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Chicago, IL, United States
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Paustenbach D.J.,ChemRisk LLC | Tvermoes B.E.,ChemRisk LLC | Unice K.M.,ChemRisk LLC | Finley B.L.,ChemRisk LLC | Kerger B.D.,ChemRisk LLC
Critical Reviews in Toxicology | Year: 2013

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 g/L (8-40 weeks), while reversible hypothyroidism and polycythemia were reported in humans at ∼300 g/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 g/L. This concentration is derived by applying an uncertainty factor of 3 to the 300 g/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. © 2013 Informa UK Ltd.


Zheng W.,Purdue University | Fu S.X.,Purdue University | Dydak U.,Purdue University | Dydak U.,Indiana University | Cowan D.M.,ChemRisk Inc.
NeuroToxicology | Year: 2011

Manganese (Mn), upon absorption, is primarily sequestered in tissue and intracellular compartments. For this reason, blood Mn concentration does not always accurately reflect Mn concentration in the targeted tissue, particularly in the brain. The discrepancy between Mn concentrations in tissue or intracellular components means that blood Mn is a poor biomarker of Mn exposure or toxicity under many conditions and that other biomarkers must be established. For group comparisons of active workers, blood Mn has some utility for distinguishing exposed from unexposed subjects, although the large variability in mean values renders it insensitive for discriminating one individual from the rest of the study population. Mn exposure is known to alter iron (Fe) homeostasis. The Mn/Fe ratio (MIR) in plasma or erythrocytes reflects not only steady-state concentrations of Mn or Fe in tested individuals, but also a biological response (altered Fe homeostasis) to Mn exposure. Recent human studies support the potential value for using MIR to distinguish individuals with Mn exposure. Additionally, magnetic resonance imaging (MRI), in combination with noninvasive assessment of γ-aminobutyric acid (GABA) by magnetic resonance spectroscopy (MRS), provides convincing evidence of Mn exposure, even without clinical symptoms of Mn intoxication. For subjects with long-term, low-dose Mn exposure or for those exposed in the past but not the present, neither blood Mn nor MRI provides a confident distinction for Mn exposure or intoxication. While plasma or erythrocyte MIR is more likely a sensitive measure, the cut-off values for MIR among the general population need to be further tested and established. Considering the large accumulation of Mn in bone, developing an X-ray fluorescence spectroscopy or neutron-based spectroscopy method may create yet another novel non-invasive tool for assessing Mn exposure and toxicity. © 2010 Elsevier Inc.


Galbraith D.,ChemRisk Inc. | Gross S.A.,ChemRisk Inc. | Paustenbach D.,ChemRisk Inc.
Critical Reviews in Toxicology | Year: 2010

Over the last century, benzene has been a well-studied chemical, with some acute and chronic exposures being directly associated with observed hematologic effects in humans and animals. Chronic heavy exposures to benzene have also been associated with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) in humans. Other disease processes have also been studied, but have generally not been supported by epidemiologic studies of workers using benzene in the workplace. Within occupational cohorts with large populations and very low airborne benzene exposures (less than 0.11.0ppm), it can be difficult to separate background disease incidence from those occurring due to occupational exposures. In the last few decades, some scientists and physicians have suggested that chronic exposures to various airborne concentrations of benzene may increase the risk of developing non-Hodgkin's lymphoma (NHL) (Savitz and Andrews, 1997, Am J Ind Med 31:287295; Smith et al., 2007, Cancer Epidemiol Biomarkers Prev 16:385391), multiple myeloma (MM) (Goldstein, 1990, Ann NY Acad Sci 609:225230; Infante, 2006, Ann NY Acad Sci 1076:90109), and various other hematopoietic disorders. We present a state-of-the-science review of the medical and regulatory aspects regarding the hazards of occupational exposure to benzene. We also review the available scientific and medical evidence relating to benzene and the risk of developing various disorders following specific levels of exposure. Our evaluation indicates that the only malignant hematopoietic disease that has been clearly linked to benzene exposure is AML. Information from the recent "Benzene 2009," a symposium of international experts focusing on the health effects and mechanisms of toxicity of benzene, hosted by the Technical University of Munich, has been incorporated and referenced. © 2010 Informa Healthcare USA, Inc.


Shay E.,ChemRisk LLC | De Gandiaga E.,ChemRisk LLC | Madl A.K.,ChemRisk LLC
Critical Reviews in Toxicology | Year: 2013

