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1.
BMC Pharmacol Toxicol ; 25(1): 62, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39243062

RESUMO

Higher olefins (HO) are a category of unsaturated hydrocarbons widely used in industry applications to make products essential for daily human life. Establishing safe exposure limits requires a solid data matrix that facilitates understanding of their toxicological profile. This in turn allows for data to be read across to other members of the category, which are structurally similar and have predictable physico-chemical properties. Five independent subchronic oral toxicity studies were conducted in Wistar rats with Oct-1-ene, Nonene, branched, Octadec-1-ene, Octadecene and hydrocarbon C12-30, olefin-rich, ethylene polymn. by product, at doses ranging from 20 to 1000 mg/kg bw. These HO were selected considering gut absorption, carbon chain length, double-bond position and carbon backbone structural variations. Generally, limited and non-adverse toxicity effects were observed at the end of the treatment for short carbon chain HO. For instance, alpha 2u-globulin nephropathy in the male rats and liver hypertrophy. No clear trend in systemic toxicity was linked to the double-bond position. Key factors for hazard assessment include absorption, carbon chain length, and branching, with Nonene, branched, identified as the worst-case substance. Taken together, the no observed adverse effect level (NOAEL) of each HO in these subchronic studies was set at the highest dose tested.


Assuntos
Alcenos , Ratos Wistar , Testes de Toxicidade Subcrônica , Animais , Masculino , Alcenos/toxicidade , Feminino , Ratos , Nível de Efeito Adverso não Observado
2.
Regul Toxicol Pharmacol ; 152: 105685, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39147262

RESUMO

The mission of the Force Health Protection (FHP) program of the U.S. Air Force (USAF), sustaining the readiness of warfighters, relies on determinations of acceptable levels of exposure to a wide array of substances that USAF personnel may encounter. In many cases, exposure details are limited or authoritative toxicity reference values (TRVs) are unavailable. To address some of the TRV gaps, we are integrating several approaches to generate health protective exposure guidelines. Descriptions are provided for identification of chemicals of interest for USAF FHP (467 to date), synthesis of multiple TRVs to derive Operational Exposure Limits (OpELs), and strategies for identifying and developing candidate values for provisional OpELs when authoritative TRVs are lacking. Rodent bioassay-derived long-term Derived No Effect Levels (DNELs) for workers were available only for a minority of the substances with occupational TRV gaps (19 of 84). Additional occupational TRV estimation approaches were found to be straightforward to implement: Tier 1 Occupational Exposure Bands, cheminformatics approaches (multiple linear regression and novel nearest-neighbor approaches), and empirical adjustment of short term TRVs. Risk assessors working in similar contexts may benefit from application of the resources referenced and developed in this work.


Assuntos
Militares , Exposição Ocupacional , Humanos , Exposição Ocupacional/normas , Exposição Ocupacional/prevenção & controle , Exposição Ocupacional/efeitos adversos , Valores de Referência , Animais , Medição de Risco , Estados Unidos , Nível de Efeito Adverso não Observado , Testes de Toxicidade/normas , Testes de Toxicidade/métodos , Substâncias Perigosas/toxicidade
3.
Regul Toxicol Pharmacol ; 152: 105684, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39151719

RESUMO

Allyl alcohol (C3H6O; prop-2-en-1-ol; CAS RN 107-18-6; EINECS 203-470-7) is used as an intermediate/monomer in polymerization reactions producing chemicals/optical resins or as a coupling/cross-linking agent for unsaturated polyester and alkyd resins. Human exposure to allyl alcohol (AA) is restricted to workplace manufacturing facilities where it is used in enclosed systems, which limits release and impact on environmental receptors. To address regulatory questions about possible developmental toxicity, two OECD Guideline studies were conducted. A rat developmental toxicity study found fetal and maternal toxicity, in the form of resorptions and decreased body weight and food consumption, but no teratogenic effects. A rabbit developmental toxicity study was subsequently conducted upon request by the European Chemical Agency in 2011 under the REACH program and likewise reported maternal toxicity in the form of reductions in body weight gain and food consumption, but neither fetal toxicity or teratogenic effects. The results of both studies are presented and compared in this paper. Based on our review of the collective results of these studies, AA is considered non-teratogenic, yet does elicit increased post-implantation loss and reduced fetal body weight, possibly resulting from concomitant maternal toxicity. Based on the results of these studies, a maternal and developmental toxicity No Observed Adverse Effect Level of 10 mg/kg/day was apparent for both species.


