Neurological Aspects

John C. Leffingwell, Ph.D. Leffingwell & Associates. Olfaction: The Trigeminal Sense in the Olfactory Epithelium.
http://www.leffingwell.com/olfaction.htm.

"It must also be recognized that the olfactory epithelium contains another sensory system in the form of "Trigeminal Nerve" receptors. Whereas, the olfactory receptor system is highly localized in humans, the fifth cranial or trigeminal nerve (which is the largest cranial nerve and is the responsible sensory nerve of the face, teeth, mouth, most of the scalp, and the motor nerve of the muscles of mastication) provides a second set of nerve endings which are responsible for tactile, pressure, pain and temperature sensations in the areas of the mouth, eyes and nasal cavity. A number of chemical trigeminal stimulants produce effects described as hot, cold, tingling or irritating. For example, "leavo-menthol or (-)-menthol" produces the trigeminal feeling of cold at moderate concentrations and "hot" at high concentrations in the nasal cavity. This type of sensory "description" is often not just limited to the areas of the nose, mouth and eyes, but also occurs on skin areas not served by the 5th cranial nerve (especially, the genitalia) and thus such stimulants may effect a variety of nerve endings. Similarly "camphor" which possesses markedly more aroma than menthol, also produces the "cold" sensation via interaction with trigeminal receptors. Ohloff states that "About 70% of all odors are said to stimulate the trigemenal nerve although, in general, they may be several times less sensitive than olfactory receptors."

"The olfactory neural pathways provides both intraneuronal and extraneuronal pathways to the brain. The intraneuronal pathway involves axonal transport and requires hours to days for drugs to reach different brain areas. The extraneuronal pathway probably relies on bulk flow transport through perineural channels which deliver drug directly to the brain parenchymal tissue, to the cerebrospinal fluid (CFS), or to both. This extraneuronal pathway allows therapeutic agents to reach the CNS within minutes."

The work of Dr. Frey focuses on drug delivery through intranasal route. I contacted Dr. Frey and discussed neurological concerns related to fragrance. He indicated he also had concerns. Work by other scientists indicates small molecules with high lipophilicity are more easily transported intranasally. (These are cited as references in Dr. Frey's article) These works are specifically on fragrance, they do establish intranasal exposure as a significant route of entry of materials into the Central Nervous System.

 Ghantous H, Dencker L, Gabrielsson J, Danielsson BR, Bergman K. Pharmacol Toxicol 1990 Feb;66(2):87-92 Accumulation and turnover of metabolites of toluene and xylene in nasal mucosa and olfactory bulb in the mouse.. Department of Toxicology, Uppsala University, Sweden.

Autoradiography of male mice following inhalation of the radioactively labelled solvents, toluene, xylene, and styrene, revealed an accumulation of non-volatile metabolites in the nasal mucosa and olfactory bulb of the brain. Since no accumulation occurred after benzene inhalation, it was assumed that the activity represented aromatic acids, which are known metabolites of these solvents. This was supported by the finding that also radioactive benzoic acid (main metabolite of toluene) and salicylic acid accumulated in the olfactory bulb. High-performance liquid chromatography revealed that after toluene inhalation (for 1 hr), nasal mucosa and olfactory bulb contained mainly benzoic acid, with a strong accumulation in relation to blood plasma, and considerably less of its glycine conjugate, hippuric acid. After xylene inhalation, on the other hand, methyl hippuric acid dominated over the non-conjugated metabolite, toluic acid. The results indicate a specific, possibly axonal flow-mediated transport of aromatic acids from the nasal mucosa to the olfactory lobe of the brain. The toxicological significance of these results remains to be studied.

Both toluene and xylene and their derivatives are found either on the European Commission's list of fragrance chemicals or in Allured's Flavor and Fragrance Materials Online (subscription required). Toluene and xylene are also 2 of the nine primary starting materials for synthesis of fragrance chemicals.

"The effects of chiral fragrances (enantiomers of limonene and carvone) on the human autonomic nervous system (ANS) and on self-evaluation were studied in 20 healthy volunteers. Each fragrance was administered to each subject by inhalation using an A-A-B design. Individuals were tested in four separate sessions; in one session one fragrance was administered. ANS parameters recorded were skin temperature, skin conductance, breathing rate, pulse rate, blood oxygen saturation and systolic as well as diastolic blood pressure.

Subjective experience was assessed in terms of mood, calmness and alertness on visual analog scales. In addition, fragrances were rated in terms of pleasantness, intensity and stimulating property. Inhalation of (+)-limonene led to increased systolic blood pressure, subjective alertness and restlessness. Inhalation of (-)-limonene caused an increase in systolic blood pressure but had no effects on psychological parameters. Inhalation of (-)-carvone caused increases in pulse rate, diastolic blood pressure and subjective restlessness. After inhalation of (+)-carvone increased levels of systolic as well as diastolic blood pressure were observed. Correlational analyses revealed that changes in both ANS parameters and self-evaluation were in part related to subjective evaluation of the odor and suggest that both pharmacological and psychological mechanisms are involved in the observed effects. In conclusion, the present study indicates that: (i) prolonged inhalation of fragrances influences ANS parameters as well as mental and emotional conditions; (ii) effects of fragrances are in part based on subjective evaluation of odor; (iii) chirality of odor molecules seems to be a central factor with respect to the biological activity of fragrances."