General Principles of Toxicology
The dose-response foundation
Toxicology studies the adverse effects of xenobiotics on living systems. Paracelsus framed the central idea: dose makes the poison. Candidates must be fluent in graded versus quantal dose-response curves, thresholds, NOAEL and LOAEL, benchmark dose, LD50/LC50, ED50 and TD50, therapeutic index, and margin of safety. Also know local versus systemic, acute versus chronic, reversible versus irreversible effects, and interaction terms: additivity, synergism, potentiation, and antagonism. Mechanisms include receptor-mediated signaling, cytotoxicity, oxidative stress, mitochondrial injury, and adaptive responses such as enzyme induction and tissue repair.
Traps: LD50 is a population statistic and a comparative descriptor, not a safe/unsafe boundary; it shifts with species, route, vehicle, and husbandry. A steep dose-response curve means a small margin between effective and lethal doses. ED50 and TD50 must be drawn from the same species, route, and endpoint before computing a therapeutic index. NOAEL is an experimental dose, not a biological threshold, and no observed effect does not prove no effect. Hormesis is a real but contested pattern; low-dose stimulation should not be assumed protective. Safety is a judgment based on context, not an intrinsic property.
Rule of thumb: therapeutic index = TD50/ED50; larger is safer. A drug with ED50 5 mg/kg and TD50 50 mg/kg has TI = 10, a narrow margin that warrants monitoring; if TD50 were 500 mg/kg-day, TI = 100 and the margin is wider.