Lung Dosimetry and Risk Assessment of Nanoparticles: Evaluating and Extending Current Models in Rats and Humans

Abstract

Risk assessment of occupational exposure to nanomaterials is needed. Human data are limited, but quantitative data are available from rodent studies. To use these data in risk assessment, a scientifically reasonable approach for extrapolating the rodent data to humans is required. One approach is allometric adjustment for species differences in the relationship between airborne exposure and internal dose. Another approach is lung dosimetry modeling, which provides a biologically-based, mechanistic method to extrapolate doses from animals to humans. However, current mass-based lung dosimetry models may not fully account for differences in the clearance and translocation of nanoparticles. In this article, key steps in quantitative risk assessment are illustrated, using dose-response data in rats chronically exposed to either fine or ultrafine titanium dioxide (TiO₂), carbon black (CB), or diesel exhaust particulate (DEP). The rat-based estimates of the working lifetime airborne concentrations associated with 0.1% excess risk of lung cancer are approximately 0.07 to 0.3 mg/m³ for ultrafine TiO₂, CB, or DEP, and 0.7 to 1.3 mg/m³ for fine TiO₂. Comparison of observed versus model-predicted lung burdens in rats shows that the dosimetry models predict reasonably well the retained mass lung burdens of fine or ultrafine poorly soluble particles in rats exposed by chronic inhalation. Additional model validation is needed for nanoparticles of varying characteristics, as well as extension of these models to include particle translocation to organs beyond the lungs. Such analyses would provide improved prediction of nanoparticle dose for risk assessment.

Notes

* The terms ultrafine particle and nanoparticle are often used interchangeably, although nanoparticle generally refers to engineered particles. Both ultrafine particles and nanoparticles have primary particle diameters of less than 0.1 μ m, and are respirable (i.e., capable of depositing in the gas-exchange region of the lungs), as are fine particles (0.1–2.5 μ m) and coarse particles (2.5–10 μ m) in humans.

*This approach was used because the BMD and BMDL estimates at 10% excess risk are essentially model independent—i.e., the various models in the BMD software (U.S. EPA, 2003), including the multistage model used here, provide similar estimates. Also, model-based extrapolation beyond the range of the data is not required; since those estimates would vary depending on the model used, linear dose response is assumed below 10% excess risk.

*The inhalability adjustment multiplies the inhaled concentration by a factor that adjusts for attenuation of the probability that particles are inhaled as their size increases (CIIT & RIVM, 2002).