Research for safety factors deduction
What it's about
The aim of the health risk assessment of chemical substances is to minimise or eliminate potential hazards by setting reasonable limits for exposureExposureTo glossary.
Background
For the purpose of setting limit values, NOAELs (Non Observable Adverse Effect Levels) of relevant toxicological endpoints are generally combined with safety factors based on convention. These are intended to take into account species-specific toxicokinetic/dynamic differences as well as variabilityVariabilityTo glossary within the human species.
Derivation of data-protected safety factors for the assessment of chemicals
The focus of the work at the BfRshort forGerman Federal Institute for Risk Assessment is on the acquisition of experimental data that can be used to derive safety factors for both species extrapolation and variability within the human population that are based on actual (and thus scientifically sound) physiological differences. The project is integrated into international projects (IPCS/WHO: noncancer endpoints) that aim to replace the conventionally based safety factors (so-called ‘default’ assumptions) with data-based safety factors. The cytochrome P450 (CYP) enzyme system plays a crucial role in the breakdown of foreign substances (e.g. drugs, chemicals). These enzymes are mainly found in the liver, but also in other organs. The various isoenzymes differ in their substrate specificity. Differences in the expression of these enzymes can cause differences in susceptibility to chemicals. Differences in the expression of CYP enzymes can have genetic causes, but can also be influenced by external factors.
Projects
- CYP expression in human bone marrow stem cells
This project is of particular relevancePositive Predictive ValueTo glossary for risk assessment due to the selective bone marrow damaging effect of certain xenobiotics. In cooperation with the Institute for Transfusion Medicine of the Municipal Hospital of Braunschweig, purified bone marrow stem cells from about 30 individuals were provided to examine the expression pattern of CYP enzymes. - CYP expression in human lung
The Lung Clinic Heckeshorn, Berlin, provided healthy lung tissue from over 100 individuals in which the expression of various xenobiotic-metabolising CYP enzymes was to be quantified using Western blotting and enzyme activity measurements. Since possible external influencing factors are also recorded by means of a questionnaire, this study offers the opportunity for the first time to analyse extrahepatic CYP expression and possible influencing factors in a sample size that allows statements to be made about the variability within the human population. Since many chemicals are absorbed by inhalation, this project is of particular relevancePositive Predictive ValueTo glossary for the risk assessment of chemicals. - Study focusing on species differences in extrahepatic P450 expression
With regard to the bone marrow toxicity of benzene in different species, the expression of CYP2E1 in the bone marrow is examined, among other things. - Study focusing on inter-individual variability of extrahepatic P450 expression in humans
P450 enzymes metabolising foreign substances were immuno-quantified in human mononuclear blood cells (50 individuals) and in human colon (23 individuals).
Results:
- This completed project showed that the qualitative and quantitative P450 expression pattern in extrahepatic organs differs from that in the liver and that P450 expression also varies from organ to organ within the extrahepatic organs. In the case of organ-specific, chemical-related toxicity, the P450 expression pattern present in the affected organ should be taken into account. Additionally, it has been shown that for polymorphically expressed P450 enzymes (e.g. CYP2C19, CYP2D6), a factor of 10 for inter-individual variability may not be protective enough if such enzymes are involved in the activation of chemicals.
Cytochrome P450 (CYP 2E1)-dependent metabolisation of acrylamide in genetically modified cell lines
- Acrylamide has been shown to be carcinogenic in long-term studies in laboratory rodents. In the liver of mammals, acrylamide is metabolised by the enzyme CYP 2E1 to glycidamide, which is thought to be responsible for the carcinogenic and mutagenic effects. This project aims to use genetically modified cell lines to investigate whether there are species differences in the CYP 2E1-dependent metabolisation of acrylamide. At the same time, the DNA-damaging effect of acrylamide and glycidamide in the cell systems is to be analysed.