Assuntos
Nível de Efeito Adverso não Observado , Propanóis , Animais , Feminino , Coelhos , Ratos , Gravidez , Propanóis/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Masculino , Testes de Toxicidade/métodos , Exposição Materna/efeitos adversos
4.
Regul Toxicol Pharmacol ; 152: 105686, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39151720

RESUMO

Force Health Protection programs in the U.S. Air Force endeavor to sustain the operational readiness of the warfighters. We have previously identified hundreds of chemical substances of interest and toxicity reference value (TRV) knowledge gaps that constrain risk based-decision-making for potential exposures. Multiple approaches to occupational TRV estimation were used to generate possible guideline values for 84 compounds (18% of the substances of interest). These candidate TRVs included values from international databases, chemical similarity (nearest neighbor) approaches, empirical adjustments to account for duration differences, quantitative activity relationships, and thresholds of toxicological concern. This present work describes derivation of provisional TRVs from these candidate values. Rodent bioassay-derived long-term worker Derived No-Effect Levels (DNELs) were deemed presumptively the most reliable, but only 19 such DNELs were available for the 84 substances with TRV gaps. In the absence of DNELs, the quality of the approaches and consistency among candidate values were key elements of the weight of evidence used to select the most suitable guideline values. The use of novel nearest-neighbor approaches, empirical adjustment of short term TRVs, and occupational exposure bands were found to be options that would allow occupational TRV estimation with reasonable confidence for nearly all substances evaluated.


Assuntos
Nível de Efeito Adverso não Observado , Exposição Ocupacional , Exposição Ocupacional/normas , Exposição Ocupacional/prevenção & controle , Exposição Ocupacional/efeitos adversos , Humanos , Animais , Valores de Referência , Guias como Assunto , Medição de Risco , Militares , Substâncias Perigosas/toxicidade , Estados Unidos , Saúde Ocupacional/normas , Testes de Toxicidade/normas
5.
Arch Toxicol ; 98(10): 3269-3288, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39096368

RESUMO

Despite several screening levels for NDMA reported in water, soil, air, and drugs, the human risk assessment using biomonitoring concentrations has not been performed. In this study, gender-specific exposure guidance values were determined in humans, then biomonitoring measurements in healthy Korean subjects (32 men and 40 women) were compared to the exposure guidance values to evaluate the current exposure level to NDMA. For the human risk assessment of NDMA, the gender-specific physiologically based pharmacokinetic (PBPK) model was developed in humans using proper physiological parameters, partition coefficients, and biochemical parameters. Using the PBPK model, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty on the single model predictions. The PBPK modeling and Monte Carlo simulation allowed the estimation of the relationship between external dose and blood concentration for the risk assessment. The procedure for the human risk assessment was summarized as follows: (1) estimating a steady-state blood concentration (Cavg) corresponding to the daily no observed adverse effect level (NOAEL) administration in rats; (2) applying uncertainty factors (UFs) for deriving the human Cavg; (3) determining the exposure guidance values as screening criteria; (4) interpreting the human biomonitoring measurements by forward and reverse dosimetry approaches. Using the biomonitoring concentrations, current daily exposures to NDMA were estimated to be 3.95 µg/day/kg for men and 10.60 µg/day/kg for women, respectively. The result of the study could be used as a basis for implementing further risk management and regulatory decision-making for NDMA.


