SEARCH · bioRxiv Science

Results for “pharmacology and toxicology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 127 records · Page 7Linked to original sources

bioRxiv2018

The QNOAEL vs. BMD for Point of Departure

Quantile bootstrap (QB) methods can be applied to the problem of estimating the No Observed Adverse Effect Level (NOAEL) of a New Molecular Entity (NME) to anticipate a safe starting dose for beginning clinical trials. An estimate of the NOAEL from the extended QB method (called the QNOAEL) can be calculated using multiple disparate studies in the literature and/or from laboratory experiments. The QNOAEL is similar in some ways to the Benchmark Dose (BMD) and is superior to the BMD in others. The Benchmark Dose method is currently widely used in toxicological research.\n\nResults are used in a simulation based on nonparametric cluster analysis methods to calculate confidence levels on the difference between the Effect and the No Effect studies. The QNOAEL simulation generates an intuitive curve that is comparable to the dose-response curve.\n\nThe QNOAEL of ellagic acid (EA) will be calculated for clinical trials of its use as a component therapeutic agent (in BSN476) for treating Chikungunya infections. This will be the first application of QB to the problem of NOAEL estimation for a drug. The specific aims of the proposed study are to evaluate the accuracy and precision of the QB Simulation and QNOAEL compared to the Benchmark Dose Method, and to calculate the QNOAEL of EA for BSN476 Drug Development.

pharmacology and toxicology↗

bioRxiv2023

How important are concurrent vehicle control groups in (sub)chronic non-human primate toxicity studies conducted in pharmaceutical development? An opportunity to reduce animal numbers

Safety assessment of human pharmaceuticals demands extensive animal experiments before a compound can be tested in patients or released on the market. Such experiments typically include concurrent vehicle control groups. Reconsidering the need for concurrent controls could support the strive to reduce the use of animals for scientific purposes. We reviewed reports from 20 (sub)chronic toxicity studies that were conducted in non-human primates (NHP) to characterize hazards of novel human pharmaceuticals. Firstly, we determined the toxicological endpoints that were identified to characterize the hazard. Secondly, we evaluated if the hazard could have been identified without reference to the concurrent controls. Thirdly, we employed an alternative statistical method to test for any significant change related to dose level or time. We found that toxicologically relevant hazards were identifiable without reference to concurrent controls, because individual measurements could be compared with pre-dosing values or because individual measurements could be compared to historical reference data. Effects that could not be evaluated without reference to concurrent controls were clinical observations and organ weights for which appropriate historical reference data was not available, or immune responses that could not be compared to pre-dosing measurements because their magnitude would change over time. Our investigation indicates that concurrent control groups in (sub)chronic NHP toxicity studies are of limited relevance for reaching the study objective. Under certain conditions, regulatory (sub)chronic NHP toxicity studies represent a good starting point to implement virtual control groups rather than concurrent control groups in nonclinical safety testing.

pharmacology and toxicology↗

bioRxiv2023

Toxicogenomic analysis of the carcinogenic potential of plastic additives

Plastics are the most prevalent human-made substance in the world and are ubiquitous throughout all ecosystems. Microscopic plastic particles are routinely ingested and inhaled by humans and other organisms. Despite the frequency of plastic exposures, little is known about their health consequences. Of particular concern are plastic additives -chemical compounds that are mixed into plastics to improve functionality or are unintentionally acquired during plastic production and use. Additives are loosely bound to the plastic polymer and may be released during plastic exposures. These compounds may pose health concerns, such as cancer, but little is known about the potential impact of these chemicals on health. To better understand the health effects of plastic additives, we performed an integrated toxicogenomic analysis on 2,712 additives, focusing on cancer as a well-studied toxicological endpoint. Screening these substances across three chemical databases revealed two key observations: 1) over 150 plastic additives have known carcinogenicity and 2) the majority ([~]90%) of plastic additives lack data on carcinogenic endpoints. Analyses of additive usage patterns pinpointed specific polymers, functions, and products in which carcinogenic additives reside. Based on published chemical-gene interactions, both carcinogenic additives and additives with unknown carcinogenicity impacted similar biological pathways. The predominant pathways involved DNA damage, apoptosis, immune response, viral diseases, and cancer. This study underscores the urgent need for systematic and comprehensive carcinogenicity assessment of plastic additives and regulatory responses to mitigate the potential health risks of plastic exposure.

pharmacology and toxicology↗

bioRxiv2022

Differences in neurotoxic outcomes of organophosphorus pesticides revealed via multi-dimensional screening in adult and regenerating planarians

