Dennis J Paustenbach

University of Michigan, Ann Arbor, Michigan, United States

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Publications (259)630.38 Total impact

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    ABSTRACT: 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. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 09/2014; 34(9):939-967. · 3.17 Impact Factor
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    ABSTRACT: 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.
    Critical Reviews in Toxicology 07/2014; 44(7). · 6.41 Impact Factor
  • Dennis Paustenbach, David Galbraith, Brent Finley
    Clinical Toxicology 04/2014; · 3.12 Impact Factor
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    ABSTRACT: An updated biokinetic model for human exposures to cobalt (Co) was developed based on a comprehensive set of human pharmacokinetics data collected from five male and five female volunteers who ingested ∼1.0 mg Co/day of a Co supplement for three months. Three key experimental observations from the human dosing studies were incorporated into the model: 1) an increase in the measured fraction of large molecular serum protein bound Co from 95% during dosing to 99% after dosing; 2) a linear decrease in Co red blood cell concentration after dosing; and 3) Co renal clearance consistent with estimated glomerular filtration rates and free Co(2+) concentration. The model was refined by adding compartments accounting for 1) albumin bound Co in intravascular fluid (serum); 2) albumin bound Co in extravascular fluid with physiologic exchange rates of albumin bound Co between extravascular and intravascular fluid; and 3) a novel sequential cascade of compartments representing red blood cell ages between 1 and 120 days. Reasonable agreement between the modeled and measured urine, serum, and whole blood concentrations were observed (r>0.84, slope= 0.79 - 1.0) with gastrointestinal absorption rates between 9% and 66%. In addition, model predictions agreed well with data from several external studies representing healthy human volunteers, dialysis patients, anephric patients, a Co-poisoning incident and whole body retention studies. Our revised model considerably improves the state of knowledge on human Co kinetics, and should be helpful for evaluating elevated blood Co concentrations in currently exposed populations, such as metal-on-metal (MoM) hip implant patients.
    Chemico-biological interactions 04/2014; · 2.46 Impact Factor
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    ABSTRACT: There have been claims over the years that asbestos-containing product manufacturers did not sufficiently warn end users early enough regarding the potential health hazards associated with their products (1930s-1990s). To address this issue, we compared the content of the warnings associated with asbestos-containing friction products (brakes, clutches, and gaskets) manufactured by the US automotive industries to what was expected by regulatory agencies during the time period in which an understanding of asbestos health hazards was being developed. We ended our evaluation around 1990, since asbestos-containing manufacturer supplied automotive products were functionally removed from commerce by 1985 in the United States. We assessed the warnings issued in users’ manuals, technical service bulletins, product packaging materials, and labels placed on products themselves. Based on our evaluation, regulatory agencies had no guidelines regarding specific warning language for finished friction products, particularly when a product contained encapsulated asbestos fibers (i.e., modified by a bonding agent). Even today, federal regulations do not require labeling on encapsulated products when, based on professional judgment or sampling, user exposure is not expected to exceed the OSHA PEL. We concluded that, despite limited regulatory guidance, the US automotive industry provided adequate warnings with regards to its friction products.
