Adverse Effect Level Research Articles

P0637 Ebrasodebart (Ent001) First in Human trial in healthy volunteers: pharmacokinetic results and predicted therapeutic concentrations to preserve mucosal healing in patients with Ulcerative Colitis

Abstract Background Ebrasodebart (Ent001) is a human IgG4 monoclonal antibody that antagonizes the binding of IGFBP3 to the novel cell death receptor TMEM219, expressed on Intestinal Stem Cells (ISCs) and well conserved across human and animal species. Ebrasodebart is thus expected to inhibit TMEM219-mediated activation of Caspase-8 and the exaggerated apoptosis of ISCs observed in patients with Ulcerative Colitis (UC). Ebrasodebart is currently in clinical development as a novel first-in class investigational treatment in patients with UC. A FIH single ascending dose (SAD) study in healthy volunteers (HVs) was conducted to define the safety, tolerability and pharmacokinetics (PK) of ebrasodebart at the concentrations anticipated to be required to elicit pharmacological and therapeutic activity in patients. Methods Thirty (30) HVs were enrolled in the monocentric, randomized, double-blind, placebo-controlled SAD study, 29 subjects completed the study. In vitro and in vivo concentration-response preclinical experiments defined the pharmacologically active concentrations, measuring the inhibition of IGFBP3-induced Caspase-8 activation in human intestinal epithelial cell lines and organoids, and the exposure-response in DSS-induced chronic colitic mice, while modeling and simulation (M&S) predicted effective concentrations. Results After single intravenous (IV) doses of ebrasodebart in HVs, maximum exposure (Cmax) and systemic exposure (AUCinf) increased in an approximately dose proportional manner with a low intersubject variability at all dose levels (CV% < 20% for Cmax and AUCinf). Geometric mean t1/2 was between 17 to 19 days at the predicted therapeutic doses. Ebrasodebart achieved a Cmax of 296 µg/mL and AUC0-inf of 37646 µg/mL*h well below the No Observed Adverse Effect Level (NOAEL) from the 26-week chronic toxicity study in monkeys, but significantly higher than the minimal pharmacologically active concentration in vitro. The concentrations achieved in the FIH trial were also higher than those that significantly reduced the Disease Activity Index and both histological and endoscopic scores in mice, exceeding M&S predictions for pharmacological effectiveness in patients. Conclusion These data indicate that ebrasodebart concentrations with predictable PK and expected therapeutic efficacy can be safely reached in humans, and remained significantly below the NOAEL in monkeys, suggesting a potential for a wide therapeutic window in patients. A multicentric Phase 1b, randomized, double-blind, placebo-controlled trial is ongoing to evaluate safety, tolerability, PK, immunogenicity and preliminary efficacy of multiple ascending doses of ebrasodebart in patients with moderately to severely active UC.

26-Week Repeated-Dose Toxicity Study of a Novel Antiarrhythmic Drug Sulcardine Sulfate in Sprague-Dawley Rats.

Sulcardine sulfate (Sul) is a novel antiarrhythmic agent blocking multiple channels and exhibits unique pharmacological properties such as lower APD-dependent prolongation and reduced arrhythmia risk. Sul is currently in Phase III clinical trials, yet studies on its long-term toxicological profile and potential target organs remain unexplored. This study investigated the related toxicity of Sul in Sprague Dawley (SD) rats through repeated oral administration for 26 weeks, followed by a 4-week recovery period. Consistent with the clinical intended mode of administration, Sul was administered via oral gavage at daily doses of 0, 175, 350, and 700/525 mg/kg in rats. On account of clinically observed body weight loss of male and female rats in the high-dose group compared with the control group, with one female rat in the high-dose group dying after 8 weeks of administration, the high dose was adjusted to 525 mg/kg. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in male rats significantly increased in the medium- and high-dose groups, whereas female rats in these groups showed a significant rise in alkaline phosphatase (ALP) levels, accompanied by varying degrees of weight gain in the liver and lungs. Additionally, brownish-red pigment deposition was observed in hepatocytes and Kupffer cells across all dosing groups, along with foam cell deposition in the alveolar cavities. Concomitant toxicokinetics showed that the drug accumulated to some extent in the animals. Consequently, the liver and lungs were identified as potential target organs, and the no observed adverse effect level (NOAEL) was determined to be 175 mg/kg.

