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5.3 TOXiQTY AND RISKS INDUCED BY OCCUPATIONAL EXPOSURE TO CHEMICAL COMPOUNDS 279

occur with functional consequences without there being any visible morpho-
logical alterations in cells or tissues. 89
Chemically induced changes in DNA, i.e., mutations and chromosomal
damage, are also an important toxicity mechanism. The bases in DNA, like
bases in general, are nucleophilic (electron donors) and react with electro-
philes (electron acceptors). Strong electrophiles, such as carbonium ions and
epoxides, are formed during the metabolism of many known potent carcino-
gens. Thus, the formation of DNA adducts may cause malignant transforma-
tion of cells and lead to initiation of cancer. In the following section,
mechanisms whereby chemical compounds induce their toxicity will be dis-
7 89
cussed/' -
Receptor-mediated Toxicity
Several chemical compounds induce their toxic and other effects through
stimulating specific receptors and events occurring after receptor activation, a
process called signal transduction. Receptors themselves are protein molecules
sitting in the lipid bilayer of the cell membrane. They have the ability to recog-
nize physiological intercellular transmitters such as hormones, neurotransmit-
ters, or growth factors (also called first messengers). Normally a very small
amount of a transmitter is sufficient to activate the receptor. Many of the re-
ceptors are ion channels and their activation leads to the influx of ions into
the cell. There are specific receptor-coupled receptors for sodium, potassium,
and calcium. Increased influx of these ions usually leads to increased enzy-
matic activity, and activation of the cell. Some receptors are intimately associ-
ated with enzymes such as tyrosine kinase, adenylate cyclase, or
92 95
phospholipase C. ~
Some of the cell membrane receptors are coupled to an amplifier, called
the G-protein. Activation of a G-protein leads either to activation or inhibi-
tion of an effector enzyme on the internal side of the cell membrane (see Fig.
92
5.44). These effector enzymes are responsible for the generation of second
messengers that are essential for cellular signal transduction. Whereas first
messengers, described above, are responsible for chemical intercellular com-
munication, second messengers are responsible for transducing the informa-
tion that has reached the cell surface receptor to all parts of the cell interior.
There is also a specific enzyme machinery for inactivating the second messen-
gers to terminate the action that was initiated by the first messenger. Typical
effects of a second messenger are elevation of free intracellular calcium associ-
ated with cellular activation, activation of specific enzymes such as protein ki-
92
nase C, or production of a tertiary cellular messenger such as nitric oxide
(NO). Nitric oxide is a gaseous cellular messenger that can act as both an ul-
tra- and intercellular signal transduction factor. Being lipid-soluble, NO easily
diffuses in the cell as well as penetrating through the cell membrane and
96 97
thereby also reaching other cells. '
There are even receptors that are known to become activated only due to
interaction with a synthetic chemical, and no physiological agonist for such a
receptor has been characterized. A model receptor in this class is the so-called
Ah receptor complex that becomes activated subsequent to its exposure to
2,3,7,8-tetrachlorodibenzo-/?-dioxin (TCDD). Activation of the Ah receptor