Satellite groups

An example of the third-level acute toxicity test, a supplemented study, is given in Figure 5.13. Such tests are rarely performed but are of use when one wishes to obtain data other than descriptive toxicity data. For example, the addition of satellite groups... 

Interval or satellite groups have been discussed at two earlier points in this chapter. They allow measurement of termination parameters at intervals other than at termination of the study. They are also useftd when the manipulation involved in making a measurement (such as the collection of an extensive blood sample), while not terminal, may compromise (relative to other animals) the subject animals. Another common use of such groups is to evaluate recovery from some observed effect at study termination. 

Inclusion of additional nonroutine parameters for immunotoxicity assessment in subsequent (longer-term) toxicity assays. Can also include additional satellite groups for functional tests that may require coadministration of... 

These data may be obtained from all animals on a toxicity study, or from representative subgroups, from satellite groups, or from separate studies. 

Toxicokinetic measurements performed in the toxicity study, either in all animals or in representative subgroups or in satellite groups. 

Number/sex/group or time point (main study) Satellite groups used for toxicokinetics or recovery Age Weight... 

Exposure for at least 12 months (satellite groups) or majority of normal life span (carcinogenicity part)... 

At least three dose levels plus control At least 50 males and females per group Satellite group At least 20 males and females per group Preferred species Rat Exposure for a minimum of 4 weeks (males) or from 2 weeks prior to mating until at least postnatal day 4 (females -at least 6 weeks of exposure)... 

The ehronie-duration inhalation MRL was based on the study by Mobay Corporation (1989). Fischer 344 rats were exposed to 0, 0.005, 0.025, or 0.175 ppm HDl for 5 day a week, 6 hour a day for 2 years. A satellite group was also exposed for 1 year. Reticulocytosis (less serious LOAEL), as well as eye irritation (observed in males only, first year only), were noted at the 0.175 ppm dose. At the 0.025 ppm dose, nasal cavity hyperplasia/metaplasia, limg epithelialization, alveolar macrophage accmnulation (less serious LOAEL) were observed. Nasal cavity epithehal hyperplasia (minimal LOAEL) was also reported at the 0.005 ppm dose level in female rats and was used to derive the chronic inhalation MRL for HDL... 

Silverberg and See also point out that often proper planning will allow assessment of an excipient s toxicity in a relatively efficient manner. A less expensive study within a study can be conducted by developing new excipients concurrently with the development of new drugs. Satellite groups of animals receiving an excipient... 

Waschinski CJ, Barnert S, Theobald A et al. (2008) Insights in the antibacterial action of poly(methyloxazoline)s with a biocidal end group and varying satellite groups. Biomacromolecules 9 1764-1771... 

Waschinski CJ, Herdes V, Schueler L et al. (2005) Influence of satellite groups on telechelic antimicrobial functions of polyoxazolines. Macromol Biosci 5 149-156... 

Animals that comprise the satellite group for follow-up studies should be kept under observation for 14 days without treatment. This procedure detects persistence of toxic effects (if any), as well as manner of recovery. A careful clinical examination should be made every day. Action should be taken to minimize the loss of experimental animals, (e.g., identifying animals that are moribund, doing necropsy, refrigeration of animals that are found dead, sacrificing weak or moribund animals). 

In the subchronic toxicity study, if interim sacrifices are planned, the number of animals should be increased so that there is no shortage of animals at the termination of the study this ensures meaningful conclusions about the test chemical s toxicity. In addition, a satellite group of 20 animals (10 of each gender) may be treated with the high dose of the test chemical for 90 days. These animals should be observed for signs of adverse effects, (e.g., reversibility, persistence, delayed occurrence of toxic effects). The observation period should last for a posttreatment period of appropriate length not less than 28 days. 

The observation period for the subchronic oral toxicity should be at least 90 days. Animals in a satellite group scheduled for follow-up observations should be kept for a further period of 28 days without treatment to detect recovery from, or persistence of, toxic effects. Careful clinical examination should be made at least once each day. Additional observations should be made and appropriate actions taken to minimize loss of animals these actions include necropsy or refrigeration of those found dead, or isolation, or sacrifice of weak or moribund animals. The animals are dosed with the test chemical ideally 7 days per week for 90 days. However, based primarily on practical considerations, dosing by gavage or capsules 5 days per week is acceptable. 

The animals are treated with the test chemical ideally for at least 6 hours per day on a 7-day basis, for 21 or 28 days. However, based primarily on practical considerations, application on a 5-day-per-week basis is considered acceptable. Animals in a satellite group scheduled for follow-up observations should be kept... 

When a distinct endocrine profile of a compound is present before starting the toxicology studies, a targeted investigation can be added to the standard toxicology protocol, satellite groups may be added, or specific mechanistic studies may be initiated in the context of toxicological evaluation of the test substance. 

The duration of me treatment period should be at least seven days. It may be extended to the duration of a preceding toxicology study (28 days) where some observations for concem-were made, but no satellite groups were included for specific investigation. 

At the end of me treatment period, groups of animals are killed under minimum stress conditions, preferably by rapid decapitation. The time point 24 hours after last dosing is not always suitable, e.g. when changes in pituitary hormone contents need to be assessed, the time point 2 hours after last dosing is preferable. Satellite groups need to be included if necessary for me exact time course of changes after dosing. 

The selection of the blood sampling procedure depends on the hormone to be measured. Most hormones can be reliably measured e.g. during brief carbon monoxide anaesthesia, or preferably during brief ether anaesthesia by retroorbital venipuncture. Repeated blood sampling is not advisable in this method, when necessary satellite groups need to be added e.g. to... 

The stimulation test can be performed as a single-dose test in rats during the treatment period, preferably three to four days before the end of the study, or as a single dose test in satellite groups of animals. Stimulation of testosterone in rats can be indirect via the release of luteinizing hormone by injection of LHRH (gonadore-... 

This method may be used in the context of repeated dose treatment, on satellite groups of rats which show changes in thyroid uptake of labelled iodine. It may be sufficient to determine radio-iodine uptake in controls and in the high-dose group. 

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