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Significance of the LD50-test for the toxicological evaluation of chemical substances
Abstract
The LD50-test was developed in 1927 for the biological standardization of dangerous drugs. Then it was incorporated into the routine toxicological protocol of other classes of chemical compounds and is now part of practically all governmental guidelines which regulate toxicological testing of chemicals.
For scientific, economic, and ethical reasons it is necessary to periodically reassess all toxicological test procedures, including the LD50-test. Tests which are not optimal or that have become obsolete because of new scientific knowledge, must be changed or eliminated.
The review of the LD50-test shows that the precision of the procedure is dependent on the number of animals used. But even with large numbers of animals there are considerable variations of the test results, because the numerical value of the LD50 is influenced by many factors, such as animal species and strain, age and sex, diet, food deprivation prior to dosing, temperature, caging, season, experimental procedures, etc. Thus, the LD50 value cannot be regarded as a biological constant.
Through standardization of the test animals and the experimental conditions the variability of the LD50 determinations can be reduced but never fully eliminated.
There are several tests with which an approximate LD50 can be determined. These methods use fewer animals than the classical LD50-test, but their precision and reproducibility are sufficient for most purposes of acute toxicity testing.
Through incorporation of physiological, hematological, biochemical, pathological, and histopathological investigations in the simplified test procedures with small numbers of animals, it is possible to markedly increase the informational content of the results with regard to the toxicological spectrum and the target organs of toxicity. Such studies have already replaced the LD50-test in large animals, such as dogs and monkeys. It is also desirable to replace the LD50 in rodents with such a procedure.
With pharmacologically inert compounds that have no acute effects with single administration the classical LD50-test does not provide relevant toxicological results.
For the prediction of the human lethal dose and for the prediction of the symptomatology of poisoning after acute overdosing in man the LD50-test is of limited usefulness. An acute toxicity test with small numbers of animals combined with comprehensive studies of physiological functions, biochemical and histopathological examinations often provides more important information for emergency physicians and poison control centers.
For the selection of doses to be used in subacute and chronic toxicity experiments the LD50-test does not provide consistent and reliable results. A simple pilot experiment with few animals but repeated dosing gives more useful information.
For the evaluation of special risks for the human newborn and infant the LD50-test is poorly suited.
For the appraisal of pharmacokinetic behavior and bioavailability the LD50-test gives only semi-quantitative, often ambiguous information.
In all cases where the acute toxicity testing is mainly concerned with the evaluation of toxicological potential of the test substances, the symptomatology following acute overdosing, and the knowledge of target organs of toxicity, the classical LD50-test should be replaced by a more comprehensive short term test that can be done with small numbers of animals. The classical LD50-test should only be permitted in those rare instances where a high precision of the LD50 determination is indispensable.
... g/kg) for 50 days did not cause any evident tissue alterations in the mice. The LD50 value of B-NIPOx was 2.15 g/Kg of body weight, which is similar to the one reported for B-NPOx (2.00 g/Kg) [22] and indicates that B-NIPOx is not toxic to mice [23]. ...
... The correct synthesis of B-NIPOx was confirmed by IR, 1 H-NMR and 13 C-NMR, where its functional groups were identified. We demonstrated that B-NIPOx had no cytotoxicity on three cell lines, and no toxicity in mice (the LD50 value was 2.15 g/Kg of body weight, which indicates that B-NIPOx is not toxic to mice [23]). ...
... The median lethal dose (LD50) value of B-NIPOx was determined in CD-1 mice, according to the established requirements [23]. B-NIPOx was administered orally as solution in 5% arabic gum in water at doses of 1.50-3.00 ...
Chagas disease is caused by Trypanosoma cruzi and represents a major public health problem, which is endemic in Latin America and emerging in the rest of the world. The two drugs that are currently available for its treatment, Benznidazole and Nifurtimox, are partially effective in the chronic phase of the disease. In this study, we designed and synthesized the benzyl ester of N-isopropyl oxamic acid (B-NIPOx), which is a non-polar molecule that crosses cell membranes. B-NIPOx is cleaved inside the parasite by carboxylesterases, releasing benzyl alcohol (a molecule with antimicrobial activity), and NIPOx, which is an inhibitor of α-hydroxy acid dehydrogenase isozyme II (HADH-II), a key enzyme in T. cruzi metabolism. We evaluated B-NIPOx cytotoxicity, its toxicity in mice, and its inhibitory activity on purified HADH-II and on T. cruzi homogenates. We then evaluated the trypanocidal activity of B-NIPOx in vitro and in vivo and its effect in the intestine of T. cruzi-infected mice. We found that B-NIPOx had higher trypanocidal activity on epimastigotes and trypomastigotes than Benznidazole and Nifurtimox, that it was more effective to reduce blood parasitemia and amastigote nests in infected mice, and that, in contrast to the reference drugs, it prevented the development of Chagasic enteropathy.
... Median lethal dose (LD 50 ) was first proposed by J. W. Trevan in 1976 [1]. It is used to study acute toxicity and classify toxic substance [2]. The 95% confidence interval (95% CI, μ ± σ) is used to describe LD 50 mean [3,4]. ...
... In addition, the calculation of mKM is simple to obtain an accurately LD 50 value and standard error. However, mKM violates animal rights and increase economic pressure [2,[13][14][15]. With 3Rs principles proposed (Reduction, Replacement, Refinement) [16,17], up-and-down procedure (UDP) was advocated [14,18]. ...
... The result was calculated as follows according to the results of Table 4 and formula (1), (2). Compared with normal mice, sinomenine hydrochloride has no effect on the organ indexes (Table 5). ...
Background
Up-and-down procedure (UDP) was recommended to replace traditional acute toxicity methods. However, it was limited due to the long experimental period (20–42 days). To improve UDP, an improved UDP method (iUDP) was developed by shortening observation time between sequence dosages. The aim of this study was to test the reliability of iUDP to provide a reliable method for the acute toxicity measurement of valuable or minor amount compounds.
Methods
Oral median lethal dose (LD50) of nicotine, sinomenine hydrochloride and berberine hydrochloride were measured both by iUDP and modified Karber method (mKM).
Results
LD50 of the three alkaloids measured by iUDP with 23 mice were 32.71 ± 7.46, 453.54 ± 104.59, 2954.93 ± 794.88 mg/kg, respectively. LD50 of the three alkaloids measured by mKM with 240 mice were 22.99 ± 3.01, 456.56 ± 53.38, 2825.53 ± 1212.92 mg/kg, respectively. The average time consumed by the two methods were 22 days and 14 days respectively. Total grams of the alkaloids used by the two methods were 0.0082 and 0.0673 (nicotine), 0.114 and 1.24 (sinomenine hydrochloride), 1.9 and 12.7 (berberine hydrochloride).
Conclusion
iUDP could replace mKM to detect acute toxicity of substances with comparable and reliable result. And it is suitable for valuable or minor amount substances.
... The observed results for the highest concentration used in the measurem (120 ng/mL) allow for the assessment of the toxicity of the tested protein fraction i logical systems. Based on the presented results, the median lethal dose (LD50) wa termined using the Behrens method [32], which is presented in Table 2. The amount of the chemical substance (statistically calculated on the basis test results) that cause death in 50% of organisms after a single dose treatment for cells is 4.5% higher than for the second tested cells. ...
... The observed results for the highest concentration used in the measurements (120 ng/mL) allow for the assessment of the toxicity of the tested protein fraction in biological systems. Based on the presented results, the median lethal dose (LD50) was determined using the Behrens method [32], which is presented in Table 2. The amount of the chemical substance (statistically calculated on the basis of the test results) that cause death in 50% of organisms after a single dose treatment for U-937 cells is 4.5% higher than for the second tested cells. ...
... Based on the results of the cell survival presented in this paper, the values of the median lethal dose (LD50 median lethal dose) for cells were calculated using Behrens' method [32] with the following assumptions: the number of cells per measurement point is constant, the absorbance determined in the XTT method is correlated with the number of live cells; moreover, if the cell is experiencing a higher dose, it has survived all lower doses; if the cell dies at a lower dose, it would die at all higher doses. Then, the percentage mortality was calculated for each dose of applied venom fraction and LD50 values were obtained from the appropriate graphs. ...
Three-finger toxins are naturally occurring proteins in Elapidae snake venoms. Nowadays, they are gaining popularity because of their therapeutic potential. On the other hand, these proteins may cause undesirable reactions inside the body′s cells. A full assessment of the safety of Naja ashei venom components for human cell application is still unknown. The aim of the study was to determine the effect of the exogenous application of three-finger toxins on the cells of monocytes (U-937) and promyelocytes (HL-60), with particular emphasis on the modification of their membranes under the influence of various doses of 3FTx protein fraction (0–120 ng/mL). The fraction exhibiting the highest proportion of 3FTx proteins after size exclusion chromatography (SEC) separation was used in the experiments. The structural response of cell membranes was described on the basis of single-component and multi-component Langmuir monolayers that mimicked the native membranes. The results show that the mechanism of protein–lipid interactions depends on both the presence of lipid polar parts (especially zwitterionic type of lipids) and the degree of membrane saturation (the greatest-for unsaturated lipids). The biochemical indicators reflecting the tested cells (MDA, LDH, cell survival, induction of inflammation, LD50) proved the results that were obtained for the model.
