Special toxicity testing

Although biotechnologically derived pharmaceuticals often need customized precli-nical development programs, certain issues are common to all. These include species specificity, potential immunogenicity and its impact on the duration of dosing, and the need for special toxicity testing. 

Toxicology, including an integrated summary of toxicological effects of the drug, including results from acute, subacute, chronic, and in vitro toxicity tests, the effects on reproduction and the fetus and special toxicity tests. A detailed tabulation of toxicity data for each study should be included. 

Industry typically employs its own in-house toxicologists and risk assessors both as managers of the testing regime and as scientists. Outside consultants and laboratories are also used to perform specialized toxicity testing and risk assessments. 

The clinical studies proposed determine the duration of toxicology testing required, whether reproductive toxicology is required, and whether special toxicity tests due to the drug s route of administration are required. Prior to human exposure, in vitro tests for the evaluation of mutations and chromosomal damage are generally required. 

Because of safety concerns, all combustible and/or toxic gases must be used in outdoor test loops or in a special indoor test building with the required safety monitoring equipment. The gas cost factor makes the problem even more difficult. The problem of known gas properties adds another complication. Despite all the negative aspects just mentioned, most performance tests are closed-loop tested. 

In summary, neurotoxic effects of endosulfan are usually apparent only after acute ingestion of relatively high doses. Cumulative neurotoxicity does not appear to be significant. If the animal survives the acute toxic effects, then no long-term neurotoxic effects are evident from behavioral, gross, and microscopic observations. However, some impairment may occur that can be detected only by specialized neurobehavioral testing. 

Festing, M.W. (1979). Properties of inbreed strains and outbreed stocks, with special reference to toxicity testing, J Toxicol Environ Health 5 53-68. 

The toxic properties of the chemicals to be discussed have been learned from the many types of general and specialized animal tests discussed in Chapter 3. In many cases they have also been learned from epidemiological studies and case reports. Carcinogens, as we have already mentioned, are excluded until the next two chapters. 

The toxicity tests with Paramecium caudatum were carried out in a special plate and examined under a Laboval microscope (Carl Zeiss, Jena). The test reaction was the death of the test organisms when exposed to 0.3 mL of test solution for 1 hour, using 10 individuals of Paramecium. Analysis was conducted five times simultaneously. 

Box 3.2 shows the toxicity package t)q)ically generated before a Phase I trial. These trials are usually conducted in males, and thus do not require formal reproductive toxicity studies. In the United States, women can be included in early trials without any animal reproductive toxicity if special precautions are taken to ensure that pregnancy does not occur. A histopathological assessment of the effects of the test compound on the male reproductive tract is made in the repeat-dose toxicity tests. 

Therefore, toxicity tests, or in other words bioassays, can supply information on the total load of an investigated sample in a diverse (in terms of type and quantity) mixture of pollutants, which allows for the possibility of their interactions.8-12 Bioassays are based on the use of particularly sensitive species (bioindicators), which are characterized by their quick reaction to changes in their environment. This results from their relatively low ability to maintain a stable state of equilibrium, that is, from their narrow range of tolerance to specific toxic factors. Such organisms show a special ability to accumulate pollutants.13 Hence, they can work as so-called Biological Early Warning... 

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