In silico occupational exposure banding framework for data poor compounds in biotechnology.

Occupational exposure limits (OELs) and occupational exposure bands (OEBs) provide quantitative benchmarks for worker health protection. If empirical toxicology data are insufficient to derive an OEL, an OEB is often assigned using partial toxicology data along with other relevant hazard information. There is no consensus methodology to assign OEBs for chemicals lacking any empirical toxicology data. Thus, this study developed an in silico framework for OEB assignment of data poor compounds. It relies upon computational tools to evaluate standard toxicological end points and to assign reliability ratings, which are then used to assign Global Harmonization System (GHS) hazard categories. Subsequently, the hazard categories are entered into the National Institute for Occupational Safety and Health (NIOSH) occupational exposure banding tool to assign bands for individual end points as well as an overall OEB. As a proof-of-concept, five compounds with established OELs (i.e., "knowns") were evaluated. The knowns were assigned to overall OEBs C, D, or E, four of which were equal to or lower than the OEBs based on actual harmonized GHS categories as well as established OELs, indicating that the OEBs assigned using this framework are likely to be protective. Subsequently, five compounds with little to no experimental data and no established OELs from any U.S. agency or consensus OEL-setting organizations were evaluated (i.e., "unknowns"). The unknowns were assigned to overall OEBs D or E. It was concluded that the proposed framework can be used to assign protective OEBs to compounds with little to no toxicology testing data. As additional data become available, the compound may be de-risked, and a precautionary OEB (or an OEL) can be assigned. The proposed framework provides an example of a practical methodology to evaluate data poor compounds and shows that the output of this framework is expected to be protective of worker health.

Estimating inhalation bioavailability for peptides and proteins 1 to 10 kDa in size.

Inhalation is a critical route for occupational exposure. To protect workers from adverse effects, health-based exposure limits (HBELs) are derived using chemical-specific information including inhalation bioavailability. Inhalation bioavailability of large proteins is well studied and generally accepted to be 1% or less. However, the inhalation bioavailability of peptides and proteins 1-10 kDa in size is not well defined. The goal of this study was to expand upon previous analyses and evaluate the inhalation bioavailability of small peptides. Inhalation bioavailability data for 72 peptides and protein samples ranging from 1.1 to 10.9 kDa in size were evaluated. The median inhalation bioavailability was 20%, which is in agreement with previously published analyses. Inhalation bioavailabilities for the vast majority were below 50%. Interestingly, species, peptide size, and peptide identity did not correlate with inhalation bioavailability. Other factors including inhalation dosimetry, peptide degradation, and chemical characteristics also decrease the amount of peptide available for absorption. Together, the median bioavailability of 20% is likely an appropriate estimate of systemic exposure and is sufficiently protective in most cases for the purposes of occupational exposure safety. Thus, in the absence of peptide-specific data or concerns, an inhalation bioavailability default of 20% is recommended for 1-10 kDa peptide and proteins.

Dermal exposure and hair dye: Assessing potential bladder cancer risk from permanent hair dye.

Hair dye products include a range of chemicals, depending on the type and color. A common primary intermediate compound used to achieve the permanent effect of hair dye is para-phenylenediamine (PPD). 4-aminobiphenyl (4-ABP) has reportedly been found as a trace contaminant (presumably from the para-phenylenediamine [PPD] ingredient) in consumer permanent hair dye. While several regulatory agencies have designated 4-ABP as a human bladder carcinogen based on evidence in humans and experimental animals, only the Office of Environmental Health Hazard Assessment (OEHHA) have established a cancer risk value for 4-ABP of 0.03 µg/day based on liver tumors developed in mice. A hypothetical dermal risk assessment was performed to estimate the bladder cancer risk associated with exposure to 4-ABP from personal use of permanent hair dye potentially containing incidental 4-ABP. Previously published laboratory analyses characterizing 4-ABP concentrations in consumer hair dyes indicate the concentrations can range from below the limit of detection to 8120 ppb. Precautionary estimates of human scalp surface area, maximum skin adherence, hair dye retention factor, and percent dermal absorption were used to estimate the daily systemic exposure doses (SEDs) from dermal application of hair dye. The estimated SEDs ranged from 0.05 to 3000 pg/day. A margin of safety (MOS) was calculated as the ratio of the NSRL to the SED and ranged from 10 to 570,000. The results of this study suggest that there is no indication of increased risk of bladder cancer in humans from exposure to 4-ABP in consumer hair dye, especially as it is extremely unlikely that a consumer would use permanent hair dye on a daily basis (as this assessment models).

