Next generation risk assessment for occupational chemical safety - A real world example with sodium-2-hydroxyethane sulfonate.

Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely restricted to assessments of consumer use of cosmetics and is not currently implemented in occupational safety assessments, e.g.

Outcomes of different perioperative management strategies of patients on chronic anticoagulation in elective total hip and knee arthroplasty: a systematic review.

Introduction: There are currently different management guidelines for patients undergoing elective total hip arthroplasty (THA) or total knee arthroplasty (TKA) that are on long-term anticoagulation. The timing of discontinuation and restarting the anticoagulation is challenging during the postoperative care, which often involves general practitioners and physiotherapists.

Methods: The systematic review followed the PRISMA guidelines and included 3 databases: PubMed/MEDLINE, EMBASE, and Web of Science Core Collection.

Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment.

Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This 2-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue).

Clinical Equipoise in the Management of Patients With Femoroacetabular Impingement Syndrome and Concomitant Tönnis Grade 2 Hip Osteoarthritis or Greater: An International Expert-Panel Delphi Study.

Purpose: To gather global-expert opinion on the management of patients with femoroacetabular impingement syndrome (FAIS) and Tönnis grade 2 hip osteoarthritis (OA) or greater.

Methods: An internet-based modified Delphi methodology was used via an online platform (Online Surveys) using the CREDES (Conducting and Reporting Delphi Studies) guidelines. The expert panel comprised 27 members from 18 countries: 21 orthopaedic surgeons (78%), 5 physiotherapists (18%), and 1 dual orthopaedic surgeon-sport and exercise medicine physician (4%).

Method validation and environmental monitoring of triethanolamine ester quaternary ammonium compounds.

In this study water and sediment samples, collected from the River Nene (Northamptonshire) at several sites in the vicinity of the Great Billing sewage treatment plant (STP), were analysed for triethanolamine quaternary compounds (TEAQ, ester quats). A method was developed using liquid chromatography tandem mass spectrometry (LC/MS/MS) with a electrospray ionisation source (ESI). Ten components were determined using a characterised commercial sample of Tallow TEAQ as a standard.

ADME characterization and PBK model development of 3 highly protein-bound UV filters through topical application.

Estimating human exposure in the safety assessment of chemicals is crucial. Physiologically based kinetic (PBK) models which combine information on exposure, physiology, and chemical properties, describing the absorption, distribution, metabolism, and excretion (ADME) processes of a chemical, can be used to calculate internal exposure metrics such as maximum concentration and area under the concentration-time curve in plasma or tissues of a test chemical in next-generation risk assessment. This article demonstrates the development of PBK models for 3 UV filters, specifically octyl methoxycinnamate, octocrylene, and 4-methylbenzylidene camphor.

No evidence exists on outcomes of non-operative management in patients with femoroacetabular impingement and concomitant Tönnis Grade 2 or more hip osteoarthritis: a scoping review.

Purpose: The purpose of this scoping review was to assess the outcomes of all the non-operative modalities of management for femoroacetabular impingement (FAI) and concomitant osteoarthritis (OA) Tönnis Grade 2 or more.

Methods: A systematic search of PubMed was performed from inception to December 1st 2021 for literature on outcomes of non-operative management strategies for young adults with symptomatic FAI using the PRISMA Extension for Scoping Reviews guidelines. Cohorts investigating FAI and concomitant hip OA Tönnis Grade 2 or more were considered eligible.

PBK modelling of topical application and characterisation of the uncertainty of C estimate: A case study approach.

Combined with in vitro bioactivity data, physiologically based kinetic (PBK) models has increasing applications in next generation risk assessment for animal-free safety decision making. A tiered framework of building PBK models for such application has been developed with increasing complexity and refinements, as model parameters determined in silico, in vitro, and with human pharmacokinetic data become progressively available. PBK modelling has been widely applied for oral/intravenous administration, but less so on topically applied chemicals.

Next generation risk assessment for skin allergy: Decision making using new approach methodologies.

