Development of an adverse outcome pathway for deposition of energy
leading to cataracts
Abstract
Cataracts are one of the leading causes of blindness, with estimated 95
million people affected worldwide. A hallmark of cataract development is
lens opacification, typically associated not only with aging, but also
radiation exposure as encountered by interventional radiologists and
astronauts during the long-term space mission. To better understand
radiation-induced cataracts, the adverse outcome pathway (AOP) framework
was used to structure and evaluate knowledge across biological levels of
organization. AOPs identify a sequence of key events (KEs) connected by
key event relationships (KERs) beginning with a molecular initiating
event (MIE) to an adverse outcome (AO) of relevance to regulatory
decision-making. To construct the cataract AOP, a scoping review
methodology was used to filter, screen, and review studies based on the
modified Bradford Hill criteria. Eight KEs were moderately supported by
empirical evidence across the adjacent (directly-linked) relationships
using well-established endpoints. Over half of the evidence collected
was informed by biological plausibility. Early KEs of oxidative stress
and protein modifications could be the focus of countermeasures. Several
identified knowledge gaps and inconsistencies in the AOP can be the
basis of future research, most notably directed to experiments at low or
moderate doses and dose-rates, relevant to radiation workers and other
occupational exposures.