In general, feed and water should be provided ad libitum to animals in toxicity studies, and the diets for these studies should meet the nutritional requirements of the species4-7 for normal growth and reproduction. Unless special circumstances apply which justify otherwise, care should be taken to ensure that the diets of the compound treated groups of animals are isocaloric (equivalent in caloric density) with and contain the same levels of nutrients (e.g., fiber, micronutrients) as the diets of the control group. Unrecognized or inadequately controlled dietary variables may result in nutritional imbalances or caloric deprivation that could confound interpretation of the toxicity study results (e.g., lifespan, background rates of tumor incidences) and alter the outcome and reproducibility of the studies.
The following issues are important to consider when establishing diets for animals in toxicity studies:
When the test substance has no caloric value and constitutes a substantial amount of the diet (e.g., more than 5%), both caloric and nutrient densities of the high dose diet would be diluted in comparison to the diets of the other groups. As a consequence, some high dose animals may receive higher test article doses than expected because animals fed such diluted diets ad libitum may eat more than animals in other dosed groups to compensate for the differences in energy and nutrient content of the high dose diets. Such circumstances make it especially important that feed consumption of these animals be as closely and accurately monitored as possible in order to determine whether changes observed could be due to overt toxicity of the test substance or to a dietary imbalance. To further aid in this assessment, two control groups can be used; one group would be fed the undiluted control diet and a second group would be fed the control diet supplemented with an inert filler (e.g., methylcellulose) at a percentage equal to the highest percentage of the test substance in the diet. H. Diet:
When the vehicle for the test substance is expected to have caloric and/or nutritional values, which are greater than that of the control ration, an adjustment in the caloric and/or nutritional components may be necessary.
When administration of the test substance is expected to have an effect on feed intake because of its unpleasant taste or texture, paired feeding can be used to eliminate the differences in consumption between control and compound treated groups. When a paired feeding study design is to be employed, pairs of litter-mate weanling rats of the same sex and approximate size are selected and fed the control or the experimenta diet. Animals should be single-caged so that feed consumption can be determined daily, and the control animal is then fed an amount of food equal to that which the paired experimental animal ate on the preceding day. If the test substance is non-nutritive and composes a significant proportion of the diet, the pair-fed control animals should be fed an amount of its feed such that it consumes a nutritionally equivalent amount odiet as the paired experimental animal. Additionally, the study should include a second group of control
animals fed ad libitum to ensure that the impact on any observed experimental result is due to differences in energy or nutrient intake.
When the test substance interferes with the absorption of nutrients, leading to nutritional deficiencies or changes in nutrient ratios, this can confound assessment of the toxicological endpoints under consideration. For example, fat soluble vitamins may preferentially partition with a mineral oil or fat substitute which is largely unabsorbed, such that a potential deficiency in these vitamins may result. This potential may be eliminated by additional nutrient fortification of the feed for those groups receiving the test substance.
Appropriate levels of nutrient fortification should be determined experimentally.
It may be preferable to use a semi-purified diet prepared with known amounts of well-characterized ingredients for short-term and subchronic toxicity studies because of batch to batch variations in diet composition (e.g., fiber, mineral, vitamins, isoflavones) in some of the commonly used laboratory animal chows. The use of these semi-purified diets, however, may not be advisable in long-term and reproductive studies due to inadequate historical data related to their influences on animal survival and toxicological endpoints. For example, loss of necessary but unidentified micronutrients in the semipurified diet may interfere with normal reproduction. Related issues are discussed in the section on Diets for Toxicity Studies in Chapter IV.B.5. in the 1993 draft
"Redbook II"
The following issues are important to consider when establishing diets for animals in toxicity studies:
When the test substance has no caloric value and constitutes a substantial amount of the diet (e.g., more than 5%), both caloric and nutrient densities of the high dose diet would be diluted in comparison to the diets of the other groups. As a consequence, some high dose animals may receive higher test article doses than expected because animals fed such diluted diets ad libitum may eat more than animals in other dosed groups to compensate for the differences in energy and nutrient content of the high dose diets. Such circumstances make it especially important that feed consumption of these animals be as closely and accurately monitored as possible in order to determine whether changes observed could be due to overt toxicity of the test substance or to a dietary imbalance. To further aid in this assessment, two control groups can be used; one group would be fed the undiluted control diet and a second group would be fed the control diet supplemented with an inert filler (e.g., methylcellulose) at a percentage equal to the highest percentage of the test substance in the diet. H. Diet:
When the vehicle for the test substance is expected to have caloric and/or nutritional values, which are greater than that of the control ration, an adjustment in the caloric and/or nutritional components may be necessary.
