A study of the biological partitioning behavior of n-alkanes and n-alkanols in causing anesthetic effects.

n-Alkanes and n-alkanols are two groups of common volatile organic compounds (VOCs) having potential anesthetic effects on workers and building occupants. A partition model based on the octanol-air partition coefficient was developed in this investigation to describe the biological partitioning of n-alkanes and n-alkanols in causing general anesthesia. Data on anesthetic potency (minimum alveolar concentration, MAC) for the test groups in rats were found to fit the model. The slight difference between the n-alkanes and n-alkanols in testing the model could be largely eliminated by correcting for the potential partial pressure gradients of the long-chain alkanes across the blood-brain barrier. The corrected MAC data for the two test groups fit well onto one common activity-partition regression line. This suggests that n-alkanes and n-alkanols may share a common biophase or mechanistic pathway for anesthesia. The present findings may provide some useful insight into setting anesthesia-based health standards for VOC mixtures.

Use of partition models to evaluate guidelines for mixtures of volatile organic compounds.

Partition models based on the octanol-air parition coefficients and associated quantitative structure-activity relationships (QSARs) have been developed to describe the triggering of odor response and nasal irritation by common volatile organic compounds (VOCs). This study made use of the QSARs developed by Hau and Connell (1998, Indoor Air 8, 23-33) and Hau et al. (1999, Toxicol. Sci. 47, 93-98) to evaluate risk-based guidelines on the airborne concentrations of common VOCs in the nonindustrial environment. A new concept referred to as the "apparent internal threshold concentration" was developed for evaluating the odor and nasal pungency responses to a typical low-concentration VOC mixture described by Otto et al. (1990, Neurotoxicol. Teratol. 12, 649-652). The assessment indicated that odor can be detected at a total VOC concentration of about 3 mg/m(3), consistent with the findings of Molhave et al. (1991, Atmos. Environ. 25, 1283-1293). Nasal pungency, according to our assessment, should not ocur at a total concentration of 25 mg/m(3), which is apparently in conflict with the findings of Molhave (1986, ASHRAE Trans. 92(1A), 306-316). It can be inferred from this investigation that pure nasal pungency without the influence of odor is unlikely to result from exposure to low-concentration VOC mixtures typically found in the nonindustrial environment.

Use of partition models in setting health guidelines for volatile organic compounds.

Partition models based on the octanol-air partition coefficients and associated quantitative structure-activity relationships (QSARs) have been developed to describe the triggering of odor detection, nasal irritation, and narcosis by common volatile organic compounds (VOCs). This study made use of the QSARs developed by Hau and Connell (1998), Indoor Air 8, 23-33) and Hau et al. (1999a, Toxicol. Sci. 47, 93-98; 1999b, Environ. Toxicol. Pharmacol. 7, 159-167) to predict the odor thresholds, nasal pungency thresholds, and anesthetic potency in humans for four groups of VOCs, namely, alkanes, alcohols, ketones, and acetates. The predicted outcomes with their estimated variability were used to evaluate the relevant guidelines on the airborne concentrations of these test groups. Threshold limit values (TLVs) for the test compounds were found to be generally capable of offering adequate protection against nasal pungency and narcosis, except for the higher alcohols (C6-C8) and sec-amyl acetate. The QSARs can also be used to set tentative guidelines for those compounds not having a TLV; values of 5 and 75 ppm were proposed for heptan-1-ol and dibutyl ketone respectively as examples.

Quantitative structure-activity relationships for nasal pungency thresholds of volatile organic compounds.

A model was developed for describing the triggering of nasal pungency in humans, based on the partition of volatile organic compounds (VOCs) between the air phase and the biophase. Two partition parameters are used in the model: the water-air partition coefficient and the octanol-water partition coefficient. The model was validated using data from the literature, principally on alcohols, acetates and ketones. The model suggests that all test compounds, regardless of their chemical functional groups, bind to a common receptor site within the hydrophobic interior of the bilayer membrane of the trigeminal nerve endings. There is probably only a slight, non-specific interaction between the VOC molecule and the receptor molecule, whereas this type of non-specific interaction for the detection of odor is much stronger. In practical terms, the suggestion that all VOCs share a common irritation receptor site implies that nasal-pungency thresholds of individual VOCs may be additive. Quantitative structure-activity relationships (QSARs) for nasal-pungency thresholds were also developed from the model, which can be used to predict nasal-pungency thresholds of common VOCs. Although the present model does not offer additional precision over that of M.H. Abraham et al., 1996, Fundam. Appl. Toxicol. 31, 71-76, it requires fewer descriptors and offers a physiological basis to the QSAR. Another advantage of the present model is that it also provides a basis for comparison between the olfactory process and nasal pungency.

Mechanism of acute inhalation toxicity of alkanes and aliphatic alcohols.

This study investigated the mechanism of non-specific toxicity of non-reactive volatile organic compounds by using data reported in the literature. Inhalation toxicity data, in terms of LC(50) for alcohols and alkanes in rodents, were examined in relation to their partitioning behaviour in the biological system. Regression analysis of the data showed that, after the elimination of the kinetic influence in the absorption process, lethal toxicity increases linearly with the octanol-air partition coefficient in a homologous series. Comparing this relationship with that for anaesthesia, it could be concluded that lethal toxicity of the test chemical series probably acts on the lipid bilayer plasma membrane through a non-specific biophysical mechanism similar to anaesthesia. The critical concentration hypothesis appears to be valid for lethal toxicity of the test series. It was also shown that toxicity data for the test series by other routes, namely oral, intraperitoneal and intravenous, give a similar toxicity-partition relationship to that by inhalation.