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A reference table is presented for rapid determination of 50% lethal doses or 50% infective doses after administering 10-fold serial dilutions of toxins, viruses, sera, etc., to six animals per dilution.
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The intraperitoneal (i.p.) and intragastric (i.g.) mouse approximate 50% lethal dose values (ALD50S) were determined for 15 food and clinical isolates of Listeria monocytogenes. Although all strains gave i.g. ALD50S comparable to or less than their i.p. ALD50S, the i.g. feeding of most strains produced more deaths within the first 3 days of the 6-day test than did i.p. injection. ALD50S ranged from 50 to 4.4 x 10(5) cells with approximately 1-log 95% confidence intervals. Of five strains tested by suspension in milk or by growth in milk, none gave i.g. ALD50S that were lower than those of washed cells. Results with 10- to 21-g mice supported the use of 15-g mice for i.g. testing; 21-g mice were more resistant to i.g. infection. These results indicate that i.g. feeding permits an evaluation of the role of the carrier (such as milk) in the determination of listerial virulence, permits strain characterization by i.p. and i.g. ALD50S, and emphasizes a potentially more rapid infection when the bacterium is introduced i.g.
The relationship between resistance detected in the faecal egg count reduction test (FECRT) and the lethal dose 50% (LD50) in the egg hatch assay (EHA) for benzimidazoles (BZs) and a larval development assay (LDA) for BZs, levamisole (LEV) and ivermectin (IVM) was examined on 13 sheep farms and 12 goat farms in Denmark. Out of 10 farms where resistance to BZs was detected according to the FECRT, nine (90%) had LD50 values above 0.5 microM thiabendazole (TBZ) (0.1 microg TBZ/ml) in the EHA, indicating resistance to BZs. However, four out of the 12 isolates susceptible to BZs in the FECRT had LD50 values higher than 0.5 microM TBZ in the EHA. For all isolates examined, LD50 values for TBZ in the LDA were lower than in the EHA. Four out of 11 and five out of 12 farms with worm populations resistant to BZs according to the FECRT and EHA respectively, had LD50 values lower than 0.5 microM TBZ in the LDA. Using the same cut-off point for resistant isolates in the LDA as in the EHA (0.5 microM TBZ), these isolates would be considered susceptible to BZs. All 10 isolates susceptible to BZs according to the FECRT and EHA and two isolates with suspect BZ resistance had LD50 values lower than 0.5 microM TBZ in the LDA. The above results indicated fairly good agreement in the detection of BZ resistance between the FECRT, EHA and the LDA. Groups of farms where resistance to LEV was detected according to the FECRT had higher mean LD50 values compared to those with LEV-susceptible or suspected resistant isolates. However, only four out of 12 farms having isolates resistant to LEV had LD50 values higher than 1.2 microM LEV (0.28 microg LEV/ml) recorded previously for a LEV-susceptible strain of Ostertagia circumcincta. This indicated discrepancies in declaring resistance to LEV between the FECRT and the LDA. Isolates from four farms where resistance to IVM was detected in the FECRT had LD50 values higher than the susceptible isolates. These were 2.5 to 7.5 times higher than those recorded previously for IVM-susceptible strains.
Three experiments were conducted to assess mortality rate, blood chemistry, and histologic changes associated with acute exposure to T-2 mycotoxin in adult bobwhite quail. In Experiment 1, adult quail were orally dosed with T-2 toxin to determine the lethal dose that resulted in 50% mortality of the affected population (LD50), and that dose was determined to be 14.7 mg of T-2 toxin per kilogram of body weight (BW). A second experiment was performed to study the effects of 12-18 mg/kg BW T-2 toxin on blood chemistry and liver enzyme profiles. Posttreatment uric acid, aspartate aminotransferase, lactic dehydrogenase, and gamma glutamyltransferase increased as compared with pretreatment values. In contrast, posttreatment plasma total protein, cholesterol, and triglyceride levels numerically decreased as compared with pretreatment values. Changes in blood chemistry values were consistent with liver and kidney damage after T-2 toxin exposure. In Experiment 3, histologic analyses of bone marrow, spleen, liver, small intestine, kidney, and heart were conducted on birds dosed in Experiment 2. Marked lymphocyte necrosis and depletion throughout the spleen, thymus, bursa, and gut-associated lymphoid tissue in the small intestine were observed in birds dosed with 15 and 18 mg/kg BW T-2 toxin. Necrosis of liver and lipid accumulation as a result of malfunctioning hepatocytes were also observed. Little or no morphologic change was observed in bone marrow and heart tissue. The LD50 for adult bobwhite quail as found in this study is two to three times higher than that reported for other species of commercial poultry. Results from these data confirm previous reports of immunosuppressive and/or cytotoxic effects of T-2 toxin in other mammalian and avian species. T-2 toxin may have a negative impact on the viability of wild quail populations.
