Glyphosate exposure is commonly assessed using either passive dosimetry or biomonitoring. This study tests the hypothesis that internal dose estimates derived from passive dosimetry are higher and more uncertain than those derived from biomonitoring by comparing concurrently collected passive dosimetry and biomonitoring data from a controlled simulation of heavy residential herbicide application. The two predominant exposure routes were evaluated separately: six applicators were protected from dermal exposures with hooded Tyvek® coveralls and gloves and six were protected from inhalation exposure with a respirator. Urine was serially collected from all applicators between 30 min prior to and up to 36 h after application, while breathing-zone air samplers (left and right lapel) and four dermal patches were collected from dermally protected applicators. Internal doses were independently estimated from air and dermal patch measurements (passive dosimetry) and from urinary glyphosate residues (biomonitoring; dilution-adjusted). Average total internal daily doses of glyphosate estimated from passive dosimetry were approximately seven times greater than biomonitoring-based estimates. This overestimation appeared attributable to the dermal pathway and was consistent with the uncertainty in the assumed dermal absorption and clothing penetration factors as well as with the uncertainty introduced by extrapolating a limited number of dermal patch measurements to larger body regions. Even so, the highest individual internal daily dose of glyphosate derived from passive dosimetry remained below the internal-dose benchmark derived from conservative regulatory health-based guidance values (60 µg/kg/day), suggesting a low likelihood of adverse health effects under the tested conditions. By directly comparing concurrently collected passive dosimetry and biomonitoring data in applicators with detectable urinary glyphosate, this study provides empirical support for using biomonitoring to evaluate and refine dermal passive-dosimetry assumptions in glyphosate exposure assessment.

Introduced in the 1950s, acetaminophen is one of the most widely used antipyretics and analgesics worldwide. In 1999, the International Agency for Research on Cancer (IARC) judged the available data inadequate to determine carcinogenicity, and in 2024 an IARC Advisory Group recommended high-priority re-evaluation. Given this context, we conducted a quantitative weight-of-evidence (QWoE) analysis of in vivo rodent carcinogenicity studies using a previously developed framework for biological relevance and methodological quality (Kougias et al., 2025a; Kougias et al., 2025b). A total of 192 QWoE entries were derived from 32 publications assessing two main carcinogenicity-related endpoints-tumorigenicity and tumor-promoting potential-with additional analyses of tissue-specific tumorigenicity. Mean outcome and methods scores (0-4 scale) were calculated overall and by sex for each endpoint. Across endpoints, mean methods scores ranged from 2.1 to 2.5, indicating moderate data quality, while mean outcome scores ranged from 0.0 to 0.4, indicating minimal evidence for biologically relevant carcinogenic responses. Isolated tumor findings were infrequent, inconsistent, not reproducible, and they generally occurred under conditions involving high toxicity and/or interpretive limitations. Accordingly, our quantitative synthesis concludes that there is inadequate evidence to support a carcinogenic effect of acetaminophen, as reflected by the lack of consistent, reproducible, or biologically relevant indications of carcinogenic or tumor-promoting activity in male or female rodents across tested exposure levels.

Mouthwashes containing ethanol for antiseptic properties have a long history of use and well-established oral hygiene benefits by significantly enhancing the control of dental biofilm and reducing gingival inflammation. Despite the substantial health benefits from ethanol-containing mouthwashes, there has been ongoing scrutiny by regulatory and health authorities of products containing ethanol resulting from the classification of consumption of alcohol-containing beverages as a potential carcinogen. Unlike alcohol-containing beverages, mouthwash products are not intended to be ingested, and the potential ethanol exposure is substantially lower for mouthwash products. Therefore, we conducted a risk assessment that benchmarked estimated and modeled incidental exposure to ethanol in mouthwash products against endogenous blood levels, dietary exposure, and health-based guidance values for ethanol. All mouthwash-use scenarios, including average, 90th-percentile, and maximum-label use, resulted in relatively low estimated ethanol exposures that were below various reference and health-based guidance values (HBGVs), including the HBGV of 1 g/day for ethanol (16.7 mg/kg/day in a 60-kg human), a conservative value that is considered to be protective against all chronic health endpoints, including cancer. The findings suggest that ethanol from mouthwash does not significantly contribute to systemic levels of ethanol, falls within dietary intake levels, and remains below HBGVs. Taken together, this assessment concludes that incidental oral exposure of ethanol-containing mouthwashes represents a de minimis health risk.