Assuntos
Monitoramento Biológico , Dimetilnitrosamina , Modelos Biológicos , Método de Monte Carlo , Humanos , Medição de Risco , Masculino , Feminino , Monitoramento Biológico/métodos , Dimetilnitrosamina/toxicidade , Dimetilnitrosamina/farmacocinética , Adulto , Nível de Efeito Adverso não Observado , Fatores Sexuais , Animais , Pessoa de Meia-Idade , Adulto Jovem , Ratos , República da Coreia , Exposição Ambiental/efeitos adversos
6.
Hum Exp Toxicol ; 43: 9603271241269022, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39101688

RESUMO

BACKGROUND: One of the challenges to using some flavor chemicals in aerosol products is the lack of route of administration specific toxicology data. METHODS: Flavor chemicals (88) were divided into four different flavor mixtures based upon chemical compatibility and evaluated in 2-week dose-range-finding and subsequent 90-day nose-only rodent inhalation studies (OECD 413 and GLP compliant). Sprague-Dawley rats were exposed to vehicle control or one of three increasing concentrations of each flavor mixture. RESULTS: In the dose-range-range-finding studies, exposure to flavor mixture four resulted in adverse nasal histopathology in female rats at the high dose, resulting in this flavor mixture not being evaluated in a 90-day study. In the 90-day studies daily exposures to the three flavor mixtures did not induce biologically meaningful adverse effects (food consumption, body weights, respiratory physiology, serum chemistry, hematology, coagulation, urinalysis, bronchoalveolar lavage fluid analysis and terminal organ weights). All histopathology findings were observed in both vehicle control and flavor mixture exposed animals, with similar incidences and/or severities, and therefore were not considered flavor mixture related. CONCLUSION: Based on the absence of adverse effects, the no-observed-adverse-effect concentration for each 90-day inhalation study was the highest dose tested, 2.5 mg/L of the aerosolized high dose of the three flavor mixtures.


Assuntos
Aromatizantes , Nível de Efeito Adverso não Observado , Ratos Sprague-Dawley , Animais , Feminino , Aromatizantes/toxicidade , Masculino , Exposição por Inalação , Ratos , Relação Dose-Resposta a Droga , Administração por Inalação , Ingestão de Alimentos/efeitos dos fármacos
7.
Food Chem Toxicol ; 191: 114846, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38960084

RESUMO

2,4-dinitroaniline (2,4-D), a widely used dye intermediate, is one of the typical pollutants, and its potential health risks and toxicity are still largely unknown. To explore its subchronic oral toxicity, Wistar rats (equal numbers of males and females) were used as test animals, and a 90-day oral dosing experiment was conducted, divided into control group, low-dose group (0.055 mg/kg), medium-dose group (0.22 mg/kg), medium-high dose group (0.89 mg/kg), and high-dose group (3.56 mg/kg). The body weight data, clinical appearance, and drug reactions of each test rat within 90 days of dosing were recorded; morning urine samples were collected four times to test for eight urinary indicators; blood samples were collected to test for nineteen hematological indicators and sixteen biochemical indicators; tissue samples were collected for pathological analysis; moreover, the no-observed-adverse-effect level (NOAEL) was determined, and the benchmark dose method was used to support this determination and provide a statistical estimate of the dose corresponding. The results indicated that the chronic toxicity of 2,4-dinitroaniline showed certain gender differences, with the eyes, liver, and kidneys being the main potential target organs of toxicity. Moreover, the subchronic oral NOAEL for 2,4-dinitroaniline was determined to be 0.22 mg/kg body weight (0.22 mg/kg for males and 0.89 mg/kg for females), and a preliminary calculation of the safe exposure limit for human was 0.136 mg/kg. The research results greatly enriched the safety evaluation data of 2,4-dinitroaniline, contributing to a robust scientific foundation for the development of informed safety regulations and public health precautions.


