Frontiers in Toxicology, Год журнала: 2025, Номер 6

Опубликована: Янв. 21, 2025

IntroductionThe well-known dictum "the dose makes the poison" is familiar to every student of toxicology, though it important add that there no risk adverse effects without exposure. This essential point sometimes overlooked when new and emerging risks such as engineered nanomaterials are being discussed (1). The question a poisonous substance or toxicant relates toxicology scientific discipline – science poisons, has evolved into "science safety"? (2). Furthermore, we ready shed predominantly observational past usher in predictive toxicological future? Fifteen years ago, Thomas Hartung lamented studies search for rare events using imperfect models usually addressing one at time (3). He then listed strategic developments required implement regulatory including need standardization validation approaches, well systematic integration these approaches testing strategies is, what should serve benchmark given conventional processes often rely on animal tests may lack adequate themselves (4). Notwithstanding, evident from discussions both basic an applied science. objectives thus two-fold: uncover mechanisms substances biological systems while also leveraging this knowledge protect human health environment. To facilitate translation practice, flow information be bidirectional. Indeed, promote field, dialogue between researchers regulators identify kind needed.Grand challengesThe authors editorial editors different sections Frontiers Toxicology, journal was launched 5 ago (in 2019). Toxicology multidisciplinary committed presenting latest research substances, particles, mixtures living organisms ecosystems, molecular population effects. received its first impact factor 2024. However, believe true lies providing forum exchange community. Here, address five grand challenges, with aim stimulating further discussion.Challenge 1: investigation towards mechanistic toxicologyToxicology viewed descriptive tasked cataloguing drug candidates. devoted understanding toxicity covers spectrum chemicals, which turn unearth fundamental mechanisms. Thus, not afterthought. For instance, have delivered critical insights biology improved role gut microbiome xenobiotic metabolism (5), receptors environmental sensors aryl hydrocarbon receptor (AhR) disease (6). so-called investigative (or mechanistic) gaining momentum pharmaceutical sciences (7). Some "game-changing" technologies according recent survey conducted among medium-sized large companies, organ-on-a-chip microphysiological systems, genomic profiling, high-content imaging-based assays perception other use stem cells had barely changed compared previous It emphasized, however, ultimate goal investigations differs public disciplines. In case, minimize so balance beneficial favor (which implies some degree considered acceptable), whereas second obvious society does tolerate any toxicity. challenge occupational medicine highest level exposure effect elicited. Nevertheless, lessons can learned sciences. Computational leveraged discovery (8), physics-driven (quantum mechanics) data-driven (artificial intelligence) based been footing too (9).Challenge 2: problem multiscale comparisonsBiological pathways defined series interactions molecules lead certain product change cell (though noted extracellular pathways). Pathway "thinking", i.e., view best understood terms their disruption molecular) pathways, come fore contemporary explicit development outcome (discussed below). suggested perspective tenet recontextualized disrupts pathway" order better guide understand results (10). design experiments allow opposed reductionist gene protein making sure model relevant our humans. addition, simultaneous several chemicals common, currently clear if overall affected situation (for remains whether mixture individual components present concentration below no-effect-level induce toxic result "dose addition" wherein each component acts same target). Considerable advances made respect living, breathing lung mimic (11). Using bio-inspired device, demonstrated cyclic mechanical strain accentuated inflammatory responses silica nanoparticles. promising adenocarcinoma line, NCl-H441, used impersonate real epithelial cells. (see below) instead lines could potentially bridge gap vitro situation. Moreover, amenable high-throughput screening (11), additional cost complexity hamper use.This brings us major challenges testing, namely, how divide vivo say models; instead, they outcomes humans after all, main goal). impacts play out across multiple spatial temporal scales, yet tend test static replicate organism. (12). integrate approach occur levels organization input toxicokinetic toxicodynamic modeling happens introduced body.The devil details. culture techniques adopted variety purposes, reduction replacement experiments. animal-derived products meaning methods completely animal-free. fetal bovine serum (FBS), supplement medium, only gives rise welfare concerns, but raises questions related batch-to-batch variation ill-defined nature FBS, mention species differences call relevance obtained standard medium. push fully humanized protocols chemically media (13).Challenge 3: computation beware drowning sea dataThe term "omics" genomics, transcriptomics, proteomics, metabolomics, epigenomics coupled investigate underlying action toxicants. Sydney Brenner famously complained become, his words, "low input, high throughput, output science", omics-based equated hypothesis-free research, misguided suggestion lists genes proteins metabolites light methodologies above merely tools, albeit very sophisticated ones, computational deconvolution needed make sense data. Hence, will necessarily reveal (novel) mechanism anchored firm question. On hand, yield global perturbations triggered by overcome tendencies toxicology. note portfolio omics rapidly expanding, single-cell transcriptomics proteomics