Evaluating the Impact of Hair Care Product Exposure on Hair Follicle and Scalp Health.

Human hair follicles traverse the epidermis and dermis, and are comprised of specialised cells including dermal papilla cells (DPCs). DPCs play a critical role in the development and growth of both hair and follicle structure. While exposure of DPCs to undiluted exogenous compounds is unlikely, exposure to diluted compounds is possible should dermal penetration occur. The goal of this study was to evaluate the impact on hair and scalp health following application of a hair care product. Due to the lack of standardised and validated test systems for evaluating hair follicle health, the HairSkin® model, which uses intact human scalp samples, was adapted to evaluate hair follicle and scalp health. Similarly, the Franz diffusion cell assay and matrix-assisted laser desorption ionisation-Fourier transform ion cyclotron resonance (MALDI-FTICR) were adapted to evaluate dermal penetration. The results of this study demonstrate that application of the hair care product does not result in appreciable dermal penetration, suggesting that DPCs are unlikely to be exposed to undiluted product. Additionally, hair follicle health was not impacted following product application. While this study is exploratory, these results suggest that the combination of test systems utilised herein provides valuable insight and warrants further development and validation.

The utility of hERG channel inhibition data in the derivation of occupational exposure limits.

Inhibition of the human ether-à-go-go (hERG) channel may lead to QT prolongation and fatal arrhythmia. While pharmaceutical drug candidates that exhibit potent hERG channel inhibition often fail early in development, many drugs with both cardiac and non-cardiac indications proceed to market. In this study, the relationship between in vitro hERG channel inhibition and published occupational exposure limit (OEL) was evaluated. A total of 23 cardiac drugs and 44 drugs with non-cardiac indications with published hERG channel IC50 and published OELs were identified. There was an apparent relationship between hERG IC50 potency and the OEL for cardiac and non-cardiac drugs. Twenty cardiac and non-cardiac drugs were identified that had a potent hERG IC50 (≤25 µM) and a contrastingly large OEL value (≥100 µg/m3). OELs or hazard banding corresponding to ≤100 µg/m3 should be sufficiently protective of effects following occupational exposure to the majority of APIs with hERG IC50 values ≤ 100 µM. It is important to consider hERG IC50 values and possible cardiac effects when deriving OEL values for drugs, regardless of indication. These considerations may be particularly important early in the drug development process for establishing exposure control bands for drugs that do not yet have full clinical safety data.

Setting impurity limits for endogenous substances: Recommendations for a harmonized procedure and an example using fatty acids.

Endogenous substances, such as fatty, amino, and nucleic acids, are often purposefully used in parenterally pharmaceuticals, but may be present as impurities. Currently, no consensus guidance exists on setting impurity limits for these substances. Specific procedures are needed, as the amount and types of toxicity data available for endogenous substances are typically far less than those for other chemical impurities. Additionally, the parenteral route of administration of these substances is inherently non-physiological, resulting in potentially different or increased severity of toxicity. Risk Assessment Process Maps (RAPMAPs) are proposed as a model to facilitate the development of health-based exposure limits (HBELs) for endogenous substances. This yielded a framework that was applied to derive HBELs for several fatty acids commonly used in parenteral pharmaceuticals. This approach was used to derive HBELs with further vetting based on anticipated perturbations in physiological serum levels, impacts of dose-rate, and consideration of intermittent dosing. Parenteral HBELs of 100-500 mg/day were generated for several fatty acids, and a proposed class-based limit of 50 mg/day to be used in the absence of chemical-specific data. This default limit is consistent with the low toxicity of this chemical class and ICH Q3C value for Class 3 solvents.

Derivation of an occupational exposure limit for ß-glucans.

ß-Glucans are abundant bacterial, yeast, and fungal cell wall polysaccharides that have been shown to activate the immune system. Establishment of an occupational exposure limit (OEL) for ß-glucan exposure is critical to the protection of worker health, as these exposures have been linked to immunosuppressive and inflammatory reactions and possibly the development of respiratory diseases. Detectable concentrations of ß-glucans have been identified in common occupational inhalation exposure scenarios, such as in the agricultural and waste management sectors. However, no published exposure benchmarks for inhalation of ß-glucans are available for workers or the general population. Thus, a health-based OEL for inhalation exposure of workers to ß-glucans was derived based on consideration of human and non-human effect data for this class of compounds and contemporary risk assessment methods. The weight of the evidence indicated that the available data in humans showed significant methodological limitations, such as lack of a representative study size, appropriate control population, and clear dose-response relationship. Thus, an OEL of 150 ng/m3 was derived for ß-glucans based on the most relevant nonclinical study. This OEL provides an input to the occupational risk assessment process, allows for comparisons to worker exposure, and can guide risk management and exposure control decisions.

