Fall 2026

Can What You Breathe Reach Your Brain? Exploring the Nose-to-Brain Pathway

By Nicholas Drury, Ph.D., Peter Andrew, Ph.D., and Steven Boomhower, Ph.D., ERT, ATS

Products that generate aerosols (e.g., small particles or droplets suspended in the air), including consumer, industrial, and medical products, can release chemicals that are inhaled.  For example, welding, combustion processes (e.g., in steel manufacturing), and the application of some pesticides and herbicides can generate ultrafine particles (UFPs), typically defined as particles with aerodynamic diameters less than 100 nanometers.  Due to their small size, UFPs can penetrate deeply into the lungs, where they may enter the bloodstream and distribute throughout the body, including the brain (Schraufnagel, 2020; Ueno, 2009).  Once in the blood, a chemical’s ability to enter the brain depends largely on its capacity to cross the blood-brain barrier (BBB), which serves as a highly selective barrier that limits the entry of many substances.  However, growing experimental and modeling evidence suggests that some inhaled particles may reach the brain through the olfactory nerve pathway – an alternative route that bypasses the BBB and connects the nasal cavity indirectly to the brain (Han et al., 2023; Tian et al., 2019).

The olfactory nerve pathway provides a potential “nose-to-brain” route of exposure that may underlie neurotoxicity.”

The olfactory nerve pathway provides a potential “nose-to-brain” route of exposure that may underlie neurotoxicity.  The olfactory nerves originate in specialized sensory tissue located in the upper nasal cavity and project directly to the olfactory bulb, a structure at the base of the brain (see Figure).  Following inhalation, the likelihood that particles reach this region depends on several factors, including particle size, solubility, and interactions with the nasal tissues.  Smaller particles diffuse more readily through the airways and are more likely to deposit in the upper regions of the nasal cavity where the olfactory epithelium is located (Garcia and Kimbell, 2009).  Moreover, solubility may influence retention and uptake of particles.  For example, particles with poor solubility may potentially remain in contact with the olfactory epithelium for longer periods of time (Han et al., 2023).  In addition, after the particles are deposited, some particles may be taken up by cells of the olfactory epithelium, including olfactory sensory neurons, and subsequently transported along neuronal processes into the olfactory bulb.

Overview of Olfactory Nerve Pathway and Anatomy

Some evidence suggests that the olfactory nerve pathway may contribute to brain exposure for certain inhaled substances.  One of the most studied of these substances is manganese, a metal present in some welding fumes.  For example, studies of inhaled manganese in laboratory animals have demonstrated its transport to the olfactory bulb and other brain regions (Elder et al., 2006), while neuroimaging studies in welders have reported elevated manganese accumulation in the olfactory bulb and basal ganglia relative to unexposed populations (Lee et al., 2015; Sen et al., 2011).  Similar evidence has been reported in animal studies for combustion-derived UFPs, which have been detected in the olfactory bulb and other brain regions following inhalation exposure (Hopkins et al., 2018; Patten et al., 2021).  Collectively, these findings suggest that inhaled UFPs can access the brain through both systemic circulation and, potentially, the olfactory nerve pathway.

Despite this evidence, demonstrating that a chemical reaches the brain specifically through the olfactory nerve pathway remains technically challenging.  In most cases, chemicals detected in the brain could have arrived either through direct nose-to-brain transport or through systemic absorption followed by passage across the BBB.  As a result, animal studies are typically required to evaluate experimentally the contribution of the olfactory nerve pathway.  While in vitro systems and isolated tissue preparations can provide useful mechanistic information, such as demonstrating particle uptake by olfactory neurons, they cannot replicate the complete sequence of events involved in transport from the nasal cavity to the brain.

In addition, interpretation of animal studies requires careful consideration of several methodological and biological factors.  One important consideration is verifying that detected chemicals are truly present within brain tissue rather than remaining in blood vessels within the brain.  Since the brain is highly vascularized, incomplete removal of blood prior to tissue analysis can lead to overestimation of brain concentrations.  Accordingly, studies should use vascular perfusion (i.e., removal of blood by flushing with saline or fixative) before tissue collection or employ imaging approaches that enable direct visualization of particles relative to blood vessels.  Another challenge is that inhaled particles can induce respiratory inflammation, which may increase BBB permeability and, thereby, enhance blood-to-brain transport, making it more difficult to distinguish between systemic and olfactory routes of exposure (Peters et al., 2006).  Finally, important anatomical differences exist between laboratory animals and humans.  For example, rodents are obligate nose breathers, meaning that nearly all inhaled air passes through the nasal passages, including the olfactory region (Stucki et al., 2024).  In contrast, humans breathe through both the nose and mouth, particularly during exercise or heavy exertion, resulting in a smaller proportion of inhaled air reaching the olfactory region under many real-world conditions (Stucki et al., 2024).  These species differences should be considered when extrapolating findings from animal studies to human exposures.

Due to the BBB, the brain is often considered to be insulated from most environmental exposures; however, emerging evidence suggests that there are various pathways, such as the olfactory nerve pathway, by which certain substances, and even particles, can enter the brain.  Although additional research is needed to better understand the contribution of these pathways to overall brain exposure, it is critical that researchers consider the anatomical and methodological uncertainties inherent in animal models.