The exposure-response patterns with beryllium sensitization (BeS), chronic beryllium disease (CBD) and lung cancer are influenced by a number of biological and physicochemical factors. Recent studies have suggested dermal exposure as a pathway for BeS. In light of the current non-health-based DOE Beryllium Rule surface criteria, the feasibility of deriving a human health-based surface dust cleanup criteria (SDCC) for beryllium was assessed based on toxicology and health risk factors via all potential routes of exposure. Beryllium-specific and general exposure factors were evaluated, including (1) beryllium physicochemical characteristics, bioavailability and influence on disease prevalence, and (2) chemical dissipation, resuspension and transfer. SDCC for non-cancer (SDCCNC) and cancer (SDCCCA) endpoints were derived from a combination of modern methods applied for occupational, residential and building reentry surface dust criteria. The most conservative SDCCNC estimates were derived for dermal exposure (5-379 μg/100 cm2 for 0.1-1% damaged skin and 17-3337 μg/100 cm2 for intact skin), whereas the SDCCCA for inhalation exposure ranged from 51 to 485 μg/100 cm2. Considering this analysis, the lowest DOE surface criterion of 0.2 μg/100 cm2 is conservative for minimizing exposure and potential risks associated with beryllium-contaminated surfaces released for non-beryllium industrial or public sector use. Although methodological challenges exist with sampling and analysis procedures, data variability and interpretation of surface dust information in relation to anthropogenic and natural background concentrations, this evaluation should provide useful guidance with regard to cleanup of manufacturing equipment or remediation of property for transfer to the general public or non-beryllium industrial facilities. © 2013 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.


Donovan E.P.,ChemRisk LLC | Donovan B.L.,ChemRisk LLC | McKinley M.A.,ChemRisk LLC | Cowan D.M.,ChemRisk LLC | Paustenbach D.J.,ChemRisk LLC
Critical Reviews in Toxicology | Year: 2012

The potential for para-occupational (or "take-home") exposure to a number of chemicals has been recognized for over 60 years. We conducted a literature review in order to characterize reported cases of asbestos-related disease among household contacts of workers occupationally exposed to asbestos. Over 200 published articles were evaluated. Nearly 60 articles described cases of asbestos-related disease thought to be caused by para-occupational exposure. Over 65% of these cases were in persons who lived with workers classified as miners, shipyard workers, insulators, or others involved in the manufacturing of asbestos-containing products, with nearly all remaining workers identified as craftsmen. 98% of the available lung samples of the persons with diseases indicated the presence of amphibole asbestos. Eight studies provided airborne asbestos concentrations during (i) handling of clothing contaminated with asbestos during insulation work or simulated use of friction products; (ii) ambient conditions in the homes of asbestos miners; and (iii) wearing previously contaminated clothing. This review indicates that the literature is dominated by case reports, the majority of which involved household contacts of workers in industries characterized, generally, by high exposures to amphiboles or mixed mineral types. The available data do not implicate chrysotile as a significant cause of disease for household contacts. Also, our analysis indicates that there is insufficient information in the published literature that would allow one to relate airborne asbestos concentrations in a workplace to those that would be generated from subsequent handling of contact with clothing that had been contaminated in that environment. Ideally, a simulation study could be conducted in the future to better understand the relationships between the airborne concentrations in the workplace and the fiber characteristics that influence retention on fabric, as well as the concentrations that can be generated by handling the contaminated clothing by the persons in the home. © 2012 Informa Healthcare USA, Inc.


Phelka A.D.,ChemRisk LLC | Finley B.L.,ChemRisk LLC
Critical Reviews in Toxicology | Year: 2012

Until the late 1970s, chrysotile asbestos was an ingredient in most industrial and consumer drywall accessory products manufactured in the US. In 1977, the Consumer Product Safety Commission (CPSC) issued a ban of consumer patching compounds containing "respirable, free-form asbestos" based on their prediction of exceptionally high rates of asbestos-related diseases among individuals using patching compounds for as little as a few days. Although hundreds of thousands of workers and homeowners handling these products may have experienced exposure to asbestos prior to the ban, there has been no systematic effort to summarize and interpret the information relevant to the potential health effects of such exposures. In this analysis, we provide a comprehensive review and analysis of the scientific studies assessing fiber type and dimension, toxicological and epidemiological endpoints, and airborne fiber concentrations associated with joint compound use. We conclude that: 1) asbestos in drywall accessory products was primarily short fiber (< 5 m) chrysotile, 2) asbestos in inhaled joint compound particulate is probably not biopersistent in the lung, 3) estimated cumulative chrysotile exposures experienced by workers and homeowners are below levels known to be associated with respiratory disease, and 4) mortality studies of drywall installers have not demonstrated a significantly increased incidence of death attributable to any asbestos-related disease. Consequently, contrary to the predictions of the CPSC, the current weight of evidence does not indicate any clear health risks associated with the use of asbestos-containing drywall accessory products. We also describe information gaps and suggest possible areas of future research. © 2012 Informa Healthcare USA, Inc.


Tvermoes B.E.,ChemRisk LLC
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2013

Recently, there has been an increase in the marketing and sales of dietary supplements, energy drinks, and other consumer products that may contain relatively high concentrations of essential elements. Cobalt-containing supplements are readily available in the U.S. and have been marketed to consumers as energy enhancers. However, little information is available regarding cobalt (Co) body burden and steady-state blood concentrations following the intake of Co dietary supplements. We assessed Co whole blood concentrations in four healthy adult male volunteers who ingested a commercially available Co supplement (0.4 mg Co/day) for 15 or 16 days. Pre-supplementation blood Co concentrations were less than the reporting limit of 0.5 μg/L, consistent with background concentrations reported to range between 0.1 and 0.4 μg/L. The mean whole blood Co concentration in the volunteers after 15 or 16 days of dosing was 3.6 μg Co/L and ranged from 1.8 to 5.1 μg Co/L. The mean observed concentration in the study group was approximately 9-36 times greater than background concentrations. Further studies of Co whole blood concentrations following supplementation over longer time periods with additional monitoring of physiological parameters may provide useful information for evaluating the health of persons who take various doses of Co. Copyright © 2012 Elsevier Ltd. All rights reserved.


