The desire to reduce human exposure to toxic chemicals associated with consumer products that are marketed globally demands the creation of comparative toxicity assessment tools that are based on uniform thresholds of acceptable risks and guidelines for materials use across international boundaries. The Toxic Potential Indicator (TPI) is a quantitative model based on European Union (EU) regulatory standards for toxicity and environmental quality. Here, we describe a version of TPI that we developed with US regulatory thresholds for environmental and human health impacts of toxic materials. The customized US-based TPI (USTPI) model integrates occupational permissible exposure limits (PELs), carcinogen categories based on the scheme of the International Agency for Research on Cancer (IARC), and median effect concentration for acute aquatic toxicity (EC50s). As a case study, we compare calculated scores for EU-based TPI (EUTPI) and USTPI for a large group of chemicals including 578 substances listed in the US Toxics Release Inventory (TRI). Statistical analyses show that the median difference between USTPI and EUTPI scores do not approximate to zero, implying a general discrepancy in TPI score results. Comparison of chemical ranking with Spearman's correlation coefficient suggests a positive but imperfect rank correlation. Although some discrepancies between EUTPI and USTPI may be explained by missing toxicity information in some regulatory categories, disparities between the 2 models are associated mostly with different input parameters, i.e., different regulatory thresholds and guidelines. These results demonstrate that regional differences in regulatory thresholds for material toxicity may compromise the ideals of international agreements, such as the Globally Harmonized System (GHS) of Classification and Labeling of Chemicals, and emphasis needs to be placed on eliminating inconsistencies in hazard assessment frameworks for substances.