Use of gene and protein expression analyses in the risk assessment of chemicals

Robust, toxicological data are the prerequisite for authorisation for new chemicals and the health assessment of so-called "existing substances". If the annual production of a substance exceeds a certain volume, longitudinal animal experiments in laboratory rodents must be carried out to generate the necessary data (e.g. 90 days or 2-year studies in rats). Sub-acute toxicity testing in rats (28-day test with repeated administration of the test substance) is the basic toxicological test for new chemical substances that are to be placed on the market (from a production volume of 1 tonne/year).

The use of gene expression analyses could quickly lead already on the level of sub-acute toxicity testing to robust information on the toxicity mechanisms of substances and thus reduce the number of distressing longitudinal animal studies. BfR is testing biological methods of this kind, called toxicogenomics, in order to identify potentially dangerous substances more quickly and with fewer animal experiments than had been needed up to now.

Once a substance’s mechanism of action has been identified, conclusions about its toxic properties can be drawn. Whenever they are in contact with a substance, genes, proteins or metabolites "react" in a certain way, the toxicological "fingerprint". Vice versa this fingerprint permits conclusions about the mechanism of action, the pathway of the toxic reaction. The mechanism of action for man is of major importance for the assessment of toxic potential and thus the risk posed to man by the substance.

For the purposes of analysis tissue samples from experimental animals and cell cultures are examined. With the help of toxicogenomics thousands of sequences of the genome are recorded simultaneously and changes in the complex activity patterns caused by an added substance can be observed. By analysing gene and protein expression, reactions to as yet non-toxic levels can already be recorded. Knowledge about the molecular mechanisms of action, therefore, constitutes major progress when it comes to transferring findings from animal experiments to man. It is expected that this development will revolutionise the risk assessment of substances.

Research areas

• Identification of hepatocellular biomarkers for the early detection of the carcinogenic effects of chemical substances
• Detection of protein biomarkers in human serum after exposure to dioxin