The Use Of The LD50 Test

Background

The LD50 test was designed to give a numerical index of acute toxicity. However, substantial experience has shown that data from such tests are highly variable between differing experiments and laboratories. Nevertheless, some regulatory authorities still call for such a study.

Current Situation

Pharmaceuticals:

The pharmaceutical industry is considered to have made the most progress in abandoning the LD50 test and there is now no regulatory need for such studies prior to the first administration of a potential new medicine to man. Both the UK Medicines Control Agency and the International Committee on Harmonisation (ICH) propose that a dose escalation study is an acceptable alternative to the single dose design to support applications for a Clinical Trial Certificate or Exemption. The registration of pharmaceuticals, equally, although needing acute data, does not require form LD50 studies. However, despite these proposals, certain countries outside the ICH process still require LD50 tests to be carried out.

Industrial chemicals:

In the European Community (EC), the Notification of New Substance Regulations, which apply to chemicals and to pharmaceutical intermediates, replaces the LD50 test with a fixed-dose procedure. Unfortunately, the original test protocol for the LD50 (OECD401) is still in existence and is favoured by a number of non-EC countries, such as Canada and Japan, because a number of fixed-dose procedures still exist and the use of the LD50 is therefore seen to avoid confusion. Currently the OECD is recommending acceptance of yet another study design, the ‘Up and Down’ procedure, for acute oral toxicity.

Agrochemicals:

The US Environmental Protection Agency recognises that acute toxicity studies are required for the protection of public health and the environment, but does not encourage the use of animals solely for the calculation of an LD50. However, although use of the ‘Limit’ test is proposed, it is custom-and-practice to conduct an acute toxicity in the rat using four groups of at least 5 male and 5 female animals. This study design also meets EC and Japanese guidelines.

Recommendations

• The LD50 test adds little to the risk assessment process and alternative tests are available. Its use should be avoided wherever possible.

• Continuing existence of the test protocol for the LD50 in OECD guidelines creates confusion and may be seen to encourage the continuing use of the LD50 test. This test should be removed from OECD guidelines.

• Guidance should be provided, through regulatory processes such as ICH, on which alternative test is the most appropriate to meet all regulatory needs, having regard for animal welfare considerations.

* Until such time as alternative methods to the LD50 test are adopted by all countries, it may be necessary to permit use of this test in the UK to avoid these studies being conducted in countries with less concern for animal welfare. Such cases should be regarded as exceptional and require special justification