Assuntos
Compostos de Anilina , Nível de Efeito Adverso não Observado , Ratos Wistar , Testes de Toxicidade Subcrônica , Animais , Compostos de Anilina/toxicidade , Masculino , Feminino , Administração Oral , Ratos , Relação Dose-Resposta a Droga , Peso Corporal/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos
8.
Int J Toxicol ; 43(5): 503-510, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39037331

RESUMO

Etripamil is a calcium channel blocker currently in Phase 3 trials for the treatment of paroxysmal supraventricular tachycardia (PSVT). Systemic and local toxicity following once-weekly intranasal administration of etripamil was evaluated in cynomolgus macaques to support clinical development. Groups of animals (N = 8, 4 males and 4 females) were administered etripamil into the left nostril weekly at dose levels of 0 (vehicle), 1.9, 3.8, or 5.7 mg/kg/dose for 26 doses. Persistence, reversibility, and progression of findings were examined following a 28-day recovery period. Clinical signs were transient and were related to the intranasal administration (e.g., nasal discharge, sneezing, etc.) of etripamil. There were no macroscopic or systemic microscopic findings at any dose. Etripamil-related adaptive and reactive local changes affecting the nasal cavity, larynx, and nasopharynx were observed at ≥1.9 mg/kg/dose. Minimal to severe dose-dependent nasal epithelial damage was observed, mainly affecting respiratory and transitional epithelium. Following the 28-day recovery period, microscopic changes were confined to the left nasal cavity and nasopharynx. These changes were significantly lower in incidence and severity, with noticeable reversal of the adaptive and reactive changes, indicating partial to complete recovery of the epithelial lining. Based on the lack of systemic toxicity and the minimal and transient nasal changes, the systemic, no observable adverse effect level (NOAEL) of etripamil in monkeys was the high dose, 5.7 mg/kg/dose. The NOAEL for local toxicity was 1.9 mg/kg/dose. Collectively, these data support further study of etripamil in human trials as a potential treatment for PSVT.


Assuntos
Bloqueadores dos Canais de Cálcio , Macaca fascicularis , Sprays Nasais , Animais , Masculino , Feminino , Bloqueadores dos Canais de Cálcio/toxicidade , Bloqueadores dos Canais de Cálcio/administração & dosagem , Taquicardia Supraventricular/tratamento farmacológico , Taquicardia Supraventricular/induzido quimicamente , Administração Intranasal , Avaliação Pré-Clínica de Medicamentos , Nível de Efeito Adverso não Observado , Humanos , Relação Dose-Resposta a Droga
9.
J Pharm Sci ; 113(9): 2895-2903, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38945365

RESUMO

Interspecies scaling of the pharmacokinetics (PK) of CB 4332, a 150 kDa recombinant complement factor I protein, was performed using traditional and model-based approaches to inform first-in-human dose selection. Plasma concentration versus time data from four preclinical PK studies of single intravenous and subcutaneous (SC) CB 4332 dosing in mice, rats and nonhuman primates (NHPs) were modeled simultaneously using naive pooling including allometric scaling. The human-equivalent dose was calculated using the preclinical no observed adverse effect level (NOAEL) as part of the dose-by-factor approach. Pharmacokinetic modeling of CB 4332 revealed species-specific differences in the elimination, which was accounted for by including an additional rat-specific clearance. Signs of anti-drug antibodies (ADA) formation in all rats and some NHPs were observed. Consequently, an additional ADA-induced clearance parameter was estimated including the time of onset. The traditional dose-by-factor approach calculated a maximum recommended starting SC dose of 0.9 mg/kg once weekly, which was predicted it to result in a trough steady-state concentration lower than the determined efficacy target range for CB 4332 in humans. Model simulations predicted the efficacy target range to be reached using 5 mg/kg once weekly SC dosing.


