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1.
Chemosphere ; 313: 137614, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36565768

RESUMO

Development of science has taken over our lives and made it mandatory to live with science. Synthetic technology takes more than it has given for our welfare. In the process of meeting the demand of the consumers, industries supported synthetic products to meet the same. One such sector that employs synthetic azo dyes for food coloring is the food industry. The result of the process is the production of a variety of colored foods which looks more appealing and palatable. The process not only meets the consumer's demand it also has an impact on customers' health because the consumption of azo-toxic dye-treated foods regularly or in direct contact with synthetic azo dyes can also cause severe human health consequences. Nanotechnology is a rapidly evolving branch of research in which nanosensors are being developed for a variety of applications, including sensing various azo-toxic dyes in food products, which provides a wider scope in the future, with the innovation in designing different nanosensors. The current review focuses on the different types of nanosensors, their key role in sensing, and the sensing of azo toxic dyes using nanosensors, their advantages over other sensors, applications of nanomaterials, and the health impacts of azo dyes on humans, appropriate parameters for maximum permissible limits, and an Acceptable Daily Intake (ADI) of azo toxic dye to be followed. The regulations followed on the application of colorants to the food are also elaborated. The review also focuses on the application of enzyme-based biosensors in detecting azo dyes in food products.


Assuntos
Corantes , Nanoestruturas , Humanos , Corantes/toxicidade , Compostos Azo/toxicidade , Nanoestruturas/toxicidade , Nível de Efeito Adverso não Observado
2.
Int J Pharm ; 631: 122510, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36549406

RESUMO

In our previous study, a long-acting injectable (LAI) formulation of finasteride was prepared as a new dosage form of PROPECIA®, and in vivo pharmacokinetics (PKs)-pharmacodynamics (PDs) was evaluated in beagle dogs. The resulting PK-PD profiles of the formulation showed pharmacological effects and achievability for monthly delivery. In this study, a first-in-human (FIH) dose of the LAI formulation loaded with finasteride was predicted. The three approaches were used for estimating a FIH dose of the LAI formulation: (1) No observed adverse effect level (NOAEL)-based approach; (2) Pharmacokinetically-guided approach; (3) Pharmacokinetic/pharmacodynamic model-based approach. The advantage, assumptions, limitations, and estimated FIH dose from each approach was discussed and compared since there is no consensus on the best approach. For the prediction of clinical exposures and estimation of FIH doses, the clinical PK-PD parameters were allometrically scaled from the nonclinical data, extracted from reported clinical studies, or fixed from published literature. The starting dose range of the LAI formulation (as finasteride) was estimated to be 16.80-81.06 mg from the three approaches, and the PK/PD model-based approach suggests the most optimal starting dose (16.80 mg) of the LAI formulation. The approaches for estimating starting doses presented in the study could be used as a basis for an Investigational New Drug (IND) application of new dosage forms.


Assuntos
Finasterida , Humanos , Finasterida/administração & dosagem , Injeções , Nível de Efeito Adverso não Observado , Farmacocinética
3.
Regul Toxicol Pharmacol ; 136: 105286, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36372263

RESUMO

Bisphenol F (BPF, 4,4'-methylenediphenol) has recently been selected as an alternative to bisphenol A (BPA), which is used in the manufacturing of polycarbonates and epoxy resins. This study aimed to investigate the general, and reproductive/developmental effects of BPF. Therefore, BPF at dose levels of 0, 1, 5, 20, and 100 mg/kg/day was administered daily by oral gavage to Sprague-Dawley rats during the pre-mating, mating, gestation, and early lactation periods, and reproductive and developmental toxicities including general systemic toxicities were investigated. A decrease in body weight and food consumption was observed in the female rats treated with BPF at 20 and 100 mg/kg/day during the pre-mating and gestation periods. Additionally, gamma glutamyl transpeptidase levels were increased in the female rats administered 100 mg/kg/day. At 100 mg/kg/day, ovarian weight decreased and vaginal mucification increased according to a necropsy and histopathological examination, respectively. Moreover, the number of implantation sites and litter size decreased at 100 mg/kg/day. However, no significant BPF-related changes were observed in the male rats. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of BPF for general systemic and reproductive effects were 5 and 20 mg/kg/day, respectively.