Inhalation exposure to cross-linked polyacrylic acid induces pulmonary disorders.

Organic polymers, widely used in food, daily necessities, and medicines, include cross-linked polyacrylic acid (CL-PAA), which has been reported to induce severe lung disease. While previous studies mainly used intratracheal instillation, our research focused on inhalation exposure to corroborate these findings. We conducted 5-day (short-term) and 13-week (subchronic) inhalation exposure studies with CL-PAA. In the short-term study, male F344 rats inhaled CL-PAA at 0.2, 2.0, or 20 mg/m³ for 6 hours/day over 5 days. Rats were dissected 3 days and 1 month post-exposure. In the subchronic study, rats inhaled CL-PAA at 0.2 or 2.0 mg/m³ for 6 hours/day, 5 days/week for 13 weeks, with dissections from 3 days to 6 months post-exposure. To investigate the mechanism of pulmonary disorders, an additional short-term study with 20 mg/m³ CL-PAA included intraperitoneal injections of the antioxidant N-acetylcysteine (NAC) (200 mg/kg) with dissection the day after exposure. Short-term exposure led to concentration-dependent increases in neutrophil influx, cytokine-induced neutrophil chemoattractant (CINC), total protein, lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in lung tissue. Histopathology showed concentration-dependent neutrophil infiltration. Subchronic exposure caused persistent increases in BALF total protein and lung HO-1, with ongoing neutrophil infiltration and fibrosis. NAC administration reduced neutrophils, total protein, LDH, and CINC in BALF, and HO-1 in lung tissue, improving histopathological findings. Inhalation of CL-PAA caused concentration-dependent lung inflammation and persistent fibrosis. The no observed adverse effect level (NOAEL) for chronic pulmonary disorders was 0.2 mg/m³. Oxidative stress linked to CL-PAA-induced inflammation was mitigated by NAC administration.

Analysis of Acute and Short-Term Fluoride Toxicity in Zebrafish Embryo and Sac–Fry Stages Based on Bayesian Model Averaging

Acute and short-term toxicity tests are foundational to toxicology research. These tests offer preliminary insights into the fundamental toxicity characteristics of the chemicals under evaluation and provide essential data for chronic toxicity assessments. Fluoride is a common chemical in aquatic environments; however, the findings of toxicological data, such as LC50 for aquatic organisms, often exhibit inconsistency. Consequently, this study employed zebrafish as a model organism during their early life stages to assess the acute and short-term toxicity of fluoride exposure. Bayesian model averaging was utilized to calculate the LC50/EC50 values and establish baseline concentrations. The results indicated a dose–response relationship between water fluoride concentration and harmful outcomes. The 20 mg/L group was identified as the lowest observed adverse effect level (LOAEL) for the majority of toxicity indicators and warrants special attention. Based on the BBMD model averages, the LC50 of fluoride for 1 to 5 days post-fertilization (dpf) zebrafish was 147.00, 80.80, 61.25, 56.50, and 37.50 mg/L, while the EC50 of cumulative malformation rate for 5 dpf zebrafish was 59.75 mg/L. As the benchmark response (BMR) increased, both the benchmark concentrations (BMCs) and benchmark dose levels (BMDLs) also increased. The research aims to provide essential data for the development of environmental water guidelines and to mitigate ecological risks associated with fluoride in aquatic ecosystems.

Short-term repeated oral intake of low dose cannabidiol: effects on liver enzyme activity and creatinine concentration during intense exercise.

