Nongenotoxic (NGTX) carcinogens induce cancer via other
mechanisms
than direct DNA damage. A recognized mode of action for NGTX carcinogens
is induction of oxidative stress, a state in which the amount of oxidants
in a cell exceeds its antioxidant capacity, leading to regenerative
proliferation. Currently, carcinogenicity assessment of environmental
chemicals primarily relies on genetic toxicity end points. Since NGTX
carcinogens lack genotoxic potential, these chemicals may remain undetected
in such evaluations. To enhance the predictivity of test strategies
for carcinogenicity assessment, a shift toward mechanism-based approaches
is required. Here, we present an adverse outcome pathway (AOP) network
for chemically induced oxidative stress leading to (NGTX) carcinogenesis.
To develop this AOP network, we first investigated the role of oxidative
stress in the various cancer hallmarks. Next, possible mechanisms
for chemical induction of oxidative stress and the biological effects
of oxidative damage to macromolecules were considered. This resulted
in an AOP network, of which associated uncertainties were explored.
Ultimately, development of AOP networks relevant for carcinogenesis
in humans will aid the transition to a mechanism-based, human relevant
carcinogenicity assessment that involves a substantially lower number
of laboratory animals.