scholarly journals Prediction of Human Lethal Doses and Concentrations of MEIC Chemicals from Rodent LD50 Values: An Attempt to Make Some Reparation

2021 ◽  
pp. 026119292199475
Author(s):  
John C. Dearden ◽  
Mark Hewitt
Keyword(s):  
Lethal Dose ◽  
Lethal Concentration ◽  
Toxicity Tests ◽  
Vast Number ◽  
Routes Of Administration ◽  
Animal Toxicity ◽  
Lethal Doses

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 LD50 test. However, there is a vast number of historical LD50 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 LD50 values obtained for four different routes of administration. The best correlations were found with mouse and rat intraperitoneal LD50 values (r2 = 0.838 and 0.810 for human lethal dose, and r2 = 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 LD50 values, thus offering some reparation for the millions of rodent lives sacrificed in LD50 testing.

Prediction of Human Lethality of Psychoactive Drugs From Rodent LD50 Values

2019 ◽  
Vol 4 (2) ◽  
pp. 1-27 ◽  
Author(s):  
John C. Dearden
Keyword(s):  
Lethal Dose ◽  
Psychoactive Drugs ◽  
Commercial Software ◽  
Routes Of Administration ◽  
Drug Doses ◽  
Toxicity Relationship ◽  
Lethal Doses

The number of deaths from the abuse of psychoactive drugs is increasing year after year, and new designer psychoactive drugs of unknown toxicity frequently appear on the streets. Human lethal drug doses generally do not correlate well with animal LD50 values. In order to investigate whether that holds for psychoactive drugs, human lethal dose values and rat and mouse LD50 values for several routes of administration for eighteen such drugs were collected from the literature. Quantitative toxicity-toxicity relationship (QTTR) regression correlations of human and rodent lethal doses were poor for both rat and mouse oral and intraperitoneal lethal doses, but both rat and mouse intravenous LD50 values correlated very well with human lethal doses (r2 = 0.823 and 0.756, respectively). Rat and mouse intravenous LD50 values predicted from commercial software also correlated reasonably well with human lethal doses (r2 = 0.631 and 0.678, respectively). This means that it should be possible to use these correlations to predict the human lethal doses of new psychoactive drugs.

scholarly journals Comparable Long-Term Rabies Immunity in Foxes after IntraMuscular and Oral Application Using a Third-Generation Oral Rabies Virus Vaccine

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 49
Author(s):  
Verena te Kamp ◽  
Virginia Friedrichs ◽  
Conrad M. Freuling ◽  
Ad Vos ◽  
Madlin Potratz ◽  
...  
Keyword(s):  
Immune Response ◽  
Rabies Virus ◽  
Specific Binding ◽  
Lethal Dose ◽  
Genetically Engineered ◽  
Routes Of Administration ◽  
Safety Studies ◽  
Oral Rabies Vaccine ◽  
Cellular Immune

The live genetically-engineered oral rabies virus (RABV) variant SPBN GASGAS induces long-lasting immunity in foxes and protection against challenge with an otherwise lethal dose of RABV field strains both after experimental oral and parenteral routes of administration. Induction of RABV-specific binding antibodies and immunoglobulin isotypes (IgM, total IgG, IgG1, IgG2) were comparable in orally and parenterally vaccinated foxes. Differences were only observed in the induction of virus-neutralizing (VNA) titers, which were significantly higher in the parenterally vaccinated group. The dynamics of rabies-specific antibodies pre- and post-challenge (365 days post vaccination) suggest the predominance of type-1 immunity protection of SPBN GASGAS. Independent of the route of administration, in the absence of IgG1 the immune response to SPBN GAGAS was mainly IgG2 driven. Interestingly, vaccination with SPBN GASGAS does not cause significant differences in inducible IFN-γ production in vaccinated animals, indicating a relatively weak cellular immune response during challenge. Notably, the parenteral application of SPBN GASGAS did not induce any adverse side effects in foxes, thus supporting safety studies of this oral rabies vaccine in various species.

scholarly journals A SPECIFIC POISON IN THE LIVER EXTRACTS OF RABBITS INOCULATED WITH TYPHOID AND PRODIGIOSUS BACILLI INTRAVENOUSLY

1918 ◽  
Vol 28 (5) ◽  
pp. 571-583
Author(s):  
Julia T. Parker
Keyword(s):  
Anaphylactic Shock ◽  
Liver Extract ◽  
Lethal Dose ◽  
Toxic Substance ◽  
Normal Liver ◽  
Immune Serum ◽  
Minimum Lethal Dose ◽  
Lethal Doses

1. The livers of rabbits inoculated with cultures of Bacillus typhosus or Bacillus prodigiosus under certain conditions contain a toxic substance extractable with salt solution. When the toxic extracts are injected intravenously into normal rabbits the latter animals develop symptoms resembling those of anaphylactic shock and succumb. The lethal doses of the toxic extracts are far smaller than those of normal liver extract. 2. The livers of rabbits injected with typhoid antigen also yield a toxic extract. 3. Boiling as well as filtration through a Berkefeld filter only partially detoxicates the extract. 4. Tolerance to one to two lethal doses of the poisonous extracts can be induced by cautious immunization. 5. Rabbits actively immunized to Bacillus typhosus or Bacillus prodigiosus usually resist one lethal dose of the homologous liver poison; and animals tolerant to the typhoid liver poison resist one minimum lethal dose at least of Bacillus typhosus. 6. Typhoid immune serum is not detoxicating either in vivo or in vitro for the typhoid liver poison. 7. The liver poisons are specific, since rabbits actively immunized to either Bacillus typhosus or Bacillus prodigiosus withstand at least one minimum lethal dose of the homologous but not of the heterologous-liver poisons.

