PRINCIPLES OF TOXICOLOGY - Biology East Borneo

16.2 BASIC PRINCIPLES 373Once absorbed, solvents may be transported to other areas of the body by the blood, to organswhere biotransformation may occur, resulting in the formation of metabolites that can be excreted.Significant differences exist between the uptake and potential for adverse effects from solvents,based on the route of exposure. Absorption following ingestion or dermal exposure results inabsorption into the venous circulation, from which materials are rapidly transported to the liverwhere they may be metabolized. Following inhalation exposure, however, much of the absorbedchemical is introduced into the arterial circulation via the alveoli. This means that the absorbedsolvent may be distributed widely in the body prior to reaching the liver for metabolism,degradation, and subsequent excretion.Since solvents constitute a heterogeneous group of chemicals, there are many potentialmetabolic breakdown pathways. However, in many instances there is involvement of the P450enzyme system and the glutathione pathways, which catalyze oxidative reactions and conjugationreactions to form substances that are water-soluble and can be excreted in the urine and, perhaps,the bile. Several pathways may exist for the biotransformation of a specific solvent and some ofthe excreted metabolites form the basis for biological monitoring programs that can be used tocharacterize exposure (e.g., phenols from benzene metabolism, trichloroacetic acid obtained fromtrichloroethene, and mandelic acid from styrene). These metabolic processes are discussed ingreater detail in Chapter 3.Although it is well recognized that the metabolism of most solvents occurs primarily in the liver,other organs also exhibit significant capacity for biotransformation (e.g., kidney, lung). Some organsmay be capable of only some of the steps in the process, potentially leading to accumulation of toxicmetabolites if the first steps of the biotransformation pathway are present, but not the subsequent steps.For example, whereas an aldehyde metabolite may be metabolized readily in the liver, the samealdehyde may accumulate in the lung and cause pulmonary damage due to a lack of aldehydedehydrogenase enzyme in that organ. In addition to the generally beneficial aspects of biotransformationand excretion, metabolism may generate products that are more toxic than the parent compound.This process is termed metabolic activation or bioactivation, and the resultant reactive metabolicintermediates (e.g., epoxides and radicals) are considered to be responsible for many of the toxic effectsof solvents, especially those of chronic character (see Chapter 3).Enzymes that are critical to the metabolic processes may be increased in activity, or “induced,” byvarious types of previous or concomitant exposures to chemicals, such as those from therapeutic drugs,foods, alcohol, cigarette smoke, and other industrial exposures, including other solvents. Competitiveinteractions between solvents in industrial contexts also may influence the toxic potential, complicatingthe question of whether exposure to multiple chemicals always should be considered to be worse thanindividual exposures. A well-described example of interactive effects relates to methanol and ethanol,both of which are substrates that compete for the alcohol dehydrogenase pathway. This observation ofbiochemical competition led to the use of ethanol as an early treatment for acute methanol intoxication.As another example, induction of the enzyme that is active in the biotransformation of trichloroethene(TCE), as a result of chronic ethanol consumption, may influence sensitivity to the adverse effects ofTCE. Interactions between alcohols (e.g., ethanol, 2-propanol) and other solvents (e.g., carbontetrachloride, trichloroethene) have been described.Saturation of the typical metabolic pathways that are responsible for biological breakdown maycause a qualitative shift in metabolism to different pathways. Whereas the normal pathway may be oneof detoxification, saturation of that pathway may result in “shunting” to another pathway, resulting inbioactivation. Examples in which this phenomenon has been demonstrated include 1,1,1-trichloroethane,n-hexane, tetrachloroethene, and 1,1-dichloroethene.In addition to the process of biotransformation and subsequent urinary excretion described above,many solvents may be eliminated in changed or unchanged form by exhalation, an action that varieswith workload. This observation forms the basis for the practice of sampling expired air as a measureof possible occupational exposure in some industrial medical surveillance programs.