Cell injury/death leads to Decrease, Growth

This KER describes the causal and predictive relationship whereby an increase in cell injury and/or cell death leads to a decrease in growth. The upstream KE, cell injury/death, represents loss of cellular viability or severe cellular damage resulting in apoptosis, necrosis, or other forms of lethal cellular injury. The downstream KE, decreased growth, represents reduced accumulation of biomass, body size, length, cell density, tissue mass, or other growth-related endpoints at organ, organism, or population levels. The biological logic of the KER is that growth requires a positive balance between production of new cellular material and loss of existing cells. When cell injury/death is sufficiently frequent, persistent, or spatially distributed across growth-relevant tissues, net cell accumulation is reduced and tissue or organismal growth is impaired. In unicellular systems, increased cell death directly reduces viable cell density and biomass accumulation. In multicellular organisms, the relationship depends on the affected tissue, the ability to compensate through proliferation or regeneration, and the timing of injury relative to developmental or growth windows.

This relationship is not intended to imply that all decreases in growth are caused by cell death. Growth can also decrease through reduced cell proliferation, altered energy allocation, endocrine disruption, nutrient limitation, or developmental delay without overt lethality. Rather, the KER applies when increased cell injury/death is of sufficient magnitude or duration to reduce the viable cellular pool needed for growth or to damage growth-relevant tissues. Within the ROS-growth AOP network, this KER provides a terminal convergence relationship for pathways in which oxidative stress, DNA strand breaks, or ATP depletion produce cytotoxicity that contributes to reduced growth.

Evidence for this KER was assembled using the same AI-human hybrid strategy applied across the ROS-growth AOP network. Initial evidence identification used AOP-Wiki relationship and key event mapping, prior ROS-growth concordance tables, and targeted literature searches. Search terms combined upstream and downstream concepts such as “cell death”, “cell injury”, “cytotoxicity”, “apoptosis”, “necrosis”, “viability”, “growth inhibition”, “growth retardation”, “developmental delay”, “biomass”, “cell density”, “condition index”, and “organism growth”, together with taxa and stressor terms including algae, Daphnia, copepod, bivalve, fish embryo, mammalian embryo, paraquat, cadmium, methanol, rotenone, gamma radiation, and oxidative stress. AOP-Wiki was consulted to confirm that Relationship 2767 links Event 55 to Event 1521 and to identify related AOP reuse contexts.

Candidate studies were prioritized when they measured both cell injury/death and a growth-related outcome in the same biological system, reported dose or concentration and exposure duration, or provided information relevant to temporal, dose-response, or incidence concordance. Large language model assistance was used only as an auxiliary screening and structuring tool to extract study metadata, identify potentially relevant endpoints, and prioritize records for expert review. Final inclusion decisions, interpretation of endpoints, and weight-of-evidence judgments were made by manual expert curation against the original article text. Mechanistic reviews were used to support biological plausibility, while primary experimental studies were used preferentially to support empirical concordance.

Overall call: Low to moderate. Quantitative understanding is limited because the relationship between cell injury/death and growth depends on the proportion of cells affected, tissue location, developmental timing, compensatory proliferation, regenerative capacity, and organismal energy allocation. At a conceptual level, the linkage is quantitative: growth rate reflects the balance between biomass accumulation and biomass or cell loss, so increasing the frequency or magnitude of cell death should reduce net growth if cell replacement or compensatory growth is insufficient. However, few studies provide response-response models that predict growth reduction from a measured degree of cell injury/death across taxa or stressors.

The KER is applicable to biological systems in which growth depends on maintenance or expansion of viable cell number or biomass. This includes unicellular populations, developing embryos, juvenile organisms, growing tissues, and adult organisms in which tissue condition or somatic growth is assessed. Taxonomic applicability is broad across eukaryotes, but empirical support is strongest for algae, aquatic invertebrates, mollusks, fish, and mammalian embryo or cell models. The KER is not sex-specific, but sex, endocrine status, life stage, and environmental context may modulate sensitivity. The relationship is most relevant when cell injury/death is sufficiently extensive, sustained, or located in growth-relevant tissues. It is less predictive when growth is reduced by upstream mechanisms that suppress proliferation or metabolism without substantial cell death.

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