Lethal chronotoxicity induced by seven metal compounds in mice

Area of Science:

• Environmental Toxicology
• Chronobiology
• Pharmacokinetics

Background:

• Circadian rhythms influence physiological processes, potentially affecting toxicological responses.
• Metal compounds are common environmental and occupational exposures.
• Understanding temporal variations in toxicity is crucial for accurate risk assessment.

Purpose of the Study:

• To investigate the "chronotoxicity" of seven metal compounds (Hg, Pb, Ni, Cr, Cu, Zn, Fe).
• To assess how metal compound toxicity varies with circadian periodicity.
• To evaluate the implications of chronotoxicity for animal experiments and human risk assessment.

Main Methods:

• Male ICR mice were administered seven metal compounds (Hg, Pb, Ni, Cr, Cu, Zn, Fe) via intraperitoneal injection.
• Injections were performed at six different time points across a 24-hour cycle (zeitgeber time [ZT]: ZT2, ZT6, ZT10, ZT14, ZT18, ZT22).
• Mortality was monitored for 14 days post-injection to determine toxicity levels.

Main Results:

• Significant variations in metal compound toxicity were observed across different times of day.
• Mice showed tolerance to Nickel (Ni) during the dark phase and to Chromium (Cr) during the light phase.
• Mercury (Hg) and Lead (Pb) exhibited biphasic chronotoxicity, while Copper (Cu) and Zinc (Zn) showed increased susceptibility during the light-dark transition. Iron (Fe) toxicity was not time-dependent.

Conclusions:

• Chronotoxicity significantly influences metal compound toxicity, highlighting the importance of injection timing in toxicity evaluation and animal study reproducibility.
• These findings suggest chronotoxicology is a critical factor in risk assessment, particularly for night shift workers exposed to toxicants at varying times.
• The study underscores the need to incorporate circadian rhythms into toxicological assessments for more accurate and relevant safety evaluations.