations following installation were 0.038 and 0.022 ppm for Products 1 and 2 respectively, and 7 days after flooring removal the concentrations returned to background pre-installation levels. Both products were also evaluated in a small chamber (ASTM D6007) using Deconstructive (de-laminated product) and Non-Deconstructive (intact product) methods. Deconstructive testing showed that Product 1 exceeded the applicable CARB emission standard by 4-fold, while Product 2 was equivalent to the standard. Non-Deconstructive measurements were far below the Deconstructive results and were used to predict 24-hr steady-state room air concentrations. Based on the products that we tested (one of which was found to not be compliant with the CARB standard), the airborne formaldehyde concentrations measured following installation in a real-world setting would not be expected to elicit adverse acute health effects.

Review of cobalt toxicokinetics following oral dosing: Implications for health risk assessments and metal-on-metal hip implant patients.

Cobalt (Co) can stimulate erythropoietin production in individuals at doses exceeding 25 mg CoCl2/day. Co has also been shown to exert effects on the thyroid gland, heart and nervous system at sufficient doses. The biological activity of Co is dictated by the concentration of free (unbound) ionic Co(2+). Blood concentrations, as well as, urinary excretion rates of Co are reliable biomarkers for systemic Co exposure. A recent series of human volunteer Co-supplement studies simultaneously measured Co blood and urine concentrations, as well as, Co speciation in serum, and a number of biochemical and clinical parameters. It was found in these studies that peak Co whole blood concentration as high as 117 µg/L were not associated with changes in hematological parameters such as increased red blood cell (RBC) count, hemoglobin (Hgb) or hematocrit (Hct) levels, nor with changes in cardiac, neurological or, thyroid function. Using a Co biokinetic model, the estimated Co systemic tissue concentrations (e.g., liver, kidney, and heart) following 90-days of Co-dietary supplementation with ∼1 mg Co/day were found to be similar to estimated tissue concentrations in implant patients after 10 years of exposure at continuous steady state Co blood concentration of ∼10 µg/L. This study is the first to present modeled Co tissue concentrations at various doses following sub-chronic and chronic exposure. The modeled steady state tissue Co concentrations in combination with the data on adverse health effects in humans should help in the characterization of potential hazards associated with increased blood Co concentrations due to exposure to dietary supplements or cobalt-chromium (Co-Cr) containing implants.

Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants Part I: physicochemical properties in patient and simulator studies.

The objective of Part I of this analysis was to identify the relevant physicochemical characteristics of wear particles from cobalt-chromium alloy (CoCr) metal-on-metal (MoM) hip implant patients and simulator systems. For well-functioning MoM hip implants, the volumetric wear rate is low (<1mm(3) per million cycles or per year) and the majority of the wear debris is composed of oxidized Cr nanoparticles (<100nm) with minimal or no Co content. For implants with surgical malpositioning, the volumetric wear rate is as high as 100mm(3) per million cycles or per year and the size distribution of wear debris can be skewed to larger sizes (up to 1000nm) and contain higher concentrations of Co. In order to obtain data suitable for a risk assessment of wear debris in MoM hip implant patients, future studies need to focus on particle characteristics relevant to those generated in patients or in properly conducted simulator studies. FROM THE CLINICAL EDITOR: Metallic implants are very common in the field of orthopedics. Nonetheless, concerns have been raised about the implications of nano-sized particles generated from the wear of these implants. In this two-part review, the authors first attempted to identify and critically evaluate the relevant physicochemical characteristics of CoCr wear particles from hip implant patients and simulator systems. Then they evaluated in vitro and animal toxicology studies with respect to the physicochemistry and dose-relevance to metal-on-metal implant patients.

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.

Effects of the NFL's Amendments to the Free Kick Rule on Injuries during the 2010 and 2011 Seasons.