Toxicity assessment and demonstration of innocuousness of chemical compounds have been part of the research studies conducted in the fields of pharmacy, agriculture and chemical industry for years. Acute systemic toxicity studies are an important element of the safety evaluation. They remain compulsory for regulatory purposes and important for the public opinion that does not accept the risk anymore. Evolutions of the ethics in animal experiments foster a necessary reduction of the number of animals involved in this type of experiments, following the well-known principle of the three Rs rule of Russell and Burch (1959) (Reduction, refinement and replacement). These two views seem in contradiction. Using the example of acute toxicity testing and focusing on the now very criticized parameter lethal dose 50, we will present approaches, including statistical ones, that a toxicologist can use, when free to choose, to keep on conducting the indispensable in vivo studies while abiding by ethical recommendations.
If circadian variations in tolerance to drugs have been often demonstrated, such observations about heavy metals are still very scarce. The present study proposes to determine if circadian variations occur in the tolerance of Mice to single lethal dose of mercuric chloride. 360 female Mice, kept in cages on a 8.00 - 20.00 L/D cycle, receive I.P. a single mercuric chloride injection at different concentrations (100 to 300 X 10(-6)) at different hours in the day (8.00 - 14.00 - 20.00 or 2.00). Death number is determined each during 10 consecutive days. For the highest doses causing death (from 200 x 10(-6)), the mortality percentage is a function of the time of the mercury administration. The metal is the most toxic at 20.00 (LD50: 4,14 +/-0,47) mg/kg) and least at 2.00 (LD50: 5,54 +/- 0,18 mg/kg). Moreover, death occurs later at 2.00 than at other times. So a susceptibility to mercuric chloride in Mice clearly appears.
UNLABELLED: Cofactors such as stress have been suspected to play a role in the susceptibility to opportunistic infections. Toxoplasma gondii is one of the major opportunistic infectious agents in immunocompromised individuals, and infection can be modulated by external factors such as stress. OBJECTIVE: The purpose of this study was to examine the in vivo and in vitro role of cold stress (CS) in the pathogenesis of T. gondii infection and its impact on regulatory cytokines in this model. METHODS: Mice subjected to CS and control animals were infected intraperitoneally with an LD(50) of PD2 T. gondii tachyzoites, and the outcome of the infection was determined. In addition, peritoneal macrophages obtained from CS and non-stressed mice were infected in vitro with T. gondii. The number of infected macrophages, the number of intracellular parasites and the production of interferon (IFN)-gamma, interleukin (IL)-12, and tumor necrosis factor (TNF)-alpha were determined. RESULTS: CS applied before intraperitoneal inoculation increased susceptibility against T. gondii infection. Peritoneal cells from CS mice contained significantly higher numbers of intracellular parasites and infected macrophages compared to those from non-stressed animals. IFN-gamma production was initially high in the CS group but decreased significantly after 36 h. Opposite results were found in the non-stressed group. Macrophages from CS mice persistently produced high levels of TNF-alpha and IL-12 and peaked after 36 h. Levels of these cytokines were lower or absent in the non-stressed group. CONCLUSION: These results suggest that CS increased the host susceptibility to intraperitoneal T. gondii infection by modulating the function of macrophages and the production of cytokines (IFN-gamma) involved in the early control of infection.
