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4.4.2: The Lethal Dose

  • Page ID
    225694
  • Learning Objectives

    • Describe the LD50 value and its limitations.
    • Know the LD50 value of various substances.

    The LD50 is a standardized measure for expressing and comparing the toxicity of chemicals. The LD50 is the dose that kills half (50%) of the animals tested (LD = "lethal dose"). The animals are usually rats or mice, although rabbits, guinea pigs, hamsters, and so on are sometimes used. In all these tests, the dose must be calculated relative to the size of the animal. The most common units are milligrams of chemical per kilogram of test animal (mg/kg or ppm). (Table \(\PageIndex{1}\)) provides examples of LD50 values for various substances.

    As a measure of toxicity, lethal dose is somewhat unreliable and results may vary greatly between testing facilities due to factors such as the genetic characteristics of the sample population, animal species tested, environmental factors and mode of administration.[11]

    There can be wide variability between species as well; what is relatively safe for rats may very well be extremely toxic for humans (cf. paracetamol toxicity), and vice versa. For example, chocolate, comparatively harmless to humans, is known to be toxic to many animals. When used to test venom from venomous creatures, such as snakes, LD50 results may be misleading due to the physiological differences between mice, rats, and humans. Many venomous snakes are specialized predators of mice, and their venom may be adapted specifically to incapacitate mice; and mongooses may be exceptionally resistant. While most mammals have a very similar physiology, LD50 results may or may not have equal bearing upon every mammal species, including humans.

    Table \(\PageIndex{1}\) LD50 Values of Various Substances. Source: Wikipedia

    Substance
    Animal Route
    LD50 (mg/kg)
    Water rat, oral 90,000
    Sucrose (table sugar) rat, oral 29,700
    Glucose (blood sugar) rat, oral 25,800
    Monosodium glutamate (MSG) rat, oral 16,600
    Cadmium sulfide rat, oral 7,080
    Ethanol (grain alcohol) rat, oral 7,060
    Methanol human, oral 810
    Sodium chloride (table salt) rat, oral 3,000
    Metallic arsenic rat, oral 763
    Arsenic trisulfide rat, oral 185-6400
    Sodium cyanide rat, oral 6.4
    Hydrogen cyanide mouse, oral 3.7
    Ibuprofen rat, oral 636
    Aspirin rat, oral 200
    Caffeine rat, oral 192
    Cocaine mouse, oral 96
    Nicotine rat, oral 50
    Heroin (diamorphine) mouse, intravenous 21.8
    Methamphetamine rat, intraperitoneal 57
    Mercury(II) chloride rat, oral 1
    Strychnine human, oral 1-2
    Sarin mouse, subcutaneous injection 172 microgram/kg
    Ricin (from castor oil plant) rat, oral 20-30
    Botulinum toxin (Botox) human, oral injection, inhalation 1 ng/kg

    (Table \(\PageIndex{2}\)) gives the LD50 values of some insecticides. In each case, the chemical was fed to laboratory rats. Note that the lower the LD50, the more toxic the chemical. Even adjusting for the test animal's weight, the LD50 for one species is often quite different from that for another. Thus any LD50 value gives only a rough estimate of the risk to humans. The way in which the chemical is administered also has a marked effect on LD50 values. The chemical may be fed, injected, applied to the animal's skin, etc., and each method usually generates a different LD50.

    Table \(\PageIndex{2}\): LD50 Values of Insecticides.

    Chemical Category Oral LD50 in Rats (mg/kg)
    Aldicarb ("Temik") Carbamate 1
    Carbaryl ("Sevin") Carbamate 307
    DDT Chlorinated hydrocarbon 87
    Dieldrin Chlorinated hydrocarbon 40
    Diflubenzuron ("Dimilin") Chitin inhibitor 10,000
    Malathion Organophosphate 885
    Methoprene JH mimic 34,600
    Methoxychlor Chlorinated hydrocarbon 5,000
    Parathion Organophosphate 3
    Piperonyl butoxide Synergist 7,500
    Pyrethrin Plant extract 200
    Rotenone Plant extract 60

    The Botox Enigma

    Botulinum toxin (Botox) is a neurotoxic protein produced by the bacterium Clostridium botulinum and related species. It is the most poisonous substance known. Intoxication can occur naturally as a result of either wound or intestinal infection or by ingesting preformed toxin in food. The estimated human lethal dose is 1 ng/kg. Commercial forms are marketed under the brand names Botox (onabotulinumtoxinA), Dysport/Azzalure (abobotulinumtoxinA),[10] Xeomin/Bocouture (incobotulinumtoxinA),[11] and Jeuveau (prabotulinumtoxinA).[12][13]

    Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including

    • cerebral palsy,[5][6]
    • post-stroke spasticity,[14]
    • post-spinal cord injury spasticity,[15]
    • spasms of the head and neck,[16] eyelid,[17] vagina,[18] limbs, jaw, and vocal cords.[19]

    Similarly, botulinum toxin is used to relax the clenching of muscles, including those of the oesophagus,[20] jaw,[21] lower urinary tract and bladder,[22] or clenching of the anus which can exacerbate anal fissure.[23] Botulinum toxin appears to be effective for refractory overactive bladder.[24]

    Botulinum toxin is also used to treat

    • chronic migraine,
    • disorders of hyperactive nerves including excessive sweating,[35]
    • neuropathic pain,[38] and
    • some allergy symptoms.[19]

    In addition to these uses, botulinum toxin is being evaluated for use in treating chronic pain.[39] Studies show that botulinum toxin may be injected into arthritic shoulder joints to reduce chronic pain and improve range of motion.[40]

    In cosmetic applications, botulinum toxin is considered safe and effective for reduction of facial wrinkles, especially in the uppermost third of the face.[37] Commercial forms are marketed under the brand names Botox Cosmetic/Vistabel from Allergan, Dysport/Azzalure from Galderma and Ipsen, Xeomin/Bocouture from Merz, and in the US only, Jeuveau from Evolus, manufactured by Daewoong.[13] The effects of current botulinum toxin injections for glabellar lines ('11's lines' between the eyes) typically last two to four months and in some cases, product-dependent, with some patients experiencing a longer duration of effect.[37] Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin.[37] Smoothing of wrinkles is usually visible three-five days after injection, with maximum effect typically a week following injection.[37] Muscles can be treated repeatedly to maintain the smoothed appearance.[37]

    While botulinum toxin is generally considered safe in a clinical setting, there can be serious side effects from its use. The use of botulinum toxin A in cerebral palsy children is safe in the upper and lower limb muscles.[5][6] Most commonly, botulinum toxin can be injected into the wrong muscle group or with time spread from the injection site, causing temporary paralysis of unintended muscles.

    Side effects from cosmetic use generally result from unintended paralysis of facial muscles. These include partial facial paralysis, muscle weakness, and trouble swallowing. Side effects are not limited to direct paralysis however, and can also include headaches, flu-like symptoms, and allergic reactions.[41]

    Summary

    • The LD50 is the dose that kills half (50%) of the animals tested (LD = "lethal dose"). It is a standardized measure for expressing and comparing the toxicity of chemicals.
    • LD50 values are given for common drugs (e.g. ibuprofen and aspirin), common household ingredients including water, table sugar (sucrose), salt (sodium chloride), insecticides (e.g. DDT and pyrethrin), and harmful drugs (e.g. cocaine and heroin).

    Sources

    Wikipedia

    Libretext: Biology (Kimball)

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