... The first step in ascertaining the safety profile of an unknown plant extract is acute toxicity studies (Lorke, 1983) [24] and its index is LD 50 . Consequently, it is best recognized as providing, a ballpark estimate of human lethality (Zbinden and Flury, 1981) [39] , seeks to determine its possible collateral effect and prevent acute intoxication due to overdose of any substance which may interfere with the results of experiments. The current results of the oral acute toxicity in the albino rats used established that the LD 50 of both the aqueous and ethanolic crude leaf extracts of T. preussii was beyond 5000mg/kg body weight of the rats since the experimental rats tolerated the extracts without any symptoms of acute toxicity e.g. ...
... The first step in ascertaining the safety profile of an unknown plant extract is acute toxicity studies (Lorke, 1983) [24] and its index is LD 50 . Consequently, it is best recognized as providing, a ballpark estimate of human lethality (Zbinden and Flury, 1981) [39] , seeks to determine its possible collateral effect and prevent acute intoxication due to overdose of any substance which may interfere with the results of experiments. The current results of the oral acute toxicity in the albino rats used established that the LD 50 of both the aqueous and ethanolic crude leaf extracts of T. preussii was beyond 5000mg/kg body weight of the rats since the experimental rats tolerated the extracts without any symptoms of acute toxicity e.g. ...
... 30 The simple tool, that's frequently used to get general information on the toxicity of a chemical substance; is the determination of the LD50. 31 The intra-peritoneal administration of the methanol extract of R. montana L., caused different symptoms including: Erect hairs, difficulty of walk (paralysis), regrouping in the corner of the cage, tachycardia, difficulty in breathing followed by cyanosis. Mortality was recorded from the first hour of treatment (after almost 15 minutes) up to the 24 th hour. ...
... mg/kg. In this experiment the value of the LD50 of the extract was between 500 and 5000 mg/kg and according to, 31 our extract is considered as moderately toxic substance, and as slightly toxic substance according to. 32 Advanced subchronic toxicity studies in animal model can contribute in the prevision of the toxic effect of the plant extracts, from which, a possible interpolation of the response may be correlated with humans. ...
Ruta montana L. locally known as fidjel belongs to the rutaceae family. This plant is used in traditional medicine as an aphrodisiac, abortive and as hypoglycemic. The aim of this research is to evaluate the mean lethal dose (LD50) and subchronic toxicity of methanol extract of Ruta montana L. on female rat. To determine the LD50, 30 female rats were divided into 5 groups; each group received intraperitoneally, a single dose (800, 1000, 1200, 1400 and 1600 mg/kg bw) of the extract, toxicity symptoms and mortality were registered for 14 consecutive days. In subchronic toxicity (45 days), 14 female rats were divided into 2 groups; treated group received intraperitoneally 38,7149 mg/kg bw = 1/30 LD50 of the extract and control group received physiological water. Body weight, relative organ masses, reproductive hormones, haematological, biochemical and histopathological parameters were evaluated. The LD50 value was calculated to be 1161.4486 mg/kg by Litchfield and Wilcoxon method. In the subchronic study, there was a significant reduction in body weight in the 2nd and 7th week (P<0.05). Relative mass of the brain and ovaries registered a significant decrease and increase, respectively(P<0.05). Follicle stimulating hormone (FSH), luteinizing hormone (LH) and biochemical parameters did not record significant difference. Haematological parameters presented significant increase and decrease in mean corpuscular haemoglobin (MCH) and red cell distribution width (RDW), respectively (P<0.05). The histopathology revealed no abnormalities in different studied tissues. The current study revealed that the methanol extract of Ruta montana at the tested dose had no toxic effect on subjected organs.
... Rodents are the most popular animal model for LD 50 studies. Despite the fact that LD 50 is criticized for low reproducibility [19], it is used for assigning substances to a toxicity class [20]. However, LD 50 gives little information about the toxic effects of substances, yet is one of the most-known indicators of acute toxicity [21]. ...
... ity [19], it is used for assigning substances to a toxicity class [20]. However, LD50 gives little information about the toxic effects of substances, yet is one of the most-known indicators of acute toxicity [21]. ...
Toxicity and pharmacological activity scales of molecules, in particular toxicants, xenobiotics, drugs, nutraceuticals, etc., are described by multiples indicators, and the most popular is the median lethal dose (LD50). At the molecular level, reversible inhibition or binding constants provide unique information on the potential activity of molecules. The important problem concerning the meaningfulness of IC50 for irreversible ligands/inhibitors is emphasized. Definitions and principles for determination of these quantitative parameters are briefly introduced in this article. Special attention is devoted to the relationships between these indicators. Finally, different approaches making it possible to link pharmacological and toxicological properties of molecules in terms of molecular interactions (or chemical reactions) with their biological targets are briefly examined. Experimental trends for future high-throughput screening of active molecules are pointed out.
... In exception of part of one study (Facury Neto et al., 2004), the comparison groups (CG) have been reported accordingly, thus configurating controlled preclinical trials. In this case, the experimental protocol used for assessing the LD50 and LD100 did not required a comparison (Lorke, 1983;Zbinden & Flury-Roversi, 1981). The CGs (sham treatments) were saline solution (Facury Neto et al., 2004), distillated water (Paula-Freire et al., 2014), standard diet (Bucciarelli et al., 2010), and aqueous surfactant solutions (Ferrari et al., 2012;Ferreira et al., 2014). ...
... Both the number of experimental groups and the number of animals per group varied widely as a function of the experimental protocols carried out for toxicity assessment. According to the information provided by the researchers, majority (60 %) of the studies followed official guidelines (Brasil, 2004;OECD/OCDE, 2001) in the investigation of the toxicity of herbal products (Bucciarelli et al., 2010;Ferrari et al., 2012;S A Ferreira et al., 2014), while others (Facury Neto et al., 2004;Paula-Freire et al., 2014) performed the experiments according to other protocols (Lorke, 1983;Zbinden & Flury-Roversi, 1981 Water consumption as well as food intake in all groups were similar. The body weight was not affected in any group. ...
Arnica" extracts are widely used in folk medicine to treat acute and chronic inflammatory ailments. Nevertheless, their toxic effects upon systemic use are still not fully understood. Therefore, this work provides a systematic review on the safety of arnica extracts following preclinical trials covering their oral and intraperitoneal administration in animal models. Henceforth, PRISMA guideline was followed and the study protocol was registered in PROSPERO (CDR42020167112). Searches were performed in PubMed (MEDLINE), Scopus, Science Direct, Web of Science (Science Citation Index), and Health Virtual Library (BVS) databases; while SYRCLE's Risk of Bias tool and CAMARADES checklist were used to assess scientific quality. From 382 articles, five studies met eligibility criteria and underwent qualitative analysis. Data of acute toxicity was reported in all the selected articles, and the treatment time was up to 14 days. Moreover, the following species were reported: Solidago chilensis (hazard categories of 4 and 5 for i.p and v.o administration, respectively); Solidago microglossa (hazard category of 3, i.p); Lychnophora trichocarpha (hazard category of ≥ 4, i.p); and Lychnophora pinaster (hazard category of ≥ 4, v.o). The alcoholic extracts showcased greater toxic potential, which increased in a dose-dependent manner after 100 mg/Kg. Concerning organ-specific toxicity, the articles reported hepatotoxicity and nephrotoxicity following histopathological analysis. However, the safety of S. chilensis, L. pinaster, L. trichocarpha, and S. microglossa following systemic administration remains unclear due to the limited experimental quality of the included papers, as well as the lack of reported chronic toxicity, pharmacokinetics, and mutagenicity studies.
... However, LD 50 and LC 50 have limited usage as they cannot be directly extrapolated across species and to low doses. In fact, their application as a measure of toxicity has been criticized by many toxicologists (see Zbinden and Flury-Roversi, 1981;LeBeau, 1983 There is a large body of literature in toxicology that describes the properties and applications of each of the abovementioned measures of toxicity. In addition, the measures are not independent and many of them are interrelated. ...
... J. A. Staffa and M. A. Mehlman eds. Pathotox Publishers, Inc. Zbinden, G. and Flury-Roversi, M. (1981). Signifcance of the LD50-test for the toxicological evaluation of chemical substances. ...
... The acute toxicity testing conducted on T. diversifolia leaf extract revealed no instances of mortality, even at the highest tested dose of 5,000 mg/kg. This finding strongly indicates the safety of the extract for oral usage (Zbinden & Flury-Roversi, 1981). The absence of any deaths, even at the maximum administered dose, led to the conclusion that the T. diversifolia leaf extract is generally safe for oral consumption based on the results of the acute toxicity analysis conducted in the current study. ...
Objectives: The objective of this study was to evaluate the phytochemical composition and gastroprotective properties of Tithonia diversifolia extract. Methods: Gas Chromatography-Mass Spectrophotometry (GC-MS) was used to quantify the chemical constituents present in the extract. Fourier Transform Infrared (FT-IR) spectroscopy was employed to identify functional groups in the extract. An acute toxicity study was conducted on rats to assess the safety of the extract. For the gastroprotective study, Wistar rats were divided into different groups and pretreated with different doses of T. diversifolia extract before ulcer induction with aspirin. Results: GC-MS analysis revealed the presence of twenty-eight chemical constituents in the extract,with benzyl alcohol, p-hydroxy-alpha-[(methylamino) methyl] being the most prominent. FT-IR analysis identified several functional groups in the extract. The acute toxicity study showed no signs of toxicity or mortality. Both the T. diversifolia extract and omeprazole (standard drug) significantly reduced ulcer parameters, antioxidant activity, phase Journal of Namibian Studies, 34 S2(2023): 2538-2573 ISSN: 2197-5523 (online) 2539 II enzymes, matrix metalloproteinase activity, prostaglandin E2 levels, and inflammatory biomarkers compared to the negative control group. The percentage inhibition of ulcers followed a dose-dependent trend. Conclusions: The findings of this study suggest that the decoction of Tithonia diversifolia has potential gastroprotective properties against aspirin-induced ulcers. The extract exhibited significant reduction in ulcer parameters and modulation of various biochemical markers associated with ulcers. These results support the traditional use of T. diversifolia in ethnomedicine for the treatment of ulcers. Further studies are warranted to explore the specific mechanisms of action and potential clinical applications of T. diversifolia extract in gastroprotection.