Recognizing the chronic health effects associated with playing football, the National Football League (NFL) has enacted policies and rules aimed at improving player health and safety. Prior to the 2011 season, amendments to the Free Kick rule were implemented, whereby the restraining line was moved from the 30- to the 35-yard line and all kicking team players other than the kicker were required to line up no more than 5 yards behind their restraining line. The objective of this analysis was to evaluate the effects of these rule changes on injury rates. Data for injuries occurring on special teams plays during the 2010 and 2011 NFL seasons were obtained from publically available NFL gamebooks and injury reports. Injury rates for kickoff plays across seasons were statistically compared using incidence rate ratios (RR) and 95% confidence intervals. To evaluate whether injury rate changes could be attributable to the rule amendments, comparisons were made with punt injury rates (presumably unaffected by the Free Kick rule changes) and distributions of potential confounders were assessed across seasons. Incidence of injuries occurring on kickoff plays fell from 2010 to 2011 (RR: 0.45, 95% CI: 0.28-0.73), although on kickoff plays where the ball was returned, this decrease became non-significant (RR: 0.67, 95% CI: 0.41-1.08). While the incidence of head injuries decreased by approximately 3-fold during kickoff plays, this change was not statistically significant (RR: 0.33, 95% CI: 0.09-1.21). No difference was observed in injury incidence during punts between the two seasons, and the distribution of confounding factors was largely uniform across seasons. The observed decrease in injuries occurring during kickoffs was likely directly attributable to the Free Kick rule amendments, principally from the increased frequency of touchbacks. The absence of a significant change in head injuries during kickoffs was unexpected, but may be attributable to small sample size. Despite the injury rate reductions, the rule changes likely had little effect on player safety during active gameplay.

Correlation of blood Cr(III) and adverse health effects: Application of PBPK modeling to determine non-toxic blood concentrations.

Chromium (Cr) (III) is a trace metal essential to human health and exposure typically occurs via the diet on a daily basis. Some groups of individuals, such as those consuming Cr(III) supplements or patients with Cr-containing implants, may have elevated blood Cr(III) concentrations. Although blood Cr(III) levels are thought to be an accurate metric of exposure, little is known about the relationship between these concentrations and possible adverse health risks. This study evaluated the various effects reported in animal and human epidemiological studies of Cr(III) exposure in an attempt to correlate them with blood Cr(III) concentrations. The target endpoints identified in this analysis included the hematological, hepatic, and renal systems. Animal and human physiological-based pharmacokinetic (PBPK) models were used to estimate steady state blood Cr(III) concentrations from a variety of dosing regimens. Based on the animal studies, our results suggest that blood Cr(III) concentrations as high as 480-580 µg/L are not associated with any responses. For each of the three health endpoints considered in this analysis (hematological, hepatic, and renal) no adverse effects were observed below 3,700 µg/L. Some hematological responses were observed at 3,700 µg/L, and adverse effects clearly occurred at 7,500 µg/L. These findings can be used to assess potential health risks to individuals with elevated blood Cr(III) concentrations.

Diacetyl and 2,3-pentanedione exposures associated with cigarette smoking: implications for risk assessment of food and flavoring workers.

Diacetyl and 2,3-pentanedione inhalation have been suggested as causes of severe respiratory disease, including bronchiolitis obliterans, in food/flavoring manufacturing workers. Both compounds are present in many food items, tobacco, and other consumer products, but estimates of exposures associated with the use of these goods are scant. A study was conducted to characterize exposures to diacetyl and 2,3-pentanedione associated with cigarette smoking. The yields (µg/cigarette) of diacetyl and 2,3-pentanedione in mainstream (MS) cigarette smoke were evaluated for six tobacco products under three smoking regimens (ISO, Massachusetts Department of Public Health, and Health Canada Intense) using a standard smoking machine. Mean diacetyl concentrations in MS smoke ranged from 250 to 361 ppm for all tobacco products and smoking regimens, and mean cumulative exposures associated with 1 pack-year ranged from 1.1 to 1.9 ppm-years. Mean 2,3-pentanedione concentrations in MS smoke ranged from 32.2 to 50.1 ppm, and mean cumulative exposures associated with 1 pack-year ranged from 0.14 to 0.26 ppm-years. We found that diacetyl and 2,3-pentanedione exposures from cigarette smoking far exceed occupational exposures for most food/flavoring workers who smoke. This suggests that previous claims of a significant exposure-response relationship between diacetyl inhalation and respiratory disease in food/flavoring workers were confounded, because none of the investigations considered or quantified the non-occupational diacetyl exposure from cigarette smoke, yet all of the cohorts evaluated had considerable smoking histories. Further, because smoking has not been shown to be a risk factor for bronchiolitis obliterans, our findings are inconsistent with claims that diacetyl and/or 2,3-pentanedione exposure are risk factors for this disease.

Toxicology-based cancer causation analysis of CoCr-containing hip implants: a quantitative assessment of genotoxicity and tumorigenicity studies.