An in vitro human assay for evaluating immunogenic and sensitization potential of a personal care and cosmetic product.

With the reduction or elimination of animal testing, manufacturers are left with limited options, as few robust in vitro tests are available and human studies are costly. Recently, concerns have been raised regarding potential adverse health effects associated with use of WEN by Chaz Dean (WCD) cleansing conditioners. The purpose of this study was to evaluate the immunogenic potential of a WCD hair cleansing conditioner by utilizing a novel in vitro human skin explant test. Peripheral blood mononuclear cells (PBMCs) and human skin biopsies were obtained from healthy volunteers. Monocyte derived dendritic cells (MoDCs) were generated, primed by 0.01% WCD cleansing conditioner exposure for 24 h, co-cultured with autologous lymphocytes for 4 days, and then cultured with skin biopsies for 3 days. The skin biopsies then underwent histopathological evaluation, and T cell proliferation and IFNγ levels were determined. Overall, this study showed that treatment with 0.01% WCD cleansing conditioner resulted in a negative prediction for in vivo immune response. Further, this analysis shows that the skin explant test is a viable alternative to animal testing for complex mixtures or commercially available products.

PBPK modeling characterization of potential acute impairment effects from inhalation of ethanol during e-cigarette use.

Objective: Ethanol is used as a solvent for flavoring chemicals in some electronic cigarette (e-cigarette) liquids (e-liquids). However, there are limited data available regarding the effects of inhalation of ethanol on blood alcohol concentration (BAC) during e-cigarette use. In this study, a modified physiologically based pharmacokinetic (PBPK) model for inhalation of ethanol was used to estimate the BAC time-profile of e-cigarette users who puffed an e-liquid containing 23.5% ethanol. Materials and Methods: A modified PBPK model for inhalation of ethanol was developed. Use characteristics were estimated based on first-generation and second-generation e-cigarette topography parameters. Three representative use-case puffing profiles were modeled: a user that took many, short puffs; a typical user with intermediate puff counts and puff durations; and a user that took fewer, long puffs. Results and Discussion: The estimated peak BACs for these three user profiles were 0.22, 0.22, and 0.30 mg/L for first-generation devices, respectively, and 0.85, 0.58, and 0.34 mg/L for second-generation devices, respectively. Additionally, peak BACs for individual first-generation users with directly measured puffing parameters were estimated to range from 0.06 to 0.67 mg/L. None of the scenarios modeled predicted a peak BAC result that approached toxicological or regulatory thresholds that would be associated with physiological impairment (roughly 0.01% or 100 mg/L). Conclusions: The approach used in this study, combining a validated PBPK model for a toxicant with peer-reviewed topographical parameters, can serve as a screening-level exposure assessment useful for evaluation of the safety of e-liquid formulations. Abbreviations: BAC: blood alcohol concentration; e-cigarette: electronic cigarette; e-liquid: e-cigarette liquid or propylene glycol and/or vegetable glycerin-based liquid; HS-GC-FID: headspace gas chromatography with flame-ionization detection; HS-GC-MS: headspace gas chromatography-mass spectrometry; PBPK: physiologically based pharmacokinetic; Cair: puff concentration expressed as ppm; Cair,mass: ethanol air concentration expressed on a mass basis; Cv: ethanol concentration in the venous blood; ρ: density; EC: ethanol concentration in the liquid; PLC: liquid consumption per puff; PAV: air volume of the puff; Cair,mass: puff concentration expressed as ppm; MW: molecular weight; P: pressure; T: temperature; PK: pharmacokinetic.

Devising a Tier-based Skin Sensitisation Screening Strategy for Personal Care and Cosmetic Products.

