Why LD50 Fails Human Safety
The Median Lethal Dose (LD50), a standard metric in toxicology since 1927, represents the single dose of a substance required to kill 50% of a test population, typically rodents (Pillai et al., 2021). Whilst historically used to classify chemical hazards, modern science increasingly views LD50 values as irrelevant—and potentially misleading—when applied to human risk assessment.
The primary limitation lies in fundamental interspecies variation. Differences in anatomy, physiology, and biochemistry mean that metabolic pathways in rats or mice often differ significantly from those in humans (Erhirhie et al., 2018). For instance, the rate at which a liver enzyme bioactivates or detoxifies a compound can vary by orders of magnitude between species, rendering a “safe” animal dose lethal to a human. A notable example is the herbicide paraquat; its $LD_{50}$ in rats suggested relatively low toxicity, yet human fatalities occurred at significantly lower exposure levels due to unique pulmonary sensitivities.
Furthermore, LD50 is a crude “all-or-nothing” metric. It focuses exclusively on mortality, failing to provide data on sublethal effects such as chronic organ damage, reproductive toxicity, or carcinogenic potential. These qualitative nuances are far more critical for clinical safety and the development of antidotes than a statistical midpoint of death (Pillai et al., 2021).
Consequently, regulatory bodies are shifting towards New Approach Methodologies (NAMs). By integrating in vitro human cell assays and in silico modelling, researchers can more accurately predict human systemic toxicity without the scientific—and ethical—shortcomings of traditional animal-based lethal dosing (Erhirhie et al., 2018).
References for further reading
Erhirhie, E. O., Ihekwereme, C. P., & Ilodigwe, E. E. (2018). Advances in acute toxicity testing: strengths, weaknesses and regulatory acceptance. Interdisciplinary Toxicology, 11(1), 5–12. https://doi.org/10.2478/intox-2018-0001
Pillai, S. K., Kobayashi, K., Michael, M., Mathai, T., Sivakumar, B., & Sadasivan, P. (2021). John William Trevan’s concept of Median Lethal Dose (LD50/LC50) – more misused than used. Journal of Pre-Clinical and Clinical Research, 15(3), 137–141. https://doi.org/10.26444/jpccr/139588