Researchers at the University of Santiago de Compostela in Spain, led by Luis Rodríguez-Santos and Manuel Botana, carried out a 28-day repeated-dose oral toxicity study in mice, comparing the three principal diarrhetic shellfish toxins: okadaic acid, dinophysistoxin-1 and dinophysistoxin-2. The work, published in Current Research in Food Science, was designed to answer a question that regulatory agencies, including the World Health Organization and the Food and Agriculture Organization, have explicitly flagged as unresolved: what happens to the body when these toxins are ingested day after day at low doses, rather than in a single large serving?

The experimental design is notable for its attempt to mimic real human dietary exposure. Rather than forcing toxin solutions into the animals by gavage, the standard but stressful technique, the team delivered the toxins inside small pieces of bread that the mice voluntarily ate, a welfare-friendly approach that avoids confounding the results with handling stress. The daily dose of 90 micrograms per kilogram of body weight was calibrated to model a high-intake human dietary scenario derived from the European regulatory limit of 160 micrograms of okadaic acid equivalents per kilogram of shellfish meat. That calculation assumes a large 400-gram portion of contaminated bivalves for a 70-kilogram adult, then applies the standard 100-fold uncertainty factor used in toxicology to bridge the gap between animal and human exposure.

Over four weeks, the mice showed a pattern of persistent, cumulative toxicity that single-dose studies simply cannot capture. Dinophysistoxin-1 emerged as the most troublesome analogue, producing the greatest number of non-specific clinical signs and the most severe diarrhea, with significant effects in both sexes throughout the first three weeks of the study. Okadaic acid also caused significant clinical signs and diarrhea, particularly in females, whose fecal consistency scores became significantly worse than controls from the second week onward. Dinophysistoxin-2, by contrast, behaved remarkably differently: it produced almost no significant diarrhea at any point, reinforcing its reputation as the mildest of the three toxins.

That difference in clinical severity tracks closely with the toxins’ behavior inside the body. Using ultra-performance liquid chromatography coupled with tandem mass spectrometry, the researchers measured toxin concentrations in feces, intestinal contents and organs. Dinophysistoxin-2 was excreted rapidly and abundantly in feces while remaining barely detectable in tissues, suggesting poor gastrointestinal absorption and fast clearance that limits its systemic bioavailability. Dinophysistoxin-1 showed the opposite profile: the lowest fecal excretion but proportionally greater retention in the intestinal wall, indicating prolonged contact between the toxin and the gut lining. Okadaic acid fell somewhere in between, with high initial fecal excretion that declined over the study period. The highest tissue concentrations of all three toxins were found in the small and large intestines, precisely where the diarrheic damage occurs.

The microscopic evidence added another layer of concern. After 28 days of exposure, mice receiving okadaic acid and dinophysistoxin-1 showed significant thinning of the gastric mucosa, the protective lining of the stomach, a change the authors interpret as chronic epithelial alteration. Kidney sections revealed vascular congestion, tubular damage and an enlarged Bowman’s space, the cup-like structure where blood filtration begins, in animals treated with okadaic acid or dinophysistoxin-1, while dinophysistoxin-2-treated animals showed essentially preserved renal morphology. In the liver, dinophysistoxin-1 caused mild vascular changes, including dilated sinusoids and red blood cell extravasation, though hepatocyte architecture remained largely intact. Male mice given okadaic acid also showed a significant increase in relative heart weight, an intriguing systemic signal that warrants follow-up.

Perhaps the most striking findings involved sex. Female mice reduced their water intake significantly from day 14 onward, particularly those receiving okadaic acid, and showed trends toward lower urine output and higher urine protein-to-creatinine ratios, hints of subtle renal stress that the authors caution are qualitative rather than definitive proof of kidney dysfunction. Males, meanwhile, displayed more non-specific clinical symptoms overall, while females suffered more pronounced gastrointestinal effects. This sexual dimorphism in toxin response is a critical consideration for risk assessment, since most toxicological reference values are derived without fully accounting for sex-specific vulnerability.

The team also pioneered a novel biomarker approach, examining cyclophilin A and cyclophilin C, evolutionarily conserved proteins released into the extracellular space during inflammatory responses, in the intestinal contents of exposed mice. Detectable cyclophilin A and C appeared exclusively in the small intestinal contents of dinophysistoxin-1-treated animals, consistent with that toxin’s longer residence time in the gut and its harsher clinical profile. Cyclophilin C was absent from the intestinal contents of dinophysistoxin-2-treated animals across all replicates, mirroring that toxin’s milder effects. Because luminal contents lack stable housekeeping proteins for normalization, the authors present these results as descriptive qualitative support rather than quantified proof of inflammation, but the correlation with the toxicokinetic and clinical data is compelling.