Concerns regarding the use of potential skin sensitisers in personal care and cosmetic products continue to grow. The goal of this study was to develop a proof-of-concept tier-based screening strategy for the assessment of skin sensitisation potential by using non-animal methodologies. As a case example, this screening framework was applied to three WEN® by Chaz Dean cleansing conditioners. The first tier of testing utilised the Organisation for Economic Co-operation and Development (OECD) Quantitative Structure Activity Relationship Toolbox profiler to evaluate the skin sensitisation potential of individual ingredients within the formulation; a literature review was performed on the substances that generated in silico alerts. Tier 2 testing utilised the OECD in chemico Test Guideline (TG) 442C to evaluate these substances. Tier 3 testing adapted OECD TG442C to evaluate the formulated product. The literature review on the four substances that generated in silico alerts revealed that they were not sensitising at the concentrations reported in the formulated products. Tier 2 testing demonstrated that these substances were not sensitising at the concentrations tested. Finally, Tier 3 testing revealed that the evaluated cleansing conditioners had low mean percentage peptide depletion at the concentrations tested. Together, the results obtained suggest that the products tested are unlikely to induce skin sensitisation under the given experimental conditions. These findings are in agreement with other in vitro and clinical studies. The proposed tier-based testing approach may be used as a conceptual framework for the prospective safety screening of other personal care and cosmetic products. However, to establish the validity of the proposed testing strategy, further studies must be performed, including comparisons with established models.

Hair dye and risk of skin sensitization induction: a product survey and quantitative risk assessment for para-phenylenediamine (PPD).

BACKGROUND: Para-Phenylenediamine (PPD) is a commonly used dye intermediate in permanent hair dye formulations, and exposure to PPD has been associated with allergic contact dermatitis at certain doses. PURPOSE: Determine the concentration of PPD in a survey of self-application permanent hair dye products, and perform a quantitative risk assessment to determine the risk of skin sensitization induction following application of these products. METHODS: Consumer exposure levels (CELs) to PPD following application of hair dye products were estimated using the maximum amount of hair dye that can adhere to the surface area of the scalp, the measured concentration of PPD in the hair dye product, a retention factor, the dermal absorption of PPD, and the surface area of the scalp. CELs were calculated for various exposure scenarios, and were stratified by hair dye shade. RESULTS: All estimated CELs did not exceed the acceptable exposure level. Specifically, margins of safety ranged from 2.3 to 1534 for black dyes, 2.9 to 5031 for brown dyes, and 26 to 5031 for blonde dyes. CONCLUSIONS: Findings suggest that use of the evaluated permanent hair dyes, under the evaluated exposure scenarios, would not be expected to induce skin sensitization due to PPD exposure at concentrations ≤0.67%.

Tier-based skin irritation testing of hair cleansing conditioners and their constituents.

Purpose/Aim: The U.S. Food and Drug Administration (FDA) does not require specific testing to demonstrate the safety of personal care and cosmetic products or their ingredients. Recently, there have been reports of skin irritation associated with the use of commercially available cleansing conditioners. The goal of this study was to implement a tier-based safety assessment to evaluate the skin irritation potential of six commercially available cleansing conditioners and their ingredients. MATERIALS AND METHODS: The first tier of testing utilized the Organization for Economic Co-operation and Development (OECD) QSAR Toolbox to perform an in silico evaluation of the skin irritation potential of the product ingredients, and the second tier of testing utilized an OECD in vitro guideline test to evaluate the skin irritation potential of each product. RESULTS: Thirty-two ingredients were evaluated using the OECD QSAR Toolbox profiler for the tier one analysis; nine ingredients received a structural alert for skin irritation/corrosion. In the tier two in vitro analysis, the evaluated cleansing conditioner products were all classified as non-irritants. CONCLUSIONS: These results provide evidence that use of the evaluated commercially available cleansing conditioners would not be expected to cause skin irritation among consumers. Additionally, this study demonstrates that the presence of structural alerts does not always accurately predict the safety of a product, as focused tier-based testing is necessary to comprehensively evaluate a product. This study illustrates a tier-based safety assessment approach, applicable to a wide variety of health endpoints, which efficiently and adequately evaluates the safety of personal care and cosmetic products and their ingredients.

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.

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.

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.

A BMP-FGF morphogen toggle switch drives the ultrasensitive expression of multiple genes in the developing forebrain.

Borders are important as they demarcate developing tissue into distinct functional units. A key challenge is the discovery of mechanisms that can convert morphogen gradients into tissue borders. While mechanisms that produce ultrasensitive cellular responses provide a solution, how extracellular morphogens drive such mechanisms remains poorly understood. Here, we show how Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) pathways interact to generate ultrasensitivity and borders in the dorsal telencephalon. BMP and FGF signaling manipulations in explants produced border defects suggestive of cross inhibition within single cells, which was confirmed in dissociated cultures. Using mathematical modeling, we designed experiments that ruled out alternative cross inhibition mechanisms and identified a cross-inhibitory positive feedback (CIPF) mechanism, or "toggle switch", which acts upstream of transcriptional targets in dorsal telencephalic cells. CIPF explained several cellular phenomena important for border formation such as threshold tuning, ultrasensitivity, and hysteresis. CIPF explicitly links graded morphogen signaling in the telencephalon to switch-like cellular responses and has the ability to form multiple borders and scale pattern to size. These benefits may apply to other developmental systems.