Assuntos
Especificidade da Espécie , Animais , Humanos , Ratos , Camundongos , Modelos Biológicos , Masculino , Feminino , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/administração & dosagem , Nível de Efeito Adverso não Observado , Relação Dose-Resposta a Droga , Ratos Sprague-Dawley , Injeções Subcutâneas
10.
Food Chem Toxicol ; 191: 114839, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38942165

RESUMO

The human gut microbiome plays a crucial role in immune function. The synbiotic consortium or Defined Microbial Assemblage™ (DMA™) Medical Food product, SBD121, consisting of probiotic microbes and prebiotic fibers was designed for the clinical dietary management of rheumatoid arthritis. A 28-day repeated administration study was performed to evaluate the oral toxicity of SBD121 in male and female rats (age/weight at study start: 60 days/156-264 g) administered levels of 0, 4.96 x 1010, 2.48 x 1011, or 4.96 x 1011 colony forming units (CFU)/kg-bw. No treatment related changes were observed in ophthalmological effects, mortality, morbidity, general health and clinical observations, urinalysis, hematology, serum chemistry, absolute or relative organ weights, gross necropsy, or histopathology. A significant decrease in body weight was reported in females in the low and high-concentration groups, which corresponded in part with a significant decrease in food consumption. Results of the functional observation battery indicated front grip strength was significantly greater in the high-concentration males compared to the controls; however, this effect was not considered adverse. Based on these findings, the administration of the Medical Food SBD121 to male and female rats has a no-observable adverse effect level (NOAEL) at the highest level tested of 4.96 x 1011 CFU/kg-bw.


Assuntos
Inocuidade dos Alimentos , Simbióticos , Animais , Masculino , Feminino , Ratos , Simbióticos/administração & dosagem , Ratos Sprague-Dawley , Peso Corporal/efeitos dos fármacos , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos
11.
Toxicol Ind Health ; 40(9-10): 497-503, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38836427

RESUMO

Bis-(2-Chloroisopropyl) ether (BCIPE) was used as a solvent for fats, greases, paint, varnish removers, and in spotting and cleaning solutions. However, BCIPE has not been commercially manufactured or used for numerous years. In experimental animal studies, BCIPE is moderately toxic following acute oral, dermal, and inhalation routes of exposure. BCIPE is a severe eye irritant but not a dermal irritant or dermal sensitizer. BCIPE was not genotoxic or mutagenic in in vitro and in vivo assays; it was not toxic in a 3-generation reproductive dietary study in rats. Short-term, repeated inhalation and oral exposure in rats produced increased liver and kidney weights and congestion; dermal exposure in rabbits did not produce any observable adverse effects. BCIPE did not produce a statistically significant increase in tumors in two different 2-year dietary studies in mice and rats. In mice, technical grade BCIPE produced increased incidences of alveolar/bronchiolar adenomas in females, hepatocellular carcinomas in males, and a low incidence of forestomach hyperplasia (in both sexes at the high-dose). Further investigation with technical grade BCIPE concluded that these effects were species- and dose-specific with limited, if any, relevance to humans. The NOAEL of 400 ppm (15 mg/kg/day) from the 2-year dietary study in female rats was considered the point of departure for the health-based WEEL derivation. After adjustment for duration of exposure, interindividual variability, and intraindividual variability, an 8-h time-weighted average (TWA) WEEL value of 3 ppm (21 mg/m3) was derived. This exposure limit is expected to provide a significant margin of safety against any potential adverse health effects in workers.


Assuntos
Nível de Efeito Adverso não Observado , Animais , Ratos , Feminino , Coelhos , Masculino , Humanos , Camundongos , Solventes/toxicidade , Relação Dose-Resposta a Droga , Exposição Ocupacional/efeitos adversos , Éteres/toxicidade
12.
Reprod Toxicol ; 128: 108649, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38942216