There is a growing interest in the development of reliable analytical methods for characterizing tire and road wear particles (TRWP). The current research extends the use of single particle analysis techniques to various experimental biota samples. TRWP and cryogenically milled tire tread (CMTT) were identified using a weight of evidence framework including density separation, optical microscopy, and chemical mapping (scanning electron microscopy coupled with energy dispersive X-ray spectroscopy). Our techniques successfully identified CMTT particles in laboratory earthworms exposed to soil spiked with CMTT. A river biota sample (bivalves) collected from the Seine with no detectable TRWP was spiked with road dust containing TRWP. Particle identification was performed after a biota digestion protocol and density separation of particles > 1.5 g/cm3 and < 2.2 g/cm3 which resulted in sufficient TRWP for identification and characterization. The average TRWP particle size from the road dust spiked biota sample was 126 μm by number and 220 μm by volume (range: 9 -572 μm). The size distribution overlay of TRWP identified from spiked biota were consistent with TRWP identified from the original road dust sample suggesting that the current method for biota digestion, dual density separation, and TRWP characterization is feasible for similar samples.

We previously developed a quantitative weight-of-evidence (QWoE) framework using prespecified scoring criteria for preclinical acetaminophen data to characterize potential developmental neurotoxicity outcomes with considerations for biological relevance of the response to adverse outcomes and the strength of methods and study design. The current analysis uses this framework to characterize potential developmental and reproductive toxicity (DART) outcomes following exposure to acetaminophen. Two-hundred forty-two QWoE entries were documented from in vivo rodent studies identified in 110 publications across five categories: DART endpoints in the context of (1) periadolescent/adulthood (nonpregnancy) exposures; (2) pregnant female exposures; and, for in utero or other developmental exposures, (3) anatomical abnormalities, (4) reproductive development, and (5) other physical development. A mean outcome score and methods score were calculated for 242 QWoE entries. Data analyzed in our framework were of moderate quality showing no consistent evidence of DART in male and female rodents following exposure to acetaminophen at therapeutic and/or non-systemically toxic doses. Similar results were found for the individual context- and outcome-related endpoint analyses and as segregated by sex. Overall, this QWoE analysis on the in vivo rodent data demonstrated no consistent evidence of adverse effects following exposure to therapeutic and/or non-systemically toxic acetaminophen on development or on the structure and function of the reproductive system.

Tire and road wear particles (TRWP) consist of tread rubber elastomers with pavement encrustations generated from tire-road friction. Our previous work utilized density separation and chemical mapping to characterize chemical and physical properties of individual TRWP. The current research extends the use of chemical mapping methods to urban river samples including sediment from the Seine River (France). TRWP were identified using a weight of evidence framework including density separation, optical imaging, scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM/EDX) mapping, and Fourier-transform infrared (FTIR) spectroscopy. River sediment collected immediately downstream of the Rouen urban area (with an average TRWP concentration of 930 mg TRWP/kg sediment; n = 3) subsequently density separated demonstrated an average TRWP size of 133 µm by number and 171 µm by volume. Sediment from a second location (190 mg TRWP/kg sediment; n = 1) was density separated and showed an overlap in features of tire tread and bitumen/asphalt in the FTIR signatures (operationally defined as weathered bitumen/TRWP). Average particle size for weathered bitumen/TRWP were 250 µm and 981 µm by number and volume, respectively. Pulverization pre-treatment of the second location sediment sample reduced larger particle agglomerates to an average weathered bitumen/TRWP particle size of 97 µm and 116 µm by number and volume, respectively. A quantitative TRWP or bitumen/TRWP size distribution in filtered suspended river solids (3300 mg TRWP/kg suspended solid) could not be determined due to lack of TRWP enrichment in pre- or post-density separation steps; however, average particle size for all collected river particles were 27 µm and 160 µm by number and volume, respectively. Additionally, TRWP were not identified in a river biota sample (bivalves) with or without chemical digestion and future research was discussed. Taken together, our single particle analysis methodologies were useful for the determination of particle size distribution (including bitumen and TRWP) in urban river sediment samples. These results are expected to help advance the methods for identification and characterization of TRWP and potentially other microplastics in various environmental matrices.