Our aim is to develop and apply next generation approaches to skin allergy risk assessment (SARA) that do not require new animal test data and better quantify uncertainties. Significant progress has been made in the development of New Approach Methodologies (NAMs), non-animal test methods, for assessment of skin sensitisation and there is now focus on their application to derive potency information for use in Next Generation Risk Assessment (NGRA). The SARA model utilises a Bayesian statistical approach to infer a human-relevant metric of sensitiser potency and a measure of risk associated with a given consumer exposure based upon any combination of human repeat insult patch test, local lymph node, direct peptide reactivity assay, KeratinoSens™, h-CLAT or U-SENS™ data.

Inconclusive and Contradictory Evidence for Outcomes After Hip Arthroscopy in Patients With Femoroacetabular Impingement and Osteoarthritis of Tönnis Grade 2 or Greater: A Systematic Review.

Purpose: To investigate whether hip arthroscopy (HA) is effective in patients with femoroacetabular impingement and concomitant hip osteoarthritis (OA) of Tönnis grade 2 or greater.

Methods: This review was registered in the International Prospective Register for Systematic Reviews and Meta-analysis (PROSPERO, CRD42020210936). It followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines and included multiple databases: MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library.

A hypothetical skin sensitisation next generation risk assessment for coumarin in cosmetic products.

Next generation Risk Assessment (NGRA) is an exposure-led, hypothesis-driven approach which integrates new approach methodologies (NAMs) to assure safety without generating animal data. This hypothetical skin allergy risk assessment of two consumer products - face cream containing 0.1% coumarin and deodorant containing 1% coumarin - demonstrates the application of our skin allergy NGRA framework which incorporates our Skin Allergy Risk Assessment (SARA) Model.

Outcomes of Hip Arthroscopy in Patients with Femoroacetabular Impingement and Concomitant Tönnis Grade II Osteoarthritis or Greater: Protocol for a Systematic Review.

Introduction: Outcomes of hip arthroscopy for femoroacetabular impingement and concomitant moderate- to advanced hip osteoarthritis (Tönnis Grade II or greater) is still a matter of debate as findings in the literature are controversial. This study aims to investigate whether hip arthroscopy is effective in treating patients with femoroacetabular impingement and Tönnis hip osteoarthritis Grade II or greater.

Methods And Analysis: The protocol follows the PRISMA-P guidelines.

Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells.

Haptenation of model nucleophiles, representing the key MIE in skin sensitisation, is routinely measured in chemico to provide data for skin allergy risk assessment. Better understanding of the dynamics of haptenation in human skin could provide the metrics required to improve determination of sensitiser potency for risk assessment of chemicals. We have previously demonstrated the applicability and sensitivity of the dual stable isotope labelling approach to detect low level haptenation in complex mixtures of proteins.

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products.

Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion.

Use of human liver and EpiSkin™ S9 subcellular fractions as a screening assays to compare the in vitro hepatic and dermal metabolism of 47 cosmetics-relevant chemicals.

The abundance of xenobiotic metabolizing enzymes (XMEs) is different in the skin and liver; therefore, it is important to differentiate between liver and skin metabolism when applying the information to safety assessment of topically applied ingredients in cosmetics. Here, we have employed EpiSkin™ S9 and human liver S9 to investigate the organ-specific metabolic stability of 47 cosmetic-relevant chemicals. The rank order of the metabolic rate of six chemicals in primary human hepatocytes and liver S9 matched relatively well.

Measurement of the penetration of 56 cosmetic relevant chemicals into and through human skin using a standardized protocol.

OECD test guideline 428 compliant protocol using human skin was used to test the penetration of 56 cosmetic-relevant chemicals. The penetration of finite doses (10 μL/cm ) of chemicals was measured over 24 hours. The dermal delivery (DD) (amount in the epidermis, dermis and receptor fluid [RF]) ranged between 0.

Comparison of the metabolism of 10 cosmetics-relevant chemicals in EpiSkin™ S9 subcellular fractions and in vitro human skin explants.

An understanding of the bioavailability of topically applied cosmetics ingredients is key to predicting their local skin and systemic toxicity and making a safety assessment. We investigated whether short-term incubations with S9 from the reconstructed epidermal skin model, EpiSkin™, would give an indication of the rate of chemical metabolism and produce similar metabolites to those formed in incubations with human skin explants. Both have advantages: EpiSkin™ S9 is a higher-throughput assay, while the human skin explant model represents a longer incubation duration (24 hours) model integrating cutaneous distribution with metabolite formation.