Organophosphorus pesticides (OPs) are a chemically diverse class of commonly used insecticides. Epidemiological studies suggest that low dose chronic prenatal and infant exposures can lead to life-long neurological damage and behavioral disorders. While inhibition of acetylcholinesterase (AChE) is the shared mechanism of acute OP neurotoxicity, OP-induced developmental neurotoxicity (DNT) can occur independently and/or in the absence of significant AChE inhibition, implying that OPs affect alternative targets. Moreover, different OPs can cause different adverse outcomes, suggesting that different OPs act through different mechanisms. These findings emphasize the importance of comparative studies of OP toxicity. Freshwater planarians are an invertebrate system that uniquely allows for automated, rapid and inexpensive testing of adult and developing organisms in parallel to differentiate neurotoxicity from DNT. Effects found only in regenerating planarians would be indicative of DNT, whereas shared effects may represent neurotoxicity. We leverage this unique feature of planarians to investigate potential differential effects of OPs on the adult and developing brain by performing a comparative screen to test 7 OPs (acephate, chlorpyrifos, dichlorvos, diazinon, malathion, parathion and profenofos) across 10 concentrations in quarter-log steps. Neurotoxicity was evaluated using a wide range of quantitative morphological and behavioral readouts. AChE activity was measured using an Ellman assay. The toxicological profiles of the 7 OPs differed across the OPs and between adult and regenerating planarians. Toxicological profiles were not correlated with levels of AChE inhibition. Twenty-two "mechanistic control compounds" known to target pathways suggested in the literature to be affected by OPs (cholinergic neurotransmission, serotonin neurotransmission, endocannabinoid system, cytoskeleton, adenyl cyclase and oxidative stress) and 2 negative controls were also screened. When compared with the mechanistic control compounds, the phenotypic profiles of the different OPs separated into distinct clusters. The phenotypic profiles of adult vs regenerating planarians exposed to the OPs clustered differently, suggesting some developmental-specific mechanisms. These results further support findings in other systems that OPs cause different adverse outcomes in the (developing) brain and build the foundation for future comparative studies focused on delineating the mechanisms of OP neurotoxicity in planarians.

pharmacology and toxicology↗

bioRxiv2024

Anti-inflammatory assessment of zinc oxide nanoparticles mediated Aframomum citratum (C. Pereira) K. Schum (Zingiberaceae) in Wistar rats

IntroductionZinc oxide nanoparticles (ZnONPs) have been synthesized using a wide range of techniques, including green chemistry, because of their versatility, cost effectiveness, and environmentally friendly nature, offering thereby interesting and inexpensive therapeutic options. This study aimed to develop zinc oxide nanoparticles as an anti-inflammatory agent using Aframomum citratum seed extract. MethodologyZnONPs were prepared by the reaction between zinc nitrate and an alkalineaqueous extract of A. citratum seeds. The isolated nanoparticles were then characterized using UV-Vis, FTIR, SEM/EDX, PXRD and TEM techniques. The toxicological profile was assessed at a limited dose of 2000 mg/kg in rats, and methods for heat denaturation of egg albumin, stabilization of red blood cell membranes and inhibition of carrageenan-induced plantar oedema were studied to assess anti-inflammatory properties. ResultsThe formation of ZnONPs was observed by a color change and the appearance of the plasmon resonance peak at 360 nm in the UV-Vis spectrum while FTIR confirmed the presence of secondary metabolites; SEM confirmed the presence of multiform aggregates, and TEM visualize point like particles. EDS confirmed the presence of Zn atoms within the synthetized material. The toxicological profile studied showed no harmful signs; zinc oxide nanoparticles synthesized from A. citratum seed extract showed high inhibition percentages of 86 (1mg/mL); 77 (0.6mg/mL) and 79(1mg/mL) when subjected to inhibition of heat-induced egg albumin denaturation, red cell membrane stabilization and oedema induction by carrageenan respectively, not significatively different compared with diclofenac sodium as positive controls. ConclusionZinc oxide nanoparticles synthesized and characterized from A. citratum seed extract act as a potent anti-inflammatory agent and are devoid of acute oral toxicity.

