LD 50

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A PRESENTATION ON DETERMINATION OF LD 50 PREPARED BY: GUIDED BY: PRIYA PATEL HIRAL MODI Q.A ( 1 ST SEM.) ASSISTANPROFFESER PHARMACOLOGY(M.PHARM) QUALITY ASSURANCE DEPARTMENT SARASWATI INSTITUTE OF PHARMACEUTICAL SCIENCE DHANAP, GANDHINAGAR. ACEDEMIC YEAR 2012-2013

CONTENTS:

CONTENTS Introduction Importance of ld 50 Significance of ld 50 Comparison of toxicity Alternative test Methodology Calculation of ld 50 References

INTRODUCTION:

INTRODUCTION LD stands for "Lethal Dose”, it figures a substance's acute toxicity . The test was created by J.W. Trevan in 1927. Median Lethal Dose is quantity of the chemical that is estimated to be fatal to 50% of the organisms. 2,3

IMPORTANCE OF LD50:

IMPORTANCE OF LD50 Different chemicals cause different toxic effects, comparing the toxicity of one with another is hard. To compare the toxic potency or intensity of different chemicals, researchers must measure the same effect. One way is to carry out lethality testing (the ld 50 tests) by measuring how much of a chemical is required to cause death. 4

SIGNIFICANCE OF LD50:

SIGNIFICANCE OF LD50 As an aid in developing emergency procedures in case of a major spill or accident. To help develop guidelines for the use of appropriate safety clothing and equipment. For the development of transportation regulations. As an aid in establishing occupational exposure limits. As a part of the information in Material Safety Data Sheets. 5

COMPARISON OF TOXICITY:

COMPARISON OF TOXICITY The smaller the ld 50 value, the more toxic is the chemical and larger the ld 50 value, lower is the toxicity of that particular chemical. Ld 50 gives a measure of the immediate or acute toxicity of a chemical in the strain, sex, and age group of a particular animal species being tested. Two most common scales used are the Hodge and Sterner Scale Gosselin, Smith and Hodge Scale 4

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Routes of Administration Oral LD 50 Inhalation LC 50 Dermal LD 50 Toxicity Rating Commonly Used Term (single dose to rats) mg/kg (exposure of rats for 4 hours) ppm (single application to skin of rabbits) mg/kg Probable Lethal Dose for Man 1 Extremely Toxic 1 or less 10 or less 5 or less 1 grain (a taste, a drop) 2 Highly Toxic 1-50 10-100 5-43 4 ml (1 tsp) 3 Moderately Toxic 50-500 100-1000 44-340 30 ml (1 fl. oz.) 4 Slightly Toxic 500-5000 1000-10,000 350-2810 600 ml (1 pint) 5 Practically Non-toxic 5000-15,000 10,000-100,000 2820-22,590 1 litre (or 1 quart) 6 Relatively Harmless 15,000 or more 100,000 22,600 or more 1 liter (or 1 quart) Table 1: Toxicity Classes: Hodge and Sterner Scale 4

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Probable Oral Lethal Dose (Human) Toxicity Rating or Class Dose For 70-kg Person (150 lbs) 6 Super Toxic Less than 5 mg/kg 1 grain (a taste - less than 7 drops) 5 Extremely Toxic 5-50 mg/kg 4 ml (between 7 drops and 1 tsp) 4 Very Toxic 50-500 mg/kg 30 ml (between 1 tsp and 1 fl ounce) 3 Moderately Toxic 0.5-5 g/kg 30-600 ml (between 1 fl oz and 1 pint) 2 Slightly Toxic 5-15 g/kg 600-1200 ml (between 1 pint to 1 quart) 1 Practically Non-Toxic Above 15 g/kg More than 1200 ml (more than 1 quart) Table 2: Toxicity Classes: Gosselin, Smith and Hodge 4

ALTERNATIVE TEST:

