Introduction: Cellular response to xenobiotics and environmental mutagens is a complex phenomenon and involves participation of diverse classes of genes that orchestrate DNA repair, cell cycle control, signal transduction, apoptosis and oncogenesis. Although it is difficult to ascertain the specific biological endpoints from diverse sources of genomic instability, such elucidations are highly relevant to risk assessments based upon the toxic levels of environmental agents. Isocyanates are the group of ubiquitous chemicals with a wide range of industrial activities. Yet, the patho-physiological implications resulting from their occupational and large scale accidental exposures are hitherto unknown. Objective: To appraise the genomic instability caused by isocyanates on human colon epithelial cells.Materials & Methods: We performed our varied experiments on the cultured human colon epithelial-FHC cell line using N-succinimidyl N-methyl carbamate, a surrogate chemical to methyl isocyanate. Evaluation of DNA damage kinetics was done through Qualitative and quantitative assessment of extent of phosphorylation states of γH2AX, ATM, ATR and p53. Quantification of secreted nucleosomes pre and post treatment and annexin-V FITC/PI assay, active caspase 3 assay, TUNEL, apoptotic DNA laddering, were done to infer the apoptotic index and the apoptotic DNA fragmentation respectively. Cytometric bead array provided the means of assaying secreted inflammatory cytokines in culture supernatant previous to and following exposure. Abnormalities at chromosomal and microsatellite level of the genome following exposure were measured through cytogenetic analysis and inter simple sequence repeat PCR respectively.Results: All the DNA damage responsive parameters displayed an increasing trend along with significant higher apoptotic index and elevated inflammatory cytokine levels in isocyanate treated cells in contrast to their control counterparts. Interestingly, cytogenetic analyses revealed varied chromosomal anomalies and also the analyses through inter simple sequence repeat PCR presented a greater instability at the microsatellite level thus giving the credence as the endpoints of genomic instability. Conclusion: Together these results imply that the isocyanates are potent enough to cause genomic instability under both occupational and accidental exposures. The loss of genomic stability seems to be crucial molecular and patho-physiologic stride that lead to the transformation of normal colonic epithelium to colon adenocarcinoma. We anticipate our findings would invoke better approaches in risk assessment and management of future industrial disasters.