    Regulatory Toxicology and Pharmacology 04/2014; · 2.14 Impact Factor
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    ABSTRACT: The potential for para-occupational (or take-home) exposures from contaminated clothing has been recognized for the past 60 years. To better characterize the take-home asbestos exposure pathway, a study was performed to measure the relationship between airborne chrysotile concentrations in the workplace, the contamination of work clothing, and take-home exposures and risks. The study included air sampling during two activities: (1) contamination of work clothing by airborne chrysotile (i.e., loading the clothing), and (2) handling and shaking out of the clothes. The clothes were contaminated at three different target airborne chrysotile concentrations (0-0.1 fibers per cubic centimeter [f/cc], 1-2 f/cc, and 2-4 f/cc; two events each for 31-43 minutes; six events total). Arithmetic mean concentrations for the three target loading levels were 0.01 f/cc, 1.65 f/cc, and 2.84 f/cc (National Institute of Occupational Health and Safety [NIOSH] 7402). Following the loading events, six matched 30-minute clothes-handling and shake-out events were conducted, each including 15 minutes of active handling (15-minute means; 0.014-0.097 f/cc) and 15 additional minutes of no handling (30-minute means; 0.006-0.063 f/cc). Percentages of personal clothes-handling TWAs relative to clothes-loading TWAs were calculated for event pairs to characterize exposure potential during daily versus weekly clothes-handling activity. Airborne concentrations for the clothes handler were 0.2-1.4% (eight-hour TWA or daily ratio) and 0.03-0.27% (40-hour TWA or weekly ratio) of loading TWAs. Cumulative chrysotile doses for clothes handling at airborne concentrations tested were estimated to be consistent with lifetime cumulative chrysotile doses associated with ambient air exposure (range for take-home or ambient doses: 0.00044-0.105 f/cc year).
    Risk Analysis 02/2014; · 2.28 Impact Factor
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    ABSTRACT: Over-the-counter cobalt supplements are available for sale in the United States, but little is known regarding their clinical effects and biokinetic distribution with long-term use. We assessed blood kinetics, biochemical responses, and clinical effects in 5 adult men and 5 adult women who voluntarily ingested ∼1.0 mg Co/d (0.080-0.19 mg Co ⋅ kg(-1) ⋅ d(-1)) of a commercially available cobalt supplement over a 3-mo period. Volunteers were instructed to take the cobalt dietary supplement in the morning according to the manufacturer's label. Blood samples were collected and analyzed for a number of biochemical variables before, during, and after dosing. Hearing, vision, cardiac, and neurologic functions were also assessed in volunteers before, during, and after dosing. After ∼90 d of dosing, mean cobalt blood concentrations were lower in men than in women. Mean cobalt whole blood and serum concentrations in men were 20 μg/L (range: 12-33 μg/L) and 25 μg/L (range: 15-46 μg/L), respectively. In women, mean cobalt whole blood and serum concentrations were 53 μg/L (range: 6-117 μg/L) and 71 μg/L (range: 9-149 μg/L), respectively. Estimated red blood cell (RBC) cobalt concentrations suggested that cobalt was sequestered in RBCs during their 120-d life span, which resulted in a slower whole blood clearance compared with serum. The renal clearance of cobalt increased with the serum concentration and was, on average, lower in women (3.5 ± 1.3 mL/min) than in men (5.5 ± 1.9 mL/min). Sex-specific differences were observed in cobalt absorption and excretion. There were no clinically significant changes in biochemical, hematologic, and clinical variables assessed in this study. Peak cobalt whole blood concentrations ranging between 9.4 and 117 μg/L were not associated with clinically significant changes in basic hematologic and clinical variables. This study was registered at as NCT01990794.
    American Journal of Clinical Nutrition 02/2014; 99(3). · 6.50 Impact Factor
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    ABSTRACT: Carbon monoxide (CO) is a well-known asphyxiant. As part of an incident investigation involving two fatalities, a study was conducted to determine key factors that influence CO concentrations inside motor homes/recreational vehicles. Test parameters examined included the condition of the on-board generator exhaust pipe (attached/detached), generator load (<1-20 amps), position of ventilation hatches (open/closed), parking location (adjacent/perpendicular to a masonry wall), and weather conditions (breezy/calm). A tracer gas test was also performed of the motor home undercarriage because of concerns for possible damage (no visible damage was observed). Results showed that all five parameters affected the CO concentrations detected within the motor home, but the generator exhaust tailpipe was found to have the greatest impact. Further, a specific combination of conditions, along with documented invisible undercarriage leaks, was necessary for CO concentrations to become high enough to produce acutely toxic and fatal conditions inside the motor home.
    International Journal of Vehicle Safety 01/2014; 7(3/4):409 - 424.