RESUMO

We investigated the level of protection of reproductive and developmental toxicity offered through occupational exposure limits (OELs) and Derived No-Effect Levels for workers' inhalation exposure (wDNELs). We compared coverage of substances that have a harmonised classification as reproductive toxicant 1 A or 1B (Repr.1 A/B), numerical values and scientific basis of 12 lists of OELs and wDNELs from REACH Registrants' and the Committee for Risk Assessment. Across the 14 sources of OELs and wDNELs, 53 % of the Repr1A/B-substances had at least one exposure limit (counting groups of metals as one entry). Registrants' wDNELs covered the largest share, 40 %. The numerical values could be highly variable for the same substance across the lists. How often reproductive toxicity is identified as the critical effect varies between the examined lists, both due to different assessments of the same substance and different substance coverage. Reviewing the margin of safety to reproductive toxicity cited in the documents, we found that 15 % of safety margins were lower to reproductive toxicity than the critical effect. To conclude, neither the REACH nor work environment legislation supply wDNELs or OELs for a substantial share of known reproductive toxicants. EU OELs cover among the fewest substances in the range, and in many cases national OELs or wDNELs are set at more conservative levels.


Assuntos
Exposição Ocupacional , Reprodução , Humanos , Reprodução/efeitos dos fármacos , Medição de Risco , Nível de Efeito Adverso não Observado , Exposição por Inalação/efeitos adversos , Animais , Substâncias Perigosas/toxicidade
13.
Int J Toxicol ; 43(5): 472-490, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38897632

RESUMO

The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUClast and Cmax at Day 91) was greater in males than females, suggesting sex differences. AUClast and Cmax at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed Tmax and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.


Assuntos
Rabeprazol , Bicarbonato de Sódio , Animais , Cães , Rabeprazol/farmacocinética , Rabeprazol/toxicidade , Rabeprazol/administração & dosagem , Masculino , Feminino , Administração Oral , Bicarbonato de Sódio/farmacocinética , Bicarbonato de Sódio/toxicidade , Bicarbonato de Sódio/administração & dosagem , Toxicocinética , Nível de Efeito Adverso não Observado , Área Sob a Curva , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Testes de Toxicidade Subcrônica
14.
Artigo em Inglês | MEDLINE | ID: mdl-38870606

RESUMO

Jinmao Jiedu granule is a Chinese medicine preparation consisting of Actinidia valvata Dunn, Salvia chinensis Benth, Iphigenia indica Kunth, and chicken gizzard. For many years, it has been employed in adjuvant therapy for cancer, especially liver cancer. However, the potential toxicity of the granule has not been reported. The present study aimed to assess the repeated-dose toxicity of orally administered Jinmao Jiedu granules for Sprague-Dawley (SD) rats. SD rats were orally administered Jinmao Jiedu granules at doses of 2.85, 5.70, and 11.40 g/kg in a 28-day subchronic toxicity study. No adverse clinical signs associated with treatment were noted throughout the experiment. There were no treatment-related toxicity alterations in body weight, hematology, clinical biochemistry, urinalysis, necropsy, and histopathology in rats compared with the control group. The No Observed Adverse Effect Level (NOAEL) of the Jinmao Jiedu granule was higher than 11.40 g/kg/day in rats.


Assuntos
Medicamentos de Ervas Chinesas , Ratos Sprague-Dawley , Animais , Medicamentos de Ervas Chinesas/toxicidade , Medicamentos de Ervas Chinesas/administração & dosagem , Ratos , Masculino , Administração Oral , Feminino , Nível de Efeito Adverso não Observado , Peso Corporal/efeitos dos fármacos , Testes de Toxicidade Subcrônica , Tamanho do Órgão/efeitos dos fármacos
15.
Food Chem Toxicol ; 190: 114843, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38944142

RESUMO

Mulberry (Morus alba L) fruit is traditionally used in Chinese medicine and has several beneficial effects, such as hypoglycemic, hypolipidemic, and anti-oxidative effects. We previously developed the synbiotic mulberry (SM) containing probiotic Lactobacilli, prebiotic inulin, and mulberry powder. In food supplement development, toxicity is the most important criterion in food and drug regulations before commercialization. Thus, this study aimed to investigate the subchronic toxicity of SM in male and female Wistar rats to evaluate its biosafety. The subchronic toxicity study was conducted by daily oral administration of SM at doses of 250, 500, and 1000 mg/kgBW for 90 days. Male and female rats were evaluated for body weight, organ coefficients, biochemical and hematological parameters, and vital organ histology. The results showed no mortality or toxic changes in the subchronic toxicity study. These results suggested that no observed adverse effect level (NOAEL) of SM in male and female rats has been considered at 1000 mg/kgBW for subchronic toxicity study.


