Organ toxicity

The following is only a very brief introduction to the topic of organ toxicity. There are multiple guidelines e.g. for detection of hepatotoxicity and other toxicities and many publications on particular organ toxicities including e.g. cardiotoxicity, nephrotoxicity, myelotoxicity, immunotoxicity or reproductive toxicity. Please refer to the relevant literature for further information.

Hepatotoxicity is among the most frequent reasons for abandoning further development of drugs. In vitro 3D cultures of hepatocytes have been advocated in recent years for its early detection. Hepatocytes are often supplemented by co-culture with other cell types, resulting in organoid 3D structures.

It is important to differentiate organ toxicity from stress reactions, which may be induced easily in animals exposed to higher doses of chemicals in general and drugs in particular.

Especially endocrine disruption has received significant attention during the past decades. Also other effects, e.g. toxicity to the male reproductive system (see also Basis of the male reproductive system and Practice for its detection) or changes of the ECG, in particular increased QT time, are on the radar of regulating authorities since many decades. Please consult the relevant guidelines and other publications.

Chemicals and drugs may also induce addiction, which must be investigated if needed, e.g. by testing for drug discrimination, self-administration or withdrawal symptoms.

The normally tested animals are healthy and tolerate often only low, sometimes even subclinical doses of drugs acting on the central nervous system (see also presentation on Central nervous system). Low tolerance of test animals constitutes per se no reason for abandoning the development of such drugs.

Generally, it is difficult to mimic certain chemical/drug-associated diseases in test animals, e.g.  different types of allergic reactions. Thus, this type of adverse reaction is difficult or even impossible to investigate by preclinical testing of animals.