  • Dennis J Paustenbach, Matthew H Le
    Health physics 12/2013; 105(6):486-7. · 0.92 Impact Factor
  • Dennis J Paustenbach, David A Galbraith, Brent L Finley
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    ABSTRACT: Introduction. There has been some recent concern regarding possible systemic health effects resulting from elevated blood cobalt concentrations in patients with cobalt containing hip implants. To date there are no blood cobalt criteria to help guide physicians when evaluating an individual hip implant patient's risk of developing systemic health effects because historically there was little or no concern about systemic cobalt toxicity in implant patients. Objective. Our purpose is to describe recently completed research regarding the relationship between blood cobalt concentrations and clinical health effects. We discuss the possibility of systemic health effects in patients with metal containing implants and propose various blood cobalt concentrations that are not associated with an increased risk of developing certain adverse effects. Methodology. The primary literature search was conducted using PubMed and Web of Science using the following search terms: cobalt AND (toxicity OR health effects OR cardiotoxicity OR hematological OR endocrine OR immunological OR reproductive OR testicular effects OR neurological OR case report OR cohort OR Roncovite). The searches identified 6786 papers of which 122 were considered relevant. The Agency for Toxic Substances and Disease Registry toxicological profile for cobalt and the U.S. Environmental Protection Agency Office of Research and Development's National Center for Environmental Assessment's documentation on the provisional peer-reviewed toxicity value for cobalt were also utilized to identify secondary literature sources. Results. Our review of the toxicology and medical literature indicates that highly elevated blood cobalt concentrations can result in certain endocrine, hematological, cardiovascular, and neurological effects in animals and/or humans. These studies, in addition to historical clinical findings involving the therapeutic use of cobalt, indicate that significant systemic effects of cobalt will not occur below blood cobalt concentrations of 300 μg/L in most persons. Some individuals with specific risk factors for increased susceptibility (e.g., severe and sustained hypoalbuminemia) may exhibit systemic effects at lower cobalt blood concentrations. This review also describes several cobalt dosing studies performed with human volunteers that consumed cobalt for 15, 30, or 90 days. Overall, the results of these dosing studies indicate that sustained blood cobalt concentrations averaging 10-70 μg/L for up to 90 days cause no significant clinical effects (maximum concentrations approached 120 μg/L). Some proposed blood criteria for assessing implant wear and local tissue damage have been suggested by several medical groups. For example, the UK Medicines and Healthcare Products Regulatory Agency has proposed a blood cobalt guidance value of 7 μg/L, and the Mayo Clinic has suggested serum cobalt concentrations greater than 10 μg/L, but both of these values are primarily intended to address implant wear and to alert physicians to the possibility of an increased incidence of local effects. There is a clear lack of consensus regarding how to identify a specific numerical blood concentration of concern and whether whole blood or serum is a better matrix to assess total cobalt concentration. Conclusions. Based on currently available data, only under very unusual circumstances should a clinician expect that biologically important systemic adverse effects might occur in implant patients with blood cobalt concentrations less than 300 μg/L. Patients with metal-containing hip implants who exhibit signs or symptoms potentially related to polycythemia, hypothyroidism, neurological, or cardiac dysfunction should be clinically evaluated for these conditions. Polycythemia appears to be the most sensitive endpoint.
    Clinical Toxicology 11/2013; 52(2). · 3.12 Impact Factor
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    ABSTRACT: Chemistry enables more than 95% of products in the marketplace. Over the past 20 years, various entities began to generate inventories of chemicals ("chemical watch lists") potentially associated with human or environmental health risks. Some lists included thousands of chemicals, while others listed only a few chemistries with limited properties or toxicological endpoints (e.g., neurotoxicants). Enacted on October 1, 2013, the California Safer Consumer Products Regulation (SCP) utilized data from chemical inventory lists to create one master list. This paper aimed to discuss the background and requirements of this regulation. Additionally, we wanted to understand the universe of Candidate Chemicals identified by the Regulation. Data from all 23 chemical lists identified in the SCP Regulation were entered into a database. The most prevalent chemicals among the ∼2900 chemicals are identified, including the most prevalent chemical, lead, appearing on 65% of lists, followed by DEHP (52%), perchloroethylene (48%), and benzene (48%).Our results indicated that the most prevalent Candidate Chemicals were either persistent, bioaccumulative, carcinogenic, or reprotoxic. This regulation will have wide-ranging impact in California and throughout the global supply chain, which is highlighted through selected examples and case studies.