When administration of the test substance is expected to have an effect on feed intake because of its unpleasant taste or texture, paired feeding can be used to eliminate the differences in consumption between control and compound treated groups. When a paired feeding study design is to be employed, pairs of litter-mate weanling rats of the same sex and approximate size are selected and fed the control or the experimenta diet. Animals should be single-caged so that feed consumption can be determined daily, and the control animal is then fed an amount of food equal to that which the paired experimental animal ate on the preceding day. If the test substance is non-nutritive and composes a significant proportion of the diet, the pair-fed control animals should be fed an amount of its feed such that it consumes a nutritionally equivalent amount odiet as the paired experimental animal. Additionally, the study should include a second group of control
animals fed ad libitum to ensure that the impact on any observed experimental result is due to differences in energy or nutrient intake.
When the test substance interferes with the absorption of nutrients, leading to nutritional deficiencies or changes in nutrient ratios, this can confound assessment of the toxicological endpoints under consideration. For example, fat soluble vitamins may preferentially partition with a mineral oil or fat substitute which is largely unabsorbed, such that a potential deficiency in these vitamins may result. This potential may be eliminated by additional nutrient fortification of the feed for those groups receiving the test substance.
Appropriate levels of nutrient fortification should be determined experimentally.
It may be preferable to use a semi-purified diet prepared with known amounts of well-characterized ingredients for short-term and subchronic toxicity studies because of batch to batch variations in diet composition (e.g., fiber, mineral, vitamins, isoflavones) in some of the commonly used laboratory animal chows. The use of these semi-purified diets, however, may not be advisable in long-term and reproductive studies due to inadequate historical data related to their influences on animal survival and toxicological endpoints. For example, loss of necessary but unidentified micronutrients in the semipurified diet may interfere with normal reproduction. Related issues are discussed in the section on Diets for Toxicity Studies in Chapter IV.B.5. in the 1993 draft
"Redbook II"
| In general, feed and water should be provided ad libitum to animals in toxicity studies, and the diets for these studies should meet the nutritional requirements of the species4-7 for normal growth and reproduction. 一般来说,饲料和水应提供广告libitum动物毒性的研究,这些研究应满足食谱的营养需求的species4-7的正常的生长和繁殖。Unless special circumstances apply which justify otherwise, care should be taken to ensure that the diets of the compound treated groups of animals are isocaloric (equivalent in caloric density) with and contain the same levels of nutrients (e.g., fiber, micronutrients) as the diets of the control group. 除特殊情况外,否则申请证明,要小心谨慎,确保复合膳食治疗组isocaloric动物(等值热量密度)与包含相同的营养水平(如、纤维素、微量元素),对照组的饮食。Unrecognized or inadequately controlled dietary variables may result in nutritional imbalances or caloric deprivation that could confound interpretation of the toxicity study results (e.g., lifespan, background rates of tumor incidences) and alter the outcome and reproducibility of the studies.未知的或未充分控制饮食变量可能会导致营养失衡或热量可以使解释剥夺的毒性试验结果(例如,寿命长,背景肿瘤发病率率)和改变结果和重现性研究。 3 1 2 3 下一页 尾页 |