PT - JOURNAL ARTICLE AU - J. M. BARNES AU - F. A. DENZ TI - EXPERIMENTAL METHODS USED IN DETERMINING CHRONIC TOXICITY DP - 1954 Jun 01 TA - Pharmacological Reviews PG - 191--242 VI - 6 IP - 2 4099 - http://pharmrev.aspetjournals.org/content/6/2/191.short 4100 - http://pharmrev.aspetjournals.org/content/6/2/191.full SO - Pharmacol Rev1954 Jun 01; 6 AB - In their final report to the U. S. Congress, the Delaney Committee investigating the "Use of Chemicals in Food and Cosmetics" expressed their conviction that "chemicals have been utilised in and on the food supply of the Nation without adequate and sufficient testing of their long-range injurious effects" (76). They recommended legislation to ensure that the public was safeguarded by making it compulsory to have adequate tests carried out before an article reached the market. A possible sequel to such legislation would be the adoption of some standard form of toxicity testing. Such a danger was recognised by at least one expert who gave evidence before this Committee when he stated (p. 749) "Investigations of this type make heavy demands upon the general technical knowledge and experience of the investigator whose interest in a problem and whose ingenuity in approaching it should not he thwarted by the necessity of adhering to a stereotyped procedure for the sake of obtaining uniform data on toxicity for comparative purposes," and (p. 757) ". . . I would not wish to be bound by anybody's specifications as to what is necessary to establish the facts with reference to the safety of this or that" (164). This is valid criticism of any stereotyped toxicity test. A second criticism is that the conventional type of chronic toxicity test is not the best way of providing safeguards against human poisoning. The assessment of a toxic hazard can be properly based only on some knowledge of the fate and behaviour of a compound after its introduction into the body. A study of the absorption, distribution and elimination of a compound might take longer and prove more exacting than a routine feeding test. But such work would lead logically to biochemical and physiological studies. This approach would be scientific in contrast to the empirical method of chronic toxicity tests. The criteria used in the routine type of feeding or inhalation tests are complex and little understood. A disturbance of growth or fertility or even an increased mortality adds little to our knowledge of the mode of action of a toxic material. The value of such criteria is further depreciated by the fact that they are apparently so insensitive as indices of poisoning. With some knowledge about the behaviour of a compound in laboratory animals, it becomes possible to consider means of finding out how the same compound behaves when given to man. Only when some information of this kind is available would it be worth considering that the results of long-term feeding experiments in animals have any bearing on the problem with regard to man. There would appear to be a much bigger place for the subacute type of test on animals in order to find out just what biological processes are disturbed. Tests of longer duration have little value until something is known about the mode of action of a compound, so that the effects of such an action can, if desired, be studied specifically over long periods. Into this category would fall the tests carried out for carcinogenicity. The value of routine long-term feeding tests as measures of administrative expediency is not a question for discussion here. The use of such an experimental approach should not be confused with a scientific attack on a difficult problem.