Assuntos
Reprodução , Ratos , Masculino , Feminino , Animais , Ratos Sprague-Dawley , Relação Dose-Resposta a Droga , Nível de Efeito Adverso não Observado
4.
BMC Pharmacol Toxicol ; 23(1): 83, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36289546

RESUMO

BACKGROUND: Toxicological problem associated with herbal medicine is a significant public health problem. Hence, it is necessary to elaborate on the safety of herbal medicine. Salvianolic acid A (SAA) is a major active compound isolated from Danshen, a popular herbal drug and medicinal food plant in China. The aim of the present study was to explore the toxicological profile of SAA. METHODS: The acute toxicity studies were performed in mice and Beagle dogs with single administration with SAA. A 4-week subchronic toxicity was test in dogs. SAA was intravenously administered at doses of 20, 80 and 300 mg/kg. Clinical observation, laboratory testing and necropsy and histopathological examination were performed. The genotoxic potential of SAA was evaluated by 2 types of genotoxicity tests: a reverse mutation test in bacteria and bone marrow micronucleus test in mice. RESULTS: In acute toxicities, the LD50 of SAA is 1161.2 mg/kg in mice. The minimum lethal dose (MLD) and maximal non-lethal dose (MNLD) of SAA were 682 mg/kg and 455 mg/kg in dogs, respectively. The approximate lethal dose range was 455-682 mg/kg. In the study of 4-week repeated-dose toxicity in dogs, focal necrosis in liver and renal tubular epithelial cell, the decrease in relative thymus weight, as well as abnormal changes in biochemical parameters, were observed in SAA 80 or 300 mg/kg group. The no observed adverse effect level (NOAEL) of SAA was 20 mg/kg. Thymus, liver and kidneys were the toxic targets. These toxic effects were transient and reversible. These results indicated that it should note examination of liver and kidney function during the administration of SAA in clinic. Furthermore, SAA had no mutagenic effect at any tested doses. CONCLUSION: These results provide new toxicological information of SAA for its clinical application and functional food consumption.


Assuntos
Ácidos Cafeicos , Lactatos , Camundongos , Animais , Cães , Nível de Efeito Adverso não Observado , Dano ao DNA , Testes de Mutagenicidade
5.
Toxicol Ind Health ; 38(11): 713-716, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36190179

RESUMO

The WEEL guide for dimethyl ether (DME) was originally established in 1996 and updated in 2010. Literature searches to identify new toxicity information were performed in November 2020 and evaluated by the WEEL Revisions Subcommittee. No new studies or data relevant to the WEEL guide were identified. DME has very low acute inhalation toxicity with a 4 h LC50 in rats of 164,000 ppm, and a cardiac sensitization threshold in dogs of >200,000 ppm. In repeated inhalation studies of up to 2 years in the rat, DME was not carcinogenic and produced minimal toxicity at 25,000 and 10,000 ppm: the NOAEC was 2000 ppm. DME was not teratogenic in pregnant rats up to 40,000 ppm; slight maternal and fetal toxicity were observed at >5000 ppm. DME was not mutagenic in vitro or in vivo. The primary finding with inhalation exposure was a reversible CNS depression. Based on a clear NOAEC of 2000 ppm for all effects in a lifetime inhalation study in rats, and the general low level of toxicity found in acute and subchronic toxicity studies, a WEEL of 1000 ppm (v/v; 8-h time-weighted average) was reaffirmed in 2021 and should provide an adequate margin of safety.