Due to the widespread application of glyphosate, a nonselective herbicide, to a variety of resistant food crops, the general population is exposed to glyphosate through dietary intake. Despite this, dietary exposures to glyphosate are considered low in comparison to application-related exposures. Although previous studies have evaluated exposure to horticultural and agricultural workers, to date only one study, which we recently conducted, has characterized exposure to glyphosate in consumers following heavy residential application of a glyphosate-containing herbicide in a residential yard and garden setting. In this previous study, we demonstrated that urinary glyphosate concentrations in these applicators were similar to or in some circumstances greater than those in occupational applicators, likely due to the nature of the simulation study, which ensured a heavy application protocol. However, it is unknown whether these urinary glyphosate concentrations in consumer applicators correspond to internal doses that may be of concern. Therefore, the purpose of this study is to provide a comprehensive risk assessment of glyphosate exposure in consumer applicators using a margin of safety approach. Here, we incorporated data collected from multiple spot urine samples across time from our previous study that assessed consumer exposure to glyphosate from Roundup® application. Estimated internal doses, even with the use of conservative assumptions across unique approaches, were below internal doses estimated from established health-based guidance values. Overall, this study demonstrates that glyphosate exposure from even heavy consumer application of a commercially available glyphosate-containing herbicide does not appear to be a health concern.

Tire and road wear particles (TRWPs) are generated from friction between tires and the road and contain polymer tread with pavement encrustations. Single particle analysis (SPA) of tire source contribution in environmental samples has been limited by interferences in common spectroscopic polymer techniques. This study extends a density separation and chemical mapping protocol for road simulator generated TRWPs toward the identification and characterization of individual TRWPs in more complex road dust, roaddust-spiked artificial sediment, tunnel dust, and environmental settling pond sediment samples. TRWPs were identified by a combination of physical (elongated/round shape with variable amounts of mineral encrustation) and elemental surface characteristics [colocalization of (S + Zn/Na) +/- (Si, K, Mg, Ca, and Al)]. Organic surface markers (C7H7+), overlapping FTIR spectra with tread reference material, and resistance to heat-induced deformation were selectively used to confirm particle identification. The TRWP size displayed an increasing average trend of 54, 158, and 267 mu m by number (94, 224, and 506 mu m by volume) in tunnel dust, road dust, and environmental sediment, respectively. TRWP size distributions within road dust 10x diluted with artificial sediment agreed with those of pure road dust. Our SPA methodologies determined the size distribution of TRWPs in environmental sample types with increasing sample complexity.

