Establishment of safety factors

The goal of the health risk assessment of chemical substances is to minimise or rule out a potential hazard by establishing reasonable limit values for exposure. Up to now NOAELs (Non Observable Adverse Effect Levels) of relevant toxicological end points have been assigned to conventional safety factors taking into account species-specific, toxicokinetic/dynamic differences and inter-species variability.

Establishment of data-based safety factors for chemical assessment

The main focus of the work within BfR is on obtaining experimental data as the basis for the establishment of safety factors based on existing (and therefore scientifically founded) physiological differences both for species extrapolation as well as for variability within the human population. This project is integrated into international consortia (IPCS/WHO: noncancer endpoints) aiming to replace safety factors based on a convention (so-called default assumptions) with data-based safety factors. The cytochrome P450 (CYP) enzyme system plays a decisive role in the degradation of foreign substances (e.g. medicinal substances, chemicals). These enzymes are mainly to be found in the liver as well as in other organs. The various isoenzymes differ in terms of their substrate specificity. Differences in the expression of these enzymes can also lead to a different susceptibility to chemicals. Differences in the expression of CYP enzymes may be due to genetic causes but may also be influenced by external factors.

Research areas

• CYP expression in human bone marrow stem cells
  Given the selective bone marrow-damaging effect of certain foreign substances, this project is of special relevance for risk assessment. In co-operation with the Institute for Transfusion Medicine at Städtisches Klinikum Braunschweig purified bone marrow stem cells from approximately 30 individuals were provided to examine the expression pattern of CYP enzymes.

• CYP expression in the human lung
  The Heckeshorn Lung Clinic Berlin made available healthy lung tissue for more than 100 individuals in which the expression of various CYP enzymes that metabolise foreign substances was to be quantified using Western Blotting and enzyme activity measurements. Since other possible contributory factors are recorded using questionnaires, this study offers  the possibility for the first time of conducting extrahepatic CYP expression and possible contributory factors on a sampling scale that would permit statements about variability within the human population. As many chemicals are inhaled, this project is of particular relevance for the risk assessment of chemicals.

• Examination focussing on species differences in extrahepatic P450 expression
  The expression of CYP2E1 in bone marrow, amongst other things, is examined from the angle of the bone marrow toxicity of benzene in various species.

• Examination focusing on interindividual variability of extrahepatic P450 expression in man
  P450 enzymes that metabolise foreign substances were immunoquantified in human mononuclear blood cells (50 individuals) and in the human colon (23 individuals).
  
  Results:
  This now completed project showed that the qualitative and quantitative P450 expression pattern in extrahepatic organs differs from that in the liver and that even within the extrahepatic organs P450 expression varies from organ to organ. In the case of organ-specific, chemical-related toxicity, the P450 expression pattern in the organ affected should be taken into account. Furthermore, the project showed that in the case of polymorphic expressed P450 enzymes (e.g. CYP2C19, CYP2D6) a factor of 10 for interindividual variability might not offer sufficient protection in cases where enzymes of this kind are involved in chemical activation.

• Cytochrome P450 (CYP 2E1)-dependent metabolisation of acrylamide in gene modified cell lines
  In longitudinal studies acrylamide has been shown to be carcinogenic in laboratory rodents. In the liver of mammals acrylamide is metabolised by the CYP 2E1 enzyme into glycidamide which is responsible for the carcinogenic and mutagenic effects. Using genetically modified cell lines, this project aims to examine 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 is to be examined in the cell systems.