Assuntos
Exposição por Inalação , Éteres Metílicos , Ratos , Cães , Animais , Nível de Efeito Adverso não Observado , Exposição por Inalação/efeitos adversos , Mutagênicos/toxicidade
7.
Neurotoxicology ; 93: 233-243, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36228753

RESUMO

In addition to age and traumatic brain injury, environmental exposure to pesticides is a potential risk factor for neurodegenerative diseases and cognitive impairments in humans. Deltamethrin is a type II pyrethroid insecticide widely used in agriculture and homes for pest control. Previously, we reported that repeated exposure of mice to 3 mg/kg deltamethrin for 30 or 60 days caused a marked increase in the endoplasmic reticulum (ER) stress and reduced adult hippocampal neurogenesis that was accompanied by impaired learning and memory. However, it is unknown whether an acute exposure to low doses of deltamethrin elicits similar effects. Here, we sought to characterize the dose-related effects of deltamethrin on ER stress and hippocampal neurogenesis at different time points following acute exposure. Following oral administration of 0, 0.3, 1, or 3 mg/kg deltamethrin, doses below, at, and above the acute NOAEL, mice were euthanized at 24 h, 48 h, 7 d, or 14 d to assess the acute and intermediate-term effects of deltamethrin on neural progenitor cells (NPCs). Deltamethrin at both 1 and 3 mg/kg elicited ER stress response and activation of apoptotic signaling. Data revealed that a dose as low as 1 mg/kg of deltamethrin, considered the acute NOAEL, produced a significant reduction in BrdU+ and Ki-67+ neural stem cells in the subgranular zone of the dentate gyrus of the hippocampus as early as 48 h after exposure. Furthermore, mice treated with 1 and 3 mg/kg deltamethrin exhibited a decreased number of immature neurons, determined by counting DCX-positive cells 7 days after exposure. These data establish that 0.3 mg/kg should be considered a NOAEL and that the previously established acute NOAEL of 1 mg/kg shows significant effects on ER stress and apoptotic pathways accompanied by deficits in aspects of adult hippocampal neurogenesis.


Assuntos
Neurogênese , Piretrinas , Humanos , Animais , Camundongos , Nível de Efeito Adverso não Observado , Piretrinas/farmacologia , Hipocampo
8.
Front Biosci (Landmark Ed) ; 27(8): 228, 2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-36042166

RESUMO

BACKGROUND: In the past 60 years, Cannabis sativa L. has been an object of increasing interest because of the psychotropic effects of some of its constituents. These effects mainly arise from the cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). C. sativa species also synthesize and accumulate the non-psychotropic compound cannabidiol (CBD). Due to their therapeutic potential, both cannabinoids are an object of medical research and drug development. More recently, CBD has received increasing interest as an ingredient in electronic cigarette liquids (e-liquids). This trend may have been reinforced by health and disease-related claims, often based on clinical studies, which are used to advertise CBD. CBD liquids may be based on full-spectrum hemp extracts, CBD isolates, or synthetic CBD, all of which may contain some residual levels of Δ9-THC from either natural content (in the extracts) or from possible degradation of CBD to Δ9-THC, which may occur during storage. There is uncertainty about safety regarding the consumption of CBD (and Δ9-THC) in e-liquids. The aim of this publication was to present an approach for a toxicological risk assessment of CBD and Δ9-THC relevant to e-liquids by using the benchmark dose (BMD) approach. MATERIALS AND METHODS: Before an analysis to estimate a reference dose (RfD) for both cannabinoids, a systematic review of dose-response data was conducted. The data obtained were analyzed using the BMD approach to derive a benchmark dose lower confidence limit (BMDL). The BMDL was used as a point of departure to estimate the RfD. RESULTS: No adequate human data suitable for dose-response modeling were identified. Based on animal data, the RfD values for the most sensitive endpoints were selected. For CBD, an RfD for acute exposure of 1 mg/kg body weight (bw) was estimated. For Δ9-THC, an acute RfD was found to be 0.006 mg/kg bw. Additionally, the RfD for chronic exposure to CBD was estimated to be 4 mg/kg bw per day. The respective endpoints for CBD were a reduction in norepinephrine turnover and a reduction in uterus weight. The endpoint for Δ9-THC was a change in blood pressure. CONCLUSIONS: Because of the limited availability and quality of dose-response data, it cannot be excluded that the estimated RfD values might be afflicted with considerable uncertainties. Therefore, it is recommended to conduct further research on dose-response data, preferably from human studies.