... LD50 dose or the semi-lethal dose is the concentration of colchicine that kills 50% of the sample in one application and its estimation is important to determine the potential toxicity of the concentration of the chemical [13,19]. Evaluation of LD50 dose of colchicine treatment can be observed through the ocular toxicity method i.e., an easy visual observation, while mathematical methods like the Spearman-Karber method and statistical (graphical) method Abstract: Colchicine is a toxic mutation-inducing chemical substance widely used to induce polyploidy for plant improvement. ...
Colchicine is a toxic mutation-inducing chemical substance widely used to induce polyploidy for plant improvement. Being toxic, dose estimation to plant tissue is necessary for polyploidy induction studies. LD50 dose or the semi-lethal dose is the amount of a toxic substance that can kill half of the biological test sample in a single application. It is generally helpful to estimate the toxic nature of a chemical substance. In the present study, the callus of three genotypes FRIH12, FRIH22, and AFRIC1 of Azadirachta indica (neem) was incubated on an MS medium with various doses of colchicine under in vitro conditions. The survival percentage of callus of each genotype under varying concentrations of colchicine was observed. Ocular toxicity, mathematical (Spearman-Karber), and statistical (Miller-Tainter) methods were used to determine the LD50 dose of colchicine for the three genotypes. Miller-Tainter method is the most efficient and accurate for determining the LD50 dose of colchicine and for the three genotypes FRIH12, FRIH22, and AFRIC1, the LD50 dose was found to be 50.1mg/l, 60.3mg/l and 50.1mg/l respectively. Amongst genotypes, FRIH22 was most resilient against the treatments of colchicine.
... It, thus, shows a large inter-laboratory variability, even when study designs seem comparable (Gad and Chengelis 1998). It has also been acknowledged for a long time that approximate lethal doses with comprehensive studies of the pathophysiological mechanisms of the toxic effects provide more important information for emergency physicians than precise LD 50 -values alone (Zbinden and Flury-Roversi 1981). Nevertheless, LD 50 -values are convenient metrics for classification and comparing the acute toxicity of two substances. ...
Uranium and thorium are heavy metals, and all of their isotopes are radioactive, so it is impossible to study chemical effects entirely independent of the radiation effects. In the present study, we tried to compare the chemo- and radiotoxicity of both metals, taking into account deterministic radiation damages reflected by acute radiation sickness and stochastic radiation damages leading to long-term health impairments (e.g., tumor induction). We made at first a literature search on acute median lethal doses that may be expected to be caused by chemical effects, as even acute radiation sickness as a manifestation of acute radiotoxicity occurs with latency. By simulations based on the biokinetic models of the International Commission on Radiological Protection and using the Integrated Modules for Bioassay Analysis software, we determined the amounts of uranium at different enrichment grades and thorium-232 leading to a short-term red bone marrow equivalent dose of 3.5 Sv considered to cause 50% lethality in humans. Different intake pathways for incorporation were considered, and values were compared to the mean lethal doses by chemotoxicity. To assess stochastic radiotoxicity, we calculated the uranium and thorium amounts leading to a committed effective dose of 200 mSv that is often considered critical. Mean lethal values for uranium and thorium are in the same order of magnitude so that the data do not give evidence for substantial differences in acute chemical toxicity. When comparing radiotoxicity, the reference units (activity in Bq or weight in g) must always be taken into account. The mean lethal equivalent dose to the red bone marrow of 3.5 Sv is reached by lower activities of thorium compared to uranium in soluble compounds. However, for uranium as well as thorium-232, acute radiation sickness is expected only after incorporation of amounts exceeding the mean lethal doses by chemotoxicity. Thus, acute radiation sickness is not a relevant clinical issue for either metal. Concerning stochastic radiation damages, thorium-232 is more radiotoxic than uranium if incorporating the same activities. Using weight units for comparison show that for soluble compounds, thorium-232 is more radiotoxic than low-enriched uranium in the case of ingestion but even more toxic than high-enriched uranium after inhalation or intravenous administration. For insoluble compounds, the situation differs as the stochastic radiotoxicity of thorium-232 ranges between depleted and natural uranium. For acute effects, the chemotoxicity of uranium, even at high enrichment grades, as well as thorium-232 exceeds deterministic radiotoxicity. Simulations show that thorium-232 is more radiotoxic than uranium expressed in activity units. If the comparison is based on weight units, the rankings depend on the uranium enrichment grades and the route of intake.
... It is usually expressed as the weight of the sample administered in milligrams per kilogram body weight of the animal. It is an important indicator for the prediction of the human lethal dose and for predicting the dose that would cause toxicity symptoms in humans [47]. The human equivalent dose (HED) is a dose in humans expected to provide the same degree of effect as that of the animals tested at a given dose [27]. ...
The increasing prevalence of non-communicable diseases (NCDs) such as diabetes mellitus and dyslipidemia has prompted health research to investigate the use of indigenous crops as functional food ingredients. Bignay fruits are indigenous berries in the Philippines which have distinct health benefits. However, toxicity studies on these berries remain scarce, which are needed to ensure its safety for human consumption and development into food supplements. The primary objective of this study is to determine the possible toxic effects in vivo induced by oral subacute administration of bignay extracts. Using ICR mice of both sexes, aqueous bignay extracts were administered via oral gavage once daily for 28 days. The animals were observed daily for any abnormal behavior, and body weights and feed and water intake were also recorded. Gross and histopathology analysis were done to check for any abnormalities in key organs such as the brain, heart, lungs, GI tract, and kidneys. No significant changes were observed in body weight, feed and water intake, blood chemistry and hematology values in all mice groups and were comparable to published values and their respective controls. All mice groups also had appreciable body weight gain (10.89% to 21.52%) with zero morbidity and mortality. Gross and microscopic examination of the brain, heart, lungs, GI tract, liver, spleen, and kidneys showed normal architecture and histology, suggesting that the fruits did not induce any morphological abnormalities. The bignay fruits are non-toxic to both male and female ICR mice and have an LD 50 value of greater than 2000 mg/kg body weight (BW).
... ProTox-II currently includes methods for prediction of various toxicological endpoints such as cytotoxicity, mutagenicity, carcinogenicity, immunotoxicity, and LD50 [60] ( Table 2). The LD50 is the median lethal dose meaning the dose at which 50% of test subjects die upon exposure to a compound [61]. Toxicity levels are including class I: fatal if swallowed (LD50 ≤ 5), class II: fatal if swallowed (5 < LD50 ≤ 50), class III: toxic if swallowed (50 < LD50 ≤ 300), class IV: harmful if swallowed (300 < LD50 ≤ 2000) class V: may be harmful if swallowed (2000 < LD50 ≤ 5000), and Class VI: non-toxic (LD50 > 5000) [62]. ...
Background
Fibroblast growth factor receptor 3 is known as a favorable aim in vast range of cancers, particularly in bladder cancer treatment. Pharmacophore and QSAR modeling approaches are broadly utilized for developing novel compounds for the determination of inhibitory activity versus the biological target. In this study, these methods employed to identify FGFR3 potential inhibitors.
Methods
To find the potential compounds for bladder cancer targeting, ZINC and NCI databases were screened. Pharmacophore and QSAR modeling of FGFR3 inhibitors were utilized for dataset screening. Then, with regard to several factors such as Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties and Lipinski’s Rule of Five, the recognized compounds were filtered. In further step, utilizing the flexible docking technique, the obtained compounds interactions with FGFR3 were analyzed.
Results
The best five compounds, namely ZINC09045651, ZINC08433190, ZINC00702764, ZINC00710252 and ZINC00668789 were selected for Molecular Dynamics (MD) studies. Off-targeting of screened compounds was also investigated through CDD search and molecular docking. MD outcomes confirmed docking investigations and revealed that five selected compounds could make steady interactions with the FGFR3 and might have effective inhibitory potencies on FGFR3.
Conclusion
These compounds can be considered as candidates for bladder cancer therapy with improved therapeutic properties and less adverse effects.
... Following the learning period, each group is evaluated using a standardized test that permits comparison between the two groups [6]. The superiority of the first method, in terms of cost and time-effectiveness, is reported by the determinations of investigators who followed up the above-mentioned study design [7][8][9][10][11][12][13]. Within Europe, shifting to alternative methods has become a legislative requirement according to the European Convention 123, which absolutely prohibits students' use of animals in their basic university courses. ...