Assuntos
Morus , Simbióticos , Animais , Feminino , Masculino , Ratos , Administração Oral , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Morus/química , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ratos Wistar , Simbióticos/administração & dosagem , Testes de Toxicidade Subcrônica
16.
Regul Toxicol Pharmacol ; 151: 105653, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38825064

RESUMO

Despite two decades of research on silver nanoparticle (AgNP) toxicity, a safe threshold for exposure has not yet been established, albeit being critically needed for risk assessment and regulatory decision-making. Traditionally, a point-of-departure (PoD) value is derived from dose response of apical endpoints in animal studies using either the no-observed-adverse-effect level (NOAEL) approach, or benchmark dose (BMD) modeling. To develop new approach methodologies (NAMs) to inform human risk assessment of AgNPs, we conducted a concentration response modeling of the transcriptomic changes in hepatocytes derived from human induced pluripotent stem cells (iPSCs) after being exposed to a wide range concentration (0.01-25 µg/ml) of AgNPs for 24 h. A plausible transcriptomic PoD of 0.21 µg/ml was derived for a pathway related to the mode-of-action (MOA) of AgNPs, and a more conservative PoD of 0.10 µg/ml for a gene ontology (GO) term not apparently associated with the MOA of AgNPs. A reference dose (RfD) could be calculated from either of the PoDs as a safe threshold for AgNP exposure. The current study illustrates the usefulness of in vitro transcriptomic concentration response study using human cells as a NAM for toxicity study of chemicals that lack adequate toxicity data to inform human risk assessment.


Assuntos
Relação Dose-Resposta a Droga , Hepatócitos , Células-Tronco Pluripotentes Induzidas , Nanopartículas Metálicas , Prata , Transcriptoma , Humanos , Prata/toxicidade , Nanopartículas Metálicas/toxicidade , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Medição de Risco , Nível de Efeito Adverso não Observado , Doença Hepática Induzida por Substâncias e Drogas/genética , Benchmarking , Células Cultivadas , Perfilação da Expressão Gênica/métodos
17.
Arch Toxicol ; 98(7): 2019-2045, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38704806

RESUMO

For endocrine disrupting chemicals (EDC) the existence of "safe exposure levels", that is exposure levels that do not present an appreciable risk to human health is most controversially discussed, as is the existence of health-based reference values. Concerns have been especially raised that EDCs might not possess a threshold level such that no exposure level to EDCs can be considered safe. To explore whether or not threshold levels can be identified, we performed a screening exercise on 14 pesticidal and biocidal active substances previously identified as EDCs in the European Union. The respective substances are ideal subjects for case studies to review for endocrine activity and disruptive potential following well-defined regulatory assessment based on solid data to effectually establish adversity as consequence of endocrine disruption. Dimethomorph, metiram and propiconazole for which the weight of evidence demonstrating endocrine disruption was the strongest were used as subjects for further study. Epoxiconazole was additionally selected as its effects on the endocrine system are extensive. For all four substances, analysis of the toxicological data clearly indicated thresholds of adversity below which no adverse effects mediated through an endocrine mechanism were observed. Particular emphasis was placed on mechanistic considerations including homeostasis and the concept of adversity. As a proof of concept this study provides evidence that like other substances of toxicological concern EDCs have threshold levels for adversity. While for some EDCs the respective thresholds might indeed be very low this shows that, data allowing, for other EDCs sufficiently protective reference values can be derived.


