Toxicity long term studies

Administration of 5 ppm barium, the acetate, to mice in the drinking water in a life-time study had no observable effects on longevity, mortality, and body weights, or on the incidence of tumors (53). Long-term studies in rats exposed to Ba " in drinking water containing 5 mg/L, as acetate, or 10—250 mg/L, as chloride, resulted in no measurable toxic effects (47). 

No long-term studies of toxicity or carcinogenicity were undertaken. 

Preclinical drug development also involves animal testing [61]. Data from one rodent species and one nonrodent species are usually collected to determine the absorption, metabolism, and toxicity characteristics of the compound. Both short-term (2 weeks to 3 months) and long-term (up to several years) studies are done. The long-term studies are particularly useful for... 

Gabizon, A., Meshorer, A., and Barenholz, Y. (1986) Comparative long-term study of the toxicities of free and liposome-associated doxorubicin in mice after intravenous administration.. Natl. Cancer Inst. 77, 4594-69. 

In general, a well-conducted long-term study in two species, with no indication of immunotoxicity, based on the considerations outlined above, should be adequate to evaluate the potential for drug-induced immunotoxicity. If the results from these studies do not produce evidence of immune-specific toxicity after examination of standard and/or additional hematologic, serum chemical, and histopathologic parameters, then additional testing should not be indicated. However, if there are structure-activity considerations that may indicate a potential for concern, of if... 

Bruckner JV, Mackenzie WF, Ramanathan R, et al Oral toxicity of 1,2-dichloropropane Acute, short-term and long-term studies in rats. Fundam Appl Toxicol 12 713-730, 1989... 

Toxicity data on PS are scanty. Short-term studies have been extremely limited, and long-term studies are lacking.15,16... 

Despite widespread use as an Insecticide, nematoclde, and Intermediate In chemical processes, the toxic potential of PS has not been fully evaluated. Absence of lethal effects may well be explained by Its powerful odor, which alerts workers to Its presence In contaminated areas. Anlmal-toxlclty data suffer from variations In the methods used. One long-term study of carcinogenicity In rats was unsatisfactory because of high early mortality. 

Due to the high doses necessary for acute effects as observed in short-term toxicity tests and to the lack of effects seen at earlier time-points in long-term studies, only chronic reference doses are used in conjunction with exposure for the calculation of triazine dietary risk. Therefore, the remainder of this discussion is limited to chronic exposure and risk. 

The weight variation of animals at the commencement of the study should not exceed 20% of the mean weight. It is also important that wherever a subchronic oral toxicity study is conducted as a preliminary to a long-term study, the same species and strain should be used in all studies. At least 20 animals (1 female, 10 male) should be used for each test dose. In view of the importance of the subchronic oral toxicity study, use of more animals would be advantageous. Females should be nulliparous and nonpregnant. 

When a test chemical is administered by gavage, the dose should be given at the same specified time each day. Furthermore, the test dose should be adjusted at regular intervals (e.g., weekly or biweekly), to maintain constant dose levels in terms of the changing body weight of the animal. Also, where a subchronic oral toxicity study is used as a preliminary to a long-term study, a similar dietary regimen should be used for both studies. 

A properly conducted 21- or 28-day study will provide information on the effects of repeated dermal application of a test chemical and can indicate the need for further studies (long-term). The study also can provide information on the selection of dose levels for long-term studies. The results of the repeated-dose dermal toxicity test may be presented in tabular form, including all salient aspects. 

Test System To conduct a repeated-dose inhalation toxicity study, different species may be used. However, this guideline is intended primarily for use with rodents. When a rodent is required, the preferred species is the rat. Commonly used laboratory strains of young, healthy animals should be employed. At the commencement of the study, the weight variation of animals should not exceed 20% of the mean body weight. When a repeated-dose inhalation study is conducted as preliminary to a long-term study, the same species should be used in both studies. 

Composition of the test chemical, including major impurities, should be known prior to initiating the study. Relevant physicochemical properties, including stability of the test chemical, should be known prior to the initiation of a chronic toxicity study. The development of an analytical method for qualitative and quantitative determination of the test chemical (including major impurities when possible in the dosing medium and biologic material) should precede the initiation of long-term studies. 

In addition, Adrian also observed a hypertrophy of the caecum, liver, and kidneys, and a decrease in fertility (20,133) attributed to a certain toxicity or to nutritional deficiencies. Lee et al. (33) observed a hypertrophy of the liver and kidney and an increase of the serum transaminases (GOT and GPT) with Maillard fractions extracted from browned apricots, and Kimiagar et al. (47) observed larger changes in biological parameters after a long-term study with browned egg albumin. 

Repeat-Dose Toxicity Studies Typically toxicity studies are performed in two animal species. However, for toxicity studies for which there is only one relevant animal species, these studies may be performed using one animal species. When two animal species show the same toxicity profile in short-term studies, only one animal species may be used in long-term studies. Comparison of toxicity profiles means comparing the type and severity of any toxicity observed. However, biopharmaceuticals with a low toxicity may display no toxicity at high doses in some cases. It such cases it may still be important to select one species for assessment of chronic toxicity. More important, in cases where toxicity has not been clearly demonstrated justification of human... 

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