The side effects and safety of cannabidiol (CBD) products are currently discussed in different contexts. Of all adverse effects, hepatotoxic effects have been reported most frequently in previous studies. However, the threshold for liver toxicity of CBD in humans is uncertain due to the lack of adequately designed studies in humans below the lowest observed adverse effect level (LOAEL) of 300 mg/day. In a randomised, three-arm, double-blind, crossover study, the effects of two CBD products (oil and solubilisate (solu) containing 60 mg CBD) were investigated during a high-intensity exercise protocol. Seventeen well-trained subjects (26±4 years, 181±5 cm, 85.6±9.4 kg) participated in the intervention. All subjects were healthy and had no physiological or psychological injuries. Participants were divided into advanced (Ad) and highly advanced (Hi) athletes … They consumed 60 mg of the compound in each microcycle over 7 days. To evaluate possible effects of short-term repeated use of 60 mg CBD on oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), gamma-glutamyl transferase (GGT) and creatinine (CREA) were analysed before and after each microcycle. GOT increased significantly in both performance levels of the placebo groups (Ad: p≤0.001; Hi: p=0.003). This increase was significantly reduced in the Ad group by both CBD oil (p=0.050, ES=0.66) and CBD solu (p=0.027; ES=0.75). GPT also increased significantly in both placebo groups (Ad: p≤0.001; Hi: p=0.032). This increase was significantly reduced in the Ad group by both CBD oil (p=0.027; ES=0.75) and CBD solu (p=0.023; ES=0.77). These effects were not observed in the Hi group for either parameter. Our results show that short-term repeated use of 60 mg CBD can inhibit exercise-induced liver activity. Furthermore, under the conditions of the present study, there was no evidence for hepatotoxic effects of oral intake of CBD at 60 mg for seven days. Nevertheless, despite the inhibitory effect on exercise-induced liver activity, the study provides evidence for the pharmacological effects of CBD on the liver even at low CBD dose and does not exclude adverse effects in sensitive individuals.

Safety evaluation of the food enzyme containing endo-polygalacturonase and β-glucosidase from the non-genetically modified Aspergillus tubingensis strain ARO.

The food enzyme containing endo-polygalacturonase and β-glucosidase (EC 3.2.1.15 and EC 3.2.1.21) is produced with the non-genetically modified Aspergillus tubingensis strain ARO by DSM Food Specialties B.V. The food enzyme was free from viable cells of the production organism. It is intended to be used in five food manufacturing processes. Dietary exposure was estimated to be up to 0.609 mg total organic solids (TOS)/kg body weight per day in European populations. Genotoxicity tests did not indicate a safety concern. The systemic toxicity was assessed by means of a repeated dose 90-day oral toxicity study in rats. The Panel identified a no observed adverse effect level of 2217 mg TOS/kg bw per day, the highest dose tested, resulting in a margin of exposure of at least 3640. A search for the homology of the amino acid sequence of the food enzymes to known allergens was made and four matches with food allergens and 22 matches with respiratory allergens were found. Known sources of food allergens were used in the food enzyme manufacturing process. The Panel considered that the risk of allergic reactions upon dietary exposure cannot be excluded. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns, under the intended conditions of use.

Revised dietary exposure assessment of the food enzyme triacylglycerol lipase from the genetically modified Aspergillus oryzae strain NZYM-FL.

The food enzyme triacylglycerol lipase (triacylglycerol acylhydrolase, EC 3.1.1.3) is produced with the genetically modified Aspergillus oryzae strain NZYM-FL by Novozymes A/S. A safety evaluation of this food enzyme was made previously, in which EFSA concluded that, under the intended conditions of use, this food enzyme did not give rise to safety concerns. Due to the implementation of a new methodology to estimate the dietary exposure to food enzymes in 2016, the European Commission requested EFSA to revise the exposure assessment of this food enzyme by using this new methodology. In this assessment, EFSA realigned the intended uses of this food enzyme to two food manufacturing processes and recalculated the dietary exposure. As the food enzyme-total organic solids (TOS) are removed in one food manufacturing process, the dietary exposure to the food enzyme-TOS was estimated only for the remaining process. It was calculated to be up to 0.492 mg TOS/kg body weight (bw) per day in European populations. When combined with the no observed adverse effect level previously reported (340 mg TOS/kg bw per day, the mid-dose tested), the Panel derived a margin of exposure of at least 691. Based on the revised exposure estimate, the margin of exposure calculated thereof and the previous evaluation, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.

Bacillus subtilis ZB423: 90-Day repeat dose oral (gavage) toxicity study in Wistar rats.