pharmacology and toxicology↗

bioRxiv2025

A Comprehensive Toxicological Safety Evaluation of Anaerostipes caccae

Anaerostipes caccae CLB101 (CLB101) is an obligate, anaerobic bacteria that was isolated from the stool of a healthy infant. Due to its ability to produce butyrate and its potential promotion of microbiome health through multiple homeostatic interactions there is interest in its consumption by humans. No toxicity data are publicly available for any strain of A. caccae. Therefore, its genotoxic and toxicological potential was investigated in the current study. Due to its anaerobic nature, a genotoxicity evaluation was performed using the in vivo comet assay and the in vivo mammalian micronucleus assay, which found no evidence of clastogenicity or aneugenicity. General toxicity and potential target organs were assessed in a 90-day, repeated-dose, oral toxicity study using 0, 250, 500, and 1000 mg/kg bw/day in Wistar rats. CLB101 exposure did not result in adverse effects in male or female rats when evaluated for clinical signs, body weight, food consumption, clinical pathology, organ weight, and histopathology after administration, at any dose. Therefore, a NOAEL of 1000 mg/kg bw/day, equivalent to 1.9 x 1011 CFU/kg bw/day, was determined in both male and female Wistar rats.

pharmacology and toxicology↗

bioRxiv2025

Integration of publicly available datasets reveals potential pesticide-induced genetic changes in a wild non-target animal

Pesticide use is ubiquitous. While pesticide resistance in target species such as insects is a well-known phenomenon, it is less known how pesticide exposures affect the genetics of non-target species. Here, we demonstrate the research value of integrating existing datasets to study chemical adaptation in the wild by analyzing spatial pesticide concentration data and genetic data that were not initially generated for toxicological purposes. Specifically, we found indications that polygenic non-target site resistance to environmental pesticide exposure developed in a non-target species, the wild boar. Gene ontology (GO) terms and KEGG and Reactome pathways related to nervous system function were overrepresented for the impacted genes, especially for insecticides, which is consistent with the frequent neurotoxic mode of actions of these types of pesticides. Further, we found that external studies characterizing the molecular mechanisms of these pesticides revealed the same pesticide - GO relationships as those observed in our analysis. Our results show that pesticide-induced genetic changes may not be constrained to target species but may also have an impact on the long-term viability of other wildlife populations. This finding urges the consideration and inclusion of chemical exposure into conservation protection strategies.

pharmacology and toxicology↗

bioRxiv2024

Causal, Predictive Or Observational? Different Understandings Of Key Event Relationships For Adverse Outcome Pathways

The Adverse Outcome Pathways (AOPs) framework is pivotal in toxicology, but the terminology describing Key Event Relationships (KERs) varies within AOP guidelines. This study examined the usage of causal, observational and predictive terms in AOP documentation and their adaptation in AOP development. A literature search and text analysis of key AOP guidance documents revealed nuanced usage of these terms, with KERs often described as both causal and predictive. The adaptation of terminology varies across AOP development stages. Evaluation of KER causality often relies targeted blocking experiments and weight-of-evidence assessments in the putative and qualitative stages. Our findings highlight a potential mismatch between terminology in guidelines and methodologies in practice, particularly in inferring causality from predictive models. We argue for careful consideration of terms like causal and essential to facilitate interdisciplinary communication. Furthermore, integrating known causality into quantitative AOP models remains a challenge.

pharmacology and toxicology↗

bioRxiv2025

Unraveling the Toxicological Effects of Hydroxyacetone - A Reaction Product in Electronic Cigarette Aerosols

Hydroxyacetone has been detected at high concentrations (up to [~]12 mg/mL) in electronic cigarette (EC) aerosols, including those derived from products associated with adverse health effects. Given the limited understanding of its inhalation toxicology, we investigated hydroxyacetones impact on human airway epithelial cells. Acute exposures at the air-liquid interface (ALI) using 3D EpiAirway tissues--a surrogate for human tracheobronchial epithelium--were analyzed via proteomics. Differential expression analysis identified numerous affected proteins, with enrichment pointing to alterations in mitochondrial function and actin cytoskeletal disruption as major targets. Ingenuity Pathway Analysis (IPA) highlighted "Mitochondrial Dysfunction" and "NRF2-Mediated Oxidative Stress" among top toxicological categories, and "Nuclear Cytoskeletal Signaling" as a key canonical pathway. To validate and extend these findings, submerged cultures of BEAS-2B cells were exposed to hydroxyacetone (0.01-10 mg/mL) and assessed for mitochondrial activity, oxidative stress, and F-actin integrity. At 1 mg/mL, mitochondrial membrane potential and reactive oxygen species (ROS) increased, with elevated hydrogen peroxide detected in the culture medium. At 10 mg/mL, mitochondrial activity declined significantly, accompanied by cell rounding and apoptotic blebbing within 2 hours. F-actin destabilization occurred at 1, 3.33, and 10 mg/mL, with cytoplasmic and perinuclear filaments more affected than cortical actin. Findings from ALI and submerged models were concordant, supporting hydroxyacetone-induced mitochondrial stress, oxidative damage, and cytoskeletal disruption. These results suggest that hydroxyacetone concentrations found in EC aerosols may contribute to respiratory toxicity and warrant further investigation.

