Chronotoxicology*Dedicated to the memory of Dr Charles A. Walker who pioneered chronotoxicology

Abstract

The study of kinetics, dynamics, toxicological responses and side effects of drugs, poisons or toxic substances relative to temporal rhythms occurring in living organisms is referred to as ‘chronotoxicology’. Temporal rhythms are guided by solar time cycles (circadian = 24 hours) based upon photoperiodic stimuli derived from sunlight and further influenced by local external time cues. The ‘main biological clock’ by which rhythms are established is the suprachiasmatic nucleus (SCN) housed proximal to the optic chiasm, which receives transmitted blue light (460–480 nm) through non‐visual photosensitive retinal ganglion cells containing melanopsin in the retinohypothalamic tract. The SCN's basic ‘free‐running’ circadian rhythm then orchestrates dynamic rhythms in millions of peripheral oscillators located within the body's cells, tissues and organs that are not responsive to light, but respond through neural and humoral SCN outputs. Together these orchestrate the precisely timed events to sustain biological life by regulating physiological function of the cardiovascular, nervous, digestive, immune, reproductive, endocrine and nervous systems. Cyclical fluctuations in absorption, distribution, metabolism and excretion regulate toxic substance detoxification, drug toxicity and effectiveness. Many of these processes are further regulated at the genetic level by clock genes which establish basic transcriptional‐translation feedback oscillation loops under the control of Per 1–3, Cry 1,2, Rev‐erbα, Rev‐erbβ, Rorα, Rorβ, cAMP response element‐binding protein (CREB) and the circadian locomotor output cycles kaput/brain and muscle ARNT‐like protein 1 (CLOCK/BMAL1) heterodimers.