Repeat-dose toxicity studies endpoints

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

V. Because pharmaceuticals are normally tested for toxicity in rodent repeated dose toxicity tests and because there is no longer a requirement for an acute high dose rodent toxicity test, the assessment of genotoxicity (e.g., bone marrow micronucleus test or other tissue/endpoint) should be integrated, if feasible, into the rodent repeated dose toxicity study to optimize animal usage. 

Inclusion of Safety Pharmacology Endpoints in Repeat-Dose Toxicity Studies. 353... 

These are of two types scientific and regulatory. Together, these drivers have stimulated interest in the inclusion of safety pharmacology endpoints in repeat-dose toxicity studies on conventional pharmaceuticals (i.e. non-biologics) (Redfern and Valentin 2011 Redfern et al. 2013). 

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... 

Repeat-dose neurotoxicity studies may identify behavioral effects or impaired nerve functions that can interfere with mating or maternal care. Developmental neurotoxicity studies have been conducted for specific pesticide classes, following requirements of US-EPA. If such a study is available it can be examined not only for the study-specific endpoints on the developing brain but also compared to the prenatal toxicity study and the two-generation smdy with respect to general endpoints of pre- and postnatal development, respectively. 

The usual GLP 30- or 60-day repeat-dose toxicology study with a recovery group offers an opportunity to perform a more systematic investigation of the more subtle pharmacodynamic or toxicologic effects of biopharmaceuticals than those endpoints usually incorporated into such protocols. Some of these demand tissue samples, but many involve noninvasive biomarkers that can be carried forward into early phase human studies. These might include CNS assessments, inflammation and immune activation or suppression, cell proliferation or apoptosis in tissue samples, and end-organ toxicities. 

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