pharmacology and toxicology↗

bioRxiv2024

Network-based investigation of petroleum hydrocarbons-induced ecotoxicological effects and their risk assessment

Petroleum hydrocarbons (PHs) are compounds composed mostly of carbon and hydrogen, originating from crude oil and its derivatives. PHs are primarily released into the environment through the diffusion of oils, resulting from anthropogenic activities like transportation and offshore drilling, and accidental incidents such as oil spills. Once released, these PHs can persist in different ecosystems and cause long-term detrimental ecological impacts. While the hazards associated with such PH contaminations are often assessed by the concentrations of total petroleum hydrocarbons in the environment, studies focusing on the risks associated with individual PHs are limited. Here, we leveraged different network-based frameworks to explore and understand the adverse ecological effects associated with PH exposure. First, we systematically curated a list of 320 PHs from published reports. Next, we integrated biological endpoint data from toxicological databases, and constructed a stressor-centric adverse outcome pathway (AOP) network linking 75 PHs with 177 ecotoxicologically-relevant high confidence AOPs within AOP-Wiki. Further, we relied on stressor-species network constructions, based on reported toxicity concentrations and bioconcentration factors data for 80 PHs and 28 PHs, respectively, and found that crustaceans are documented to be affected by many of these PHs. Finally, we utilized the aquatic toxicity data within ECOTOX to construct species sensitivity distributions for polycyclic aromatic hydrocarbons (PAHs) prioritized by the US EPA, and derived their corresponding hazard concentrations (HC05) that protect 95% of species in the aquatic ecosystem. Overall, this study highlights the importance of using network-based approaches and risk assessment methods to understand the PH-induced toxicities effectively.

pharmacology and toxicology↗

bioRxiv2018

Effects Of High Copper Exposure On Development And Survival During Early Ontogenesis In The Common Toad

Exposure to environmental pollutants contributes to the global decline of amphibians. Amphibian embryos are unique models for studying the effects of various toxic agents on developmental processes. Some of the most detrimental toxic agents are heavy metals, the study of which is a priority in ecotoxicology. Copper is a microelement required in many biological systems, but it can be toxic at concentrations higher than normal physiological range. The purpose of the present study was to analyze the toxic effect of high concentrations of Cu (10, 25, and 50 mg/L) on Bufo bufo embryos. The present study shows that short-term (48 h) toxicity test can fail to register toxicological effect of Cu, whereas long-term toxicity test demonstrates that all analyzed concentrations are lethal to common toad embryos. Early stages of development (stages 4-8, Gosner 1960) are shown to be rather tolerant to copper, even at high concentrations. Effects of copper begin to manifest themselves at the blastula stage (stages 8-9, Gosner, 1960). The present study also shows that initial egg density affects copper-related mortality rate of embryos. If egg density is high, copper-related mortality rate is sometimes decreased, possibly because jelly coats of eggs bind great amounts of dissolved copper. It is also shown that clutches can differ in sensitivity to different copper concentrations. Taken together, our data demonstrate that the conditions of the experiment (such as the initial egg density) and individual sensitivity of clutches to the toxic agent considerably contribute to the results of the ecotoxicological experiment.

pharmacology and toxicology↗

bioRxiv2026

Suprachoroidal Delivery of Anti-Angiogenic Peptide Microparticles Enables Sustained Activity with Favorable Ocular Safety

