TABLE 3.

Summary of non‐adjacent key event relationships (KER)

Key event relationship (KER) title	Description	Empirical evidence
Increases in Oxidative DNA damage leads to Increases in DNA strand breaks	Biologically plausible mechanisms linking increase in oxidative DNA lesions to increase in strand breaks include: 1) Incomplete BER due to an imbalance in the glycosylase and AP site endonuclease (APE) activities resulting in AP site and SSB accumulation; 2) increase in oxidative lesions impeding the repair of neighboring lesions (possibly SSBs); 3) occurrence of SSBs in close proximity to each other during BER; 4) collision of replication fork with BER proteins and intermediates.	Concentration/Dose Concordance In Fpg‐modified comet assay, significant increase in Fpg‐sensitive sites (e.g., 8‐oxo‐dG, AP sites) occurred at lower concentrations than strand breaks in HepG2 cells exposed to a nodularin (Lankoff et al., 2006). Temporal Concordance Temporal profiles of oxidative lesions and strand breaks induced by tert butylhydroperoxide, hydrogen peroxide, and menadione showed positively correlated increases over an 8‐h period (Deferme et al., 2013)
Increases in Oxidative DNA damage leads to Increases in Mutations	It has been extensively demonstrated that 8‐oxodG, the most abundant oxidative DNA lesion, preferentially forms base pairs with incoming dA during replication causing G to T transversions, which are characteristic of oxidative DNA damage.	Temporal and Incidence Concordance Several studies have demonstrated a strong positive correlation between 8‐oxo‐dG formation and incidences of G to T transversions over time in mice and in vitro (Arai et al., 2002; Dahle et al., 2008; Klungland et al., 1999; Minowa et al., 2000). Concentration Concordance Following KBrO3 exposure, the no observed genotoxic effect level (NOGEL) in TK gene mutations could be determined, while all concentrations induced detectable responses in the Fpg‐modified comet assay for oxidative lesions (therefore, no NOGEL) (Platel et al., 2011)
Increases in DNA strand breaks leads to Increases in Mutations	Increases in SSBs and DSBs can lead to a higher incidence of erroneous repair by NHEJ and mutagenic salvage repair pathways.	Concentration/Dose and Incidence Concordance Concentration‐dependent increases observed in strand breaks after 1  h and in mutant frequency measured after 23 and 72  h after bleomycin exposure in TK6 cells (Platel et al., 2011). Several in vitro studies have shown radiation dose‐dependent increases in DSBs and concordant increases in incorrect rejoining and retention of unrepaired DSBs after a recovery period (16‐24  h) post ionizing radiation exposure (Dikomey & Brammer, 2000; Kuhne et al., 2000; Kuhne et al., 2005; Lobrich et al., 2000)
Increases in DNA strand breaks leads to Increases in Chromosomal Aberrations	Mechanistically, DSBs must occur for chromosomal aberrations to occur. If DSBs are not rejoined in a timely manner, the ends may shift away from their original position, resulting in loss of segments or rearrangement of sections.	Temporal Concordance Several in vivo and in vitro studies demonstrated the occurrence of strand breaks (via comet assay and γH2AX foci detection) at early time points (1–4  h) post exposure and micronucleus, chromatid break, or translocation at later time points (24–40  h) (Dertinger et al., 2019; Platel et al., 2009; Trenz et al., 2003; Turner et al., 2015)