The Cumulative Toxicity of Diniteo-O-cresol applied in Small Doses to Locusts

1957 ◽  
Vol 48 (2) ◽  
pp. 435-445 ◽  
Author(s):  
R. D. MacCuaig ◽  
K. F. Sawyer
Keyword(s):  
Single Dose ◽  
Schistocerca Gregaria ◽  
Locusta Migratoria ◽  
Lethal Dose ◽  
Cumulative Effect ◽  
Lethal Effect ◽  
Substantial Contribution ◽  
Successful Operation ◽  
Relative Susceptibility ◽  
Lethal Doses

SummaryBy the method of attacking flying swarms of locusts with insecticides sprayed directly into the swarm by relays of light aircraft, a proportion of the swarm receives a sub-lethal dose from each sortie. For successful operation it is essential that a substantial contribution to the final mortality should be produced by the accumulation of these sub-lethal doses on individual insects over a period of time. The object of the present experiments was to determine whether such doses applied at intervals are wholly additive in their effects. The poison used was dinitro-o-cresol (Mk. IV DNC solution) and to shorten the experimental procedure, the locusts, Schistocerca gregaria (Forsk.) and Locusta migratoria migratorioides (R. & F.), were dosed by means of a single drop of poison applied to the ventral surface of the abdomen by a micro-drop syringe.When locusts are given regular daily doses of DNC the doses are not wholly cumulative in their effect. After the second or third day the lethal effect of each dose becomes steadily less, and after the fourth or fifth day it tends to zero, representing a steady state in which the rates of application and loss of insecticidal activity in the survivors are equal.When the dose is applied in two halves with various time intervals between them, the cumulative effect during the first 24 hours is less in S. gregaria than in L. migratoria. In the latter species it is possible that sensitisation occurs. After three days, the first half-dose has fallen to an estimated 20 per cent, of its initial effectiveness in each species.These two species are equally susceptible to a single dose expressed as μg. DNC/g. body weight. The females are more resistant than the males to daily doses (relative susceptibility in S. gregaria, 1·54) but probably not to single doses (relative susceptibility, 1·09).Resistance to a daily dose correlates roughly with resistance to a single dose, the total dose required to produce 50 per cent, mortality in four days being about twice the LD50 for a single dose.If flight activity does not materially alter the present results, it is evident that the non-cumulative effects of sub-lethal doses could cause a serious loss in the efficiency of an air-spray operation if it were unduly prolonged. Thus a quantity of insecticide sufficient to kill over 99 per cent, of the locusts if applied as a single dose would kill less than 40 per cent, if the application were spread over four days.

CHEMICAL WEED KILLERS: I. RELATIVE TOXICITY OF VARIOUS CHEMICALS TO FOUR ANNUAL WEEDS

1937 ◽  
Vol 15c (7) ◽  
pp. 299-323 ◽  
Author(s):  
W. H. Cook
Keyword(s):  
Chenopodium Album ◽  
Lethal Dose ◽  
Ammonium Thiocyanate ◽  
Copper Nitrate ◽  
Toxicity Tests ◽  
Appreciable Effect ◽  
Thlaspi Arvense ◽  
Sodium Bichromate ◽  
Other Substances ◽  
Annual Weeds

Toxicity tests on four annual weeds, Thlaspi arvense L.; Brassica arvensis L. Ktze.; Chenopodium album L.; and Avena fatua L.; showed no definite evidence of a specific susceptibility of a given species to a given substance. The relative resistance of these four weeds to most substances, judging from the certainly lethal dose, was in the order 1:1:2:7. Of the 76 chemicals tested, the following most toxic compounds killed all four species at the dosages employed; selenic and chloric acids, sodium hydroxide, arsenic pentoxide, sodium arsenite, sodium and ammonium chlorate, ammonium thiocyanate, sodium cyanide, zinc chloride, sodium bichromate, sodium selenite, copper nitrate, sodium sulphide, formic acid, gasoline, phenol, creosote, tetralin, sodium benzoate, aniline, benzene and furfural. The residual toxic effect on the soil, three to four weeks after treatment, showed that of the 35 more toxic chemicals tested, only selenic acid and the five chlorates used had any appreciable effect at low and intermediate dosages, while eleven other substances depressed growth following the application of high dosages.