The novel genetically modified probiotic Bacillus subtilis ZB423 was assessed in a 90-day repeated-dose oral toxicity study adhering to Good Laboratory Practice (GLP) and Organization for Economic Cooperation and Development (OECD) guidelines. Spray-dried spores at a concentration of 1.1E12 CFU/g were administered at doses of 130, 260, and 519 mg/kg body weight/day correlating to 1.43 × 1011, 2.86 × 1011, and 5.71 × 1011 CFU/kg/day, respectively, by oral gavage to Wistar rats for a period of 90 consecutive days. Results showed no toxicologically relevant findings for B. subtilis ZB423 from measured parameters. The no observed adverse effect level (NOAEL) of B. subtilis ZB423 is 519 mg/kg body weight/day corresponding to 5.71 × 1011 CFU/kg/day for lyophilized B. subtilis ZB423 spores under the test conditions employed.

Environmental exposure to common pesticide induces synaptic deficit and social memory impairment driven by neurodevelopmental vulnerability of hippocampal parvalbumin interneurons.

Environmental exposure to pesticides at levels deemed safe by regulatory agencies has been linked to increased risk for neurodevelopmental disorders. Yet, the mechanisms linking exposure to these disorders remain unclear. Here, we show that maternal exposure to the pesticide deltamethrin (DM) at the no observed adverse effect level (NOAEL) disrupts long-term potentiation (LTP) in the hippocampus of adult male offspring three months after exposure, a phenotype absent in female offspring. Clonazepam, a GABAa receptor agonist, rescued this deficit, indicating impaired hippocampal GABAergic signaling. Recordings from CA1 pyramidal neurons, complemented by MALDI mass spectrometry imaging, showed an imbalance in excitatory/inhibitory tone. Using a combination of parvalbumin (PV)-Cre transgenic mice and hippocampal injection of designer receptors exclusively activated by designer drugs (DREADDs), we show that developmental DM exposure reduces hippocampal PV interneuron intrinsic firing. DREADD activation rescued both PV interneuron firing and LTP deficits. Complementary behavioral experiments revealed a deficit in social memory, a behavior relevant to autism spectrum disorder (ASD) symptomatology, which was restored by DREADD activation. Overall, these results establish a novel mechanistic link between maternal exposure to DM at the NOAEL and known cellular, circuital, and behavioral vulnerabilities, indicating it is a potential driver in the exposome of ASD.

Life Course Considerations in Environmental Health: Developmental Neurotoxicity of Domoic Acid at Doses Below Acute Effect Levels in Adult Humans.

Current US federal action levels for domoic acid (DA) in seafood are based on acute toxicity observed in exposed adult humans. Life course considerations have not been incorporated. The potential for developmental neurotoxicity (DNT) at permissible DA levels has previously been noted, but not methodically assessed. Studies of DNT following DA exposure in experimental and wild animals were identified through a comprehensive search strategy. Evidence from papers meeting inclusion criteria was evaluated for specific outcomes reported for doses at which adverse effects were observed. Exposure levels associated with DNT were compared with those known to cause adult toxicity. The findings are discussed in the context of the well-characterized mechanism of DA neurotoxicity, as well as the toxicokinetics of DA across species and life stages. DNT outcomes were reported with a no observed adverse effect level (NOAEL) 10 times lower than the NOAEL of 0.75 mg DA/kg for acute effects in adults. Apart from reviewing current regulatory action levels, public health outreach messaging to health care professionals and sensitive populations, such as pregnant or breastfeeding women, should be considered as a means of increasing awareness about risk for DNT from consumption of potentially DA-contaminated seafood.

Revised dietary exposure assessment of the food enzyme triacylglycerol lipase from the genetically modified Aspergillus oryzae strain NZYM-LH.

The food enzyme triacylglycerol lipase (triacylglycerol acylhydrolase, EC 3.1.1.3) is produced with the genetically modified Aspergillus oryzae strain NZYM-LH by Novozymes A/S. A safety evaluation of this food enzyme was made previously, in which EFSA concluded that, under the intended conditions of use, this food enzyme did not give rise to safety concerns. Due to the implementation of a new methodology to estimate the dietary exposure to food enzymes in 2016, the European Commission requested EFSA to revise the exposure assessment of this food enzyme by using this new methodology. In this assessment, EFSA realigned the intended uses of this food enzyme to two food manufacturing processes and recalculated the dietary exposure. Dietary exposure to the food enzyme-TOS was calculated to be up to 0.284 mg TOS/kg body weight (bw) per day in European populations. When combined with the no observed adverse effect level previously reported (1080 mg TOS/kg bw per day, the highest dose tested), the Panel derived a margin of exposure of at least 3803. Based on the revised exposure estimate, the margin of exposure calculated thereof and the previous evaluation, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.

