Given a collection ℬ of balls in a three-dimensional space, we wish to explore the cavities, voids, and tunnels in the complement space of ∪ℬ. We introduce the pathway axis of ℬ as a useful subset of the medial axis of the complement of ∪ℬ and prove that it satisfies several desirable geometric properties. We present an algorithm that constructs the pathway graph of ∪ℬ, a piecewise-linear approximation of the pathway axis. At the heart of our approach is an approximation scheme that constructs a collection K of same-size balls that approximate ℬ so that the Hausdorff distance between ∪ℬ and ∪ K is bounded by a prescribed parameter. We prove a bound on the ratio between the number of balls in K and the number of balls in ℬ. We employ this bound and the approximation scheme to show how to approximate the persistence diagrams for ∪ℬ, which can be used to extract major topological features such as the large voids and tunnels in the complement of ∪ℬ. We show that our approach is superior in terms of complexity to the standard point-sample approaches for the two problems that we address in this paper: approximating the pathway axis of ℬ and approximating the persistence diagrams for ∪ℬ. In a companion paper we introduce MolAxis, a tool for the identification of channels in macromolecules that demonstrates how the pathway graph and the persistence diagrams are used to identify plausible pathways in the complement of molecules.