Assuntos
Canabidiol , Canabinoides , Cannabis , Sistemas Eletrônicos de Liberação de Nicotina , Animais , Benchmarking , Canabidiol/farmacologia , Dronabinol/farmacologia , Feminino , Humanos , Nível de Efeito Adverso não Observado , Psicotrópicos/farmacologia
9.
Food Chem Toxicol ; 168: 113329, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35948142

RESUMO

The human gut microbiome plays a crucial role in skeletal homeostasis. The synbiotic consortium or Defined Microbial Assemblage™ (DMA™) food product, SBD111, consisting of probiotic microbes and prebiotic fibers was designed to promote bone health based on its capacity to produce short chain fatty acids (SCFA), the presence of genes for vitamin K2 production, and its ability to degrade plant fibers. A 28-day repeated administration study was performed to evaluate the oral toxicity of SBD111 in female rats (age/weight at study start: 5-7 weeks/120-180 g) administered levels of 0, 2.0 x 1010, 9.8 x 1010, or 2.0 x 1011 colony forming units (CFU)/kg-bw. No mortality or morbidity occurred during the study. There were no significant differences in body weights, hematology, serum chemistry, coagulation, organ weights, or food consumption in the test groups compared to the controls. Liver weight to body weight ratios were signficantly decreased at 9.8 x 1010 CFU/kg-bw when compared to controls. No treatment related changes in motor activity, sensory stimuli, or grip strength were observed. Based on these findings, SBD111 administered to female rats has a no-observable adverse effect level (NOAEL) at the highest level tested of 2.0 x 1011 CFU/kg-bw.


Assuntos
Probióticos , Simbióticos , Animais , Inocuidade dos Alimentos , Humanos , Lactente , Nível de Efeito Adverso não Observado , Ratos , Vitamina K 2
10.
Sci Total Environ ; 852: 158273, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36028035

RESUMO

The evidence for hormetic responses with chemical effects at doses lower than the no-observed-adverse-effect-level (sub-NOAEL) is increasing, creating a need for meta-analyses of sub-NOAEL effects across studies. However, the distinct features of hormetic responses complicate the procedures of meta-analyses aiming to study sub-NOAEL, hormetic effects, and there is no standardized methodology to serve as a guideline. In this piece, a protocol is proposed, which covers the selection of more holistic keywords to be integrated into the literature search queries, the designation of control, and the identification of NOAEL (and thus sub-NOAEL dose responses). It also considers the selection of the response indicators and the incorporation of time and dose as sources of variation. This protocol can serve as a reference point for a harmonized and more robust methodology to meta-analyze sub-NOAEL effects of chemicals on living organisms.


Assuntos
Hormese , Nível de Efeito Adverso não Observado , Relação Dose-Resposta a Droga
11.
Bull Environ Contam Toxicol ; 109(5): 900-909, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35980462

RESUMO

The present study assessed the residue levels of six parent neonicotinoids (p-NEOs) and four metabolites (m-NEOs) in indoor dust collected from 12 cities of China. Acetamiprid (ACE) and imidacloprid (IMI) were the predominated p-NEOs (detection rates: 98%) with the median values at 4.54 and 7.48 ng/g dry weight (dw), respectively. N-demethyl-acetamiprid (N-dm-ACE) was the most important m-NEO with the median value at 0.69 ng/g dw, while other m-NEOs were rarely detected (detection rates: < 15%). Significant correlation between ACE and thiacloprid (THD) was observed (p < 0.01), indicating their probably concurrent applications. ACE was significantly correlated to N-dm-ACE (p < 0.01), implicating the degradation of ACE in indoor environment. The estimated daily intake (EDIing) of NEOs via dust ingestion were far lower than the acceptable daily intake for NEOs. To our knowledge, this study provided a baseline nationwide investigation on the occurrence of NEOs in indoor dust of China.


