LD50 testing

Acute poison and random data 

A matter we do not try to deal with on the site is the cruelty aspect of animal testing.  However, there is a great deal of opposition, due to extreme cruelty, to the Lethal Dose 50 (LD50) test.  This test involves giving a test drug or other chemical to a group of animals at increasing doses.  The intention is to find the dose that kills 50% during the test.  This statistic was originally claimed to be of value in determining safety policies, although nobody still claims this is still the case.

Aside from the criticism of cruelty, this is a good example of a pointless area of experiments which generates data which has no value to human medicine.

Pointless data

The tests provide data which means nothing for humans, and experts describe it as “only marginally informative, toxicologically inadequate, and misleading.” [1]  Results differ enormously between species, even similar ones.  Rats can tolerate twice as much ethanol as mice (relative to bodyweight) according to the test.  In the case of carbon tetrachloride rats con tolerate just over a quarter of the dose mice tolerate.  Paracetamol differs far more: a seventh of the dose for one species is that for the other, while for Nicotine the difference is a factor of over 16, and for Mercury (II) Chloride the LD50 dose differs 17 times.[2]

This may raise the question of which species should provide the dose that applies to humans.  It also raises the point that if results differ between two rodents, how much more do we expect them to differ when applying them to humans?

The data has also been found to be affected by other factors, including:

  • The species of animal selected[3]
  • The strain of animal used[4]
  • Ages of animals used[5]
  • The animals’ weights[6]
  • Whether animals are male or female[7]
  • Type of food they have been fed on[8], and whether they were fed before the test[9]
  • Method of administering the drug/chemical[10]
  • Temperature[11]

    This is an ongoing problem with animal tests, which is covered in more detail here.

    Because of all these differences, the LD50 is little more than an expensive method of generating random numbers that have no value to anyone.  An investigation commissioned by European regulators found that LD50 results on the same chemical by different laboratories were often twelve times the level in one lab when compared with another.  They tried to standardise conditions to ensure labs could create standard results, but they were still very much different.[12]

Could humans use the data?

The foolhardy nature of actually basing medical or regulatory details on data this unreliable is easy to understand, but there are a number of other reasons why the data should never be used for humans.

All the LD50 only measures death rates.  So if a chemical, at low doses, causes a high incidence of non-lethal reactions, this will be ignored.

The vast majority of poisonings involve very young children under five years of age.  Their reactions are generally unlike adult reactions.  Studying chemicals in very young animals is not practical and could not be applied to human children.[13]

Half of adult overdoses and 90% of overdoses with recreational drugs involve mixtures of drugs.  The LD50 aims to study single chemicals.[14]

What other options do we have?

Elsewhere on this site (click here) we’ve detailed some of the modern technological methods that use human cells and human data to study toxicity. 

Cell cultures have already been compared with animal tests and proven to be more effective, but are still used.  Dr David Rall was a director of the National Toxicology Program (USA) when he wrote in March 1983, “[the LD50] is now an anachronism….I do not think the LD50 test provides much useful information about the health hazards to humans.”[15]

Studying humans in the real world is also invaluable, as experts have noted: “Whilst the data from the animal studies required by regulatory bodies provide some basic information of the mechanism of toxicity and relative toxicity, it cannot be assumed that this information will be entirely relevant for man. Furthermore, whilst these studies may give indications as to the appropriate treatment for acute overdosage, they are unlikely to indicate the efficacy of treatment. Experience gained from a careful assessment of patients suffering from acute overdosage of drugs is potentially much more useful than that obtained from animal tests.” (our emphasis) [16]

References

1 Sperling F. Nonlethal parameters as indices of acute toxicity: inadequacy of the acute LD50. New concepts of safety evaluation 1976; John Wiley and Sons, NY: p.177.
2 (NIOSH/Registry of Toxic Effects of Chemical Substances)
3 Morrison JK et al. The purpose and value of LD50 determinations. Modern Trends in Toxicology 1968; Butterworths, London: p.1.
4 Dieke SH, Richter CP. Acute toxicity to rats in relation to age, diet, strain, and species variation. J Pharmacol Exp Ther 1945;83:195-202.
5 Goldenthal EI. A compilation of LD50 values in newborn and adult animals. Toxicol Appl Pharmacol 1971;18:185-207.
6 Balazs T, Arena E, Barron CN. Protection against the cardiotoxic effect of isoproterenol HCl by restricted food intake in rats. Toxicol Appl Pharmacol 1972;21(2):237.
7 Goldenthal EI. A compilation of LD50 values in newborn and adult animals. Toxicol Appl Pharmacol 1971;18:185-207.
8 Goldenthal EI. A compilation of LD50 values in newborn and adult animals. Toxicol Appl Pharmacol 1971;18:185-207.
9 Quinton RM, Reinert H, cited by Morrison et al.; 1968.
10 Ferguson HC. Dilution of dose and acute toxicity. Toxicol Appl Pharmacol 1962;4:759-62.
11 Fuhrman GJ, Fuhrman FA. Effects of temperature on the action of drugs. Ann Rev Pharmacol 1961;1:65-78.. Wiehe WH. The effect of ambient temperature on the action of drugs. Ann Rev Pharmacol 1973;13:409-25.
12 Hunter WJ et al. An intercomparison study conducted by the Commission of the European Communities on the determination of the single administration toxicity in rats. Communicated by the Health and Safety Directorate (unpublished). 1977, Commission of the EC and United States EPA, 1979.
13 Goldenthal EI. A compilation of LD50 values in newborn and adult animals. Toxicol Appl Pharmacol 1971;18:185-207.
14 Kaufmann SR, Cohen MJ. The clinical relevance of the LD50. Vet Hum Toxicol 1986:29(1):39-41.
15 Kaufmann SR, Cohen MJ. The clinical relevance of the LD50. Vet Hum Toxicol 1986:29(1):39-41.
16 Dr Roy Goulding and Dr Glyn Volans, of the Guy's Hospital Poisons Information Centre, quoted in the Bulletin of the Lord Dowding Fund, no: 10.