Virtual simulation-based learning has opened a vista for surmounting ethical issues with the use of animals in compliance with one of the '3Rs' in ethical principles for animal use, which is 'replacement.' It's effective in terms of time, place, and cost. For instance, the time for drug application in cancer models would be less with virtual simulations, and the cost of maintenance and update of the software is less than that of breeding and feeding experimental animals. This paper examines the effects of utilizing a virtual computer tool simulating real pharmacology laboratory equipment in the second semester of a large-scale basic medical course. We looked at the theories of education and instructional designs and used them to develop a virtual computer lab that could help our students meet the intended learning outcomes. We analyzed, developed, implemented, and finally evaluated the students' reactions (at the Kirkpatrick level) using a self-administered questionnaire with responses on a three-point Likert scale. Feedback was obtained from 60 out of 82 (73.2 %) level 4 medical undergraduate students of both sexes, 39/60 (65%) were from the male section of the college. Sixty percent of the students admitted that the software is simple. Sixty percent agreed that it was good. Fifty-seven percent denied previous exposure to the simulation lab. Fifty-two percent reported that the practical lab's content was good, 53.3% rated the achievement of the practical objectives as good, 48.3% rated the practical enforcement of theoretical knowledge as good, 61.7% estimated getting realistic results, 48.3% agreed that the simulation lab encourages formulating a live experiment to test the hypothesis, and 51.7 % decided that the time framework was long. Thirty-eight percent appreciated the learning experience, and 45% felt that it should be repeated elsewhere. Students from the female section opted to record different determinations. The experience of using the virtual computer lab as part of the teaching program in pharmacology confirms the educational value of simulation. By adding a flexible reliable teaching method, we believe it served as a valuable tool for assisting teaching and learning in our context. Moreover, it is perceived as favorable by a good number of our students.
... LD50 (median lethal dose) is commonly adopted to reflect the lethal dose of a metallic element. 17 Thus, it can serve as the upper limit for BMs. The third and the most important one is human/clinicalrelated biocompatibility. ...
Biodegradable metals, designed to be safely degraded and absorbed by the body after fulfil the intended functions, are of particular interest in the 21st century. The marriage of advanced biodegradable metals with clinical needs have yield unprecedented possibility. Magnesium, iron, and zinc-based materials constitute the main components of temporary, implantable metallic medical devices. A burgeoning number of studies on biodegradable metals have driven the clinical translation of biodegradable metallic devices in the fields of cardiology and orthopaedics over the last decade. Their ability to degrade as well as their beneficial biological functions elicited during degradation endow this type of material with the potential to shift the paradigm in the treatment of musculoskeletal and cardiovascular diseases. This review provides an insight into the degradation mechanism of these metallic devices in specific application sites and introduces state-of-the-art translational research in the field of biodegradable metals, as well as highlighting some challenges for materials design strategies in the context of mechanical and biological compatibility.
... We want to emphasize that our approach is not a conventional meta-analysis but a step to obtain a broad understanding of whether different functional/taxonomic groups show any rare response to three selected climate extremes. For this purpose, we adapted the concept of median lethal dose (LD 50 ) from toxicology, in which the LD 50 concentration of a chemical causes 50% mortality in a test population (Zbinden and Flury-Roversi, 1981). Accordingly, if a climate extreme caused 50% or more population mortality of a species, we considered this as a ''rare response.'' ...
Anthropogenic climate change is increasing the incidence of climate extremes. Consequences of climate extremes on biodiversity can be highly detrimental, yet few studies also suggest beneficial effects of climate extremes on certain organisms. To obtain a general understanding of ecological responses to climate extremes, we present a review of how 16 major taxonomic/functional groups (including microorganisms, plants, invertebrates, and vertebrates) respond during extreme drought, precipitation, and temperature. Most taxonomic/functional groups respond negatively to extreme events, whereas groups like mosses, legumes, trees, and vertebrate predators respond most negatively to climate extremes. We further highlight ecological recovery after climate extremes are challenging to predict purely based on ecological responses during or immediately after climate extremes. By accounting for the characteristics of the recovering species, resource availability, and species interactions with neighbouring competitors or facilitators, mutualists, and enemies, we outline a conceptual framework to better predict ecological recovery in terrestrial ecosystems.
... However, the question remains whether this time interval can be made sufficiently small to allow for effective therapeutic intervention. The standard for making such a determination relies on the LD50, or the median lethal dosage of ricin or any other toxin in a human population [26,27]. This lethal dose is expressed as a mass fraction of toxin quantity compared to the average human body weight, and for ricin this value has been estimated to be 5-10 µg/kg [28]. ...
Background: In the event of a biological warfare attack, prompt real-time detection methods are necessary to
identify the presence of a pathogen well before victims begin exhibiting symptoms in order to allow sufficient time for therapeutic intervention. Current techniques for detecting the presence of biological warfare agents in high-risk environments are exclusively structure-based, relying on the identification of key structural components of specific pathogens that are already well-known and studied. These techniques provide no defense against the modern capability to synthesize new and unfamiliar pathogens of an arbitrary structure that could evade these detection mechanisms.
Methods/Results: This investigation tested the prospect of using electrochemical impedance spectroscopy (EIS) to create a real-time function-based biosensor to identify any cytotoxic substance, whether known or unknown, without regard to its structure. The concept was tested by exposing A549 epithelial adenocarcinoma cells to ricin in several concentrations, ranging from 1 ng/mL to 1000 ng/mL, and observing the effect on the measured impedance of the cells. With as few as three unique trials for each concentration, a statistically significant difference was observed between the impedance data for ricin-exposed cells and that of a ricin-free control group. By comparing the change in the impedance of each sample over periods of 60 minutes and 4 hours, statistically significant detection was achieved within timeframes ranging from 65 minutes after adding 1000 ng/mL ricin to 45 hours after adding 1 ng/mL ricin.
Conclusion: EIS provides a highly sensitive, real-time, and non-destructive method to identify the presence of a cytotoxin. EIS demonstrates rapid detection times that become faster as the concentration increases. Further analysis describes how the design of a potential biosensing device could be used to convert an arbitrary airborne concentration to a media concentration sufficiently large as to achieve detection within the window of time necessary for therapeutic intervention.
... 3.6.1. Acute toxicity study and determination of LD 50 An estimation of the lethal dose, which is expected to cause 50% death of test animals observed over a specified period, is required to specify the acute toxicity endpoints or safety of any synthesized chemicals [65]. Chemicals with higher LD 50 values are regarded as safer for biological systems than those with lower LD 50 values [66]. ...
The prescribed use of non-steroidal anti-inflammatory drugs is associated with numerous life-threatening side effects. There is a great need to develop low-dose NSAID formulations to prevent the rate of adverse events while retaining the therapeutic efficacy. In this context, we prepared nanoformulated naproxen using MgO as a nanocarrier and PVA as coating agent and investigated its biological activity in comparison to free form naproxen sodium (NPRS) and standard anti-inflammatory drugs. MgO nanoparticles with a hydrodynamic size of approximately 140–484 nm were prepared and conjugated with NPRS and capped with hydrophilic polymer (PVA) successfully. Conjugation of NPRS with MgO nanoparticles was confirmed by UV–Visible, FTIR, XRD, DLS, LIBS techniques. The hydrodynamic size and surface charge of nanoformulated naproxen were found to be 161 nm and −8.85 mV, respectively. Nanoformulated naproxen showed maximal and sustained release (>95%) at pH 6.8 within 24 h. Investigation of thermal attributes showed that the nanoformulated naproxen was more stable at a higher temperature than free NPRS. In vivo anti-inflammatory, analgesic, and antipyretic activities of nanoformulated naproxen revealed that in all cases, the potency and efficacy of nanoformulated naproxen were found to be higher than NPRS. Moreover, nanoformulated naproxen was well tolerated up to 2000 mg/kg b.w with an LD50 of 2574.77 mg/kg. The ratio between the minimum effective dose (1 mg/kg) and LD50 indicated a broader therapeutic window. Since the concentration of NPRS in nanoformulated naproxen was only 43.2 ± 2%, our results indicated that conjugation to MgO nanocarrier boosts the biological activity of NPRS by approximately 2.3 times. In addition, nanoformulated naproxen is found to be biocompatible and hemocompatible. We conclude that the nanosizing of a drug offer much promise as a better alternative to standard anti-inflammatory drugs for the treatment of various diseases.
... Therefore, conducting toxicity studies are clinically important since they provide significant health-related information, such as, dose-response curve, safety assessment of new chemicals, venoms, antivenoms, drugs or food additives, and useful data for epidemiological studies [30,43]. Although, LD50 tests have their limitations and disadvantages, such as using large number of animals, causing considerable pain in them, and the confounding factors, e.g., species differences in gender, age, diet, genetic strain, health, degree of starvation, and method of dosing [44,45], they are still being used. ...
Background: Poisoning due to the bites and stings of venomous snakes and scorpions is a neglected public health problem, particularly in rural areas. Poor health facilities and inadequate knowledge of health care personnel are the major factors that result in envenomated human victims not receiving adequate care and medical attention. There is a great need for up-to-date and effective healthcare knowledge and awareness of the potency and lethality of venomous creatures in Iran. Assessment of the potency, acute toxicity, and lethal effects of venomous creatures come from a variety of specific tests, such as the 50% median lethal dose (LD50) and ample animal experimentations.
Methods: In the present study, using modified Reed-Muench method, the LD0, LD50, and LD100 values of the venoms from five Iranian vipers and one scorpion were determined. The studied venomous creatures were: Macrovipera lebetina, Vipera albicornuta, Vipera raddei, Caucasicus intemedius agkistrodon, Montivipera latifii, and one scorpion Hemiscorpius lepturus. The venoms were injected in Albino mice (n=204) intraperitoneally, and their toxicities determined.
Results: The results revealed that the LD50 values of the above-mentioned creatures were 3.87, 2.05, 1.63, 1.45, 0.84, and 6.33 mg/kg, respectively. Among the vipers, M. latifii had the most potent venom while M. lebetina’s venom had the lowest toxicity.
Conclusion: Theoretically, the determined LD50 values provide for objective comparisons of the toxicity among of the venoms. However, comparison becomes complicated due to variations in the venoms’ LD50. Further, based on the venoms’ toxicity levels, H. lepturus’ venom caused the lowest toxicity in the Albino mice.