Safety evaluation of the food enzyme fructan β-fructosidase from the genetically modified Trichoderma reesei strain AR-577.

The food enzyme fructan β-fructosidase (β-d-fructan fructohydrolase; EC 3.2.1.80) is produced with the genetically modified Trichoderma reesei strain AR-577 by AB Enzymes GmbH. The genetic modifications do not give rise to safety concerns. The food enzyme is free from viable cells of the production organism and its DNA. The food enzyme is intended to be used in the processing of cereals and other grains for the production of baked products and cereal-based products other than baked. Dietary exposure was estimated to be up to 0.181 mg total organic solids (TOS)/kg body weight (bw) per day in European populations. Genotoxicity tests did not indicate a safety concern. The systemic toxicity was assessed by means of a repeated dose 90-day oral toxicity study in rats. The Panel identified a no observed adverse effect level of 1000 mg TOS/kg bw per day, the highest dose tested, which when compared with the estimated dietary exposure, results in a margin of exposure of at least 5495. A search for homology of the amino acid sequence of the food enzyme to known allergens was made and no match was found. A known source of food allergens was used in the food enzyme manufacturing process. The Panel considered that the risk of allergic reactions upon dietary exposure cannot be excluded but the likelihood is low. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns, under the intended conditions of use.

Revised dietary exposure assessment of the food enzyme endo 1,4-β-xylanase from the genetically modified Aspergillus oryzae strain NZYM-FB.

The food enzyme endo 1,4-β-xylanase (4-β-d-xylan xylanohydrolase, EC 3.2.1.8) is produced with the genetically modified Aspergillus oryzae strain NZYM-FB by Novozymes A/S. A safety evaluation of this food enzyme was made previously, in which EFSA concluded that, under the intended conditions of use, this food enzyme did not give rise to safety concerns. Due to the implementation of a new methodology to estimate the dietary exposure to food enzymes in 2016, the European Commission requested EFSA to revise the exposure assessment of this food enzyme by using this new methodology. In this assessment, EFSA realigned the intended uses of this food enzyme to five food manufacturing processes and recalculated the dietary exposure. As the food enzyme-total organic solids (TOS) are removed in two food manufacturing processes, the dietary exposure to the food enzyme-TOS was estimated only for the remaining three processes. It was calculated to be up to 0.383 mg TOS/kg body weight (bw) per day in European populations. When combined with the no observed adverse effect level previously reported (106 mg TOS/kg bw per day, the lowest dose tested), the Panel derived a margin of exposure of at least 277. Based on the revised exposure estimate, the margin of exposure calculated thereof and the previous evaluation, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.

Revised dietary exposure assessment of the food enzyme triacylglycerol lipase from the genetically modified Aspergillus oryzae strain NZYM-AL.

The food enzyme triacylglycerol lipase (triacylglycerol acylhydrolase, EC 3.1.1.3) is produced with the genetically modified Aspergillus oryzae strain NZYM-AL by Novozymes A/S. A safety evaluation of this food enzyme was made previously, in which EFSA concluded that, under the intended conditions of use, this food enzyme did not give rise to safety concerns. Due to the implementation of a new methodology to estimate the dietary exposure to food enzymes in 2016, the European Commission requested EFSA to revise the exposure assessment of this food enzyme by using this new methodology. In this assessment, EFSA realigned the intended uses of this food enzyme to four food manufacturing processes. The dietary exposure was calculated to be up to 0.089 mg TOS/kg body weight (bw) per day in European populations. When combined with the no observed adverse effect level previously reported (49.1 mg TOS/kg bw per day, the lowest dose tested), the Panel derived a margin of exposure of at least 552. Based on the revised exposure estimate, the margin of exposure calculated thereof and the previous evaluation, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.

