Standard toxicity studies parameters

Since many biotechnology products are designed to modulate the immune system, basic immunotoxicity parameters have traditionally been evaluated as part of standard toxicity studies. Over time more and more immunotoxicity specific parameters have been validated in toxicology species, including primates. These parameters (humoral and cell-mediated) should be measured as appropriate. Other specific issues for biopharmaceuticals include immunogenicity, as previously discussed. 

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... 

The standard repeated dose toxicity guidehne studies include a number of parameters relevant for the evaluation of a substance s immunotoxic potential. While some information on potential immunotoxic effects may be obtained from the evaluation of hematology, lymphoid organ weights, and histopathology in these studies, there are data which demonstrate that these endpoints alone are not sufficient to predict immunotoxicity. In addition to these standard studies, the US-EPA has developed a specific test guideline for immunotoxicity testing in rodents (OPPTS 870.7800). This... 

The standard repeated dose toxicity guideline studies include a number of parameters relevant for the evaluation of a substance s neurotoxic potential. In addition to these standard... 

Hattis et al. (1987) examined the variability in key pharmacokinetic parameters (elimination half-lives (Ty ), area under the curve (AUC), and peak concentration (C ax) in blood) in healthy adults based on 101 data sets for 49 specific chemicals (mostly drugs). For the median chemical, a 10-fold difference in these parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, a 10-fold difference would correspond to only about 2.5 standard deviations in the population. The authors remarked that the parameters studied are only components of the overall susceptibility to toxic substances and did not include contributions from variability in exposure- and response-determining parameters. The study also implicitly excluded most human interindividual variability from age and diseases. When these other sources of variability are included, it is likely that a 10-fold difference will correspond to fewer standard deviations in the overall population and thus a greater number of people at risk of toxicity. 

If the chemical composition of the samples is known or at least partly known (in a stepwise TIE approach) or existing data allow for QSAR calculation, the samples can be ranked by TUs. Arts et al. (2006) studied, in 12 outdoor ditch mesocosms, the effects of sequential contamination with 5 pesticides in a regression design. They applied dosages equivalent with 0.2%, 1%, and 5% of the predicted environmental concentration (PEC) subsequently over 17 weeks. Endpoints recorded over 30 weeks included community composition of macroinvertebrates, plankton, and macrophytes, and leaf litter decomposition as functional ecosystem parameters. TUs were calculated in relation to acute toxicity data for the most sensitive standard species Daphnia magna and Lemna minor. Principal response curves (PRCs), a special form of constrained PCA, and Williams test (NOEC, class 2 LOEC) were used to identify the most sensitive taxa. Next to direct effects on certain species, also indirect effects, for example, how the change in abundance of a sensitive species affects the abundance of another, more tolerant species, can be detected only in mesocosm or in situ experiments. All observed effects were summarized in effect classes in a descriptive manner. 

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