... Besides, the presentation of the observational data and the results of related statistical tests comparing the effects of different treatment doses to control is often lacking. While LD 50 (with or without associated uncertainty) values are usually reported, their numerical value can be greatly influenced by factors such as the number, age or diet of animals tested, food deprivation prior to dosing, housing, or other experimental conditions; therefore, they should not be regarded as biological constants (Zbinden and Flury-Roversi 1981). Nevertheless, findings so far generally implied that present field-realistic concentrations of this neonicotinoid have a minor acute and chronic effect on bumblebee mortality irrespective of the form of application (i.e. ...
Due to recent changes in regulation, acetamiprid has become the only neonicotinoid that can be applied without restrictions and in open field cultivations in the EU from 2021. We provide an overview of the current knowledge on the effects of this insecticide on bumblebees and assessed whether available empirical evidence supports the claim that acetamiprid poses negligible risk to these pollinators. We found that there is limited data on the lethal and sublethal effects of this pesticide on bumblebees. While risk assessment results suggest that field-realistic concentrations of acetamiprid have minor acute and chronic toxicity, detrimental sublethal effects, including reduced reproductive output, have been observed when bumblebees were exposed to high doses of this insecticide. We propose that further research on the topic is warranted as the more extensive application of acetamiprid may lead to such high concentrations in the field.
... New drugs and compounds require to be tested for their toxicology profile before human application. 45 In vitro cytotoxicity tests have proven to be an effective alternative for animal experiments in acute toxicity experiments as estimations are possible with high accuracy. 46 The measurement of IC 50 in NPs allows to identify the potential toxic effect related with their persistent accumulation in organs, 47 as concerns have been raised on the potential risk of using NPs in medical applications. ...
... It could be used as an agent for cytoprotective [100] . Furthermore, the LD50 of FVCO is determined as 5000mg/kg, considering that amount has been reported to have no lethal activity [101] . ...
This review summarizes the background of Cocos nucifera, the benefits of the isolated virgin coconut oil (VCO), such as its potential as an adjunctive treatment for COVID-19, and its pharmacological effects, including antiviral and anti-inflammatory properties that could be applicable for therapeutic purposes against viral diseases. Observational studies, randomized, double-blind controlled intervention trials, and nonrandomized studies comprise this review that served as a basis. Consequently, from these summarized reports, the substances present in the VCO exhibit antiviral and immunomodulatory activity adjunct with antiviral drugs, which could prevent host cell infection and viral infection replication or reduce the inflammatory effects of COVID-19. Even though there are several studies of VCO in relation to its pharmacological properties, no recent studies have considered the implementation of the secondary metabolites present in virgin coconut oil as an adjunct to COVID-19 treatment. Therefore, further human clinical and observational studies for VCO are needed to suffice the need for evidence in regard to its potential use as an adjunctive treatment against COVID-19.
... These results revealed that the LD50 value of P. americana seed was estimated to be greater than 5000 mg/kg. This places the seed fraction in class 5 status (LD50 > 5000 mg/kg), i.e., in the lowest toxicity class [49] according to OECD labelling and classification of acute systemic toxicity. The ethyl acetate fractions of these plants are considered generally safe for animal consumption up to 5,000 mg/kg b.wt. ...
Aims: Persea americana (P. americana) dubbed ‘green gold’ is a highly sought after fruit today, with insatiable export market. Different parts of avocadoes have been consumed both for nutritional and health benefits across regions of the world. Therefore, this study investigates the bioactive composition of P. americana seed ethyl acetate fraction and acute toxicological effects. Place and duration of study: Department of Biochemistry, Federal University of Technology Owerri, Imo State, Nigeria; between May 2019 and October, 2019. Methodology: Quantitative phytochemical composition was assessed using gas chromatography fitted with flame ionization detector (GC-FID) and acute toxicity determined using standard method. Results: Result of quantitative phytochemical composition of P. americana seed fraction shows a rich presence of phytochemicals such as epicatechin, kaempferol, proanthocyanin, rutin, resveratrol, ribalinidine, naringin, spartein, quinine, flavan-3-ol, anthocyanin, lunamarin, sapogenin, flavonones, flavones. The quantitative phytochemical composition of P. americana seed shows that among other phytochemicals, the seed is relatively rich in anthocyanin, quinine, epicatechin, tannin and proanthocyanin with concentrations of 69.39 ± 8.33 µg/g, 22.16 ±1.77 µg/g, 21.88 ± 2.53 µg/g, 19.86 ± 1.19 µg/g and 10.98 ± 0.55 µg/g respectively. The acute toxicity studies on the seed reveal that the ethyl acetate fraction of P. americana seed did not elicit any lethal signs of morbidity and mortality at doses up to 5000mg/Kgb.wt. and are therefore considered generally safe. Conclusion: P. americana seed ethyl acetate fraction contains essential phytochemicals with useful phyto-medicinal and nutraceutical benefits. The implications of these findings are further discussed.
... Based on the results, the values of the median lethal dose (LD 50 ) for cells were calculated using Behrens' method (Zbinden & Flury-Roversi, 1981). ...
Currently, we are dealing with ever-increasing pollution of the environment with metal and metal oxide nanoparticles. One type of these, zinc oxide nanoparticles (ZnO-NPs), are increasingly used in areas such as cosmetology, electrical engineering, medicine, and even in the food and textile industries. As a consequence, ZnO-NPs may enter the human body in many ways. Their influence on the body is still not clear. Here, we define the mechanism of the initial toxicity of ZnO-NPs to cells based on interaction with the lipid part of the native and model cell membrane. The selected cell lines react differently to contact with nanoparticles. We found a disruption of the native membranes of B16-F0 cells and to a lesser extent of COLO 679. In turn, the membrane of COLO 679 cells was more peroxidated, and cell viability was much lower. A model of the lipid part of the membrane was created for B16-F0 cells and compared with previously published studies on immune cells. On the basis of physicochemical parameters obtained for individual lipids and a mix representing the native membrane of the tested cells, we concluded that exposure to nanoparticles resulted in a change within the model membranes (specifically with the polar parts of lipids). The greatest interaction has been noticed between ZnO-NPs and zwitterionic phospholipids (PC and PE), cholesterol, and negatively charged phosphatidylglycerol. Assessing the interactions between the membrane and nanoparticles will help to better understand the first steps of its toxicity mechanism.
... OECD Guidance Document 34) (OECD, 2005). It is in itself a challenge to estimate an LC 50 in rodents (Sperling and McLaughlin, 1976;Zbinden and Flury-Roversi, 1981), so comparison to the outcome of a mechanistically anchored in vitro method, with the aim of a correlation, seems hardly possible. ...
To date there are no OECD validated alternative approaches to study toxicity following inhalation exposure to airborne chemicals. The available OECD test guidelines for acute inhalation toxicity aim to estimate a value of the lethal air concentration of the test chemical leading to the death of 50% of the exposed animals (LC50), to satisfy hazard classification and labelling requirements. This paper explores the view that alternative approaches must compare to outcomes of existing guideline methods to become accepted and implemented in a regulatory context. This case study describes the initiatives taken to validate the lung surfactant bioassay, an in vitro cell-free method, and discusses the challenges faced. While the lung surfactant bioassay could not predict the GHS classification for acute inhalation toxicity of 26 chemicals, the assay successfully predicted the clinical signs of respiratory toxicity observed during or shortly after exposure in vivo as reported in registration dossiers. The lung surfactant bioassay is a promising alternative approach to assess the potential of chemicals to cause changes to respiration remaining after exposure (indicating impaired lung function), and can be combined with other test methods in an integrated approach to testing and assessment of inhaled substances.
... Ultimately, studies prior to genetics or epigenetics are used to assess occupational health, and the development of occupational exposure levels (OELs) should affect occupational exposure and the onset of toxicity (Gallo et al. 2011). Computational biology and the use of toxic pathways will increasingly focus on consistent physiological changes between groups of similar toxic chemicals (Jennings 2013;MacKay et al. 2013), the development of non-animal assays could provide more predictable tools or other in vivo observations using pathway-based machine information (BéruBé 2013), and should be sufficient to predict and manage potential human side effects (Chapman et al. 2010;Seidle et al. 2010;Zbinden and Flury-Roversi 1981). As a method to be applied directly to the semiconductor manufacturing process, constant monitoring of the and it is also necessary to construct a web-based system, such as AOP-KB, in the workplace of the future, so that the web-based AOP system can be used efficiently. ...
Background
To solve current issues using big data, solve current issues related to the semiconductor and electronics industry, I tried to establish the data for each toxicity mechanism for adverse outcome pathway (AOP) for the exposure.ObjectiveI planned to increase the efficiency of human hazard assessment by searching, analyzing, and linking test data on the relationship between key events occurred at each level, which are the biological targets of chemicals in semiconductor manufacturing.ResultsIt was found that 48 kinds of chemicals had 11 AOPs, while 103 chemicals had multiple AOPs, and 26 had case evidence. As a result of AOP analysis, it was found that a total of 320 chemicals had 42 AOPs, and 190 major chemicals corresponded to 11 AOPs. It was found necessary to develop a complex AOP and secure an (inhalation or dermal) exposure scenario for combined exposure at work. As a comparative search (41 out of 190 chemicals) of biomarkers specific to occupational diseases, 12 biomarkers were found to be related to breast cancer. The AOPs for 50 specific chemicals were presented, together with occupational disease-specific AOPs and key events relationship from 50 chemicals, and taxonomic classification for each AOP analysis could be found. With a comparative search, 41 out of 190 chemicals were associated with specific biomarkers for occupational diseases, and 12 mRNA or protein biomarkers were found to be related to breast cancer by cross-validation with the attached Table 24 of the Enforcement Regulations of the OSHAct and the CTD.Conclusion
The mechanism of occupational diseases caused by chemicals was presented, together with pathological preventions. I believe that a strategy is needed to expand the target organization for each chemical by linking with activities, such as work environment measurement, and cooperating with screening items and methods suitable for toxic chemicals, like AOP tools.
