Chronic toxicity studies rodents

The traditional acute, subchronic, and chronic toxicity studies performed in rodents and other species also can be considered to constitute multiple endpoint screens. Although the numerically measured continuous variables (body weight, food consumption, hematology values) generally can be statistically evaluated individually by traditional means, the same concerns of loss of information present in the interrelationship of such variables apply. Generally, traditional multivariate methods are not available, efficient, sensitive, or practical (Young, 1985). 

Metabolism and pharmacokinetic studies have greater relevance when conducted in both sexes of young adult animals of the same species and strain used for other toxicity tests with the test substance. The number of animals used in metabolism and pharmacokinetic studies would be sufficient to reliably estimate population variability. This usually means a separate (but parallel) set of groups of animals in rodent studies. A single set of intravenous and oral dosing results from adult animals, when combined with some in vitro kinetic results, may provide an adequate data set for the design and interpretation of short-term, subchronic and chronic toxicity studies. 

Repeated dose chronic toxicity studies are performed on two species of animals a rodent and nonrodent. The aim is to evaluate the longer-term effects of the drug in animals. Plasma drug concentrations are measured and pharmacokinetics analyses are performed. Vital functions are studied for cardiovascular, respiratory, and nervous systems. Animals are retained at the end of the study to check toxicity recovery. Table 5.2 shows the duration of the animal studies, which depends on the duration of the intended human clinical trial. Appendix 6 summarizes the information to be submitted to regulatory authorities. 

Chronic toxicity feeding study of at least one year in a rodent — usually undertaken as a combined carcinogenlcity/chronic toxicity study,... 

Public concern has focused on the possible carcinogenic effects of drugs and other chemicals. Long-term chronic toxicity studies in a variety of species have been started in the hope of minimizing potential risk of cancer in man. However, the results of such studies are difficult, sometimes impossible, to interpret. Yet their economic impact can be enormous, as shown by the withdrawal of cyclamates when bladder cancer was observed in a limited number of rodents. Inevitably drugs will be affected too already the safety of certain oral contraceptives has been questioned because of possible carcinogenic effects in the breasts of dogs after extended use. 

As discussed above, the extent of additional repeated-dose studies are generally outlined in Tables 6.2 and 6.3. The maximum duration of chronic studies is generally 6 months. The ICH guidelines describe situations where studies of 9-12 months duration in a non-rodent species may be necessary, particularly for the US FDA. The ICH has issued a guideline relative to the duration of chronic toxicity studies. 

Toxicological Chronic toxicity Carcinogenicity Fertility study (multi-generation) Embryotoxicity (non-rodent) Acute/subacute toxicity in 2nd species Toxicokinetics... 

Chronic Toxicity. Traditionally, chronic toxicity of new pharmaceuticals in the United States was assessed in studies of one-year duration in both the rodent and the nonrodent species of choice. The European view was that studies of six months are generally sufficient. The resulting guideline (S4A) was a compromise. Studies of six months duration were recommended for the rodent, as rodents would also be examined in two-year studies. For the nonrodent (dog, nonhuman primate, and pig) studies of nine months duration were recommended. 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

B.26 Sub-Chronic Oral Toxicity Test Repeated Dose 90-Day Toxicity Study in Rodents (2001)... 

B.29 Sub-Chronic Inhalation Toxicity Test 90-Day Repeated Inhalation Dose Study Using Rodent Species (1988) B.30 Chronic Toxicity Test (1988)... 

B.26 Sub-chronic oral toxicity test. Repeated dose 90-day toxicity study in rodents B.27 Sub-chronic oral toxicity test Repeated dose 90-day toxicity study in non-rodents B.28 Sub-chronic dermal toxicity test 90-Day repeated dermal dose study using rodent species B.29 Sub-chronic inhalation toxicity test 90-Day repeated inhalation dose study using rodent species B.30 Chronic toxicity test... 

B.33 Combined chronic toxicity/carcinogenicity test B.43 Neurotoxicity study in rodents... 

An ICH guideline entitled Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing) indicates that a non-rodent study of 9 months may be acceptable in the United States, Japan and EU. 

Chronic Toxicity The effect of a chemical (or test substance) in a mammalian species (usually rodent) following prolonged and repeated exposure for the major part of the lifetime of the species used for the test. Chronic exposure studies over two years are often used to assess the carcinogenic potential of chemicals. 

IPEC-US (intended clinical route)a Acute oral and dermal toxicity, skin and eye irritation, and skin sensitization. Bacterial gene mutation and chromosome damage. ADME (intended route). 28-day toxicity (2 species by intended clinical route) Short-term use studies. 90-day toxicity (most appropriate species). Teratology (rat and/or rabbit). Genotoxicity assays. Additional assays (conditional) 1 Short-/midterm studies. One-generation reproduction. Chronic toxicity (rodent and nonrodent) and carcinogenicity (conditional)... 

Such a dichotomy cannot be resolved in a generic manner. Although it may be advisable that chronic effect results be obtained from both a rodent and nonrodent, the selection of appropriate species for chronic toxicity tests should be based upon practical reasons and the results of previously conducted studies. In some cases, testing with a single species may provide sufficient data for assessing test chemical hazards. Strains of test animals should be well characterized for commonly found diseases and their resistance, and should be free from congenital defects. 

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