A Comparison of Ecotoxicological Tests

2002 ◽  
Vol 30 (5) ◽  
pp. 539-550 ◽  
Author(s):  
James L. Botsford
Keyword(s):  
Lethal Dose ◽  
Correlation Coefficients ◽  
Rat Hepatocytes ◽  
In Vitro Cytotoxicity ◽  
Test Results ◽  
Average Correlation ◽  
Ecotoxicological Tests ◽  
Present Test ◽  
Lethal Doses

A simple, inexpensive and rapid method of determining toxicity by using a bacterium as the indicator organism was developed and compared with 23 other tests. The average correlation coefficient when comparing these 23 tests with the present test was 0.800, ranging from 0.580 to 0.950. Eleven of the tests were compared in detail by using 35 of the chemicals on the Multicentre Evaluation of In Vitro Cytotoxicity list of test chemicals. Comparing results from the present test with test results for these 35 chemicals with Microtox™, Biotox™, Daphnia magna, rat hepatocytes and ascites tumour cell resulted in correlation coefficients ranging from 0.871 to 0.933. Comparisons of the test data with rodent LD50 values, human lethal dose estimates from autopsies and human lethal doses obtained from the literature provided correlation coefficients ranging from 0.580 to 0.770, indicating that the test compares less favourably with these methods. This test provides data comparable to data from other ecotoxicological tests.

In vivo protection studies of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl) acetamide derivatives against sarin poisoning in mice

2016 ◽  
Vol 36 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Devyani Swami ◽  
Hitendra N Karade ◽  
Jyotiranjan Acharya ◽  
Pravin Kumar
Keyword(s):  
Time Course ◽  
Lethal Dose ◽  
Nerve Agent ◽  
Ache Inhibition ◽  
Inhibition Concentration ◽  
Time Course Study ◽  
Dose Dependent ◽  
Protection Index ◽  
Lethal Doses

In vivo antidotal efficacy of new bis- quaternary 2-(hydroxyimino)- N-(pyridin-3yl) acetamide derivatives (HNK series), to counter multiples of lethal doses of nerve agent sarin (GB) and reactivation of acetylcholinesterase (AChE), was evaluated in Swiss albino mice. [Protection index PI; median lethal dose (LD50) of sarin with treatment/LD50 of sarin] was estimated, using 0.05, 0.10, and 0.20 LD50 as treatment doses of all the oximes with atropine against sarin poisoning. Dose-dependent time course study was conducted at 0.2, 0.4 and 0.8 LD50 dose of sarin for estimating maximum AChE inhibition. At optimized time (15 min), in vivo enzyme half inhibition concentration (IC50) was calculated. AChE reactivation efficacy of HNK series and pralidoxime (2-PAM) were determined by plotting shift of log IC50 doses. HNK-102 with atropine showed three fold higher PI compared to 2-PAM. In vivo IC50 of sarin for brain and serum AChE was found to be 0.87 LD50 (139.2 µg/kg) and 0.48 LD50 (77.23 µg/kg), respectively. Treatment with HNK-102 and HNK-111 (equal to their 0.20LD50) significantly reactivated sarin-intoxicated AChE ( p < 0.05) at 2× IC50 dose of sarin, compared to 2-PAM. The study revealed that HNK-102 oxime was three times more potent as antidote, for acute sarin poisoning compared to 2-PAM in vivo.

scholarly journals Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker from the Marine Ciliate Euplotes crassus

2004 ◽  
Vol 48 (10) ◽  
pp. 3828-3833 ◽  
Author(s):  
Dianella Savoia ◽  
Claudio Avanzini ◽  
Tiziano Allice ◽  
Emanuela Callone ◽  
Graziano Guella ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Leishmania Major ◽  
Lethal Dose ◽  
J774 Cell ◽  
Marine Ciliate ◽  
Euplotes Crassus ◽  
Taxonomic Marker ◽  
Solubility Enhancers ◽  
J774 Cell Line ◽  
Lethal Doses

ABSTRACT Strains of the marine ciliate protist Euplotes crassus produce exclusive terpenoids called euplotins that play an ecological role. Among these derivatives, euplotin C is the main of four secondary metabolites isolated from cultures of this protozoon and represents the sesquiterpene taxonomic marker from E. crassus. Because different terpenoid metabolites of plant origin showed a certain antimicrobial activity, we assessed the compound euplotin C, purified by high-pressure liquid chromatography and solubilized in two solubility enhancers, against the protozoa Leishmania major and Leishmani infantum, the fungus Candida albicans, and nine strains of gram-positive and gram-negative microorganisms. An activity of euplotin C against Leishmania promastigotes was demonstrated (50% lethal doses were 4.6 or 8.1 μg/ml depending on the agent used to solubilize the compound), while the effect was less evident on Candida and nearly absent on bacteria. A nonsignificant cytotoxicity (50% lethal dose, >200 μg/ml) against the J774 cell line was observed. A leishmanicidal activity was also shown by the living, euplotin-producing cells of E. crassus cultured together with promastigotes; this activity increased with time from 10 min to 6 h of incubation. This study provides an initial rationale for the evaluation of euplotin C and other similar natural products as alternative or possibly synergistic compounds for current antiprotozoon chemotherapeutics.

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