Introduction
Organic solvents are volatile and generally soluble in body fat (lipophilic), although some of them, e.g., methanol and acetone, are water soluble (hydrophilic) as well. They have been extensively employed not only in industry but in consumer products, such as paints, inks, thinners, degreasers, dry-cleaning agents, spot removers, repellents, and so on. Although it is possible to apply biological monitoring to detect health effects, for example, effects on the liver and the kidney, for the purpose of health surveillance of workers who are occupationally exposed to organic solvents, it is best to use biological monitoring instead for “exposure” monitoring in order to protect the health of workers from the toxicity of these solvents, because this is an approach sensitive enough to give warnings well before any health effects may occur. Screening workers for high sensitivity to solvent toxicity may also contribute to the protection of their health.
Summary of Toxicokinetics
Organic solvents are generally volatile under standard conditions, although the volatility varies from solvent to solvent. Thus, the leading route of exposure in industrial settings is through inhalation. The rate of absorption through the alveolar wall of the lungs is much higher than that through the digestive tract wall, and a lung absorption rate of about 50% is considered typical for many common solvents such as toluene. Some solvents, for example, carbon disulphide and N,N-dimethylformamide in the liquid state, can penetrate intact human skin in amounts large enough to be toxic.
When these solvents are absorbed, a portion is exhaled in the breath without any biotransformation, but the greater part is distributed in organs and tissues rich in lipids as a result of their lipophilicity. Biotransformation takes place primarily in the liver (and also in other organs to a minor extent), and the solvent molecule becomes more hydrophilic, typically by a process of oxidation followed by conjugation, to be excreted via the kidney into the urine as metabolite(s). A small portion may be eliminated unchanged in the urine.
Thus, three biological materials, urine, blood and exhaled breath, are available for exposure monitoring for solvents from a practical viewpoint. Another important factor in selecting biological materials for exposure monitoring is the speed of disappearance of the absorbed substance, for which the biological half-life, or the time needed for a substance to diminish to one-half its original concentration, is a quantitative parameter. For example, solvents will disappear from exhaled breath much more rapidly than corresponding metabolites from urine, meaning they have a much shorter half-life. Within urinary metabolites, the biological half-life varies depending on how quickly the parent compound is metabolised, so that sampling time in relation to exposure is often of critical importance (see below). A third consideration in choosing a biological material is the specificity of the target chemical to be analysed in relation to the exposure. For example, hippuric acid is a long-used marker of exposure to toluene, but it is not only formed naturally by the body, but can also be derived from non-occupational sources such as some food additives, and is no longer considered a reliable marker when toluene exposure is low (less than 50 cm3/m3). Generally speaking, urinary metabolites have been most widely used as indicators of exposure to various organic solvents. Solvent in blood is analysed as a qualitative measure of exposure because it usually remains in the blood a shorter time and is more reflective of acute exposure, whereas solvent in exhaled breath is difficult to use for estimation of average exposure because the concentration in breath declines so rapidly after cessation of exposure. Solvent in urine is a promising candidate as a measure of exposure, but it needs further validation.
Biological Exposure Tests for Organic Solvents
In applying biological monitoring for solvent exposure, sampling time is important, as indicated above. Table 1 shows recommended sampling times for common solvents in the monitoring of everyday occupational exposure. When the solvent itself is to be analysed, attention should be paid to preventing possible loss (e.g., evaporation into room air) as well as contamination (e.g., dissolving from room air into the sample) during the sample handling process. In case the samples need to be transported to a distant laboratory or to be stored before analysis, care should be exercised to prevent loss. Freezing is recommended for metabolites, whereas refrigeration (but no freezing) in an airtight container without an air space (or more preferably, in a headspace vial) is recommended for analysis of the solvent itself. In chemical analysis, quality control is essential for reliable results (for details, see the article “Quality assurance” in this chapter). In reporting the results, ethics should be respected (see chapter Ethical Issues elsewhere in the Encyclopaedia).
