Toxicology of Industrial Compounds

In this chapter, first the basic toxicokinetic concepts concerning the dis
tribution, elimination and biotransformation of xenobiotics will be
summarized. Subsequently, the relevance of these concepts will be
illustrated and evaluated with the aid of a number of toxicokinetic studies
in animals and humans concerning the nematocide 1,3-dichloropropene,
the fungicide etridiazol, the chemical monomer 1,3-butadiene and the
industrial solvent, 1,1,2-tri-chloroethylene. Apart from interspecies
differences in the toxicokinetics, special attention will be given to
interindividual differences in the toxicokinetics, among other things, as a
result of genetically determined deficiencies in biotransformation enzymes
as well as to its importance for the risk assessment of human exposure to
industrial chemicals.
Disposition of xenobiotics
N.P.E.VERMEULEN ET AL. 13
The overall fate of xenobiotics in an organism is determined by various
toxicokinetic processes notably the route of administration, absorption,
distribution and elimination. Chemicals may enter the body via various
routes. Main routes are the lung, skin and gastrointestinal tract. The
intraperitoneal, intramuscular, intravenous and subcutaneous routes are
largely confined to experimental toxicological and therapeutic agents.
Following absorption, xenobiotics enter the systemic or portal blood
circulation. Distribution of chemicals in blood, organs and tissues usually
occurs rapidly. The final plasma concentration depends on the ability of
the chemicals to pass cell membranes and on their affinity to various
macromolecular proteins and tissues. Distribution to the kidney may result
in direct excretion of the unchanged parent chemical. The physicochemical
characteristics, such as lipophilicity and binding to plasma proteins, play an
important role in the ultimate fate of a chemical in the body. The
disposition of xenobiotics in the body is shown schematically in Figure 2.1.
Its schematic relationship with biological/ toxicological effects is shown in
Figure 2.2.
Biotransformation plays an important role in the disposition of
xenobiotics in vivo. The liver is quantitatively the most important organ in
the process of biotransformation. It receives a relative high bloodflow
directly from the gastrointestinal tract via the portal vein, sometimes giving
rise to the so-called hepatic ‘first-pass effect’ due to the presence of high
concentrations of phase I and phase II metabolizing enzymes.
Other important organs in biotransformation are the lungs, kidneys and
the intestine. The primary object of biotransformation generally is to
increase the hydrophilicity of chemicals, thus facilitating excretion by the
kidneys in the urine or by the liver in the bile. Phase I reactions involve
oxidation, reduction and hydrolysis reactions and phase II reactions
conjugation or synthetic reactions. Phase I metabolic reactions generally