In 2017, the European Union (EU) Committee for Risk Assessment (RAC) recommended the classification of metallic cobalt (Co) as Category 1B with respect to its carcinogenic and reproductive hazard potential and Category 2 for mutagenicity but did not evaluate the relevance of these classifications for patients exposed to Co-containing alloys (CoCA) used in medical devices. CoCA are inherently different materials from Co metal from a toxicological perspective and thus require a separate assessment. CoCA are biocompatible materials with a unique combination of properties including strength, durability, and a long history of safe use that make them uniquely suited for use in a wide-range of medical devices. Assessments were performed on relevant preclinical and clinical carcinogenicity and reproductive toxicity data for Co and CoCA to meet the requirements under the EU Medical Device Regulation triggered by the ECHA re-classification (adopted in October 2019 under the 14th Adaptation to Technical Progress to CLP) and to address their relevance to patient safety. The objective of this review is to present an integrated overview of these assessments, a benefit-risk assessment and an examination of potential alternative materials. The data support the conclusion that the exposure to CoCA in medical devices via clinically relevant routes does not represent a hazard for carcinogenicity or reproductive toxicity. Additionally, the risk for the adverse effects that are known to occur with elevated Co concentrations (e.g., cardiomyopathy) are very low for CoCA implant devices (infrequent reports often reflecting a unique catastrophic failure event out of millions of patients) and negligible for CoCA non-implant devices (not measurable/no case reports). In conclusion, the favorable benefit-risk profile also in relation to possible alternatives presented herein strongly support continued use of CoCA in medical devices.

Cobalt (Co) is an essential element with human exposure occurring from the diet, supplement ingestion, occupational sources, and medical devices. The European Chemical Agency (ECHA) recently voted to classify Co metal as a Reproductive Hazard Category 1B; presumed human reproductive toxicant due to adverse testicular effects in male rodents. A weight of evidence evaluation of the preclinical reproductive and developmental toxicity studies and available clinical data was performed to critically evaluate the relevance of this proposed classification for Co in medical devices. Reproductive responses to Co are limited to the male testes and sperm function following high systemic exposure in rodents, only at Co concentrations/doses that result in overt toxicity (i.e., above the maximum tolerable dose (MTD)). The potential mechanisms of Co reproductive/developmental toxicity, including its indirect mode of action in the testes and relevance to humans, are discussed. The available preclinical and clincial evidence suggests that it would be more appropriate to classify Co as a Reproductive Hazard Category 2 compound: suspected human reproductive toxicant and, in the case of Co-containing medical devices, it should not be considered a reproductive hazard.

The exceptional physical and chemical properties of nickel nanomaterials have been exploited in a range of applications such as electrical conductors, batteries, and biomaterials. However, it has been suggested that these unique properties may allow for increased bioavailability, bio-reactivity, and potential adverse health effects. Thus, the purpose of this review was to critically evaluate data regarding the toxicity of oxidic nickel nanoparticles (nickel oxide (NiO) and nickel hydroxide (Ni(OH)2) nanoparticles) with respect to: (1) physico-chemistry properties; (2) nanomaterial characterization in the defined delivery media; (3) appropriateness of model system and translation to potential human effects; (4) biodistribution, retention, and clearance; (5) routes and relevance of exposure; and (6) current research data gaps and likely directions of future research. Inhalation studies were prioritized for review as this represents a potential exposure route in humans. Oxidic nickel particle size ranged from 5 to 100 nm in the 60 studies that were identified. Inflammatory responses induced by exposure of oxidic nickel nanoparticles via inhalation in rodent studies was characterized as acute in nature and only displayed chronic effects after relatively large (high concentration and long duration) exposures. Furthermore, there is no evidence, thus far, to suggest that the effects induced by oxidic nickel nanoparticles are related to preneoplastic events. There are some data to suggest that nano- and micron-sized NiO particles follow a similar dose response when normalized to surface area. However, future experiments need to be conducted to better characterize the exposure–dose–response relationship according to specific surface area and reactivity as a dose metric, which drives particle dissolution and potential biological responses.

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 Cocontaining 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.