    Regulatory Toxicology and Pharmacology 11/2013; · 2.13 Impact Factor
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    ABSTRACT: 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.
    Journal of Toxicology and Environmental Health Part A 11/2013; 76(21):1210-1224. · 1.83 Impact Factor
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    ABSTRACT: Abstract The mechanism(s) underlying asbestos toxicity associated with the pathogenesis of mesothelioma has been a challenge to unravel for more than 60 years. A significant amount of research has focused on the characteristics of different fiber types and their potential to induce mesothelioma. These mechanistic studies of fiber toxicity have proceeded along two lines: those demonstrating biochemical mechanisms by which fibers induce disease and those investigating human susceptibility. Most recent studies focused on in vitro genotoxic effects induced by asbestos as the mechanism responsible for asbestos-induced disease. Although asbestos exerts a genotoxic effect at certain concentrations in vitro, a positive response in these tests does not indicate that the chemical is likely to produce an increased risk of carcinogenesis in exposed human populations. Thus far, findings from studies on the effects of fiber type in mesothelial cells are seriously flawed by a lack of a dose response relationship. The common limitation of these in vitro experiments is the lack of attention paid to the complexities of the human anatomy, biochemistry and physiology, which make the observed effects in these experimental systems difficult to extrapolate to persons in the workplace. Mechanistic differences between carcinogenic and genotoxic processes indicate why tests for genotoxicity do not provide much insight regarding the ability to predict carcinogenic potential in workers exposed to asbestos doses in the post-Occupational Safety and Health Administration era. This review discusses the existing literature on asbestos-induced genotoxicity and explains why these studies may or may not likely help characterize the dose-response curve at low dose.
    Inhalation Toxicology 08/2013; 25(9):553-67. · 1.89 Impact Factor
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    ABSTRACT: Benzene, a known carcinogen, can be generated as a by-product during the use of petroleum-based raw materials in chemical manufacturing. The aim of this study was to analyze a large data set of benzene air concentration measurements collected over nearly 40 years during routine employee exposure monitoring at a petrochemical manufacturing facility. The facility used ethane, propane, and natural gas as raw materials in the production of common commercial materials such as polyethylene, polypropylene, waxes, adhesives, alcohols, and aldehydes. In total, 3607 benzene air samples were collected at the facility from 1962 to 1999. Of these, in total 2359 long-term (>1 h) personal exposure samples for benzene were collected during routine operations at the facility between 1974 and 1999. These samples were analyzed by division, department, and job title to establish employee benzene exposures in different areas of the facility over time. Sampling data were also analyzed by key events over time, including changes in the occupational exposure limits (OELs) for benzene and key equipment process changes at the facility. Although mean benzene concentrations varied according to operation, in nearly all cases measured benzene quantities were below the OEL in place at the time for benzene (10 ppm for 1974-1986 and 1 ppm for 1987-1999). Decreases in mean benzene air concentrations were also found when data were evaluated according to 7- to 10-yr periods following key equipment process changes. Further, an evaluation of mortality rates for a retrospective employee cohort (n = 3938) demonstrated that the average personal benzene exposures at this facility (0.89 ppm for the period 1974-1986 and 0.125 ppm for the period 1987-1999) did not result in increased standardized mortality ratio (SMRs) for diseases or malignancies of the lymphatic system. The robust nature of this data set provides comprehensive exposure information that may be useful for assessing human benzene exposures at similar facilities. The data also provide a basis for comparable measured exposure levels and the potential for adverse health effects. These data may also prove beneficial for comparing relative exposure potential for production versus nonproduction operations and the relationship between area and personal breathing zone samples.