Assuntos
Poluição do Ar em Ambientes Fechados , Inseticidas , Humanos , Poeira/análise , Inseticidas/análise , Neonicotinoides/análise , Inquéritos e Questionários , Nível de Efeito Adverso não Observado , China , Poluição do Ar em Ambientes Fechados/análise
12.
Food Chem Toxicol ; 168: 113325, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35963474

RESUMO

No observed adverse effect level (NOAEL) is an identified dose level which used as a point of departure to infer a safe exposure limit of chemicals, especially in food additives and cosmetics. Recently, in silico approaches have been employed as effective alternatives to determine the toxicity endpoints of chemicals instead of animal experiments. Several acceptable models have been reported, yet assessing the risk of repeated-dose toxicity remains inadequate. This study established robust machine learning predictive models for NOAEL at different exposure durations by constructing high-quality datasets and comparing different kinds of molecular representations and algorithms. The features of molecular structures affecting NOAEL were explored using advanced cheminformatics methods, and predictive models also communicated the NOAEL between different species and exposure durations. In addition, a NOAEL prediction tool for chemical risk assessment is provided (available at: https://github.com/ifyoungnet/NOAEL). We hope this study will help researchers easily screen and evaluate the subacute and sub-chronic toxicity of disparate compounds in the development of food additives in the future.


Assuntos
Cosméticos , Animais , Aditivos Alimentares/toxicidade , Aprendizado de Máquina , Nível de Efeito Adverso não Observado , Medição de Risco
13.
Food Chem Toxicol ; 168: 113328, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35940331

RESUMO

7-Methyl-2H-1,5-benzodioxepin-3(4H)-one (Calone®) is used in fragrances to impart a marine note. It is produced industrially at volumes requiring repeated dose and developmental/reproductive toxicology data (OECD TG 422) under European chemicals legislation (i.e., REACH). Additionally, Japanese chemicals legislation requires evaluation of Calone® biodegradability and identification of metabolites in an environmental biodegradation test. 7-Methyl-2H-1,5-benzodioxepin-3-ol (Calol) was the sole metabolite identified following biodegradation and a 28-day repeated dose toxicity study (OECD TG 407) would normally be required to support registration in Japan. The current paper presents results showing no adverse effects in the parental, reproductive, or developmental phases of an OECD TG 422 study following dietary administration of Calone® to rats at targeted doses of up to 1000 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) was the highest administered dose of 791 and 922 mg/kg/day for males and females, respectively. An in vitro metabolism study conducted with rat and human liver microsomes demonstrated that greater than 90% of Calone® was metabolically reduced into Calol, the same metabolite observed in the environmental biodegradation test. Accordingly, the results from the OECD TG 422 study with Calone® are directly applicable to Calol and it would be expected to have the same NOAEL.


Assuntos
Benzoxepinas , Perfumes , Animais , Biodegradação Ambiental , Feminino , Humanos , Masculino , Nível de Efeito Adverso não Observado , Ratos
15.
Braz J Biol ; 84: e264320, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35946729

