Styrene lung cancer risk assessment: an alternative evaluation of human lung cancer risk assuming mouse lung tumors are potentially human relevant and operating by a threshold-based non-genotoxic mode of action

• Published in: Journal of toxicology and environmental health. Part B, Critical reviews Critical reviews, 2024-10, Vol.27 (7), p.264-286
• Main Authors: Bus, J. S., Su, S., Li, W., Goodman, J. E.
• Format: Article
• Language: English
• Subjects: Animals; Carcinogens; Carcinogens - toxicity; Dosage; Dose-Response Relationship, Drug; Epidemiology; Exposure; Fiber composites; Genotoxicity; Health risks; Humans; In vivo methods and tests; Inhalation; Inhalation Exposure - adverse effects; Inhalation Exposure - analysis; Lung cancer; lung cancer risk assessment; Lung Neoplasms - chemically induced; Lung Neoplasms - epidemiology; Metabolites; Mice; Mode of action; Modelling; non-genotoxic mode-of-action; Occupational exposure; Occupational Exposure - adverse effects; Occupational Exposure - analysis; Pharmacokinetics; physiologically based pharmacokinetic (PBPK) modeling; Protective equipment; Respiration; Risk Assessment; Rodents; Styrene; Styrene - toxicity; styrene oxide; Styrenes; Tumors
• ISSN: 1093-7404; 1521-6950; 1521-6950
• DOI: 10.1080/10937404.2024.2380449

Rodent inhalation studies indicate styrene is a mouse lung-specific carcinogen. Mode-of-action (MOA) analyses indicate that the lung tumors cannot be excluded as weakly quantitatively relevant to humans due to shared oxidative metabolites detected in rodents and humans. However, styrene also is not genotoxic following in vivo dosing. The objective of this review was to characterize occupational and general population cancer risks by conservatively assuming mouse lung tumors were relevant to humans but operating by a non-genotoxic MOA. Inhalation cancer values reference concentrations for respective occupational and general population exposures (RfC car-occup and RfC car-genpop ) were derived from initial benchmark dose (BMD) modeling of mouse inhalation tumor dose-response data. An overall lowest BMDL 10 of 4.7 ppm was modeled for lung tumors, which was further duration- and dose-adjusted by physiologically based pharmacokinetic (PBPK) modeling to derive RfC car-occup/genpop values of 6.2 ppm and 0.8 ppm, respectively. With the exception of open-mold fiber reinforced composite workers not using personal protective equipment (PPE), the RfC car-occup/genpop values are greater than typical occupational and general population human exposures, thus indicating styrene exposures represent a low potential for human lung cancer risk. Consistent with this conclusion, a review of styrene occupational epidemiology did not support a conclusion of an association between styrene exposure and lung cancer occurrence, and further supports a conclusion that the conservatively derived RfC car-occup is lung cancer protective.