Proteomic analysis of haptenation by skin sensitisers: Diphencyprone and ethyl acrylate.

The potential risk of skin sensitisation, associated with the development of allergic contact dermatitis (ACD), is a consideration in the safety assessment of new ingredients for use in personal care products. Protein haptenation in skin by sensitising chemicals is the molecular initiating event causative of skin sensitisation. Current methods for monitoring skin sensitisation rely on limited reactivity assays, motivating interest in the development of proteomic approaches to characterise the skin haptenome.

Use of a Simple in vitro Test to Assess Loss of Chemical due to Volatility during an in vitro Human Skin Absorption Study.

Background: We tested the cutaneous distribution of 50 chemicals in frozen human skin. The mass balance (MB) values for 48% of the chemicals were < 90%, possibly due to evaporation.

Methods: We confirmed the reduction in MB was due to evaporation for two chemicals tested in skin penetration experiments using a carbon filter above the skin to trap airborne chemical.

Comparison of the metabolism of 10 chemicals in human and pig skin explants.

Skin metabolism is important to consider when assessing local toxicity and/or penetration of chemicals and their metabolites. If human skin supply is limited, pig skin can be used as an alternative. To identify any species differences, we have investigated the metabolism of 10 chemicals in a pig and human skin explant model.

A study of inter-individual variability in the Phase II metabolism of xenobiotics in human skin.

Understanding skin metabolism is key to improve in vitro to in vivo extrapolations used to inform risk assessments of topically applied products. However, published literature is scarce and usually covers a limited and non-representative number of donors. We developed a protocol to handle and store ex vivo skin samples post-surgery and prepare skin S9 fractions to measure the metabolic activity of Phase II enzymes.

A strategy for systemic toxicity assessment based on non-animal approaches: The Cosmetics Europe Long Range Science Strategy programme.

When performing safety assessment of chemicals, the evaluation of their systemic toxicity based only on non-animal approaches is a challenging objective. The Safety Evaluation Ultimately Replacing Animal Test programme (SEURAT-1) addressed this question from 2011 to 2015 and showed that further research and development of adequate tools in toxicokinetic and toxicodynamic are required for performing non-animal safety assessments. It also showed how to implement tools like thresholds of toxicological concern (TTCs) and read-across in this context.

Determination of Protein Haptenation by Chemical Sensitizers Within the Complexity of the Human Skin Proteome.

Skin sensitization associated with the development of allergic contact dermatitis occurs via a number of specific key events at the cellular level. The molecular initiating event (MIE), the first in the sequence of these events, occurs after exposure of the skin to an electrophilic chemical, causing the irreversible haptenation of proteins within skin. Characterization of this MIE is a key step in elucidating the skin sensitization adverse outcome pathway and is essential to providing parameters for mathematical models to predict the capacity of a chemical to cause sensitization.

Comparison of the Skin Penetration of 3 Metabolically Stable Chemicals Using Fresh and Frozen Human Skin.

Background: The Cosmetics Europe ADME Task Force is developing in vitro and in silico tools for predicting skin and systemic concentrations after topical application of cosmetic ingredients. There are conflicting reports as to whether the freezing process affects the penetration of chemicals; therefore, we evaluated whether the storage of human skin used in our studies (8-12 weeks at -20°C) affected the penetration of model chemicals.

Methods: Finite doses of trans-cinnamic acid (TCA), benzoic acid (BA), and 6-methylcoumarin (6MC) (non-volatile, non-protein reactive and metabolically stable in skin) were applied to fresh and thawed frozen skin from the same donors.

Comparison of protocols measuring diffusion and partition coefficients in the stratum corneum.

Partition (K) and diffusion (D) coefficients are important to measure for the modelling of skin penetration of chemicals through the stratum corneum (SC). We compared the feasibility of three protocols for the testing of 50 chemicals in our main studies, using three cosmetics-relevant model chemicals with a wide range of logP values. Protocol 1: SC concentration-depth profile using tape-stripping (measures K and D /H , where H is the SC thickness); Protocol 2A: incubation of isolated SC with chemical (direct measurement of K only) and Protocol 2B: diffusion through isolated SC mounted on a Franz cell (measures K and D /H , and is based on Fick's laws).