Although there is a major decline of heavy metal usage in most Western countries, the industrial use of the metals is not prohibited world-wide and their effects on human health are still obvious. Heavy metal resuspension, through the environmental dust and soil accumulation, make them a dangerous enemy for human health, as the exposure to them cannot be avoided. The genotoxic effects of most of the metals are mostly well-established; the most common ones have identified to be the generation of ROS and the inhibition of DNA repair pathways. However, a big variety of co-interacting mechanisms makes it particularly difficult to identify the specific action of heavy metals inside the body. The enzyme Topoisomerase-I acts on the DNA topological stability and previous works have shown inhibitory effects on the enzyme, can affect DNA sustainability. In this project, the toxicity of cadmium, lead, copper and zinc on human lung fibroblasts at physiological levels has been studied. Also, the inhibition of the enzyme Topoisomerase-I, is suggested as a potential mechanism and the purification of the protein was attempted for future work. The present study gives additional evidence of the genotoxic effects of the heavy metals and their inhibitory ability on Topoisomerase-I through cleavage and relaxation assays; and suggests further research in order for the leading pathways of heavy-metal induced cancer to be comprehended.