... We want to emphasize that our approach is not a conventional meta-analysis but a step to obtain a broad understanding of whether different functional/taxonomic groups show any rare response to three selected climate extremes. For this purpose, we adapted the concept of median lethal dose (LD 50 ) from toxicology, in which the LD 50 concentration of a chemical causes 50% mortality in a test population (Zbinden and Flury-Roversi, 1981). Accordingly, if a climate extreme caused 50% or more population mortality of a species, we considered this as a ''rare response.'' ...
... isolated or aggregated), time of day/night and time of year. 4 Many of these factors also apply to assessments of HLD values, and thus contribute to uncertainty concerning their accuracy. ...
The prediction of human toxicities from animal toxicity tests is often poor, and is now discouraged and in some cases banned, especially those involving the LD 50 test. However, there is a vast number of historical LD 50 data in both public and in-house repositories that are being put to little use. This study examined the correlations between human lethality (doses and concentrations) of 36 MEIC chemicals and the median values of a large number of mouse and rat LD 50 values obtained for four different routes of administration. The best correlations were found with mouse and rat intraperitoneal LD 50 values (r ² = 0.838 and 0.810 for human lethal dose, and r ² = 0.753 and 0.785 for human lethal concentration). The results show that excellent prediction of human lethal dose and concentration can be made, for this series of chemicals at least, by using uncurated rodent LD 50 values, thus offering some reparation for the millions of rodent lives sacrificed in LD 50 testing.
... However, LD50 is not a standard way of measuring safety as many variables such as gender, age, animal species, diet, strain, bedding, caging conditions, and ambient temperature, can affect the LD50 value. [30]. ...
Background: Pulcria crispa (P. crispa) is an herbal plant traditionally used to treat common ailments. Objective: In this study, we investigated P. crispa for its phytochemical constituents, antioxidant properties and effects on biochemical and hematological parameters as well as safety in albino rats. Methods: Phytochemical analysis of ethanolic extract of P. crispa was conducted using standard procedures. In vitro 2, 2-Diphenyl-1-picrylhydrazyl (DPPH) and reducing power assay were used for the investigation of antioxidant activity of extract. Acute effects on physical and behavioral changes and mortality were monitored up to 72 h after administration of different doses of C. crispa Chronic effects on body to organ ratio, biochemical and hematological parameters were measured after administration of rats with different doses of P. crispa extract for 30 days. Results: Alkaloids, flavonoids, phenols and tannins were the most abundant constituents found in P. crispa extract, which displayed a significant antioxidant activity measured by reducing power and DPPH assays. No physical, behavioral changes and mortality were noted following the acute treatment of rats with the extract. Similarly, no significant change in body to organ weight ratio was observed after chronic treatment. Hematological parameters including RBCs, Hb, PCV, MCV, MCH and MCHC values were unaltered while W.B.C count was elevated in P.crispa administered rats compared to control. crispa extract significantly reduced glucose, urea, creatinine, cholesterol, bilirubin, AST and ALT levels, whereas, triglycerides and total protein levels were increased in response to P.crispa treatment. Conclusions: This study demonstrates that P. crispa extract is rich in bioactive compounds and possesses significant antioxidant properties. Extract was also found to be safe and had no significant adverse effects on hematological parameters and exerted beneficial effects on biochemical parameters.
... New drugs and compounds require to be tested for their toxicology profile before human application. 45 In vitro cytotoxicity tests have proven to be an effective alternative for animal experiments in acute toxicity experiments as estimations are possible with high accuracy. 46 The measurement of IC 50 in NPs allows to identify the potential toxic effect related with their persistent accumulation in organs, 47 as concerns have been raised on the potential risk of using NPs in medical applications. ...
Cancer is a major public health problem being one of the main causes of morbidity and mortality today. Recent advances in catalytic nanomedicine have offered new cancer therapies based on the administration of nanoparticles (NPs) of platinum (Pt) dispersed in catalytic mesoporous nanomaterials (titania, TiO 2) with highly selective cytotoxic properties and no adverse effects. A half maximal inhibitory concentration (IC 50) study was carried out in cancerous cell lines (HeLa, DU-145, and fibroblasts) to evaluate the cytotoxic effect of different nanomaterials [Pt/TiO 2 , TiO 2 , and Pt(acac) 2 ] synthesized by the sol−gel method at concentrations 0−1000 μg/mL. The assays showed that IC 50 values for Pt in functionalized TiO 2 (NPt) in HeLa (53.74 ± 2.95 μg/mL) and DU-145 (75.07 ± 5.48 μg/mL) were lower than those of pure TiO 2 (74.29 ± 8.95 and 82.02 ± 6.03 μg/mL, respectively). Pt(acac) 2 exhibited no cytotoxicity. Normal cells (fibroblasts) treated with NPt exhibited no significant growth inhibition, suggesting the high selectivity of the compound for cancerous cells only. TiO 2 and NPt were identified as antineoplastic compounds in vitro. Pt(acac) 2 is not recommendable because of the low cytotoxicity observed.
Deoxynivalenol (DON) has a strong toxic effect on the gastrointestinal mucosa of poultry. In this study, we evaluated chicken embryo development and glandular stomach damage to clarify the immunotoxic effects of DON injected through the allantoic cavity of chicken embryos. The glandular stomach index, routine blood indices, plasma inflammatory factors, pathological changes in the glandular stomach, and transcriptome results were analyzed in the hatching chicks. The results showed that DON was supertoxic to chicken embryos, causing edema, shedding, and bleeding of the mucosa of the glandular stomach, which triggered inflammatory reactions. As the toxin concentration increased, the immune system was successively activated and inhibited, and regulation was carried out by the differential regulation of the mitogen-activated protein kinase (MAPK) signal pathway. These results suggested that the immunotoxic effect of DON on the glandular stomach of chicken embryos was closely related to the regulation of the MAPK signaling pathway.
Acute toxicity testing serves to detect, identify, and assess the dose–response relationship of a single administered doses of a drug or chemical entity. The current trend is either to generate increasing amounts of more sophisticated data from these tests, usually for “phase 0” studies, or to do only a limited maximum tolerated dose study to identify doses for the repeat‐dose pilot phase. Dose range finders or pilots are not required to be or normally conducted completely under the auspices of the Good Laboratory Practice Act. Acute systemic toxicity studies are performed to define the acute toxicity of a drug more completely. They are more extensive and time‐consuming than range‐finding tests or screens and are normally the type of study done to satisfy regulatory requirements or to provide a more thorough early characterization or prediction of toxicity. Screens are generally not safety studies in the regulatory sense.
Background : Intentional or unintentional ingestion of organophosphate compounds is a common cause of death due to poisoning specially in rural areas of developing countries. Objective: In this study effects of atropine sulfate and scopolamine hydrobromide were compared with respect to modification of LD50 of malathion. Design : Animal experimental study was carried out in albino mice. Result : It was observed that LD50 of Malathion was increased more by scopolamine hydrobromide than atropine sulfate.
Silver nanoparticles (AgNPs) prepared and stabilized by diverse biologically active substances seem to be especially useful in diverse biological and medical applications. The combination of AgNPs with bioactive substances, such as antioxidants, can lead to the development of new systems of desired anticancer properties. In this research, AgNPs were prepared with the use of diverse antioxidant combinations including gallic acid (GA), (-)-epicatechin-3-gallate (EGCG), and caffeine (CAF). The insightful physicochemical characteristic revealed that each type of AgNPs exhibited spherical shape, comparable size distribution and negative surface charge. Surface-enhanced Raman spectroscopy (SERS) delivered the information about the chemistry of AgNP stabilizing layers, which turned out to be a crucial factor tuning toxicity of AgNPs toward murine B16 melanoma cells (B16-F0) and human skin melanoma (COLO 679) cells. EGCGAgNPs were the most cytotoxic among all the investigated AgNPs. They strongly reduced the activity of mitochondria, damaged cell membrane integrity, and penetrated inside the cells causing DNA damage. In turn, the toxicity of GAAgNPs strongly manifested via the induction of oxidative stress in the cells. It was found that CAFGAAgNPs exhibited the lowest toxicity toward the melanoma cells, which proved that a proper combination of antioxidants enable to prepare AgNPs of differentiated toxicity. It was established that human skin melanoma cells were significantly more sensitive to AgNPs than the murine melanoma cells.
Studies on the phytochemical and macronutrient composition of the leaves of Combretum dolichopentalum were carried out. The qualitative phytochemical composition shows the presence of alkaloid, flavonoid, saponin, tannin, steroid, glycosides and resins. The quantitative phytochemical composition shows that it contains 5.765 ± 0.002 mg/100g tannin, 80±0.003 mg/100g flavonoids, 0.033±0.003 mg/100g cyanide, 8.717± 0.003 mg/100g alkaloids, 17.86 ± 0.002 mg/100g saponins and 6.969±0.005 mg/100g steroid. The macronutrients obtained include 2.101±0.003 mg/100g soluble carbohydrate and 200.0±0.002 mg/100g reducing sugar. The result of acute toxicity (LD 50), showed C. dolichopentalum leaf extract to be lethal at doses 3000 and 5000 mg/kg body weight. This study revealed that C. dolichopentalum is a rich source of phytochemical and reducing sugar, which if adequately processed will not only offer chemoprotective benefits to its users, but could also serve as a good source of nutrient.
