ABSTRACT
For nasal irritation from volatile chemicals, a version of Haber's rule (k = C(n)T) can model the trade-off between concentration (C) and duration of exposure (T) to achieve a fixed sensory impact, e.g. threshold-level irritation or a fixed suprathreshold intensity. The term k is a constant. The exponent, n, represents how well the system integrates over time. An exponent of 1 indicates complete temporal integration: an x-fold increase in stimulus duration exactly compensates for cutting the concentration 1/x. An exponent greater than 1 indicates incomplete temporal integration: more than an x-fold increase in duration is needed. In a previous study of homologous alcohols, n varied systematically with number of methylene units: integration became more complete as the length of the carbon chain increased. To explore the generality of this finding, we tested homologous esters that differ in the number of methylene units: n-ethyl propionate, n-propyl propionate, and n-butyl propionate. Nasal lateralization was used to measure irritation thresholds. Human subjects received a fixed concentration of a single compound within each experimental session. Stimulus duration was varied to find the briefest stimulus that caused lateralizable irritation. Concentration and compound varied across sessions. Consistent with results with n-alcohols, integration became more complete as the number of methylene units increased. Lipid solubility varies with chain length; hence, solubility in the nasal mucosa may play a role in the dynamics of irritation. Further, preliminary analyses suggest that, for data pooled across both chemical series, n varies systematically with molecular parameters related to solubility and diffusion.
Subject(s)
Irritants/metabolism , Irritants/toxicity , Nasal Cavity/metabolism , Propionates/metabolism , Propionates/toxicity , Adolescent , Adult , Alcohols/metabolism , Algorithms , Analysis of Variance , Calibration , Databases, Factual , Female , Humans , Inhalation Exposure , Irritants/chemistry , Male , Middle Aged , Nasal Mucosa/cytology , Nasal Mucosa/metabolism , Propionates/chemistry , Structure-Activity Relationship , Young AdultABSTRACT
Through temporal integration, sensory systems accumulate stimulus energy, e.g., photons, acoustic energy, or molecules, over time to detect weaker signals than they otherwise could. Past studies found imperfect temporal integration in detection of nasal irritation: To maintain a fixed level of detection, one must increase stimulus duration by more than twofold to compensate for cutting concentration in half. Despite this generality, integration varied widely among compounds, from nearly perfect, i.e., an increase in duration of slightly more than twofold could compensate for cutting concentration in half, to highly imperfect. How do such differences relate to molecular parameters? Perhaps molecules that more readily dissolve into the lipid-rich perireceptor environment will accumulate, and therefore integrate, better over time. To test this hypothesis, studies compared temporal integration for three compounds that differ systematically in lipid solubility: n-ethanol, n-butanol, and n-hexanol. Subjects were healthy, adult humans. Nasal lateralization was used to measure irritation threshold. Subjects received a fixed concentration of a single compound within each experimental session, and stimulus duration was varied to find the briefest stimulus subjects could reliably lateralize. Concentration and compound varied across sessions. Consistent with the hypothesis, integration did become closer to perfect as lipid solubility increased. That just one molecular parameter can help predict degree of integration suggests that a structure-activity approach to understanding temporal integration shows promise.