The LD50 of strains of L. interrogans used in the potency assay of the Cuban trivalent leptospiral vaccine intended for human use was standardized. The control of the leptospires content of the cultures by means of the adjusting dilution (10 to 12 leptospires per field) was introduced. That was the key of the standardization of the assay, since it guaranteed the reproducibility of the estimate of the LD50 value for each serogroup: 10(5.98) for canicola, 10(5.60) for icterohaemorrhagiae and 10(6.60) for pomona, with the following limits for an interval of 1 log10: 10(4.98)-10(6.98), 10(4.60)-10(6.60) and 10(5.49)-10(7.49), respectively; whereas for a 95% (+/- 2 SD) confidence interval the values were: 10(5.54)-10(6.19); 10(5.33)-10(5.75) and 10(6.35)-10(6.60), respectively. These values were lower than the previous ones, which means ever more reproducibility. The methodology described proved to be satisfactory for the standardization of the LD50 of the challenge strains and it could also be used for evaluating the virulence of other strains of L. interrogans, including those used for the vaccine production.
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Passive transfer experiments were performed to serve as a basis for analyzing the immune response of adult mice to FMDV infection. Animals were irradiated (750 rad: 1 lethal dose 50%) and reconstituted with allogeneic mononuclear cells from blood, spleen, thymus and peritoneal cavity from donors 2 and 8 days post-inoculation (p.i.). Donors were primed with 10 000 suckling mouse 50% lethal doses of FMDV strain O1 Campos. The following parameters were studied in recipient mice challenged with 10 000 suckling mouse 50% lethal doses of the same virus: (1) viremia; (b) FMDV neutralizing antibody titres; (c) sheep red blood cell (SRBC) hemagglutinating antibody titres. Viremia was substantially prolonged in irradiated control mice, which did not produce detectable antibodies to FMDV or SRBC. In contrast, the span of viremia was markedly shorter in animals reconstituted with cells obtained 8 days p.i. and its eclipse coincided with the onset of neutralizing antibody production. An equally efficient antibody response to the inoculation of SRBC was observed in these animals. No effect was detected after the transfer of cells obtained 2 days p.i. It is concluded that the humoral immune response plays a predominant role in the recovery from FMDV experimental infection in adult mice.
A new drug delivery system, cisplatin incorporated into lactic acid oligomer microspheres (CDDP-MS), was developed for the treatment of peritoneal carcinomatoses. We studied the acute toxicity and pathological effects of CDDP-MS injected intraperitoneally in mice. The 50% lethal dose was 23.8 mg/kg (21.3-26.7 mg/kg at 95% level of confidence), which was 1.76 times that of the cisplatin aqueous solution of 13.5 mg/kg (11.9-15.3 mg/kg at 95% level of confidence). The duration for the restoration of the body weight loss was prolonged when CDDP-MS at doses close to the 50% lethal dose was administered, as compared with the cisplatin aqueous solution at doses close to its 50% lethal dose. On autopsy there were no macroscopic or microscopic differences between the two dosage forms.
VP1 is a capsid protein of foot-and-mouth disease virus (FMDV) and contains epitopes of the virus. Plasmids encoding two VP1 epitopes (amino acid residues 141-160 and 200-213) and a host-self immunoglobulin molecule were constructed to produce a new type of FMD DNA vaccine. Two plasmids, namely, pCEIM and pCEIS, containing mouse immunoglobulin (IgG) or swine IgG were subjected to immunogenicity testing in mice and swine, respectively. In mice administrated pCEIM in the abdomen using a genegun, both FMDV-specific T-cell proliferation and neutralizing antibodies were detected. In swine immunized with pCEIS at the back of the ear, immune responses were achieved after the second administration. Swine showed a T-cell proliferative response with a stimulation index (SI) of up to 8.1 and a neutralizing antibody response that was able to protect suckling mice from 10(2) LD(50) (lethal dose 50) FMDV challenge. To compare the immunogenicity of the DNA-based vaccine candidate, versus the protein-based vaccine candidates, a second group of swine was immunized with the protein F1-scIgG, which was encoded by the plasmid pCEIS. Injection with F1-scIgG elicited a T-cell proliferative response of SI < 1.7 and a neutralizing antibody response that protected suckling mice from up to 10(5) LD(50) FMDV challenge. In the challenge test, three of three swine immunized with pCEIS were fully protected from FMDV challenge.
