Use of the benchmark dose approach in carcinogenic risk assessment for NNK
The Benchmark Dose (BMD) approach for Carcinogen Risk Assessment was implemented by modeling tumor data and exposure to establish a dose-response relationship. First, the Inhalation Unit Risk (IUR) was derived using linear extrapolation and then a benchmark dose lower bound (BMDL1.0) was established as the Point of Departure (POD). The Lifetime Average Daily Intake (LADI, Exposure Concentration) was calculated for NNK (Nicotine-derived nitrosamine ketone) in two commercial cigarette products under ISO and HCI smoking conditions and converted to daily doses. The excess cancer risk was calculated as the Incremental Lifetime Cancer Risk (ILCR) and compared to the IUR and POD. The maximum exposure levels, under HCI smoking conditions, resulted in exposures approximately 1/10th the IUR and below the POD. The difference in excess cancer risk in the two products was very small. At ISO smoking conditions exposure levels were approximately 1/20th the IUR and also below POD. There was a slight difference in excess cancer risk between the two products but the change in this region of the dose-response curve indicates no impact to human health. Margin-of-Exposure (MOE) for NNK were calculated at the BMDL1.0 and compared to literature values. At the BMDL1.0 the MOE could be interpreted as the Margin-of-Safety (MOS). The use of the POD as the reference for health effects can be expanded to other analytes with debatable IURs published by different agencies or in the public literature.