Table 1. Some examples of target chemicals for biological monitoring and sampling time
|
Solvent |
Target chemical |
Urine/blood |
Sampling time1 |
|
Carbon disulphide |
2-Thiothiazolidine-4-carboxylicacid |
Urine |
Th F |
|
N,N-Dimethyl-formamide |
N-Methylformamide |
Urine |
M Tu W Th F |
|
2-Ethoxyethanol and its acetate |
Ethoxyacetic acid |
Urine |
Th F (end of last workshift) |
|
Hexane |
2,4-Hexanedione Hexane |
Urine Blood |
M Tu W Th F confirmation of exposure |
|
Methanol |
Methanol |
Urine |
M Tu W Th F |
|
Styrene |
Mandelic acid Phenylglyoxylic acid Styrene |
Urine Urine Blood |
Th F Th F confirmation of exposure |
|
Toluene |
Hippuric acid o-Cresol Toluene Toluene |
Urine Urine Blood Urine |
Tu W Th F Tu W Th F confirmation of exposure Tu W Th F |
|
Trichloroethylene |
Trichloroacetic acid (TCA) Total trichloro- compounds (sum of TCA and free and conjugated trichloroethanol) Trichloroethylene |
Urine Urine Blood |
Th F Th F confirmation of exposure |
|
Xylenes2 |
Methylhippuric acids Xylenes |
Urine Blood |
Tu W Th F Tu W Th F |
1 End of workshift unless otherwise noted: days of week indicate preferred sampling days.
2 Three isomers, either separately or in any combination.
Source: Summarized from WHO 1996.
Anumber of analytical procedures are established for many solvents. Methods vary depending on the target chemical, but most of the recently developed methods use gas chromatography (GC) or high-performance liquid chromatography (HPLC) for separation. Use of an autosampler and data processor is recommended for good quality control in chemical analysis. When a solvent itself in blood or in urine is to be analysed, an application of headspace technique in GC (headspace GC) is very convenient, especially when the solvent is volatile enough. Table 2 outlines some examples of the methods established for common solvents.
Table 2. Some examples of analytical methods for biological monitoring of exposure to organic solvents
|
Solvent |
Target chemical |
Blood/urine |
Analytical method |
|
Carbon disulphide |
2-Thiothiazolidine-4- |
Urine |
High performance liquid chromatograph with ultraviolet detection (UV-HPLC) |
|
N,N-Dimethylformamide |
N-Methylformamide |
Urine |
Gas chromatograph with flame thermionic detection (FTD-GC) |
|
2-Ethoxyethanol and its acetate |
Ethoxyacetic acid |
Urine |
Extraction, derivatization and gas chromatograph with flame ionization detection (FID-GC) |
|
Hexane |
2,4-Hexanedione Hexane |
Urine Blood |
Extraction, (hydrolysis) and FID-GC Head-space FID-GC |
|
Methanol |
Methanol |
Urine |
Head-space FID-GC |
|
Styrene |
Mandelic acid Phenylglyoxylic acid Styrene |
Urine Urine Blood |
Desalting and UV-HPLC Desalting and UV-HPLC Headspace FID-GC |
|
Toluene |
Hippuric acid o-Cresol Toluene Toluene |
Urine Urine Blood Urine |
Desalting and UV-HPLC Hydrolysis, extraction and FID-GC Headspace FID-GC Headspace FID-GC |
|
Trichloroethylene |
Trichloroacetic acid Total trichloro-compounds (sum of TCA and freeand conjugated trichloroethanol) Trichloroethylene |
Urine Urine Blood |
Colorimetry or esterification and gas chromatograph with electron capture detection (ECD-GC) Oxidation and colorimetry, or hydrolysis, oxidation, esterification and ECD-GC Headspace ECD-GC |
|
Xylenes |
Methylhippuric acids (three isomers, either separately orin combination) |
Urine |
Headspace FID-GC |
Source: Summarized from WHO 1996.
Evaluation
A linear relationship of the exposure indicators (listed in table 2) with the intensity of exposure to corresponding solvents may be established either through a survey of workers occupationally exposed to solvents, or by experimental exposure of human volunteers. Accordingly, the ACGIH (1994) and the DFG (1994), for example, have established the biological exposure index (BEI) and the biological tolerance value (BAT), respectively, as the values in the biological samples which are equivalent to the occupational exposure limit for airborne chemicals—that is, threshold limit value (TLV) and maximum workplace concentration (MAK), respectively. It is known, however, that the level of the target chemical in samples obtained from non-exposed people may vary, reflecting, for example, local customs (e.g., food), and that ethnic differences may exist in solvent metabolism. It is therefore desirable to establish limit values through the study of the local population of concern.
In evaluating the results, non-occupational exposure to the solvent (e.g., via use of solvent-containing consumer products or intentional inhalation) and exposure to chemicals which give rise to the same metabolites (e.g., some food additives) should be carefully excluded. In case there is a wide gap between the intensity of vapour exposure and the biological monitoring results, the difference may indicate the possibility of skin absorption. Cigarette smoking will suppress the metabolism of some solvents (e.g., toluene), whereas acute ethanol intake may suppress methanol metabolism in a competitive manner.