In 2019, the California Office of Environmental Health Hazard Assessment initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of its genotoxicity. The objective of this analysis was to inform this review process with a weight-of-evidence assessment of more than 65 acetaminophen genetic toxicology studies that are of widely varying quality and conformance to accepted standards and relevance to humans. In these studies, acetaminophen showed no evidence of induction of point or gene mutations in bacterial and mammalian cell systems or in in vivo studies. In reliable, well-controlled test systems, clastogenic effects were only observed in unstable, p53-deficient cell systems or at toxic and/or excessively high concentrations that adversely affect cellular processes (e.g., mitochondrial respiration) and cause cytotoxicity. Across the studies, there was no clear evidence that acetaminophen causes DNA damage in the absence of toxicity. In well-controlled clinical studies, there was no meaningful evidence of chromosomal damage. Based on this weight-of-evidence assessment, acetaminophen overwhelmingly produces negative results (i.e., is not a genotoxic hazard) in reliable, robust high-weight studies. Its mode of action produces cytotoxic effects before it can induce the stable, genetic damage that would be indicative of a genotoxic or carcinogenic hazard.

Biokinetic models estimating cobalt (Co) tissue burden can help assess the potential for systemic effects. Such models, however, have not been used to estimate remote tissue concentrations associated with inhalation exposure to Co-containing dust in general environments, work spaces, or animal toxicity tests. We have therefore updated a Co biokinetic model previously developed for oral dosing to include the inhalation pathway by incorporating the International Commission on Radiological Protection (ICRP) Human Respiratory Tract Model. Further, data from animal studies allowed for characterization of testes Co tissue concentration supplementing previous predictions for the liver, heart and blood. Reasonable agreement (within a factor of two) was found between modeled and measured blood, liver, testes and tissue concentrations when animal doses were modeled using human equivalent concentrations to account for species differences in regional lung deposition. We applied the updated model to occupational inhalation exposure scenarios, and found that upper-bound plausible human systemic body burden associated with Co ingestion is much higher than the burden associated with Co inhalation. Chronic ingestion of Co at a previously proposed oral reference dose (RfD) of 0.03 mg/kg-day resulted in predicted tissue levels of 22-54 mu g/L (blood), 0.05-0.1 mu g/g (heart), 0.01-0.02 mu g/g (testes), and 0.2-0.5 mu g/g (liver), which were at least 5-fold more than the systemic burden associated with various Co inhalation occupational exposure limits (OELs) of 0.1 mg/m(3) or less (for 8 h/d and 5 d/w). Overall, our analysis indicated that Co-metal or dust induced systemic health effects, including myocardial damage, are unlikely for the inhalation pathway when personal exposures levels are below concentrations associated with local respiratory effects such as pulmonary fibrosis. (C) 2020 Elsevier B.V. All rights reserved.

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard.

Tire and road wear particles (TRWP), which are comprised of polymer-containing tread with pavement encrustations, are generated from friction between the tire and the road. Similar to environmentally dispersed microplastic particles (MP), the fate of TRWP depends on both the mass concentration as well as individual particle characteristics, such as particle diameter and density. The identification of an individual TRWP in environmental samples has been limited by inherent characteristics of black particles, which interfere with the spectroscopic techniques most often used in MP research. The purpose of this research was to apply suitable analytical techniques, including scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM/EDX) mapping and time-of-flight secondary ion mass spectrometry (ToF-SIMS) mapping, to characterize the specific physical and chemical properties of individual TRWP. Detailed elemental and organic surface maps were generated for numerous samples including bulk tread material, cryogenically milled tire tread particles, and TRWP generated from two separate road simulator methods. Key physical and chemical characteristics of TRWP for single particle identification included (1) elongated/round shape with variable amounts of mineral encrustation, (2) elemental surface characteristics including co-localization of (S + Zn/Na) ± (Si, K, Mg, Ca, and Al), and (3) co-localization of organic surface markers, such as C6H5+ and C7H7+. Comparisons of TRWP with other polymeric (polystyrene) and non-polymeric (carbon black) particle types demonstrated that a combination of physical and chemical markers is necessary to identify TRWP. Addition of a density separation step to the single particle analysis techniques allowed for the determination of average primary TRWP particle size (34 μm by number distribution and 49 μm by volume distribution) and aspect ratio (65% of TRWP with an aspect ratio > 1.5). The use of chemical mapping techniques, such as SEM/EDX and/or ToF-SIMS mapping as demonstrated herein, can support future research efforts that aim to identify complex MP.