An evaluation of the FDA adverse event reporting system and the potential for reporting bias.

BACKGROUND: The FDA maintains the Adverse Event Reporting System (CAERS) database, which contains product complaint reports for foods, dietary supplements, and cosmetics. Product line perception and subsequent adverse event reporting may be impacted by negative media attention. METHODS: The purpose of this analysis was to use the CAERS database to analyze temporal trends in adverse event reporting before and after media coverage of alleged health effects, using WEN by Chaz Dean (WCD) cleansing conditioners as a case study. WCD cleansing conditioner adverse event reports from January 2005 to December 2018 were abstracted from the CAERS database. Zero-inflated negative binomial regression models were used to analyze the rate of adverse events (WCD events/10,000 WCD cleansing conditioner units sold/month), adjusted for temporal trends in CAERS. RESULTS: There was a statistically significant higher rate of adverse event reporting after negative media coverage in December 2015 (IRR 16.71 [95% CI: 7.89-35.39]) when compared to the rate of adverse event reporting before December 2015. CONCLUSIONS: This analysis highlights the importance of assessing potential external factors, such as negative news media coverage, that may alter reporting behaviors due to societal shifts in product-specific risk perception. Consideration of these factors in post-market surveillance programs would result in more comprehensive safety evaluations.

Evaluation of potential gastrointestinal carcinogenicity associated with the ingestion of asbestos.

The inhalation of asbestos, depending on the fiber type and dose, may be associated with the development of mesothelioma and other asbestos-related diseases. However, little is known about the potential adverse effects associated with the ingestion of asbestos. Evidence of asbestos fibers released from asbestos-cement pipes used in water distribution systems has led to concerns of potentially contaminated drinking water. The purpose of this study is to determine whether ingestion of asbestos fibers may lead to cancerous effects on the gastrointestinal (GI) tract. Data from animal and human studies were analyzed using a weight-of-evidence approach to evaluate the potential risk of GI cancers associated with asbestos ingestion. Seventeen human and 23 animal studies were identified and evaluated in this study. Animal studies were conducted in multiple species with inconsistent dosing protocols. Overall, animal studies reported that the asbestos fibers, irrespective of fiber type and dose, failed to produce any definitive GI carcinogenic effect. The 17 identified human epidemiological studies reported the ingestion of asbestos-contaminated water with concentrations from 1 to 71,350 million fibers per liter (MFL). A majority of the epidemiology studies reported statistically significant increases in multiple GI-specific cancers. However, these findings are confounded due to several critical study limitations including flawed study design, small sample size, selection bias, lack of individual exposure history, lack of adequate latency, and the inability to account for confounders including occupational history, diet, and smoking history. Based on our weight-of-evidence assessment, there is insufficient evidence of causality between the ingestion of asbestos and an increased incidence of GI cancers.

Skin Sensitization Induction Risk Assessment of Common Ingredients in Commercially Available Cleansing Conditioners.

BACKGROUND: An essential step in ensuring the toxicological safety of cosmetic or personal care products is the evaluation of the skin sensitizing potential of product ingredients. OBJECTIVE: We used a standardized protocol from cosmetic trade industry and consumer safety groups to evaluate the sensitization potential of ingredients in 3 commercially available cleansing conditioners. METHODS: A total of 33 ingredients were evaluated. Each ingredient underwent (1) dermatological evaluation, (2) in silico analysis for irritation and sensitization potential, and (3) a literature evaluation to determine risk of sensitization. Consumer exposure level was compared with the weight-of-evidence no-expected sensitization induction level for the constituent. If a no-expected sensitization induction level for a specific ingredient was not available, the dermal sensitization threshold approach was used. A margin of safety was calculated for each constituent. RESULTS: The margins of safety for all evaluated ingredients in the cleansing conditioners were greater than 1. CONCLUSIONS: This analysis indicates that exposure to the individual ingredients present in these cleansing conditioners would not be expected to induce dermal sensitization in a consumer under the examined exposure scenario.

Methods for Sterilizing Clinically Relevant Wear Particles Isolated from Metal-on-Metal Hip Implants.

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.