Toxicity testing is used to assess the safety or hazards presented by substances such as industrial chemicals, consumer products, and pharmaceuticals. At present, many methods involve laboratory animals. Alternative procedures, some involving human cell-based technologies, are now being developed which reduce, refine, or replace animal usage and minimize the pain and distress caused. These new tests must protect public health and the environment at least as well as currently accepted methods.
This book describes the ever-expanding "toolbox" of methods available to assess toxicity. Such techniques often result from our growing understanding of the biochemical and cellular pathways that mediate toxicity mechanisms. This permits evaluations of information generated from several sources to generate a "weight of evidence". By combining in silico, in vitro, and ex vivo methods with technologies that rely on biochemical- and cell-based in vitro assays, toxicologists are developing mechanistically based alternatives to live animal experimentation. This text also explores the complexities associated with adequate validation, and the assessment of test reliability and relevance. It provides an essential reference source for postgraduates, academics and industrialists working in this rapidly changing area.
Background: Up-and-down procedure (UDP) was recommended to replace traditional acute toxicity methods. However, it was limited due to the long experimental period (20 - 42 days). To improve UDP, an improved UDP method (iUDP) was developed by shortening observation time between sequence dosages. The aim of this study was to test the reliability of iUDP to provide a reliable method for the acute toxicity measurement of valuable or minor amount compounds.
Methods: Oral median lethal dosage (LD50) of nicotine, sinomenine hydrochloride and berberine hydrochloride were measured both by iUDP and modified Karber method (mKM).
Results: LD50 of the three alkaloids measured by iUDP with 23 mice were 32.71 ± 7.46, 453.54 ± 104.59, 2954.93 ± 794.88 mg/kg, respectively. LD50 of the three alkaloids measured by mKM with 240 mice were 22.99 ± 3.01, 456.56 ± 53.38, 2825.53 ± 1212.92 mg/kg, respectively. The average time consumed by the two methods were 22 days and 14 days respectively. Total grams of the alkaloids used by the two methods were 0.0082 and 0.0673 (nicotine), 0.114 and 1.24 (sinomenine hydrochloride), 1.9 and 12.7 (berberine hydrochloride).
Conclusion: iUDP could replace mKM to detect acute toxicity of substances with comparable and reliable result. And it was suitable for valuable or minor amount substances.
Over a period of two years the Scandinavian Society for Cell Toxicology* has met three times (on 21 October 1983 and 6–7 June 1984 in Uppsala, Sweden, and on 6–7 September 1985 in Roskilde, Denmark), to present research advances in cell toxicology and to discuss the effects of xenobiotics in isolated and cultured cells. The first part of this report represents a summary of these discussions. In the second part, some of the individual research reports presented by the participating members are summarised. The purpose is to give a review of problems currently dealt with in Scandinavian laboratories associated with the Society for Cell Toxicology.
Less than a quarter of all experimental animals in Europe are used in toxicological experiments, and most of these are performed by the pharmaceutical industry. Acute toxicity testing, mainly LD50 tests, accounts for a large proportion of toxicological studies.
There are no defined animal numbers for special safety requirements in the Federal Republic of Germany (FRG). However, where the registration of chemical products in the FRG is concerned, numbers of animals used are documented.
Animal models are generally used to elucidate human physiology or pathology. However, attempts to extrapolate animal model findings to humans are undermined by differences in the aetiology and natural history between any animal model condition and the analogous human condition, and by unavoidable interspecies differences in anatomy and physiology. Even when working with species “closely related” to humans, such as chimpanzees, the animal model paradigm is fundamentally unsound. Unfortunately, few animal researchers seriously question the utility of animal models, and consequently they rarely consider other, perhaps more efficient and more reliable, means of conducting biomedical research.
Biomedical endeavours can be divided into three major categories: research, education, and testing. Within the context of each of these categories, activities involving whole animals have made major contributions and will continue to do so in the future. However, with technological developments in the areas of biotechnology and computers, new methods are already reducing the use of whole animals in certain areas. This article discusses the general issues of alternatives and then focuses on the development of new approaches to toxicity testing.
The adoption of herbicides as a weed control strategy has allowed farmers to reduce the short-term effects of biological adversities on crop yields. However, they have also jeopardized agroecosystem sustainability by causing negative alterations of social and environmental subsystems. The physicochemical properties of herbicides (volatility, adsorption, or water solubility) can make them persist in the soil, air, and water, changing the structure and function of key environmental compartments. The occurrence of herbicide-resistant weed populations has generated a positive feedback loop requiring the application of higher doses, aggravating negative externalities. Hence, the economic benefits of herbicides as a unique control strategy substantially decrease in time. In addition, the dependence of agricultural systems on external inputs generates an herbicidal “lock-in” process that hinders the transition towards more sustainable integrated management systems. Therefore, there is a pressing need to elucidate the principal aspects of environmental risk analysis of herbicide use in agroecosystems. The objectives of this chapter are: (1) to introduce key concepts related to the construction and application of environmental risk indicators with a focus on agricultural system risk assessment, (2) to list the potentially negative effects associated with the use of herbicides, (3) to understand the processes that regulate herbicides’ fate and behavior in farming systems, (4) to highlight the importance of decision support systems (DSS) in reducing herbicide use in favor of integrated weed management (IWM), and (5) to understand the decision-making logic behind the increasing adoption of chemical weed control despite its negative socio-environmental effects.
Rodent LD50 values have been used for almost a century as a measure of potential human toxicity from drugs and other chemicals. However, they have been found not, on the whole, to be good models for human toxicity. One reason for this could be the often-high variability of LD50 values. It has recently been shown that by using median LD50 values, very good correlations have been found with human lethal dosages. Bearing in mind the millions of rodent lives sacrificed, many with no good reason, it is proposed that some reparation could be made by more investigations using median values of already available rodent LD50 values.
Nanosized natural polymers have attained considerable attention in drug delivery applications due to their high encapsulation efficiency, non-toxic nature, sustained and targeted drug delivery. Here we have synthesized Rifampicin loaded alginate nanoparticles by green method. Physicochemical characterization of the nanoparticles was assessed using Transmission electron microscopy, Fourier transform infrared spectroscopy, Dynamic light scattering and X-ray diffraction technique. The swelling and in vitro drug release showed that the framework experiences pH-dependent swelling and release of Rifampicin. Rifampicin has lower release in acid medium and higher release in intestinal condition. Moreover, in view of the drug release results, the release kinetics and transport mechanisms were investigated and discussed. In vitro cytotoxicity assay demonstrated that the nanoparticles were non-toxic in nature. The acute oral toxicity study of the synthesized nanoparticles was done in Wistar albino rats. No systemic toxicity was observed after oral administration of nanoparticles. The present study demonstrated the potential of using alginate nanoparticles synthesized by a green method for drug delivery applications.
The third edition of Gleason, Gosselin, and Hodge remains an essential volume for any Pediatric Emergency Service or for any doctor dealing at all commonly with poisonings. With the addition of one more author, Roger P. Smith, PhD, and a change in cover color to bright blue, this new volume should be placed alongside the two prior editions rather than replace them since some of the previously listed products have been dropped as obsolete and yet, still may exist to cause a rare poisoning. Basically, the third edition is unchanged as to format; the same seven sections: (1) first aid and general treatment, (2) ingredient index and toxicity ratings, (3) therapeutic discussions of specific poisons, (4) supportive treatment, (5) trade name product index and contents, (6) general formulations of common classes of commercial products such as drainpipe cleaners or hair sprays, and (7) index of manufacturers with addresses. Much of
A log-probit graph paper is described by which a simple graphic estimation of the ED50 and its standard error may be quickly made.
This chapter discusses the experimental and clinical aspects of drug toxicity. With the development of an increasing number of new and often very potent medicaments the problem of drug-induced toxicity has become a matter of major concern. The history of every new substance is almost invariably marked by an early and enthusiastic acclaim for its novel therapeutic potential which is often followed by a condemnation due to the occurrence of the seemingly inevitable side actions. This phase is usually followed by a more realistic appraisal of the new compound and recognition of its range of usefulness, contraindications, and dangers. Since there is probably no biologically active substance which does not exhibit some undesirable effects, drug-induced toxicity will always accompany the progress made in drug therapy. It would be very desirable if the harmful effects of newly developed compounds could be recognized in animals before any damage is done to human subjects. For that reason it has become a standard practice to subject every drug to extensive trials in laboratory animals prior to their release for human use.
The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats to acetaminophen-induced liver necrosis has been examined. The fraction of low doses of acetaminophen converted to the mercapturic acid metabolite was highest in the most susceptible species (hamsters, mice), and lowest in the more resistant species (rat). Pretreatment regimens known to potentiate the hepatotoxicity increased mercapturic acid formation whereas treatments which protect from liver damage decreased mercapturic acid formation. The data suggest that the activity of the mercapturic acid-forming pathway in vivo reflects the activity of the hepatotoxic pathway. As the dose of acetaminophen was increased to hepatotoxic levels, the fraction of the dose excreted as the mercapturic acid decreased markedly, commensurate with the known depletion of hepatic glutathione under these conditions. It is suggested that the normal metabolic intermediate which conjugates with glutathione in the mercapturic acid pathway is also the electrophilic metabolite which in the absence of glutathione arylates hepatic macromolecules and causes cell death.