RESUMO

Toxicological studies are essential for developing novel medications in pharmaceutical industries including ayurvedic preparation. Hence, the present study is aimed to evaluate acute and 28-days repeated dose oral toxicity of anti-obesity polyherbal granules (PHG) in Sprague Dawley rats by OECD guidelines No 425 and 407, respectively. In an acute oral toxicity study, a single dose of 2 g/kg PHG was administered to rats and mortality, body weight, and clinical observations were noted for fourteen days. However, in the subacute oral toxicity study, the PHG was administered orally at doses of 0.3, 0.5 and 1 g/kg daily for 28 days to rats. Food intake and body weight were recorded weekly. On the 29th day, rats were sacrificed and subjected to haematological, biochemical, urine, necropsy, and histopathological analysis. In an acute oral toxicity study, no treatment-related, mortality, behavioral changes, and toxicity were found throughout fourteen days. Likewise, in the sub-acute toxicity study, no mortality and toxic effects were found in haematology, biochemical, urine, necropsy and histopathological analysis in rats for 28 days of treatment with PHG. Based on these results, the LD50 of PHG was found to be greater than 2 g/kg and the no-observed-adverse-effect level (NOAEL) of PHG for rats was found to be 0.5 g/kg/day. Thus, anti-obesity polyherbal granules showed a good safety profile in animal studies and can be considered an important agent for the clinical management of obesity.


Assuntos
Obesidade , Animais , Peso Corporal , Relação Dose-Resposta a Droga , Nível de Efeito Adverso não Observado , Obesidade/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Aguda/métodos
16.
Artigo em Inglês | MEDLINE | ID: mdl-36012048

RESUMO

OBJECTIVE: This study was conducted to evaluate the acute and subchronic toxicity of anthraquinone. An acute toxicity test was performed in female Sprague Dawley (SD) rats, and the oral median lethal dose (LD50) of anthraquinone was estimated to be >5000 mg/kg body weight (BW). In the subchronic study, groups of 10 male and 10 female rats were dosed with anthraquinone by gavage at 0, 1.36, 5.44, 21.76, and 174.08 mg/kg BW, 7 days/week for 90 days followed by a recovery period of 28 days. No appreciable toxic-related changes were observed in the 1.36 mg/kg BW group. When the animals received 5.44 mg/kg BW or more of anthraquinone, hyaline droplet accumulation in the renal tubules was observed in both the male and female rats, and anemia was observed in the females. When the anthraquinone dose reached 174.08 mg/kg BW, mild hepatocellular hypertrophy around the central vein of the hepatic lobule and hypothyroidism were observed in the female rats. During the recovery period, changes in clinical symptoms and parameters were considerably alleviated. Based on the results of this study, the no observed adverse effect level (NOAEL) for anthraquinone in rats was set at 1.36 mg/kg BW, and the lowest observed adverse effect level (LOAEL) was 5.44 mg/kg BW.


Assuntos
Antraquinonas , Administração Oral , Animais , Antraquinonas/toxicidade , Peso Corporal , Feminino , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subcrônica
17.
Food Chem Toxicol ; 168: 113301, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35868606

RESUMO

A battery of studies was conducted to examine the toxicological potential of dihydroberberine (DHBBR), a derivative of berberine (BBR). The genotoxicity studies conducted on DHBBR, including the bacterial reverse mutation test, the mouse lymphoma assay, and the in vivo micronucleus test, showed that DHBBR is non-mutagenic and non-clastogenic. An acute oral toxicity study revealed that the LD50 of DHBBR in female Sprague Dawley rats was greater than 2000 mg/kg bw. In a 14-day oral dose range finding study, the maximum tolerated dose was the high dose, 120 mg/kg bw/day. Based on a 90-day oral toxicity study in male and female Sprague Dawley rats, it was concluded that the NOAEL for DHBBR is 100 mg/kg bw/day, the highest dose tested.


