Exploration of a framework to identify cohort of concern substances in medical device risk assessment

Abstract

Cohort of concern substances (CoCs) present challenges in medical device toxicological risk assessment. They are excluded from the lifetime threshold of toxicological concern (TTC) per ISO/TS 21726, because their toxic dose is < 1.5 μg/day and they may present a higher cancer risk. Relying solely on structural similarities with known toxicants is inadequate for assessing carcinogenic potency. This study selected chemicals from the Carcinogenic Potency Database (CPDB) to establish a framework for identifying potential CoCs. To do that, a threshold of Cancer Risk Specific Dose (CRSD) < 0.025 μg/kg/day was initially applied. Chemicals meeting this criterion are recognized as CoCs. However, the risk assessment could be impeded by particular uncertainties, such as the inability to determine the CRSD. In such cases, the identified CoCs were further categorized based on their mutagenicity determined by the Ames test results. A scatterplot reveals a significant correlation between the carcinogenic potency [ Log(0.5/TD₅₀)+7] and acute systemic toxicity [Log(LD₅₀)] in the CoCs-Ames (−) group (R² = 0.72). For the CoCs-Ames (+) group (n = 124), 18 CoCs with available mutation slope data show cancer risk greater than the default risk of 1 in 100,000. This study provides a framework integrating scientific evidence and regulatory guidelines to identify potential CoCs.