Safety evaluation of the food enzyme protein‐glutamine γ‐glutamyltransferase from the non‐genetically modified Streptomyces mobaraensis strain AE‐BTG

Abstract The food enzyme protein‐glutamine γ‐glutamyltransferase (protein‐glutamine: amine γ‐glutamyltransferase; EC 2.3.2.13) is produced with the non‐genetically modified S. mobaraensis strain AE‐BTG by AJINOMOTO EUROPE SAS. The food enzyme was free from viable cells of the production organism. It is intended to be used in nine food manufacturing processes. Dietary exposure to the food enzyme–total organic solids (TOS) was estimated to be up to 0.398 mg TOS/kg body weight (bw) per day in European populations. Genotoxicity tests did not indicate a safety concern. The systemic toxicity was assessed by means of a repeated dose 90‐day oral toxicity study in rats. The Panel identified a no observed adverse effect level of 538 mg TOS/kg bw per day which when compared with the estimated dietary exposure, resulted in a margin of exposure of at least 1351. A search for homology of the amino acid sequence of the food enzyme to known allergens was made and no match was found. Known sources of food allergens were used in the food enzyme manufacturing process, and the Panel considered that the risk of allergic reactions upon dietary exposure to this food enzyme cannot be excluded. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.

Safety evaluation of the food enzyme endo-1,4-β-xylanase from the non-genetically modified Trichoderma citrinoviride strain HBI-TX01.

The food enzyme endo-1,4-β-xylanase (4-β-d-xylan xylanohydrolase; EC 3.2.1.8) is produced with Trichoderma citrinoviride strain HBI-TX01 by HBI Enzymes Inc. The food enzyme is free from viable cells of the production organism. It is intended to be used in four food manufacturing processes. Since residual amounts of food enzyme-total organic solids (TOS) are removed in two food manufacturing processes, dietary exposure was calculated only for the remaining two processes. It was estimated to be up to 1.488 mg TOS/kg body weight (bw) per day in European populations. Genotoxicity tests did not indicate a safety concern. The systemic toxicity was assessed by means of a repeated dose 90-day oral toxicity study in rats. The Panel identified a no observed adverse effect level of 1101 mg TOS/kg bw, the highest dose tested, which when compared with the estimated dietary exposure, resulted in a margin of exposure of at least 740. A search for homology of the amino acid sequence of the food enzyme to known allergens was made and no match was found. Known sources of food allergens were used in the manufacturing process. The Panel considered that the risk of allergic reactions upon dietary exposure to this food enzyme cannot be excluded, but the likelihood is low. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns, under the intended conditions of use.

Safety Assessment of Butyric Acid-Rich Triglyceride Oil: A Novel Palatable Formulation of Butyrate for the Pediatric Population.

A novel, palatable butyric acid-rich triglyceride oil has been developed and is available as a food supplement for adults in the United States and Canada. A program of safety studies was conducted with butyric acid-rich triglyceride oil for the pediatric population. The oil was tested in a microbial reverse mutation assay Ames Test OECD471 (Organisation for Economic Co-operation and Development) in which all bacterial strains showed negative responses over the complete dose range in two independently repeated experiments. All values were within the laboratory historical control data ranges. Further, data from the human lymphocyte micronucleus assay (OECD487) in the presence or absence of a metabolic activator (S9-mix), the oil did not induce a biologically relevant increase in the number of binucleated cells with micronuclei; therefore, the oil is considered not to be clastogenic or aneugenic. In a 90-day rat repeat dose toxicity study (OECD408), there were no unscheduled deaths, no treatment-related clinical signs, or effects on body weight and body weight gain, food consumption, ophthalmology, FOB parameters (including motor activity), clinical chemistry including thyroid hormones, and sperm parameters. There were no related organ weight changes, macroscopic or microscopic findings. In an extended one-generation reproductive toxicology study (EOGRTS) OECD443, there were no biologically important changes in body weight or body weight gain observed in the P generation male rats during the dosing period. At the end of the dosing period, the mean body weights in the male rats were 98% and 98% of the control group value in the 3720 and 4650 mg/kg/day dose groups, respectively. No biologically important changes in maternal body weights or body weight gains were observed during the premating, gestation, or lactation periods at dose levels up to and including 4650 mg/kg/day. Clinical signs observed in the P generation males and females were within the historical data ranges and not test substance related. There were no test substance-related changes in any other tested outcomes analyzed in the P generation males and females at doses up to and including 4650 mg/kg/day. In the F1 Generation, preweaning clinical signs observed in the males and females were within the historical data ranges and not test article related. There were no statistically significant or biologically relevant abnormalities in any of the parameters analyzed throughout the preweaning period at maternal dose levels up to and including 4650 mg/kg/day. In the postweaning period, there were also no clinical signs observed in males and females; all were within the historical data ranges and not test article related. There were no statistically significant or biologically relevant abnormalities in any of the parameters analyzed throughout the postweaning period at maternal dose levels up to and including 4650 mg/kg/day including body weights. Taken together, data from these toxicity studies show that butyric acid-rich triglyceride oil is extremely safe with a "no observed adverse effect level" (NOAEL) considered to be 4650 mg/kg/day, the highest dose tested.