Assuntos
Berberina , Animais , Berberina/análogos & derivados , Berberina/toxicidade , Feminino , Dose Letal Mediana , Masculino , Camundongos , Testes para Micronúcleos , Nível de Efeito Adverso não Observado , Ratos , Ratos Sprague-Dawley
18.
Regul Toxicol Pharmacol ; 133: 105214, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35781033

RESUMO

Rhuleave-K™ is a proprietary combination of Curcuma longa extract, Boswellia serrata extract and black sesame seed oil. Acute toxicity was evaluated as per OECD guidelines 423. Rhuleave-K™ was fed at 2000 mg/kg to overnight fasted female rats. Clinical signs of abnormality and mortality was observed daily for 14 days. Sub-chronic toxicity was studied by feeding Rhuleave-K™ at 100, 500 and 1000 mg/kg/day to rats as per OECD guidelines 408. After 90 days feeding, hematological and biochemical parameters were analyzed. Histopathology of all the major organs was also studied. In the acute toxicity study, there was no clinical sign of toxicity in any of the rats at maximum dose of 2000 mg/kg. The LD50 was computed as >2000 mg/kg in rats. The repeated dosing of Rhuleave-K™ at the maximum dose level of 1000 mg/kg for 90 days did not induce any observable toxic effects in rats, when compared to its corresponding control. The hematology and biochemistry profiles of treated rats were similar to control animals and difference was non-significant (p > 0.05). The histopathology of major organs of all the control and treated animals was normal. In this study the NOAEL for Rhuleave-K™ was calculated as 1000 mg/kg daily in rats.


Assuntos
Dor , Extratos Vegetais , Animais , Feminino , Nível de Efeito Adverso não Observado , Dor/tratamento farmacológico , Ratos , Testes de Toxicidade Aguda
19.
Chemosphere ; 305: 135460, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35752312

RESUMO

Reference dose (RfD) is an estimate of a daily dose that individual can be exposed chronically without obvious deleterious effects during a lifetime. In the area of toxicology, researchers always use the traditional approach by employing NOAEL/LOAEL or the benchmark dose (BMD) and other dose-response approaches to estimate RfD. These methods have, despite their typicalness, certain limitations. In this study, we present a novel method of the estimation of reference dose without experiments. The information of the organic chemicals is available from the Integrated Risk Information System (IRIS) of USEPA. Molecular descriptors for each molecular structure were calculated by an integrated platform, and the chemicals were classified into four categories based on molecular similarity: 128 contained benzene rings, 47 were heteroaromatics, 104 contained halogen substituents and 44 were halogenated aliphatic hydrocarbons. The predictive model of RfD was constructed by the multiple linear stepwise regression (MLR) method. Approximately 95% and 82% of the data points differ by less than 10-fold and 5-fold between the predicted values and the true values respectively. The non-experimental method improves the estimation efficiency and has a certain reference value to predict.


Assuntos
Benchmarking , Nível de Efeito Adverso não Observado , Valores de Referência , Medição de Risco/métodos , Estados Unidos , United States Environmental Protection Agency
20.
Int J Mol Sci ; 23(12)2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35743059

RESUMO

The risk-characterization of chemicals requires the determination of repeated-dose toxicity (RDT). This depends on two main outcomes: the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level (LOAEL). These endpoints are fundamental requirements in several regulatory frameworks, such as the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) and the European Regulation of 1223/2009 on cosmetics. The RDT results for the safety evaluation of chemicals are undeniably important; however, the in vivo tests are time-consuming and very expensive. The in silico models can provide useful input to investigate sub-chronic RDT. Considering the complexity of these endpoints, involving variable experimental designs, this non-testing approach is challenging and attractive. Here, we built eight in silico models for the NOAEL and LOAEL predictions, focusing on systemic and organ-specific toxicity, looking into the effects on the liver, kidney and brain. Starting with the NOAEL and LOAEL data for oral sub-chronic toxicity in rats, retrieved from public databases, we developed and validated eight quantitative structure-activity relationship (QSAR) models based on the optimal descriptors calculated by the Monte Carlo method, using the CORAL software. The results obtained with these models represent a good achievement, to exploit them in a safety assessment, considering the importance of organ-related toxicity.


Assuntos
Relação Quantitativa Estrutura-Atividade , Software , Animais , Simulação por Computador , Método de Monte Carlo , Nível de Efeito Adverso não Observado , Ratos
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