    Journal of Toxicology and Environmental Health Part A 06/2013; 76(12):723-46. · 1.83 Impact Factor
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    ABSTRACT: The presence of benzene in motor gasoline has been a health concern for potential increased risk of acute myelogenous leukemia and perhaps other lymphatic/hematopoietic cancers for approximately 40 years. Because of the widespread and increasing use of gasoline by consumers and the high exposure potential of occupational cohorts, a thorough understanding of this issue is important. The current study utilizes an evidence-based approach to examine whether or not the available epidemiologic studies demonstrate a strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers. Among 67 epidemiologic studies initially identified, 54 were ranked according to specific criteria relating to the relevance and robustness of each study for answering the research question. The 30 highest-ranked studies were sorted into three tiers of evidence and were analyzed for strength, specificity, consistency, temporality, dose-response trends and coherence. Meta statistics were also calculated for each general and specific lymphatic/hematopoietic cancer category with adequate data. The evidence-based analysis did not confirm any strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers based on the epidemiologic studies available to date. These epidemiologic findings, combined with the evidence showing relatively low occupational benzene vapor exposures associated with gasoline formulations during the last three decades, suggest that current motor gasoline formulations are not associated with increased lymphatic/hematopoietic cancer risks related to benzene.
    Human & Experimental Toxicology 06/2013; · 1.41 Impact Factor
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    ABSTRACT: A method utilizing size exclusion liquid chromatography (SEC) was developed to separate and quantify large molecular cobalt (Co) (e.g., albumin-Co) from cyanocobalamin (vitamin B12) and small molecular Co (e.g., glutathione-Co and free Co) in human serum. Highly selective and sensitive detection using inductively coupled plasma–mass spectrometry was coupled with SEC to provide a method with reliable accuracy, precision, recoveries, stability, and a detection limit of 0.037 mg/L in undiluted serum. Other divalent metal cations known to compete with Co(II) for serum albumin-binding sites (such as iron, zinc, manganese, cadmium, copper, nickel, and lead) did not significantly alter Co(II) quantification. Co–protein binding capacity determination of individual serum samples indicated that addition of 2500 mg Co/L to undiluted human serum resulted in approximately 90% distribution to the large molecular Co peak, consistent with Co binding to high-affinity divalent metal binding sites on albumin. Since serum albumin binding partially sequesters biologically active Co (II) ions, this method provides an important tool for better understanding the kinetics and toxicology of Co compounds. Thus, the proposed method might play an important role in establishing Co dose–response relationships that affect the equilibrium concentrations of free ionic Co(II).
    Toxicological and environmental chemistry 04/2013; 95(4):687-708. · 0.72 Impact Factor
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    ABSTRACT: Abstract 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.
    Critical Reviews in Toxicology 04/2013; 43(4):316-62. · 6.25 Impact Factor
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    ABSTRACT: A new analytical method for determining cobalt (Co) species in human serum by size exclusion chromatography with inductively coupled plasma mass spectrometry (SEC-ICP-MS) was applied to serum samples collected from 12 human volunteers who participated in a Co(II) chloride supplement study involving ingestion of 1 mg Co/day for up to 90 consecutive days. The study protocol included determination of serum total Co by acid digestion followed by ICP-MS. Co speciation assay measurements were conducted for up to 13 time points per individual spanning from one to two weeks before dosing began to two weeks after dosing ceased. The Co speciation assay showed good recovery >91% relative to total Co measurements. Undiluted serum demonstrated uniform fractions of large molecular Co defined as Co bound to albumin and other proteins >50 kDa at 96% and the residual as small molecular Co defined as free Co(II) and <1 kDa Co-complexes for individual serum Co concentrations up to 146 mg/L. There were no dose-related changes in Co distribution. Analysis of the same serum samples with tenfold dilution in 0.1 M acetic acid led to a lower fraction of large molecular Co at 87%, with the difference between diluted and undiluted measurements being 8.4%. The difference noted between undiluted and diluted large molecular Co may be attributed to Co release from albumin. Data demonstrated that large molecular Co was the predominant Co species in both undiluted and diluted human serum over a broad range of in vivo Co concentrations, reflecting high albumin– Co binding capacity. These data validate the Co speciation assay and may be employed in understanding further the toxicokinetics and dose-response relationships for Co species.