Uncertainty Analysis in Ecological Risk Assessment: Sensitivity Analysis of Different Exposure Models

Ecological risk assessments are used for decision making regarding releasing new products to market as well as remedial action required to address contamination at legacy sites. Uncertainty analysis is considered a key part of the process (USEPA 1997) but assessments seldom address uncertainty quantitatively. Key sources of uncertainty include: Sampling and analytical variability (soil/ sediment matrix, lab error), Choice of “Indicator” Species as Target Receptors for Different Exposure Pathways, Sample size. Bioaccumulation and Food Chain Modeling involve assumptions and uncertainty including: Linear assumption of bioaccumulation and selection of bioaccumulation factors; Other model inputs such as: Home range size, Dietary percentages, Body Weights, Ingestion Rate; Literature data on effects, Use of No Observed Adverse Effects Level (NOAEL) or Lowest Observed Adverse Effects Level (LOAEL) as a decision point. Toxicity testing where employed brings its own set of assumptions and interpretation that are subject to uncertainty. These include: Use of single organism, Correlation (or lack thereof) with Contaminants of Concern, Contaminant mixtures, and Reference area selection. Keywords: Ecotoxicology, Risk Assessment, Ecology

Toxicity study of silica nanoparticles following 94-day repeated oral administration in Sprague Dawley rats.

This study was designed to investigate the toxic response of Sprague Dawley (SD) rats following oral administration of different doses of silica nanoparticles (SiNPs) for 94 consecutive days, as well as the recovery after 30 days of withdrawal. Rats were orally administered SiNPs at dosages of 0, 125, 250, and 500mg/kg /day once a day for 94 continuous days. By the end of the study, there were no fatalities in any of the experimental animals that received SiNPs orally. Under the tested doses, no adverse effects related to SiNPs treatment were observed in a comprehensive assessment of several dimensions, including clinical signs, body weight changes, food consumption, hematological parameters, blood biochemical indices, urinalysis, organ weights and coefficients, and gross and histopathology. Based on the current study results, the No Observed Adverse Effect Level (NOAEL) for repeated oral administration of SiNPs in rats for 94 consecutive days was designated as 500mg/kg/day.

Evaluation of acute and 28-day repeated dose toxicity of Tolypocladium sinense soft capsule in Sprague-Dawley rats

Tolypocladium sinense is a new asexual strain isolated from natural Cordyceps sinensis. The mycelium produced by its fermentation culture has similar chemical components and pharmacological effects to C. sinensis. T. sinense soft capsule is primarily prepared from T. sinense mycelium, which is mainly used for the treatment of body damage induced by low-dose ionizing radiation. However, its potential toxicity remains unclear. This study was designed to assess the toxicological characteristics of T. sinense soft capsules through acute and 28-day repeated dose toxicity studies. In the acute toxicity study, no toxic symptoms or mortality were observed in rats following a single oral administration of 10 000 mg/kg of T. sinense soft capsules. The maximum tolerated dose for a single oral dose of T. sinense soft capsules in rats was over 10 000 mg/kg. During the repeated dose toxicity test, oral administration of 90, 360, and 1440 mg/kg/day of T. sinense soft capsules for 28 consecutive days did not lead to significant toxic effects in rats. The no observed adverse effect level in rats surpassed 1440 mg/kg/day. These results provide preliminary evidence that T. sinense soft capsules are relatively safe.