Future research directions to study genetic damage in germ cells and estimate genetic risk.

The late Frits Sobels developed a parallelogram model to estimate genetic risk to humans based on experimental data in somatic cells (peripheral blood) of exposed animals and humans and on data from progeny studies of exposed animals (mice). Recently, an extension to the original parallelogram model was proposed to bridge the gap of extrapolation between rodent and human germ cells by studying sperm samples. The comparison in the parallelogram of rodent/human sperm data with data from rodent progeny tests to derive at an estimate of human progeny at risk is more promising. Therefore, data on all possible end points, DNA adducts, mutations, chromosomal aberrations, and aneuploidy, should be obtained in sperm of exposed rodents and humans. The technology from somatic cell studies is available or adaptable to sperm studies. Sperm samples lend themselves to automated analyses because they are a homogeneous cell population. By flow cytometry or image analysis, large cell samples can be studied per individual. Animal experiments could be conducted in the actual range of chronic human exposure to low doses. The acceptability of extrapolation from the high acute doses so far used in animal experiments to low chronic doses of human exposure could be assessed. Proof could be obtained in human germ cells for the assumption that data from animal experiments can be extrapolated to humans. Data from transgenic rodent systems may play an important role in the extension of the parallelogram approach to genetic risk estimation by providing a link between cancer and genetic risk estimates.