Pharmacokinetics and the interpretation of results
In the UK, Maximum Exposure Limit (MEL) or Occupational Exposure Standard (OES) provide information on the relative toxicities of different compounds after chronic exposure to relatively low concentrations of vapour (some examples of MEL/OES limits are shown in Table 4.2). Inhaled compounds may rapidly attain high concentrations in well-perfused organs (brain, heart), while concentrations in muscle and adipose tissue may be very low. Should death occur, this situation is ‘frozen’ to an extent, but if exposure continues the compound accumulates in less accessible (poorly perfused) tissues, only to be slowly released once exposure ceases. Thus, the plasma concentrations of some compounds may fall mono-exponentially, while others may exhibit two (or more) separate rates of decline (half-lives).
The solubility of a volatile compound in blood is an important influence on the rate of absorption, tissue distribution and elimination of the compound. The partition coefficients of a number of compounds between air, blood and various tissues have been measured in vitro using animal tissues, and some in vivo distribution data have been obtained from postmortem tissue measurements in humans (Table 4.2). However, these data must be used with caution since there are many difficulties inherent in such measurements (sampling variations, analyte stability, external calibration, etc.). Published data on the plasma half-lives of volatile substances (such as that in Table 4.2) are not easily comparable, either because too few samples were taken or the analytical methods used did not have sufficient sensitivity to measure the final half-life accurately.
Many volatile substances, including butane, dimethyl ether, most fluorocarbon refrigerants and/or aerosol propellants, isobutane, nitrous oxide, propane, tetrachloroethylene and 1,1,1-trichloroethane, are eliminated largely unchanged in exhaled air. Others are partly eliminated in exhaled air and also metabolised in the liver and elsewhere, the metabolites being eliminated in exhaled air or in urine, or incorporated into intermediary metabolism. After ingestion, extensive hepatic metabolism can reduce systemic availability (‘first-pass’ metabolism) of certain compounds. Table 4.3 gives some examples in which blood or urinary metabolite measurements have been used to assess exposure to solvents and other volatile compounds.
