Toxicity testing in the 21st century beyond environmental chemicals

Abstract

Summary After the publication of the report titled Toxicity Testing in the 21 st Century – A Vision and a Strategy , many initiatives started to foster a major paradigm shift for toxicity testing – from apical endpoints in animal-based tests to mechanistic endpoints through delineation of pathways of toxicity (PoT) in human cell based systems. The US EPA has funded an important project to develop new high throughput technologies based on human cell based in vitro technologies. These methods are currently being incorporated into the chemical risk assessment process. In the pharmaceutical industry, the efficacy and toxicity of new drugs are evaluated during preclinical investigations that include drug metabolism, pharmacokinetics, pharmacodynamics and safety toxicology studies. The results of these studies are analyzed and extrapolated to predict efficacy and potential adverse effects in humans. However, due to the high failure rate of drugs during the clinical phases, a new approach for a more predictive assessment of drugs both in terms of efficacy and adverse effects is getting urgent. The food industry faces the challenge of assessing novel foods and food ingredients for the general population, while using animal safety testing for extrapolation purposes is often of limited relevance. The question is whether the latest paradigm shift proposed by the Tox21c report for chemicals may provide a useful tool to improve the risk assessment approach also for drugs and food ingredients.

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…In the case of the pharmaceutical industry, the situation is quite different (Rovida et al, 2015). Firstly, testing the safety and efficacy of drugs and related products before entering first clinical trials in man is not only ethically accepted, but even legally requested.…”

“…In contrast, the pharmaceutical industry, interested in new drugs and related products, is obliged to demonstrate not only product safety, but also efficacy (Rovida et al, 2015). This includes providing evidence that an active pharmaceutical ingredient (API) becomes biologically available at its intended site of action (e.g., inner organ, tissue, cell or receptor), meaning that it is able to cross relevant absorption barriers which otherwise would limit its bioavailability and therapeutic efficacy.…”

The need for strategic development of safety sciences

“…The website of the Balanced Scoreboard Institute 2 and Strategy Management Group 3 , two consultancies for organizations in strategic planning, define: "Strategic planning is an organizational management activity that is used to set priorities, focus energy and resources, strengthen though harmonized via the International Conference on Harmonization 9 , as the US, which has 6% of the world population, consumes about 60% of drugs under patent, which gives them a lighthouse function for the pharmaceutical industry (Rovida et al, 2015a Wambaugh et al, 2015), ToxCast (Richard et al, 2016), the Tox 21 collaboration with the NIH and the FDA, the Virtual Tissues 5 and computation toxicology in general (Patlewicz and Fitzpatrick, 2016) It promotes mechanism-based toxicity testing and risk assessment according to the principles laid down for toxicology for Tox21. The project will integrate advances in in vitro and in silico toxicology, read-across methods, and adverse outcome pathways.…”

BiodentineTM is cytocompatible with human primary osteoblasts

“…8,9,12,13,14,15 Actually, studies have assessed the in vitro cytocompatibility of Biodentine using immortalized cell lineages of different tissues or mammal origins, including three-dimensional spheroid pulp cell culture 15 or osteosarcoma cells, 12,13 with interesting results pointing to the biocompatibility of this material, indicating its capacity to induce proliferation and mineralization in vitro. 13 Nevertheless, these results still require some level of extrapolation either from animal-to-human models, whose limitations have been constantly discussed in light of the 21 st century toxicology paradigms, 16 or extrapolation from aneuploid/immortalized cell lineages to the unaltered primary human cells found in healthy tissues. In this regard, studies 17,18 have confirmed that, even though many similarities might be found between human primary cells and the main studied osteoblast-like cell lines, such as MC3T3, MG63, or SAOS2, differences in their response to biomaterials point to the importance of primary cell studies.…”