Over 300,000 hip replacements occurred in the USA in 2010, and the frequency is likely increasing annually. Blood Cobalt (Co) concentrations in patients with well-functioning cobalt–chromium (Co–Cr) hip implants are usually elevated above background concentrations relative to the general population. Excessive Co exposure, in rare cases, can result in cardiomyopathy. The purpose of this review was to identify cases of cardiomyopathy in metal-containing hip implant patients and to evaluate the possible cause of each patient’s cardiomyopathy. We evaluated 15 cases published between 2009 and 2016, and, based on a review of the preexisting risk factors, blood Co concentrations, and histopathological information published for each patient, they were stratified into one of four categories regarding the association between Co exposure and the development of cardiomyopathy: (1) Co was causal (five cases); (2) Co was contributory (two cases); (3) Co was possibly contributory (six cases); and (4) Co was non-causal (two cases). In all 15 cases, blood Co concentrations (14–6521 μg/L) were elevated beyond levels associated with the majority of metal-containing implant patients (0.1–10 μg/L), and, in many cases, there was evidence of a malfunctioning implant. The data indicate that individuals with well-functioning implants, even those with preexisting risk factors, are at no risk of developing cardiac effects. We conclude that blood Co measurements are informative, but should be interpreted with caution, and in context of other factors evaluated in this analysis. The mere presence of elevated Co is not sufficient to indicate causation for a patient’s cardiomyopathy.

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.

Engineered or incidental particles may contain endotoxin from contaminated environments associated with generation, production, or handling activities. Endotoxins are ubiquitous contaminants that may yield false positive responses in immunological assays if present. The purpose of this study was to develop a sterilization method for removal of endotoxin from clinically relevant wear particles isolated from metal-on-metal (MoM) hip implant lubricant. In this case, the goal of particle sterilization was to sufficiently reduce endotoxin levels to acceptable levels for sensitive biological assays while retaining the physical and chemical characteristics of the original particles. Optimization of treatment with 0.05 NaOH in 50% ethanol successfully achieved a 5-log (>99.999%) reduction of endotoxin content while retaining the size and chemistry of MoM hip implant wear particles. Using the optimized method, the concentration of endotoxin was reduced from 161,000 to 1.19 EU/mL. As particle types can vary, sterilization strategies will also differ to optimize endotoxin removal while retaining key particle characteristics. To our knowledge, this study represents the first published sterilization method for clinically relevant MoM hip implant wear particles isolated from serum-rich lubricant.

Advantages of second-generation metal-on-metal (MoM) hip implants include low volumetric wear rates and the release of nanosized wear particles that are chemically inert and readily cleared from local tissue. In some patients, edge loading conditions occur, which result in higher volumetric wear. The objective of this study was to characterize the size, morphology, and chemistry of wear particles released from MoM hip implants during normal (40° angle) and edge-loading (65° angle with microseparation) conditions. The mean primary particle size by volume under normal wear was 35 nm (range: 9-152 nm) compared with 95 nm (range: 6-573 nm) under edge-loading conditions. Hydrodynamic diameter analysis by volume showed that particles from normal wear were in the nano- (<100 nm) to submicron (<1000 nm) size range, whereas edge-loading conditions generated particles that ranged from <100 nm up to 3000-6000 nm in size. Particles isolated from normal wear were primarily chromium (98.5%) and round to oval in shape. Edge-loading conditions generated more elongated particles (4.5%) (aspect ratio ≥ 2.5) and more CoCr alloy particles (9.3%) compared with normal wear conditions (1.3% CoCr particles). By total mass, edge-loading particles contained approximately 640-fold more cobalt than normal wear particles. Our findings suggest that high wear conditions are a potential risk factor for adverse local tissue effects in MoM patients who experience edge loading. This study is the first to characterize both the physical and chemical characteristics of MoM wear particles collected under normal and edge-loading conditions. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 986-996, 2018.