Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
There are several known methods for calculating the Acceptable Intake (AI) of genotoxic carcinogens, but the points to consider may vary depending on the calculation method. Genotoxic carcinogens are substances that can increase the risk of cancer by inducing DNA damages and subsequent mutations. There is concern that this effect may lead to an increased risk of cancer without a threshold, so even low-level exposure may have health effects on humans that cannot be eliminated. Therefore, many industries and administrations have accepted an approach that calculates the AI as exposure levels below a threshold that can ignore the risk of cancer. This threshold is called the Threshold of Toxicological Concern (TTC). In scenarios where genotoxic carcinogens are contaminated as impurities in pharmaceuticals, the TTC is set at one in a hundred thousand, and the control of impurities is carried out by calculating the AI below this level. In this scenario, the common method for calculating the AI is to use the TD50, which is the dose at which tumors are induced in the most sensitive organ of the most sensitive animal species in carcinogenicity studies, and extrapolate it linearly to calculate the AI value where the tumor incidence rate becomes one in a hundred thousand. In addition, it is also possible to use benchmark doses such as the Benchmark Dose Lower Confidence Limit 10% (BMDL10), which is the estimated lowest dose that can be trusted with 95% confidence that the cancer incidence rate in rodents is below 10%. In this case, dividing the BMDL10 by 10,000 can calculate the risk level of one in a hundred thousand by linear extrapolation. On the other hand, there are no internationally harmonized guidelines for calculating Occupational Exposure Limits (OEL) for genotoxic carcinogens. In the rubber and chemical industries, there are cases where these substances are handled, so it is necessary to calculate the OEL for occupational hygiene purposes, but different approaches are taken by regulatory authorities. This discusses the extent to which these methods and derived OELs differ. Furthermore, the pros and cons of setting the AI using the No Observed Adverse Effect Level (NOAEL) from in vivo genotoxicity tests and safety factors, as well as the considerations in this case, are also discussed.