The implications for the seafood consumer are nuanced. The authors are careful to note that their findings do not demonstrate that the current European regulatory limit is inadequate, nor do they establish a tolerable daily intake for these toxins. What the study does provide is the first comparative assessment of all three diarrhetic shellfish toxins under subchronic conditions using a voluntary feeding model that closely replicates natural dietary exposure. The data suggest that current toxicity equivalency factors, which assign okadaic acid and dinophysistoxin-1 a potency of 1 and dinophysistoxin-2 a potency of 0.6 based on older in vitro and acute intraperitoneal data, may need revision in light of oral toxicity evidence showing dinophysistoxin-1 to be substantially more harmful than its legal classification implies.

With climate change intensifying harmful algal blooms worldwide and extending the periods during which shellfish carry low but persistent toxin loads, the scenario modeled in this study becomes increasingly plausible for regular seafood consumers. The researchers acknowledge limitations, including the modest sample size of five animals per sex per group, the single exposure level tested, and the 28-day subchronic window, which falls short of the 90-day or lifetime studies needed to establish formal no-observed-adverse-effect levels. Still, by demonstrating that repeated low-dose exposure produces cumulative gastrointestinal, renal and hepatic effects with distinct toxin-specific and sex-specific profiles, the study delivers exactly the kind of harmonized comparative evidence that international expert panels have demanded, and it makes a strong case that the safety of the world’s favorite shellfish deserves evaluation through a longer, more chronic lens.

Subject of Research: Subchronic oral toxicity of diarrhetic shellfish toxins (okadaic acid, DTX1 and DTX2) in mice under repeated low-dose dietary exposure

Article Title: Regular exposure to low dose of diarrheic shellfish toxins: Implications for the seafood consumer

Article References: Rodríguez-Santos, L., Louzao, M. C., Cagide, E., Alvarez, M., Vale, C., Cifuentes, J. M., Vilariño, N., Graña, A., Carrera, C., Alvariño, R., Vieytes, M. R., Lolo, M., & Botana, L. M. (2026). Regular exposure to low dose of diarrheic shellfish toxins: Implications for the seafood consumer. Current Research in Food Science, 13, Article 101574. https://doi.org/10.1016/j.crfs.2026.101574

Image Credits: AI Generated

DOI: 10.1016/j.crfs.2026.101574

Keywords: diarrhetic shellfish toxins, okadaic acid, dinophysistoxin-1, dinophysistoxin-2, harmful algal blooms, shellfish safety, subchronic toxicity, food toxicology, marine biotoxins, toxicity equivalency factors, seafood consumption, cyclophilins

Discover Toxicology was inaugurated in May 2024 as a peer-reviewed, open access platform intended to publish research across all aspects of toxicology and its applications in research, development, and society. Its founding premise, the editors explain, is to give researchers, practitioners, policymakers, and stakeholders a venue to exchange knowledge, share best practices, and collaborate on solutions to pressing toxicological challenges. Like other journals in the Discover series, it welcomes all valid research, including null results, regardless of perceived impact, provided the work meets the standards of rigor and quality associated with Springer Nature. That policy is a deliberate counterweight to publication cultures that reward only headline-grabbing findings, a bias the editors argue has left critical dynamics of toxicological mechanisms in low-resourced countries understudied.

The breadth of the journal’s ambition is reflected in its Editorial Board, whose listed expertise spans toxins and venoms, clinical and preclinical pharmacology and toxicology, bioinformatics and cheminformatics, computational chemistry, ecotoxicity, regulatory toxicology, emerging contaminants, food safety, genetic toxicology, analytical chemistry, risk assessment, mechanisms of toxicity, omics, immunotoxicology, forensic pathology, and occupational exposure assessment. In the editorial, each Section Editor introduces the domain he or she represents, offering an unusually candid view of the technical questions the journal considers most pressing.

Professor Adekunle A. Bakare of the University of Ibadan, Nigeria, anchors the genotoxicology section. His laboratory studies the genotoxicity and mutagenicity of xenobiotics, the foreign chemicals that urbanization and industrialization have made almost impossible to avoid. Using in vitro and in vivo bioassays, his group examines the cytotoxic, genotoxic, and mutagenic effects of municipal solid waste leachates, industrial effluents, pesticides, analgesics, medicinal plant extracts, antiretroviral and antituberculosis drugs, metal and metal oxide nanoparticles, and electronic waste elutriates. The stakes, he argues, are generational: DNA damage from environmental xenobiotics is implicated not only in cancer and birth defects but also in heart disease, cellular aging, immune dysfunction, altered metabolism, neurodegenerative disease, and cataracts, and germline damage may affect future as well as current generations. He invites submissions on genotoxicity testing approaches, predictive toxicology, toxicogenomics, reproductive toxicology, epigenetics, gene expression analysis of DNA toxicity, artificial intelligence applied to DNA damage, and the links between genotoxicity and carcinogenesis.