ALTERNATIVE TEST Toxicologists can use many kinds of animals but most often testing is done with rats and mice. In 2011 the U.S. Food and Drug Administration approved alternative methods to Ld 50 for testing the cosmetic drug BOTOX. The alternative tests are: Fixed dose procedure Acute toxic class method Up and down procedure 6

METHODOLOGY:

METHODOLOGY Animal selection Dose levels and dose selection Volume Route of administration Observation period 7-10

CALCULATION OF LD50:

CALCULATION OF LD50 Methods: Arithmetical method of Karber Graphical method of Miller and Tainter Lorke method Arithmetical method of Karber N is the number of animals in each group, a the dose difference and b the mean mortality 10

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Table 3: Arithmetical method of Karber 14

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Graphical method of Miller and Tainter The observed percentage mortality was converted into probit referring to the probit table For 96%, the value that is present at the intersection of 90 on the vertical line on the left and 6 in the horizontal line on the top was taken Table 4: Transformation of percentage to probit 14 Table 4: Transformation of percentage to probit 14

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The probit value was plotted against the logarithm of dose. The dose corresponding to 50% or probit 5 was taken as Ld 50 . Table 5: Graphical method of Miller and T ainter 14

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Lorke method Phase1 Three-groups of three mice. One dose was given to each group intraperitoneally. 11 The treated mice were monitored for 24 h for mortality and general behavior. Phase2 After 24 h 3–4 groups of one mouse were given doses intraperitoneally. 12,13

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The mice were again monitored for 24 h. The geographic mean of the least dose that killed mice and the highest dose that did not kill mice was taken as the median lethal dose. Advantage – Fewer animals were sacrificed. Disadvantage – Accuracy, reproducibility and reliability are questionable

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Method Karber Method of Miller and Tainter Method of Lorke No. of rodents used More than necessary More than necessary Appropriate Expenditure High High Average Accuracy of results Inaccurate Inaccurate Doubtful Table 6: comparison of methods

REFERENCES:

REFERENCES http://En.Wikipedia.Org/Wiki/Median_lethal_dose "Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for BOTOX® and BOTOX® Cosmetic (onabotulinumtoxinA)".Allergan Web site. Page last updated 24 June 2011. Retrieved 2012-08-15. "In U.S., Few Alternatives To Testing On Animals". Washington Post. Page last updated 12 April 2008. Retrieved 2011-06-26. http://www.ccohs.ca/oshanswers/chemicals/ld50.html http://animalrights.about.com/od/vivisection/f/LD50.html Deora Paramveer S.,et al,2010;2(6): pp.450-453. Ghosh M N., Toxicity studies. In Fundamentals of Experimental Pharmacology, Scientific Book Agency, Calcutta,1984, pp.153–158. Paget G. E. and Barnes, J. M., Toxicity tests. In Evaluation of Drug Activities: Pharmacometrics (eds Lawrence, D. R. and Bacharach,A. L.), Academic Press, London, 1964, pp.140–161.

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Turner R., Acute toxicity: The determination of LD50. In Screening Methods in Pharmacology, Academic Press, New York,1965, pp.300. Turner R., Quantal responses. Calculation of ED50. In Screening Methods in Pharmacology, Academic Press, New York,1965, pp.61–63. Lorke D., A new approach to practical acute toxicity testing. Arch. Toxicol.,1983;53, pp.275–289. Akah, P A., Ezike,et al, Evaluation of the antiasthmatic property of Acystasia gangetica leaf extracts. J Ethnopharmacol,2003;89,pp.25–36. Osadebe, P O. and Okoye, Antiinflammatory effects of crude methanolic extract and fractions of Alchornea cordifolia leaves. J. Ethnopharmacol,2003;89,pp.19–24. Shetty Akhila, Shyamjith, Deepa and M C.Alwar, acute toxicity studies and determination of median lethal dose,current science,10october 2007;93(7):pp.918–920.