greatly increased granularity introduction spatially resolved heralds era analysis expression tissue (14). torrential increase amount data generated requires (15), breed toxicologists versed methods.Predictive viewed, fundamentally, prediction activity chemical structure; known structure-activity relationship (16). end, useful, good quality, usable (meaning investigators must able access data). refer complex (living) observations simple ones (17). ensure outcomes, (toxicants) quantitatively qualitatively. If met, significantly overhaul assessment advent artificial intelligence (AI) expanded toolbox toxicologists. machine learning perhaps support decision (18). Machine computers ability learn explicitly programmed. "learning" anthropomorphic; AI algorithms enable pattern recognition (human) assessors. Understanding reliability AI-based tools indeed, challenge. paves way deterministic probabilistic Probabilistic Bayesian (named English statistician Bayes whose posthumous paper "An Essay Towards Solving Problem Doctrine Chances" forms basis now called Bayes' theorem) incorporating uncertainties variability provide estimates range likelihood hazard (19).Challenge 4: regulation methodologiesHistorically, mainly data, observed considerable attempts transit (animal) mechanism-based, human-relevant US Environmental Protection Agency (EPA) initiated ToxCast, "toxicity forecaster", program develop aid prioritization (20). cultures useful tool. organism, multicellular organotypic developed (21). biology, especially induced pluripotent (iPSC) technology, provided significant boost. Developmental neurotoxicology battery primary NAMs pilot assessing endpoints setting. Making predictions regarding non-trivial. (AOPs) conceptual framework knowledge, molecular-level system (22). Toxicogenomics enrich AOPs (23). important, distinguish response adaptive distinction two (24).Overall, reliable needed, (NAMs) mind. addressed, Partnership Assessment Risks Chemicals (PARC), multinational project aligned European Union's Strategy Sustainability Green Deal (www.eu-parc.eu). Similarly, NIH Common Fund's Complement Animal Research Experimentation (Complement-ARIE) aimed speeding up development, standardization, validation, (www.commonfund.nih.gov). technology methodology animals. newly methods; implementation (25). acceptance key, agencies needed. Ultimately, practices depend demonstrating merits, perspectives assessors assess associated (26).The complicated factors, systematically studies, strongly affect final effect. pre-existing diseases cause susceptibility chemicals. Co- cumulative exposures considered, sex life stage (age) exposed (27). minority groups display unpredictable sex-divergent immune were disclosed study individuals undergoing gender affirming hormone treatment (28). Traditional default uncertainty factors inter-individual inter-species differences, promise all populations (29).Ecological stepwise evaluation parameters stages sensitive assays. identification biomarkers capable reporting issues before manifest level, allowing makers act measures safeguard ecosystems. context, concerted efforts gaps current mammalian-centric assay landscape ecologically (30). Human assessments performed isolation, key therefore integrated aspects consolidated "one health" paradigm emphasized safe-and-sustainable-by-design (SSbD) circular economy vision guides innovation process creating materials more sustainable safer environment (31).Challenge 5: education fostering future toxicologistsParacelsus, Father physicians recognize chemistry medicine, believed those who practiced art knew it: patients your textbook". sought cannot achieved solely through scholastic disputations, embarked extensive travels around Europe spending year physician university professor Basel where he gave lectures own observations, ancient tracts written centuries ago. episode reminds thrives illustrates observation (data collection) enables prevailing dogma. practice thinking instilled, foremost, students future. equally convey young scientists interested full-fledged uniquely interdisciplinary nature. integrates wide fields, chemistry, pharmacology, epidemiology, statistics, mathematics, computer science, on. Due interdisciplinarity, taught various departments, broad versatile education. ample synthesis reflection. relies advanced instruments, appreciation analytical (including mass spectrometry), statistics (i.e., big analysis, cohort studies) next generation tackle many exemplified here. Closing remarksMinority Report (2002) fiction movie Tom Cruise portrays chief officer "precrime" unit stops crimes take place. clairvoyants foresee prevent impending disaster. Instead, refers methods) complementary classical toxicology; shift away "one-substance-at-a-time" holistic addresses real-life throughout lifespan (aka exposome) (32). "exposome" regarded experts nebulous concept. exposome epidemiological studies. stronger focus totality galvanize exposure-effect relationships level.Another branch involves xenobiotics ecosystems biota (the plant life) contain. Predictive early warning problems. conjunction rising contaminant climate anticipate difficult resolve require time-consuming costly restoration (33).Thus, overarching themes during 15 transformation (empirical) would account (34). integral prudent consider look (35).In article, presented attempt frame hope brief overview stimulate discussion. provides worldwide community (Figure 1). article (editorial) published focused (1), most cited date innovative detection micro- nanoplastics (36), topic great concern. third articles meet requirements (25) reproductive PFAS (per- polyfluorinated alkyl "forever chemicals") (37), respectively. close 700 board members than 50 countries, located Europe, North America, Asia-Pacific (APAC). welcome regions. Together, advance field bridging discoveries practical applications health.

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