Background While some per- and polyfluoroalkyl substances (PFAS) are immunosuppressants, whether they have an adverse effect on infectious disease morbidity is unclear. We conducted a systematic review and meta-analysis of epidemiologic data on the association between an incremental increase in serum concentration of any of 12 PFAS and the risk or rate of infectious disease (ID). Methods From 25 reports representing 18 unique study populations, we conducted meta-analyses stratified on exposure type (log-transformed or absolute scale) and outcome type (risk or rate). To synthesize data that could not be combined with meta-analysis due to different exposure or outcome types, we additionally conducted vote counting and calculated combined p-values. Results A small positive association between PFAS exposure and ID risk or rate was more frequently reported than not, though in the synthesized data statistical significance was present only in a few instances. The meta-analyses and combined p-value analyses had many similar findings. In the combined p-value analyses, statistically significant positive associations were noted between Perfluorononanoic acid and lower respiratory tract infection (LRTI) event rates, Perfluorooctanesulfonamide and LRTI event rates and LRTI risk and rates combined, Perfluorooctanoic acid and Perfluorodecanoic acid with all ID risk and rates combined, and Perfluoroundecanoic acid with all ID risk. Conclusion We identified moderate evidence of positive associations that were of variable size but usually small; the certainty of evidence was, however, generally low or very low and diminished by the possible influences of multiple testing and covariance among results not accounted for in the analyses. Prospero registration CRD42024551990.
The ongoing transition from chemical hazard and risk assessment based on animal studies to assessment relying mostly on non-animal data, requires a multitude of novel experimental methods, and this means that guidance on the validation and standardisation of test methods intended for international applicability and acceptance, needs to be updated. These so-called new approach methodologies (NAMs) must be applicable to the chemical regulatory domain and provide reliable data which are relevant to hazard and risk assessment. Confidence in and use of NAMs will depend on their reliability and relevance, and both are thoroughly assessed by validation. Validation is, however, a time- and resource-demanding process. As updates on validation guidance are conducted, the valuable components must be kept: Reliable data are and will remain fundamental. In 2016, the scientific community was made aware of the general crisis in scientific reproducibility—validated methods must not fall into this. In this commentary, we emphasize the central importance of ring trials in the validation of experimental methods. Ring trials are sometimes considered to be a major hold-up with little value added to the validation. Here, we clarify that ring trials are indispensable to demonstrate the robustness and reproducibility of a new method. Further, that methods do fail in method transfer and ring trials due to different stumbling blocks, but these provide learnings to ensure the robustness of new methods. At the same time, we identify what it would take to perform ring trials more efficiently, and how ring trials fit into the much-needed update to the guidance on the validation of NAMs.
The Epidermal Sensitization Assay (EpiSensA) is a reconstructed human epidermis (RhE)-based gene expression assay for predicting the skin sensitization potential of chemicals. Since the RhE model is covered by a stratified stratum corneum, various kinds of test chemicals, including lipophilic ones and pre-/pro-haptens, can be tested with a route of exposure akin to an in vivo assay and human exposure. This article presents the results of a formally managed validation study of the EpiSensA that was carried out by three participating laboratories. The purpose of this validation study was to assess transferability of the EpiSensA to new laboratories along with its within- (WLR) and between-laboratory reproducibility (BLR). The validation study was organized into two independent stages. As demonstrated during the first stage, where three sensitizers and one non-sensitizer were correctly predicted by all participating laboratories, the EpiSensA was successfully transferred to all three participating laboratories. For Phase I of the second stage, each participating laboratory performed three experiments with an identical set of 15 coded test chemicals resulting in WLR of 93.3%, 93.3%, and 86.7%, respectively. Furthermore, when the results from the 15 test chemicals were combined with those of the additional 12 chemicals tested in Phase II of the second stage, the BLR for 27 test chemicals was 88.9%. Moreover, the predictive capacity among the three laboratories showed 92.6% sensitivity, 63.0% specificity, 82.7% accuracy, and 77.8% balanced accuracy based on murine local lymph node assay (LLNA) results. Overall, this validation study concluded that EpiSensA is easily transferable and sufficiently robust for assessing the skin sensitization potential of chemicals.
The attempt to create services that are designed and directed by service users has been growing in prominence in many human service sectors and has spawned a wide variety of policies, systems and examples in many jurisdictions. This article has a focus on how decision-making and of this kind can be operationalized by demonstrating how organizational authority can be transferred to and employed by service users and their allies both singly and in conjunction with other parties. It describes various levels of empowerment relative to service decision making as well as the common organizational forms that user directed services have taken to-date.
