Differences in the anatomy and physiology of the human and rat respiratory tracts and impact on toxicological assessments

Abstract

Inhalation is a critical route through which substances can exert adverse effects in humans; therefore, it is important to characterize the potential effects that inhaled substances may have on the human respiratory tract by using fit for purpose, reliable, and human relevant testing tools. In regulatory toxicology testing, rats have primarily been used to assess the effects of inhaled substances as they-being mammals-share similarities in structure and function of the respiratory tract with humans. However, questions about inter-species differences impacting the predictability of human effects have surfaced. Disparities in macroscopic anatomy, microscopic anatomy, or physiology, such as breathing mode (e.g., nose-only versus oronasal breathing), airway structure (e.g., complexity of the nasal turbinates), cell types and location within the respiratory tract, and local metabolism may impact inhalation toxicity testing results. This review shows that these key differences describe uncertainty in the use of rat data to predict human effects and supports an opportunity to harness modern toxicology tools and a detailed understanding of the human respiratory tract to develop testing approaches grounded in human biology. Ultimately, as the regulatory purpose is protecting human health, there is a need for testing approaches based on human biology and mechanisms of toxicity.

Keywords: (Max 10); Chemical exposure; Human-relevance; Inhalation toxicity testing; Pulmonary toxicity; Respiratory tract; Species differences.

Figure 1.

Overview of the anatomy of the rat and human respiratory tracts with representative nasal cross section and typical branching pattern of bronchi. Illustration adapted from Harkema et al. (2013, 2012) with permission.

Figure 2.

Microscopic anatomy of the rat and human airways. Schematic representation of the rat (left) and human (right) airways with most frequent cell types and structures. Illustrated cell densities and heights serve as orientation and are not to scale. The middle diagram shows area proportion of the nasal epithelium and cell proportion in rat (left) and human (right) tracheal, bronchial, bronchiolar and alveolar regions. Information collected from Mercer et al. (1994), Gizurarson (2012), and Parent (2015). Abbreviations: Amφ, alveolar macrophage; AT1, alveolar epithelial type 1 cell; AT2, alveolar epithelial type 2 cell; N.D, not determined.