Assuntos
Disruptores Endócrinos , Disruptores Endócrinos/toxicidade , Humanos , Medição de Risco , Animais , Praguicidas/toxicidade , Exposição Ambiental/efeitos adversos , Triazóis/toxicidade , União Europeia , Nível de Efeito Adverso não Observado , Sistema Endócrino/efeitos dos fármacos , Compostos de Epóxi/toxicidade
18.
Clin Transl Sci ; 17(6): e13831, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38808564

RESUMO

The systemic exposure at the no-observed-adverse-effect-level (NOAEL) estimated from animals is an important criterion commonly applied to guard the safety of participants in clinical trials of investigational drugs. However, the discrepancy in toxicity profile between species is widely recognized. The objective of the work reported here was to assess, via simulation, the level of uncertainty in the NOAEL estimated from an animal species and the effectiveness of applying its associated exposure value to minimizing the toxicity risk to human. Simulations were conducted for dose escalation of an investigational new chemical entity with hypothetical exposure-response models for the dose-limiting toxicity under a variety of conditions, in terms of between-species relative sensitivity to the toxicity and the between-subject variability in the key parameters determining the sensitivity and pharmacokinetics. Results show a high uncertainty in the NOAEL estimation. Notably, even when the animal species and humans are assumed to have the same sensitivity, which may not be realistic, limiting clinical dose to the exposure at the NOAEL that has been identified in the animals carries a high risk of either causing toxicity or under-dosing, hence undermining the therapeutic potential of the drug candidate. These findings highlight the importance of understanding the mechanism of the toxicity profile and its cross-species translatability, as well as the importance of understanding the dose requirement for achieving adequate pharmacology.


Assuntos
Relação Dose-Resposta a Droga , Nível de Efeito Adverso não Observado , Humanos , Animais , Incerteza , Simulação por Computador , Especificidade da Espécie , Medição de Risco , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacocinética , Drogas em Investigação/efeitos adversos , Pesquisa Translacional Biomédica
19.
Toxicology ; 505: 153824, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38705560

RESUMO

We have developed a quantitative safety prediction model for subchronic repeated doses of diverse organic chemicals on rats using the novel quantitative read-across structure-activity relationship (q-RASAR) approach, which uses similarity-based descriptors for predictive model generation. The experimental -Log (NOAEL) values have been used here as a potential indicator of oral subchronic safety on rats as it determines the maximum dose level for which no observed adverse effects of chemicals are found. A total of 186 data points of diverse organic chemicals have been used for the model generation using structural and physicochemical (0D-2D) descriptors. The read-across-derived similarity, error, and concordance measures (RASAR descriptors) have been extracted from the preliminary 0D-2D descriptors. Then, the combined pool of RASAR and the identified 0D-2D descriptors of the training set were employed to develop the final models by using the partial least squares (PLS) algorithm. The developed PLS model was rigorously validated by various internal and external validation metrics as suggested by the Organization for Economic Co-operation and Development (OECD). The final q-RASAR model is proven to be statistically sound, robust and externally predictive (R2 = 0.85, Q2LOO = 0.82 and Q2F1 = 0.94), superseding the internal as well as external predictivity of the corresponding quantitative structure-activity relationship (QSAR) model as well as previously reported subchronic repeated dose toxicity model found in the literature. In a nutshell, the q-RASAR is an effective approach that has the potential to be used as a good alternative way to improve external predictivity, interpretability, and transferability for subchronic oral safety prediction as well as ecotoxicity risk identification.


Assuntos
Nível de Efeito Adverso não Observado , Compostos Orgânicos , Relação Quantitativa Estrutura-Atividade , Animais , Ratos , Compostos Orgânicos/toxicidade , Compostos Orgânicos/química , Administração Oral , Testes de Toxicidade Subcrônica/métodos , Masculino , Relação Dose-Resposta a Droga , Medição de Risco , Feminino
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