Finley B.L.,ChemRisk LLC | Monnot A.D.,ChemRisk LLC | Gaffney S.H.,ChemRisk LLC | Paustenbach D.J.,ChemRisk LLC
Journal of Toxicology and Environmental Health - Part B: Critical Reviews | Year: 2012

Cobalt (Co) is an essential component of vitamin B12. As with all metals, at sufficiently high doses, Co may exert detrimental effects on different organ systems, and adverse responses have been observed in animals, patients undergoing Co therapy, and workers exposed to respirable Co particulates. Although blood Co concentrations are postulated to be the most accurate indicator of ongoing Co exposure, little is known regarding the dose-response relationships between blood Co concentrations and adverse health effects in various organ systems. In this analysis, the animal toxicology and epidemiology literature were evaluated to identify blood Co concentrations at which effects have, and have not, been reported. Where necessary, a biokinetic model was used to convert oral doses to blood Co concentrations. Our results indicated that blood Co concentrations of 300 μg/L and less have not been associated with adverse responses of any type in humans. Concentrations of 300 μg/L and higher were associated with certain hematological and reversible endocrine responses, including polycythemia and reduced iodide uptake. Blood Co concentrations of 700-800 μg Co/L and higher may pose a risk of more serious neurological, reproductive, or cardiac effects. These blood concentrations should be useful to clinicians and toxicologists who are attempting to interpret blood Co concentrations in exposed individuals. Copyright © Taylor & Francis Group, LLC.


Paustenbach D.J.,ChemRisk LLC | Kerger B.D.,ChemRisk LLC
Chemosphere | Year: 2013

The University of Michigan Dioxin Exposure Study provides extensive data on elevated residential soil and house dust concentrations of polychlorinated dioxins and dibenzofurans (PCDD/Fs) and adult body burdens among residents near a chemical manufacturing plant in Midland, Michigan. Recent reports found no significant contribution of residential soil/dust concentrations to serum lipid PCDD/Fs in adults. Although child body burdens were not studied by the University of Michigan, internal dose modeling that incorporates recent findings on demonstrated shorter elimination half life of PCDD/Fs in children (1-2. year half life in children vs. ∼7. years in older adults) can be applied to assess this important issue. The model examines children (ages 0-7. years) with background dietary intake and exposure to residential soils at selected concentrations (10, 100 and 1000. pg/g 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents, TEQ) using the congener patterns observed in Midland. Model predictions assuming 50th percentile TEQ uptake from soil/dust-related dermal and ingestion exposures indicate no measurable changes in serum lipid TEQ concentrations up to 1000. pg/g in soil/dust. Assuming 95th percentile uptake, the model shows no measurable serum lipid TEQ change up to 100. pg/g in soil/dust, but serum lipid TEQ levels rose ∼2. pg/g at 1000. pg/g in soil/dust. Since the vast majority of soil/dust data were below 100. pg/g, Michigan children exposed to such soil/dust TEQ concentrations are not reasonably expected to exhibit measurable changes in serum lipid TEQ concentrations when compared to typical background dietary exposures. With adequate data, this approach can be applied to evaluate child dose and risk for other persistent chemicals. © 2013 Elsevier Ltd.


Finley B.L.,ChemRisk LLC | Monnot A.D.,ChemRisk LLC | Paustenbach D.J.,ChemRisk LLC | Gaffney S.H.,ChemRisk LLC
Regulatory Toxicology and Pharmacology | Year: 2012

Cobalt (Co) is an essential element in humans as a component of vitamin B12. However, at high levels Co exposure has been shown to have detrimental effects. This study was designed to identify a chronic oral reference dose (RfD) for Co. Currently available data indicate that non-cancer health effects associated with Co exposure may include hematological, neurological, immunological, reproductive, cardiovascular, and endocrine responses. This analysis employs the standard US EPA risk assessment methodology for establishing a chronic RfD. In this analysis, the Jaimet and Thode (1955) 10-week, multiple dose human study of thyroid effects (decreased iodine uptake) in children was determined to be the most robust and sensitive study for identifying a potential point of departure dose (POD). A dose of 0.9. mg. Co/kg-day was chosen as the POD. Consistent with the US EPA's previous derivation of the perchlorate RfD, which is also based on decreased iodine uptake in humans, we considered several uncertainly factors (UFs), and determined that a factor of 10 for human variability was appropriate, as well as a factor of three for database adequacy. Applying an aggregate uncertainty factor of 30 to the POD yields a chronic oral RfD of 0.03. mg/kg-day. We believe this value would be protective of non-cancer health effects in the general population for a lifetime of daily exposure to Co. © 2012 Elsevier Inc.

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