Chloropicrin dechlorination in relation to toxic action.

Area of Science:

• Environmental toxicology
• Biochemistry
• Mechanistic toxicology

Background:

• Chloropicrin (CCl3NO2) is a widely used soil fumigant.
• Its precise mechanism of acute toxicity remains unclear.
• Investigating dechlorination's role in toxicity is crucial.

Purpose of the Study:

• To elucidate the mechanism of chloropicrin (CCl3NO2) acute toxicity.
• To examine the involvement of dechlorination in CCl3NO2 toxicity.
• To assess CCl3NO2 metabolism, enzyme inhibition, cytotoxicity, and hemoprotein interactions.

Main Methods:

• Metabolic studies identifying thiophosgene and raphanusamic acid.
• Enzyme inhibition assays for pyruvate and succinate dehydrogenases.
• Cytotoxicity tests on Hepa 1c1c7+ mouse hepatoma cells.
• In vivo analysis of oxyhemoglobin in mice treated with CCl3NO2 and metabolites.

Main Results:

• A novel metabolic pathway yielding thiophosgene (raphanusamic acid) was discovered.
• CCl3NO2 potently inhibited pyruvate (IC-50 4 microM) and succinate (IC-50 13 microM) dehydrogenases.
• Dehalogenated metabolites (CHCl2NO2, CH2ClNO2) were significantly less inhibitory.
• CCl3NO2 induced elevated oxyhemoglobin in mouse liver, unlike CHCl2NO2.
• Cytotoxicity was not linked to glutathione depletion.

Conclusions:

• The acute toxicity of chloropicrin (CCl3NO2) is likely due to the parent compound or specific metabolites, not dehalogenated forms.
• Inhibition of pyruvate dehydrogenase complex and elevated oxyhemoglobin are potential key mechanisms.
• Understanding these mechanisms is vital for risk assessment and mitigation strategies.