Ten chemicals were administered orally to male albino rats by 8 industrial or commercial toxicology laboratories. In each laboratory, the LD50 for each chemical was determined using three different protocols: (a) a reference protocol using a reference stock of rats, (b) the same reference procedure using the rats commonly used by each laboratory and (c) the procedure and rats generally used by each laboratory. The results of this round robin study denoted certain laboratories with consistent bias; one, using pathogen-free rats, had high LD50's and another laboratory had consistently low LD50's. The latter laboratory also had consistently high fiducial ranges.The effects of fasting, change of stock, different diets, various intubation methods, etc. were compared between laboratories and within the same laboratory. Overall, the effects of different stocks were slight, except in a laboratory using a rapidly growing rat and in the one using the pathogen-free rat. A procedure using nonfasted, mature rats was related in one laboratory to higher LD50's. The use of female rats was related to lower LD50's.The fiducial range was again shown to be somewhat related to the geometric factor between dosage levels. The LD50's were not affected by this factor.Generally, only a few significant interlab differences in LD50's and fiducial ranges were found between the reference or nonstandard protocols.
The sigmoid dosage-mortality curve, secured so commonly in toxicity tests upon multicellular organisms, is interpreted as a cumulative normal frequency distribution of the variation among the individuals of a population in their susceptibility to a toxic agent, which susceptibility is inversely proportional to the logarithm of the dose applied. In support of this interpretation is the fact that when dosage is inferred from the observed mortality on the assumption that susceptibility is distributed normally, such inferred dosages, in terms of units called probits, give straight lines when plotted against the logarithm of their corresponding observed dosages. It is shown that this use of the logarithm of the dosage can be interpreted in terms either of the Weber-Fechner law or of the amount of poison fixed by the tissues of the organism. How this transformation to a straight regression line facilitates the precise estimation of the dosage-mortality relationship and its accuracy is considered in detail. Statistical methods are described for taking account of tests which result in 0 or 100 per cent, kill, for giving each determination a weight proportional to its reliability, for computing the position and slope of the transformed dosage-mortality curve, for measuring the goodness of fit of the regression line to the observations by the X2 test, and for calculating the error in position and in slope and their combined effect at any log. dosage. The terminology and procedures are consistent with those used by R. A. Fisher, who has contributed an appendix on the case of zero survivors. Except for a table of common logarithms, all the tables required to utilise the methods described are given either in the present paper or in Fisher's book. A numerical example selected from Strand's experiments upon Tribolium confusum with carbon disulphide has been worked out in detail.
Es wird ein Verfahren zur kollektiven Behandlung von Reihenversuchen angegeben, das gestattet, auch bei kleinerem Umfang des Kollektivs (Reihenversuch mit vier bis fnf Gruppen zu je sechs Tieren) und bei starker Streuung zu einem zahlenmigen Ausdruck des Versuchsergebnisses zu gelangen.
1.
Die individuelle Streuung der Giftempfindlichkeit von Frschen gegen Strophanthin und auch Digitalisglykoside wird sowohl bei intravenser Zufuhr wie bei Einspritzung in den Lymphsack zu rund 20% gefunden.
2.
Es wurden Untersuchungen ber die Brauchbarkeit der Vorschriften des Deutschen Arzneibuches fr die Auswertung von Digitalisglykosiden ausgefhrt, aus denen hervorgeht, da das Verfahren der Katzenmethode nicht unterlegen ist.
3.
Es wird ein neues Berechnungsverfahren beschrieben, durch das der Zentralwert mit grerer Genauigkeit erfat werden kann.
4.
Es wird ein Verfahren beschrieben, das gestattet, Versuchstieren kleine Mengen einer Giftlsung (0,01 ccm) im Verlauf 1 Stunde mit konstanter Geschwindigkeit intravens einlaufen zu lassen.
The maximal tolerated dose and the minimal lethal dose in mice are estimated for a series of twenty flucrine-containing organic compounds, four inorganic compounds of fluorine, and three nonfluorine-containing organic compounds.
A screening procedure has been described for estimating the hepatotoxic potential of industrial solvents in mice. Data on lethality, barbiturate sleeping time, and bromosulfalein retention, coupled with minimal histologic examination, were employed to determine the individual hepatotoxic potency and relative hepatotoxic potencies for nine halogenated methane derivatives. A method has been described for estimating the industrial hepatotoxic hazard by these data.
The standard method of dealing with sensitivity of dosage-mortality data is the probit technique developed by Bliss and Fisher. This paper provides an alternative technique based on a special system for obtaining such data. It has some advantages when observations must be taken on individuals rather than groups of individuals, and it may be preferred in certain other situations.
Single doses of 100, 200, 300, and 400 mg diquat ion/kg body wt were administered by stomach tube to cynomolgus monkeys. Within 4 days of dosing deaths occurred in , , , and monkeys, respectively. All animals developed diarrhea and the most severely affected became comatose. The most important histopathological changes were necrosis of the epithelium and villi of the gastrointestinal tract and of the epithelium of the proximal and distal convoluted tubules of the kidneys.
In 1977, the Commission of the European Communities initiated an intercomparison study to determine the single administration oral LD50 value in rats of each of 5 chemicals with the aims of comparing experimentation technologies, determining the degree of variation in the results and the various parameters used to establish the LD50 value, and establishing a common protocol for the determination of the LD50 value. Sixty-five laboratories in 8 countries took part in the first study. The significant variation in protocol may have led to the large interlaboratory variation observed in the results. Therefore, participating laboratories carried out a second study using a common protocol, preceded by a pilot study. A total of 100 laboratories in 13 countries participated. A majority of results of the second study are currently being analyzed, and the indications are that the interlaboratory variation has been significantly reduced.
Albino rats were fed for 28 days from weaning on diets containing no protein (group I), one-seventh of the optimal protein intake (group II), one-third of the optimal protein (group III), the optimal protein level, as 26% casein (group IV), or three times the optimal protein intake (group V). At the end of the dieting period, the acute oral LD50 ± SE of captan was found to be (in mg/kg body weight) 6·15 ± 3·1 in group I, 480 ± 110 in group II, 10,670 ± 2800 in group III, 12,600 ± 2100 in group IV and 5320 ± 1420 in group V. The interval to death extended from 5 hr to 7 days, averaged 53 hr, was shorter the higher the dose of captan, and was not consistently influenced by the amount of protein in the diet. Animals in group I were some 2000 times more susceptible to the toxic effects of captan than were controls of group IV, compared with some 12 times for lindane and monuron, eight times for carbaryl, chlorpropham and diazinon and four times for dicophane (DDT). The results indicate that further studies should be made upon captan, which could well be a hazardous pesticide to employ in countries where the diet is low in protein.
The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats to acetaminophen induced liver necrosis has been examined. The fraction of low doses of acetaminophen converted to the mercapturic acid metabolite was highest in the most susceptible species (hamsters, mice), and lowest in the more resistant species (rats). Pretreatment regimens known to potentiate the hepatotoxicity increased mercapturic acid formation whereas treatments which protect from liver damage decreased mercapturic acid formation. The data suggest that the activity of the mercapturic acid forming pathway in vivo reflects the activity of the hepatotoxic pathway. As the dose of acetaminophen was increased to hepatotoxic levels, the fraction of the dose excreted as the mercapturic acid decreased markedly, commensurate with the known depletion of hepatic glutathione under these conditions. It is suggested that the normal metabolic intermediate which conjugates with glutathione in the mercapturic acid pathway is also the electrophilic metabolite which in the absence of glutathione arylates hepatic macromolecules and causes cell death.
Isoproterenol HCl causes an ischemic myocardial necrosis in animals which is due to its exaggerated cardiovascular effects. The influence of restricted food intake on the cardiotoxicity of this compound was studied in Sprague-Dawley male rats of 3–7 mo of age. They were fed ad libitum or restrictedly (about 50%) for various periods. The latter became less susceptible to the cardiotoxic effect of isoproterenol HCl than their freely fed controls. The resistance acquired following the restricted intake of food persisted for 1 wk upon return to ad libitum feeding.The cardiac pharmacologic effect of isoproterenol HCl (the degree and duration of tachycardia) was the same in rats fed freely or restrictedly. It is postulated that restricted intake of food increased the resistance to the ischemic effect of isoproterenol.
A tabulation of LD50 values for newborn and adult mammals has been compiled from the literature and from the files of the Food and Drug Administration.
Prolonged individual caging of rats, as is sometimes employed in long-term toxicity tests, was accompanied by several changes in parameters of toxicity. In comparison to community-housed animals of same age and sex, acute LD50s might be increased or decreased. Pentobarbitone and chloral hydrate sleeping times were reduced and the induction period for the loss of righting reflex with sodium amytal was prolonged. The extent of these changes was dependent upon the length of isolation, sex, and strain. A possible explanation for these altered toxic responses was that the adrenergic or ergotropic component of the central nervous system had undergone an increase in activity in the isolated animals.
The death rates from 12 different drugs given orally to mice and rats were higher, the greater the dilution of the dose in water. A similar relationship was noted between the oral LD50 in mice and dilution of the dose of 4 different drugs.
Expert Committee of Food Additives) (1974) Toxicological evaluation of certain food additives with a review of general principles and of specification
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Morrison JK, Quinton RM, Reinert H (1968) The purpose and value of LDs0 determinations. Historical introduction. In: Boyland E, Goulding R (eds) Modern trends in toxicology Butterworths, London, p 1
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