Retinal and choroidal vascular diseases are major causes of vision loss that require frequent intravitreal anti-VEGF therapy. Anti-angiogenic peptide AXT107 demonstrated efficacy in preclinical studies and was advanced to the clinical stage. To provide for sustained delivery of the peptide and avoid complications with intravitreal injection, we evaluated suprachoroidal delivery of AXT107 microparticles (MP-AXT107). The original, soluble AXT107 formulation was ineffective at inhibiting laser-induced choroidal neovascularization (CNV) in our rat model and was consequently reformulated as microparticles. MP-AXT107 demonstrated high peptide incorporation efficiency, reproducible morphology, and physical and chemical stability for at least 9 months under refrigerated storage. In the rat CNV model, suprachoroidal MP-AXT107 significantly reduced neovascular area by approximately 60% relative to vehicle controls. Safety and durability were evaluated in a 9-month GLP toxicology study in Gottingen minipigs following a single suprachoroidal injection of vehicle or MP-AXT107 (0.125-1.25 mg/eye). Transient increases in IOP and mild ocular inflammatory findings were observed immediately following administration but resolved rapidly without lasting effects. No treatment-related adverse ocular findings were observed during the remainder of the study, and the highest tested dose (1.25 mg/eye) was established as the no-observed-adverse-effect level. Bioanalysis at study completion demonstrated persistent AXT107 localization primarily within choroid/RPE and scleral tissues, with no signs of systemic exposure. Collectively, these findings demonstrate that suprachoroidal delivery of MP-AXT107 enables sustained anti-angiogenic activity with favorable ocular safety and prolonged tissue retention, supporting further clinical development as a durable therapy for retinal and choroidal vascular diseases.

pharmacology and toxicology↗

bioRxiv2025

From Toxicogenomics Data to Cumulative Assessment Groups: A Mechanistic Framework for Chemical Grouping

The grouping of chemicals based on shared properties or molecular mechanisms of action is pivotal for advancing regulatory toxicology, reducing data gaps, and enabling cumulative risk assessments. This study introduces a novel framework usingChemical-Gene-Phenotype-Disease (CGPD) tetramers derived from the Comparative Toxicogenomics Database (CTDbase). Our approach integrates toxicogenomics data to identify and cluster chemicals with similar molecular and phenotypic effects across diverse categories, including pesticides, pharmaceuticals, and industrial chemicals such as bisphenols and per- and poly-fluoroalkyl substances (PFAS). We validated our method by comparing CGPD Tetramer-based clusters with cumulative assessment groups (CAGs) for pesticides, demonstrating strong overlap with established groupings while identifying additional compounds relevant for risk assessment. Key examples include clusters associated with endocrine disruption and metabolic disorders.By bridging omics-derived molecular data with phenotypic and disease endpoints, this framework provides a comprehensive tool for chemical grouping and supports evidence-based regulatory decision-making, facilitating the transition to next-generation risk assessment methodologies.

pharmacology and toxicology↗

bioRxiv2026

Bayesian Stacking of Quantitative Adverse Outcome Pathways Isolates Primary Drivers of Liver Steatosis

The quantification of adverse outcome pathways (qAOPs) involving multiple converging pathways remains a fundamental challenge in toxicology. This difficulty is worsened by small in vitro datasets with missing values and heteroscedasticity, which limit the estimation of non-linear response functions and the robust estimation of uncertainty. To overcome these limitations, we developed a framework for estimating a Bayesian qAOP Ensemble (Bayesian qAOPE) that combines heteroscedastic dose-response functions with continuous splines and linear models. By combining multiple converging non-linear pathways through Bayesian stacking, the most meaningful pathways are identified, and strongly correlated responses are naturally accounted for. Applying our approach to a hepatic steatosis dataset, we demonstrate by exact Bayesian leave-one-out cross-validation that our framework yields an exceptional predictive performance suitable for the derivation of a probabilistically weighted Benchmark Dose (BMD). Our framework is highly adaptable and provides a chemical-agnostic, mathematically founded blueprint for integrating multiple converging pathways in a Bayesian network.

pharmacology and toxicology↗

bioRxiv2026

Comparative analysis of transcriptomic liberality in 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed mouse liver RNA-Seq datasets

Omics methods have been envisioned to complement traditional toxicological testing for chemical risk assessment, in which identifying adverse effects is a critical step. However, the high dimensionality of transcriptomic data has historically led to reliance on context-dependent analysis. Liberality is a quantitative index that reduces genome-scale data dimensionality, with its changes reflecting underlying biological phenomena. In this study, we measured liberality in mouse liver RNA sequencing (RNA-Seq) datasets from studies in which mice were exposed to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4 days for 28 or 92 days, comparing dose-liberality relationships. Both 28- and 92-day TCDD treatments increased liberality but exhibited different dose-liberality relationships. Analysis of genes contributing to liberality revealed that longer exposure duration induced more extensive alterations in transcriptomic architecture. These findings suggest that liberality may serve as an unbiased metric to assess the extent of treatment-induced transcriptome perturbation.

pharmacology and toxicology↗

bioRxiv2026

Establishing toxicologically relevant primary alveolar macrophage models to enable a realistic assessment of nanomaterials safety