Ajay Vikram Singh, a senior scientist at the German Federal Institute for Risk Assessment (BfR) in Berlin, represents the computational and nanotoxicology frontier. Working within an institute of more than 750 scientists that advises the German government on food and product safety, chemical risks, contaminants, animal protection, and consumer health, Singh combines advanced computational models, artificial intelligence, and nanoscale characterization to decipher how chemicals, nanomaterials, and biological systems interact. The goal is proactive safety assessment: predicting toxicity before products reach the market and enabling the design of inherently safer, so-called safer-by-design materials. He highlights the integration of multi-omics data with computational approaches, the nanobiophysics of mechanistic toxicology, and the regulatory challenges posed by complex novel materials, and he welcomes manuscripts using in silico methods, AI and machine learning-driven predictive toxicology, high-throughput screening data analysis, and mechanistic studies of engineered nanomaterials.

Edmond Sanganyado, associate professor at the University of Saskatchewan, works at the intersection of analytical chemistry and systems biology, developing tools that link exposure to toxicological effect through advanced omics technologies. He frames three questions that he believes will define the field: how to detect and quantify known and unknown toxicants and their metabolites quickly, cheaply, and reliably in real samples; how complex mixtures of pollutants affect organisms, ecosystems, and humans over a lifetime; and how to identify toxic substances in ways that stand up in court, keep pace with drug trends, and support public health. Big data, artificial intelligence, high-resolution mass spectrometry, and new approach methodologies, or NAMs, are driving all three disciplines, analytical, environmental, and forensic toxicology, toward mixture-based paradigms and toward reducing and replacing animal testing. But he cautions that publication norms emphasizing narrow novelty risk leaving the toxicology of low-resourced countries chronically understudied.

Neuropharmacologist João Paulo Capela of Portugal’s Fernando Pessoa University and the University of Porto brings the journal’s coverage to drugs of abuse and clinical toxicology. His research probes the brain actions of amphetamine-type stimulants and methylphenidate, both as illicit substances and as prescribed treatments for attention deficit hyperactivity disorder and other brain disorders. His central concern is translation: whether work is done in vitro or in animals, the purpose of mechanistic toxicology is to transfer findings to the human situation in order to prevent, mitigate, or treat adverse drug effects. He sees artificial intelligence-based tools as a promising means of elevating that mechanistic understanding, and he argues that new methodologies and models are essential for surveying how drugs and toxicants inflict damage at the cellular and molecular level.

Ecotoxicologist Maranda Esterhuizen, affiliated with the University of Helsinki and Häme University of Applied Sciences in Finland, specializes in pollution impact assessment and ecological restoration through nature-based solutions, with a deliberately transdisciplinary approach bridging environmental science and policy. She describes environmental toxicology as standing at a critical juncture, confronting complex chemical mixtures and climate-induced shifts in pollutant behavior, particularly in rapidly urbanizing regions. Her section invites research using adverse outcome pathways, omics technologies, and predictive modeling to understand toxicity across biological scales, and she singles out studies integrating climate change dynamics, urbanization, and chemical mixture interactions as especially welcome, because they mirror the compounded pressures ecosystems actually face.

Food and computational toxicologist Yu-Syuan Luo of National Taiwan University completes the editorial leadership roster. His focus is on human-relevant, mechanism-informed chemical safety evaluation at a time when data gaps for emerging contaminants, low-dose exposures, and complex mixtures impede timely regulatory decisions. Food toxicology, he notes, is pivotal for assessing ingredients, contaminants, and food-contact materials, especially for endpoints such as endocrine disruption and mixture toxicity. Computational toxicology complements it with scalable predictive tools, including in silico modeling, omics-based profiling, and data-driven hazard identification and prioritization, supporting the global shift away from traditional animal testing and toward more efficient, transparent, forward-looking risk assessment.

Taken together, the editorial sketches a discipline in methodological upheaval: from single-compound testing toward mixtures, from animal models toward new approach methodologies, from reactive hazard characterization toward AI-assisted prediction and safer-by-design chemistry. By welcoming null results and prioritizing rigor over novelty, Discover Toxicology is positioning itself as a home for precisely the unglamorous, reproducible, and globally inclusive work that this transition requires, and the editors close with an open invitation to researchers worldwide to submit work spanning fundamental questions and real-world applications alike.

Subject of Research: An editorial by the section editors of the open access journal Discover Toxicology outlining research priorities across genotoxicology, computational and nanotoxicology, ecotoxicology, neurotoxicology, and food toxicology.

Article Title: Discover Toxicology, the future journal for your toxicology research

Article References: Bakare, A. A., Singh, A. V., Sanganyado, E., Capela, J. P., Esterhuizen, M., Luo, Y.-S., & Guo, Y. (2026). Discover Toxicology, the future journal for your toxicology research. Discover Toxicology, 3(1), Article 12. https://doi.org/10.1007/s44339-026-00053-1

Image Credits: AI Generated

DOI: 10.1007/s44339-026-00053-1

Keywords: Discover Toxicology, toxicology, open access publishing, genotoxicity, xenobiotics, computational toxicology, nanotoxicology, ecotoxicology, new approach methodologies, food toxicology, chemical mixtures, risk assessment