Toxicity testing risk benefits

For a drug that has never been used in humans previously, the initial step that a pharmaceutical company must take is to perform preclinical toxicity studies involving appropriate in vitro systems or whole animals. The FDA usually requires that dose-related toxicity be determined in at least two mammalian species (routinely rodents). The toxicity information obtained from these studies can then be used to make risk/benefit assessments and help determine the acceptability of the drug for testing in humans, and to estimate a safe starting dose. 

In practical terms, the assessment of relevance addresses the following question Given the information known about the alternative method, are the data provided by the assay good enough to allow its acceptance as a replacement for a given in vivo test In order to answer this question, all of the available information related to performance, operation, and mechanistic basis of an alternative method and the in vivo toxicity test it is intended to replace must be thoroughly reviewed. The benefits and risks associated with the adoption of the new method must also be defined. Once this information is available, it must be synthesized in a manner that allows those involved in a validation process to render a judgment that the performance of the alternative method is acceptable or not as a replacement for the in vivo toxicity test. 

Aside from consideration of drug toxicity, some antimicrobial use requires more in tensive risk-benefit analysis. An example of this is the decision to use isoniazid prophylactically to prevent tuberculosis. Because the hepatotoxicity of isoniazid increases in frequency with age, older persons (>45 years) who are candidates for isoniazid prophylaxis (positive skin test) must have additional risk factors for tuberculosis to balance the potential toxic effects. These include evidence of recent skin-test conversion, immunosuppression, or previous gastrectomy. Older patients without additional risk factors are more likely to suffer toxicity from isoniazid than derive benefit from its use. ... 

Because of the requirement by public health authorities that any chemical used in the production of food should pose no risk to the consumer, the safety of food chemicals has mostly been approached from the perspective of whether or not the chemical poses a toxicological hazard. If it does so then it is argued that it is likely to present some degree of risk to the consumer even if humans are exposed to very low levels of that chemical in their diets. However, if exposure is minimal, depending on the nature of the toxicity, it is likely that the risk is acceptable because it is so low. What is not considered, or even tested in the experimental systems designed to study the toxicological effects of chemicals, is whether there are levels of exposure where there might be potential health benefits. The assumption is made that any nonnatural, adventitious substance that can be shown to be toxic is unlikely to have health benefits. 

Hepatotoxicity Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease, nor a serious underlying medical condition. If liver function tests are abnormal, discontinue treatment. In patients with raised liver enzymes or an active liver disease or who have experienced liver toxicity with other drugs, do not start treatment unless the expected benefit exceeds the risk of hepatic injury. In such cases, liver enzyme monitoring is necessary. 

The goal of biopharmaceutical development is to maximize therapeutic benefit while minimizing the risk of treatment-related toxicity. To mimic putative interpatient treatment differences in test article responsiveness, it is important... 

The eyes of the rabbit differ in certain aspects from the eyes of humans. They are more sensitive, have a lower tear production and blink frequency and posses a nictitating membrane. Nevertheless, the Draize test predicts human ocular toxicity correctly in 85 % cases but overestimates in 10% and underestimates in 5 % (Gad and Chengelis 1991). In addition, ethical concerns have been raised in the use of animals and benefit vs risk of these tests for the protection of the human eye must be carefully evaluated. 

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