Alveolar macrophages (AMs) are key sentinels of the distal lung, maintaining surfactant homeostasis and clearing inhaled particles through continuous surveillance and phagocytosis. Mechanistic studies of particle-cell interactions, important to assess the respiratory safety or toxicity of particles, however, are limited by the lack of suitable in vitro models that preserve the core features of resident AMs. Here, we benchmarked six murine AM models, including short-term cultured primary AMs (AMs 3 h, AMs 24 h), primary AMs maintained with GM-CSF, TGF-{beta}, and the PPAR-{gamma} agonist rosiglitazone (AMs GTR), bone marrow-derived AM-like cells (BM-AMs), the immortalized AM cell line MH-S, and the non-transformed fetal liver-derived AM-like cell line MPI, against in vivo AMs based on surface phenotype, transcriptomic identity, and their responses to three carbon-based nanomaterials (CBNs). Both cell lines showed limited AM identity, characterized by low CD11c and SiglecF but high CD11b surface expression. In contrast, AMs GTR and BM-AMs more closely preserved resident AM-like surface marker profiles. Transcriptomic features, although differing for alterations in metabolism-related pathways, particularly oxidative phosphorylation, revealed most in vivo-like for the primary AM models. Functional, toxicological assessment using soot-like carbon nanoparticles (CNP), double-walled carbon nanotubes (DWCNT) and multi-walled carbon nanotubes (MWCNT) demonstrated strong model-dependent responses. Consistent with MWCNT-induced reduction in AM numbers observed in vivo, AMs GTR and BM-AMs exhibited the strongest in vitro responses, including cytotoxicity and inflammatory cytokine release. MH-S cells in contrast stood out for their cytotoxic sensitivity supporting their use for high throughput cytotoxicity tests. Overall, these findings identify AMs GTR and BM-AMs as the closest models for studying AMs biology and AM-intrinsic responses to poorly soluble nanoparticles like CBNs, and with regard to availability of higher cell numbers, BM-AMs might provide a scalable platform for mechanistic and higher-throughput nanotoxicology studies.

pharmacology and toxicology↗

bioRxiv2023

Intraspecific genetic variation is critical to robust toxicological predictions in Daphnia

Environmental risk assessment is a critical tool for protecting aquatic life and its effectiveness is predicated on predicting how natural populations respond to contaminants. Yet, routine toxicity testing typically examines only one genotype, which may render risk assessments inaccurate as populations are most often composed of genetically distinct individuals. To determine the importance of intraspecific variation in the translation of toxicity testing to populations, we quantified the magnitude of genetic variation within 20 Daphnia magna clones derived from one lake using whole genome sequencing and phenotypic assays. We repeated these assays across two exposure levels of microcystins, a cosmopolitan and lethal aquatic contaminant produced by harmful algal blooms. We found considerable intraspecific genetic variation in survival, growth, and reproduction, which was amplified by microcystins exposure. Finally, using simulations we demonstrate that the common practice of employing a single genotype to calculate toxicity tolerance failed to produce an estimate within the 95% confidence interval over half of the time. These results illuminate the importance of incorporating intraspecific genetic variation into toxicity testing to reliably predict how natural populations will respond to aquatic contaminants.

pharmacology and toxicology↗

bioRxiv2022

Safety and uptake of fully oxidized β-carotene

Spontaneous oxidation of {beta}-carotene yields a polymer-rich product (OxBC) also containing small amounts of many apocarotenoids. OxBC extends {beta}-carotenes benefits beyond vitamin A, finding utility in supporting health in livestock, pets, and humans. Although naturally occurring OxBC is consumed in foods and feeds, a direct demonstration here of safety of synthetic OxBC supports its increasing usage. A toxicological study in rats showed a maximum tolerated single oral dose, an LD50, and a NOAEL of 5,000, 30,079 and 1875 mg/kg body weight, respectively. The repeat-dose 90-day oral toxicity study showed no adverse physiological or pathological effects. A first study of OxBC uptake by mice over 2-5 days into a select set of tissues showed OxBC already was naturally present. The highest levels were in liver, lung, and hamstring. Despite dosing, no net increases occurred in liver, kidney, lung, and muscle. Net increases occurred in urine, intestinal content, plasma, feces, spleen, and cecum, consistent with processing of OxBC and preferential elimination of polymer. Compared to the 4:1 polymer: apocarotenoid ratio of OxBC, polymer was enriched in liver and spleen and depleted in lung, kidney, hamstring, and abdominal muscle. The apparent control of OxBC in major tissues further supports its safety.

pharmacology and toxicology↗