    Toxicological and environmental chemistry 03/2013; 95(4):709-718. · 0.72 Impact Factor
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    ABSTRACT: 1,2-Benzisothiazolin-3-one (BIT; CAS # 2634-33-5) is a preservative used in consumer products. Dermal exposure to BIT at sufficient dose and duration can produce skin sensitization and allergic contact dermatitis in animals and susceptible humans.The purpose of this study is to derive a maximal concentration of BIT in various consumer products that would result in exposures below the No Expected Sensitization Induction Level (NESIL), a dose below which skin sensitization should not occur. A screening level exposure estimate was performed for several product use scenarios with sunscreen, laundry detergent, dish soap, and spray cleaner. We calculated that BIT concentrations below the following concentrations of 0.0075%, 0.035%, 0.035%, 0.021% in sunscreen, laundry detergent, dish soap, and spray cleaner, respectively, are unlikely to induce skin sensitization. We completed a pilot study consisting of bulk sample analysis of one representative product from each category labelled as containing BIT, and found BIT concentrations of 0.0009% and 0.0027% for sunscreen and dish soap, respectively. BIT was not detected in the laundry detergent and spray cleaner products above the limit of detection of 0.0006%. Based on publically available data for product formulations and our results, we were able to establish that cleaning products and sunscreens likely contain BIT at concentrations similar to or less than our calculated maximal safe concentrations and that exposures are unlikely to induce skin sensitization in most users.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 02/2013; · 2.99 Impact Factor
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    ABSTRACT: Abstract Objectives: We present a re-analysis of a recent Health Hazard Evaluation (HHE) that was performed by the US National Institute for Occupational Safety and Health (NIOSH) regarding the pulmonary status of workers at a flavorings manufacturing facility. This facility has used acetaldehyde, acetoin, benzaldehyde, butyric acid, diacetyl and many other flavoring chemicals for many years. Methods: Ten years of spirometry testing and job descriptions data on 112 workers were analyzed by the authors and by NIOSH. Using NIOSH's exposure assessment criteria, we compared the prevalence of restrictive findings (as determined by spirometry testing) in production workers to an internal control group that had reduced or no potential for exposure to flavoring chemicals. NIOSH used multiple linear regression to evaluate changes in pulmonary function by the exposure group. After our review of the NIOSH findings, we evaluated associations between longitudinal changes in pulmonary health and workplace exposures through the use of generalized estimating equations. We then compared our results to those obtained by NIOSH. Results: We found that the prevalence of pulmonary restriction was similar in production workers and internal controls. We found no relationship between the magnitude of exposure to flavorings chemicals and observed decrements in pulmonary function. Our findings were contrary to those reported by NIOSH, most likely because of how we accounted for the longitudinal nature of the spirometric data. Conclusion: Many years of exposures to flavoring chemicals in this workplace, including diacetyl, were not found to produce an increased risk of abnormal spirometric findings.
    Inhalation Toxicology 02/2013; 25(2):107-17. · 1.89 Impact Factor

Publication Stats

3k Citations
630.38 Total Impact Points


  • 2012
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 2004–2009
    • University of California, San Francisco
      San Francisco, California, United States
  • 2000–2008
    • Exponent
      San Mateo, California, United States
  • 2001
    • University of Cincinnati
      • Department of Environmental Health
      Cincinnati, OH, United States
  • 1996
    • Idaho State University
      • College of Pharmacy
      Pocatello, ID, United States
    • University of Ottawa
      Ottawa, Ontario, Canada
  • 1994
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 1990
    • Maryland Department Of Agriculture
      Annapolis, Maryland, United States