Toxicity study evaluation

Alternatively, side effects may not emerge until after repeated or prolonged exposure to the drug these are called chronic or long-term toxicities. Studies evaluating acute toxicity are conducted over a few weeks, whereas those evaluating chronic toxicity are conducted from six months to one year. 

In additional EPA studies, subchronic inhalation was evaluated ia the rat for 4 and 13 weeks, respectively, and no adverse effects other than nasal irritation were noted. In the above-mentioned NTP chronic toxicity study ia mice, no chronic toxic effects other than those resulting from bronchial irritation were noted. There was no treatment-related increase ia tumors ia male mice, but female mice had a slight increase in bronchial tumors. Neither species had an increase in cancer. Naphthalene showed no biological activity in other chemical carcinogen tests, indicating Htde cancer risk (44). No incidents of chronic effects have been reported as a result of industrial exposure to naphthalene (28,41). 

Hazard identification, step one, means identification of new chemicals or other factors that may cause harmful health effects. Previously, novel hazards were usually observed in case studies or after accidents or other excessive exposures, usually in occupational environments. Today, thorough toxicity studies are required on all pesticides, food additives, and drugs. New chemicals also have to be studied for their potential toxic effects. Thus, earlier hazards were in most cases identified after they had caused harmful effects in humans. Today, most chemical products have been evaluated for their toxicity with experimental animals. Therefore, hazard identification has become a preventive procedure based on safety studies conducted before a chemical compound or product reaches the market, and before individuals are exposed to it. ... 

TABLE 5.24 Toxicity Studies for Safety Evaluation of Drugs, Pesticides, Food Additives, and Other Chemicais Utilizing Experimental Animals and Other Systems Required by Health Authorities... 

It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants of the compound tested preclin-ically that is intended for use in clinical trials. The maximum level of impurities in a stereoisomeric product used in clinical studies should not exceed that in the material evaluated in nonclinical toxicity studies. This point is expanded in the ICH impurities guideline (Section 13.5.3). 

GL37 Safety repeat dose chronic toxicity Studies to evaluate the safety of residues of veterinary drugs in human food Repeat-dose Chronic Toxicity Testing... 

Only a few in vivo dermal toxicity studies have been reported so far. Huczko and Lange [50] evaluated the potential of raw CNTs to induce skin irritation by conducting two routine dermatological tests (patch test on 40 volunteers with allergy susceptibilities and Draize rabbit eye test on four albino rabbits). Koyama etal. [51] showed the biological responses to four different types of carbon nanotubes (SWNTs, two types of MWNTs with different diameters, and cup-stacked carbon nanotubes) after their subcutaneous implantation in mice. Both tests [50, 51] showed no or poor irritation effects. However, the in vitro studies in epidermal cell lines exposed to CNTs, and also a more recent report on the toxic outcomes of topical exposure of mice to SWNTs [46], have raised concerns over these assessments. Clearly, this is an area requiring further scientific evaluation. 

Guidance for Industry Considerations for Developmental Toxicity Studies for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. Department of Health and Human Services, Food and Drug Administration Center for Biologies Evaluation and... 

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). 

Balazs, R. (1976). Assessment of the value of systemic toxicity studies in experimental animals. In Advances in Modern Toxicity, Vol. 1 Part 1 New Concepts in Safety Evaluation (Mahlman, M., Shapiro, R. and Blumenthal, H., Eds.). Hemisphere Publishing, Washington, D.C., pp. 141-153. 

Pharmacokinetics. All subchronic and chronic toxicity studies now incorporate (either in the study itself or in a parallel study) evaluation of the basic pharmacokinetics of a compound. This is discussed in detail in Chapter 18. 

Careful organ weight and histopathological evaluation of testes in general toxicity studies will detect most testicular toxins. 

Thus, in any case where developmental toxicity occurs at dosage levels with only moderate to severe maternal toxicity, the possibility of the developmental toxicity being secondary to the maternal toxicity can be considered. That is not to say, however, that it can be concluded that the developmental toxicity is secondary any time there is coincident maternal toxicity. To the contrary, it is usually very difficult to establish a causal relationship. Superficially similar types of maternal toxicity do not always cause the same pattern of developmental toxicity (Chemoff et al., 1990). This may be because the developmental toxicity is secondary to matemotoxicity, but, since typical developmental toxicity studies include only a very cursory evaluation of maternal toxicity, the developmental toxicity may be secondary to an aspect of matemotoxicity that is not even being measured. 

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