In this paper, quantitative methods were used to evaluate the weight of evidence regarding a causative relationship between cobalt-chromium (CoCr)-containing hip implants and increased cancer risk. We reviewed approximately 80 published papers and identified no-observed-adverse-effect level (NOAEL) and/or lowest-observed-adverse-effect level (LOAEL) values for specific endpoints of interest: genotoxic effects from in vitro studies with human cell lines as well as genotoxicity and tumor formation in animal bioassays. Test articles included Co particles and ions, Cr particles and ions, and CoCr alloy particles as well as CoCr alloy implants. The NOAEL/LOAEL values were compared with body burdens of Co/Cr particles and ions we calculated to exist in systemic tissues of hip implant patients under normal and excessive wear conditions. We found that approximately 40 tumor bioassays have been conducted with CoCr alloy implants or Co/Cr particles and ions at levels hundreds to thousands of times higher than those present in hip implant patients, and none reported a statistically significant increased incidence of systemic tumors. Results from in vitro and in vivo genotoxicity assays, which are relatively less informative owing to false positives and other factors, also indicated that DNA effects would be highly unlikely to occur as a result of wear debris from a CoCr implant. Hence, the toxicological weight of evidence suggests that CoCr-containing hip implants are unlikely to be associated with an increased risk of systemic cancers, which is consistent with published and ongoing cancer epidemiology studies involving patients with CoCr hip implants.

A review of the health hazards posed by cobalt.

Cobalt (Co) is an essential element with ubiquitous dietary exposure and possible incremental exposure due to dietary supplements, occupation and medical devices. Adverse health effects, such as cardiomyopathy and vision or hearing impairment, were reported at peak blood Co concentrations typically over 700 µg/L (8-40 weeks), while reversible hypothyroidism and polycythemia were reported in humans at ~300 µg/L and higher (≥2 weeks). Lung cancer risks associated with certain inhalation exposures have not been observed following Co ingestion and Co alloy implants. The mode of action for systemic toxicity relates directly to free Co(II) ion interactions with various receptors, ion channels and biomolecules resulting in generally reversible effects. Certain dose-response anomalies for Co toxicity likely relate to rare disease states known to reduce systemic Co(II)-ion binding to blood proteins. Based on the available information, most people with clearly elevated serum Co, like supplement users and hip implant patients, have >90% of Co as albumin-bound, with considerable excess binding capacity to sequester Co(II) ions. This paper reviews the scientific literature regarding the chemistry, pharmacokinetics and systemic toxicology of Co, and the likely role of free Co(II) ions to explain dose-response relationships. Based on currently available data, it might be useful to monitor implant patients for signs of hypothyroidism and polycythemia starting at blood or serum Co concentrations above 100 µg/L. This concentration is derived by applying an uncertainty factor of 3 to the 300 µg/L point of departure and this should adequately account for the fact that persons in the various studies were exposed for less than one year. A higher uncertainty factor could be warranted but Co has a relatively fast elimination, and many of the populations studied were of children and those with kidney problems. Closer follow-up of patients who also exhibit chronic disease states leading to clinically important hypoalbuminemia and/or severe ischemia modified albumin (IMA) elevations should be considered.

31-day study of cobalt(II) chloride ingestion in humans: pharmacokinetics and clinical effects.

The United Kingdom Expert Group on Vitamins and Minerals concluded that ingesting cobalt (Co)-containing supplements up to 1400 µg Co/d is unlikely to produce adverse health effects. However, the associated blood Co concentrations and safety of Co-containing dietary supplements have not been fully characterized. Thus, blood Co kinetics and a toxicological assessment of hematological and biochemical parameters were evaluated following Co dietary supplementation in 5 male and 5 female volunteers who ingested approximately 1000 µg Co/d (10-19 µg Co/kg-d) as cobalt(II) chloride for a period of 31 d. Supplement intake was not associated with significant overt adverse events, alterations in clinical chemistries including blood counts and indicators of thyroid, cardiac, liver, or kidney functions, or metal sensitization. A non-clinically significant (<5%) increase in hemoglobin, hematocrit, and red blood cell (RBC) counts were observed in males but not females 1 wk after dose termination. Mean Co concentrations in whole blood/serum after 31 d of dosing were approximately two-fold higher in females (33/53 µg/L) than in males (16/21 µg/L). In general, steady-state concentrations of Co were achieved in whole blood and/or red blood cells (RBC) within 14-24 d. Temporal patterns of whole blood and serum Co concentrations indicated metal sequestration in RBC accompanied by slower whole blood clearance compared to serum. Data also indicated that peak whole blood Co concentrations up to 91.4 µg/L were not associated with clinically significant changes in clinical chemistries. In addition, Co blood concentrations and systemic uptake via ingestion were generally higher in females.