chapter  12
34 Pages

Vascular Toxicology

There are a number of different ways to approach the subject of vascular toxicology. Most, if not all of these, presume a rather extensive basic knowledge of pathophysiological mechanisms that contribute to the production of a frank disease state or predispose the vasculature of an organ to susceptibility to a secondary chemical stimulus that may produce injury. It is not within the scope of this discussion to take an extensive classical approach to the pathophysiology of vasculature. Instead, a very practical pathway has been chosen by focusing on major structural and functional changes that can occur in vasculature and the relationship of agents to the mechanisms of injury production. Once the fundamental elements of pathophysiology have been delineated, agents will be discussed insofar as they affect particular vascular beds that have structural uniqueness, or in terms of agents of various chemical classes or use categories. This may involve some reiteration; however, it is important to realize that a good working knowledge of toxicology requires that inductive processes involving generalization by chemical structure of agents is as important as deduction with respect to agents that are known to affect the vasculature of specific organs only. The latter point is well illustrated by the fact that the geometry, cytoarchitecture, physiological requirements, and limitations of an organ and its sustaining vascular beds in many ways determines in advance the universe of the most probable areas of susceptibility and types· of agents that will cause injury. Thus, we see that the vasculature

of the brain is compressed into a small, rigid area and agents that produce increased vascular permeability and resulting edema cause major pathophysiological problems, exceeded only by those encountered when autoregulatory disturbances secondary to hypertension or cerebroatherosclerosis compromise oxygen perfusion. The eye, as a window on the brain, has similar high requirements for blood flow and oxygen, particularly the retina, and is also susceptible to cytotoxic substances that produce papilledema. The major focus of vascular toxicity in the eye is the retinal vessels that show many types of cerebrovascular characteristics. In the liver, the site of major metabolic biotransformation in the body, there is a particularly wide range of compounds and metabolites to which vasculature are exposed, and the potential for recycling via the enterohepatic circulatory system provides a unique opportunity for repeated exposure.