Relevant exposure routes need to be taken into account when performing chemical risk assessments for humans. Chemical risks are often assessed by performing route-to-route extrapolations based on oral repeated dose toxicity studies if route-specific toxicity data are unavailable. When performing a route-to-route extrapolation, an extrapolation factor derived from differences in absorption after exposure through different routes needs to be estimated. In this study, we used a machine learning (ML) and regression-based approach to estimate extrapolation-factor-like coefficients for oral-to-inhalation extrapolations using chemical structures and physicochemical properties. We used well-reviewed chemicals with human chronic toxicity values for specific administration routes (oral reference dose and inhalation reference concentration) available. ML regression models for predicting inhalation reference concentrations were developed using oral reference doses and molecular features as descriptors. The ML-based regression models gave better predictions than models using only molecular features or even single constant extrapolation factors, suggesting that the ML-based approach offers advantages over other oral-to-inhalation extrapolation methods.

Medication-induced hiccups, although uncommon, can significantly reduce patients’ quality of life. We had previously identified nicotine as a potential trigger of drug-induced hiccups. However, the mechanisms and risk factors, particularly those related to the route of administration, remain unclear. This study used the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to investigate nicotine-induced hiccups, particularly focusing on the routes of administration and patient factors. We analyzed 14,836,467 cases reported between January 1, 2004, and March 31, 2022, which were downloaded from the FDA website. Of the 198,556 adverse event reports for nicotine, 970 involved hiccups. We performed univariate analyses on routes of administration and drug formulations to determine their influence on the occurrence of hiccups. Furthermore, we analyzed patient information related to nicotine-induced hiccups. Men were more frequently affected by nicotine-induced hiccups than women, with a higher incidence in older patients. Oral nicotine administration via gum and lozenges was more significantly associated with the occurrence of hiccups than other routes. Nicotine-induced hiccups are influenced by the administration route, particularly oral formulations, such as gum and lozenges. These findings indicate the need for further studies to elucidate the mechanisms of nicotine-induced hiccups and to develop preventive strategies.