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AcutoX is a human in vitro test method for the evaluation of acute oral toxicity, developed using a library of 67 curated test chemicals. These chemicals cover a wide variety of chemistries, industrial sectors, rodent toxicities, and all EPA and GHS hazard categories. The test uses two different cytotoxicity endpoints (Neutral Red uptake and MTT metabolism), performed both in the presence and absence of a pooled human liver extract (S9), to produce four EC50 values. The EC50 values are used in prediction models to assign a "highly toxic" and "low toxicity" category for both EPA and GHS classification, which can be further refined to assign a hazard category. The binary "highly toxic" / "low toxicity" prediction model has an accuracy of 73.8% and 63.1% for EPA and GHS, respectively, with the subsequent hazard categorization offering a protective prediction (correct or higher category) in 90.0% and 93.3% of cases, respectively. Moreover, the AcutoX test can identify chemicals activated or detoxified by liver metabolism.

The ethical needs and concerns with use and sourcing of human materials, particularly serum, in OECD in vitro test guidelines were explored in a dedicated international workshop held in 2019. The health-related aspects of the donation procedure, including tissue screening, donor health, laboratory work health protection, permission from the donor for commercial use, payment of the donors and the potential for exploitation of low-income populations and data protection of the donors; supply, availability, and competition with clinical needs; traceability of the serum and auditability/GLP needs for the Test Guideline Programme, were examined. Here we provide the recommendations of the workshop with respect to the use of human serum, and potentially other human reagents, specifically with regard to test method development for OECD Test Guideline utility as part of the Mutual Acceptance of Data requirement across all OECD member countries. These include informed donor consent terminology, a checklist of human serum information requirements to be included with the Good Laboratory Practise report, and suitable sources for human serum to ensure waste supplies are used, that can no longer be used for medical purposes, ensuring no competition of supply for essential medical use., Competing Interests: JB was employed by Plasma Protein Therapeutics Association until the end of 2018. In 2019 he became President Emeritus of PPTA and started working as an independent consultant with JMB Consultancy BV in 2020. JF is currently employed by PAN Biotech. CT is CEO and employed by X-CellR8. CC is the owner and employed by Wepredic, holding company of Biopredic. JM is employed by Life Science Group Ltd. GS is employed by PETA Science Consortium International e.V, a non-profit organisation, which is not considered a commercial entity. The publication processing charges were paid for by UKHSA. The various serum, plasma and traceability industry participants have not contributed financially to this paper. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jacobs, Bult, Cavanagh, Chesne, Delrue, Fu, Grange, Langezaal, Misztela, Murray, Paparella, Stoddart, Tonn, Treasure, Tsukano and Versteegen.)

There is ethical debate over whether fetal calves suffer when their dam is slaughtered and fetal blood extracted by cardiac puncture for fetal bovine serum (FBS) production. Yet, the serum industry does not follow best practice, as recommended by the European Food Safety Authority (EFSA), to avoid fetal distress. We discuss the key elements of this debate, and recommend how the serum industry can alter its practices to improve animal welfare.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality., Results: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race., Conclusions: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.

The number and scope of Organisation for Economic Cooperation and Development (OECD) in vitro test guidelines (TGs) are increasing, in an effort to both improve human relevance and replace in vivo animal testing.  In vitro test methods being developed for TG use are increasing the use of human based reagents, in combination with, or replacing animal derived reagents, and demand for human reagents is likely to grow in the near future.  There are a range of issues associated with the ethical use of human reagents, particularly human serum, in the adaptation and development of in vitro TGs, especially to ensure that there is no human exploitation, legal requirements are adhered to, and that the origin of the reagent is assured. To address these concerns, the OECD has instigated a workshop on ethics, sources, availability and traceability of human based reagents for TG purposes, to be held in March, 2019. The focus is to provide guidance on acceptable sources of human serum for use in in vitro TGs, in terms of donor ethics and informed consent regarding commercial use and Quality Control for safety and consistent performance, with a view to providing guidance to support the adaptation and/or development of in vitro TGs using human reagents, and to ensure that in reporting the test results to regulators, clearly defined ethical and traceability aspects are adequately addressed, for the Mutual Acceptance of Data principle to be accepted in all OECD member countries. This thought-starter provides a discussion basis to achieve those objectives.

Skin sensitisers are substances that can elicit allergic responses following skin contact and the process by which this occurs is described as skin sensitisation. Skin sensitisation is defined as a series of key events, that form an adverse outcome pathway (AOP). Key event three in the AOP is dendritic cell activation that can be modelled by the human Cell Line Activation Test (h-CLAT) and is typified by changes in cell surface markers CD54 and CD86 in dendritic cells. The h-CLAT is accepted at a regulatory level (OECD Test-Guideline (TG)442E) and can be used to assess skin sensitisation potential as part of an integrated approach to testing and assessment (IATA). Stakeholders in the cosmetics and chemical industries have scientific and ethical concerns relating to use of animal derived material and have communicated a strong preference for fully human based in vitro methods. Therefore, we adapted the h-CLAT to animal-product-free conditions and validated the adapted method with the proficiency panel substances in Annex II of TG442E, using 3 independent batches of pooled human serum. The modified method showed equivalence to the validated reference method (VRM), as all proficiency substances were correctly classified. Comparable values for CV75 (concentration yielding 75% cell viability), EC150 and EC200 (concentration yielding RFI of ≥150 for CD86 and ≥200 for CD54) were obtained. Data generated using the adapted method may be used in European REACH submissions, provided the proficiency data is included. We are seeking formal inclusion of the adaptation into TG442E, enabling compliance with global regulations.

Skin sensitization is the process by which a substance induces an allergic reaction following skin contact. The process has been described as an adverse outcome pathway (AOP), including several key events, from skin penetration and covalent protein binding, to keratinocyte activation, dendritic cell activation and T-lymphocyte proliferation. The in vitro assay KeratinoSens™ measures the activation of keratinocytes. It is fully accepted at a regulatory level (OECD TG 442d) and complies with a range of legislation including the EU Cosmetics Regulation, REACH, and the CLP Regulation. Currently, many in vitro methods use animal-derived components in their cell culture systems. Many stakeholders in the cosmetics industry have both scientific and ethical concerns relating to this issue and have stated a strong preference for fully human in vitro test systems. We have adapted the KeratinoSens™ method to animal product-free condi­tions, and carried out an in-house validation with 21 reference substances, including those listed in the Performance Standards associated with OECD TG442d. The modified method was shown to be equivalent to the Validated Ref­erence Method (VRM), with comparable values for accuracy (85.7%), sensitivity (84.6%) and specificity (87.5%), and all acceptance criteria being met. In Europe, data generated by the adapted method may be used in REACH submissions, and we are now seeking approval to list the adaptation in OECD TG 442d, enabling formal compliance with a range of global regulations.