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1896. Keeping controls under control
METHODS FOR ASSESSING TOXICITY
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compared with the single-dose oral LDsos and with minimum effect and maximum noeffect levels obtained in 90-day feeding studies. It was found that 95 ~ of the ratios between the 7-day and 90-day minimum effect levels were 6.2 (or less) compared with values of 40 (or less) and 20 (or less) for 95 ~o of the ratios of LDso to 90-day and LDso to 7-day minimum effect levels, respectively. Of the effects seen in the feeding studies, changes in body weight and to a lesser extent in liver and kidney weight and in survival rates were the most common. Remarkably, one of the materials was much more toxic when given in the diet for 7 or 90 days than when given as a single oral dose. For several other compounds, the LDsos approximated to the maximum no-effect levels. It is concluded that the prediction of 90-day results from a 7-day test is just as accurate as the prediction of 2-yr results from a 90-day test. [This instructive study clearly shows that a 7-day pilot feeding study is a sounder investment than an acute oral study for those embarking on a 90-day feeding test. The additional expense of determining mortality, body weight and liver and kidney weights (the most sensitive parameters encountered) after 7 days' feeding seems well justified.] 1896. Keeping controls under control Weil, C. S. & Carpenter, C. P. (1969). Abnormal values in control groups during repeateddose toxicologic studies. Toxic. appL Pharmac. 14, 335. Statistical differences between a control and a test group in respect of any parameter studied in a toxicity test may not necessarily be biologically significant unless a doseresponse relationship is demonstrated. This fact is clearly illustrated by an evaluation of data for various parameters obtained at different stages of five feeding studies in rats or dogs carried out during the last 30 yr in the authors' laboratory. Abnormally low control values for the percentage of lymphocytes in dogs were responsible for an apparently significant effect of a test chemical after a certain period of feeding. This was, however, obviously a random occurrence, because the mean value for the treated group at this time did not differ significantly from the means of the control values obtained after shorter and longer periods on test, and the one low control value was completely out of line with those recorded before and after. A similar occurrence with serum urea-nitrogen values in dogs underlined the fact that an abnormally low control value can lead to a 'false positive' in a test group. In contrast, an abnormally high mortality rate, an abnormally low gain in weight and an abnormally high rate of turnout incidence recorded for the control groups in three other feeding studies could have led to a falsely negative evaluation of the results. Clearly a dose-related trend of test values away from the norm is required for the effect to be deemed biologically significant. Bearing in mind that random differences can be expected to occur in about 5 ~o of comparisons, even in adequately-designed experiments, an odd significant result only at a low dosage level can be dismissed. A single significant finding at a high dose level is more difficult to interpret, however, because it could represent either a true or a chance effect. [What this boils down to is that statistics can prove anything and there is more chance of proving what you want them to prove when the experimental design is inadequate. But even when the design is of a high standard, freak results can occur and commonsense must be applied in interpreting their significance.] rOOD 8/l--t
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compared with the single-dose oral LDsos and with minimum effect and maximum noeffect levels obtained in 90-day feeding studies. It was found that 95 ~ of the ratios between the 7-day and 90-day minimum effect levels were 6.2 (or less) compared with values of 40 (or less) and 20 (or less) for 95 ~o of the ratios of LDso to 90-day and LDso to 7-day minimum effect levels, respectively. Of the effects seen in the feeding studies, changes in body weight and to a lesser extent in liver and kidney weight and in survival rates were the most common. Remarkably, one of the materials was much more toxic when given in the diet for 7 or 90 days than when given as a single oral dose. For several other compounds, the LDsos approximated to the maximum no-effect levels. It is concluded that the prediction of 90-day results from a 7-day test is just as accurate as the prediction of 2-yr results from a 90-day test. [This instructive study clearly shows that a 7-day pilot feeding study is a sounder investment than an acute oral study for those embarking on a 90-day feeding test. The additional expense of determining mortality, body weight and liver and kidney weights (the most sensitive parameters encountered) after 7 days' feeding seems well justified.] 1896. Keeping controls under control Weil, C. S. & Carpenter, C. P. (1969). Abnormal values in control groups during repeateddose toxicologic studies. Toxic. appL Pharmac. 14, 335. Statistical differences between a control and a test group in respect of any parameter studied in a toxicity test may not necessarily be biologically significant unless a doseresponse relationship is demonstrated. This fact is clearly illustrated by an evaluation of data for various parameters obtained at different stages of five feeding studies in rats or dogs carried out during the last 30 yr in the authors' laboratory. Abnormally low control values for the percentage of lymphocytes in dogs were responsible for an apparently significant effect of a test chemical after a certain period of feeding. This was, however, obviously a random occurrence, because the mean value for the treated group at this time did not differ significantly from the means of the control values obtained after shorter and longer periods on test, and the one low control value was completely out of line with those recorded before and after. A similar occurrence with serum urea-nitrogen values in dogs underlined the fact that an abnormally low control value can lead to a 'false positive' in a test group. In contrast, an abnormally high mortality rate, an abnormally low gain in weight and an abnormally high rate of turnout incidence recorded for the control groups in three other feeding studies could have led to a falsely negative evaluation of the results. Clearly a dose-related trend of test values away from the norm is required for the effect to be deemed biologically significant. Bearing in mind that random differences can be expected to occur in about 5 ~o of comparisons, even in adequately-designed experiments, an odd significant result only at a low dosage level can be dismissed. A single significant finding at a high dose level is more difficult to interpret, however, because it could represent either a true or a chance effect. [What this boils down to is that statistics can prove anything and there is more chance of proving what you want them to prove when the experimental design is inadequate. But even when the design is of a high standard, freak results can occur and commonsense must be applied in interpreting their significance.] rOOD 8/l--t