BACKGROUND: The role of infection in the development and complications of atherosclerosis has been the focus of much attention. We reported previously that influenza vaccination was associated with reduced risk of recurrent myocardial infarction. Here, we report the effect of influenza A virus on the apolipoprotein E-deficient (apoE(-/-)) mouse, an animal model of atherosclerosis. METHODS AND RESULTS: Twenty-four apoE(-/-) mice >24 months old were injected with 1 LD(50) (lethal dose 50) of influenza A virus. Ten wild-type C57BL/6 infected mice and 11 noninfected age-matched apoE(-/-) mice served as controls. Multiple aortic sections were studied histologically 3, 5, and 10 days later. The infected mice showed markedly increased intimal cellularity compared with the noninfected apoE(-/-) mice. No aortic abnormalities were seen in infected wild-type mice. Ten infected apoE(-/-) mice had a significant subendothelial infiltrate composed of a heterogeneous group of cells that stained positively for smooth muscle cell actin, F4/80 (macrophages), and CD3 (T lymphocytes). One case of subocclusive platelet and fibrin-rich thrombus was seen. CONCLUSIONS: This study shows that influenza infection promotes inflammation, smooth muscle cell proliferation, and fibrin deposition in atherosclerotic plaques.
UNLABELLED: After a single IV injection of the water-soluble propofol prodrug propofol phosphate (PP) in mice, rats, rabbits, and pigs, propofol was produced rapidly (1-15 min), inducing dose-dependent sedative effects. In mice, the hypnotic dose (HD(50)), lethal dose (LD(50)), and safety index (defined as a ratio: LD(50)/HD(50)) were 165.4 mg/kg, 600.6 mg/kg, and 3.6, respectively. Propofol was produced with half-lives of 5.3 +/- 0.6 min in rats, 2.1 +/- 0.6 min in rabbits, and 4.4 +/- 2.4 min in pigs. The maximal concentration was dose and species dependent. The elimination half-life was 24 +/- 12 min in rats, 21 +/- 16 min in rabbits, and 225 +/- 56 min in pigs. Propofol generated from PP produced pharmacological effects similar to those described in the literature. We found a correlation between PP dose and duration of sedation with propofol concentrations larger than 1.0 microg/mL, which produced somnolence and sedation in rats and pigs. Adequate sedation and, at large enough doses, anesthetic-level sedation were produced after the administration of PP. Overall, PP, the water-soluble prodrug of propofol, seems to be a viable development candidate for sedative and anesthetic applications. IMPLICATIONS: Propofol phosphate, a water-soluble prodrug of the widely used IV anesthetic propofol, was developed and evaluated in mice, rats, rabbits, and pigs after IV injection. The results of the study clearly demonstrate the feasibility of the prodrug approach to achieve sedative and anesthetic levels of propofol in laboratory animals; this warrants further evaluation in humans.
Mice pretreated (day 0) by a single injection of lipopolysaccharide (LPS) responded with hypothermic tolerance to (LPS) challenge on day 1 and with hypothermic hyperreactivity to LPS challenge on day 4. Reciprocally, mice pretreated similarly but with a higher challenge dose were hyperreactive with respect to LPS lethality on day 1, but highly tolerant to lethality when challenged on day 4. Hyperreactivity to LPS lethality (day 1) was evident from an accelerated onset of death as well as from a reduced 50% lethal dose in pretreated mice, the level of hyperreactivity being more pronounced with higher LPS pretreatment doses. Lethal hyperreactivity, however, was only seen after challenge with a 50% lethal dose of soluble LPS. In contrast, protection to lethality occurred after challenge with a 50% lethal dose of insoluble LPS (day 1). Tolerance to LPS lethality in mice was observed on day 4 after pretreatment with one (day 0) or four daily injections of LPS. Since reciprocal hyperreactivity (day 1) and cross-tolerance to lethality (day 4) could be achieved by treatment with Salmonella smooth- or rough-form LPS as well as with free lipid A, it was concluded that lipid A represents the active principle of LPS in inducing both hyperreactivity and tolerance to the lethal effect of LPS.