Inhalation Carcinogenesis of Various Alkylating Agents

• Published in: JNCI : Journal of the National Cancer Institute 1987-08, Vol.79 (2), p.285-289
• Main Authors: Sellakumar, Arthur R., Snyder, Carroll A., Albert, Roy E.
• Format: Article
• Language: English
• Subjects: Acetates - toxicity; Alkylating Agents - toxicity; Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Epoxy Compounds - toxicity; Formates - toxicity; Formic Acid Esters; Hydrolysis; Male; Medical sciences; Methyl Methanesulfonate - toxicity; Nasal Mucosa - drug effects; Nose Neoplasms - chemically induced; Propiolactone - toxicity; Rats; Rats, Inbred Strains; Tumors
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/79.2.285

A series of earlier studies showed that inhalation exposures of rats to three water-reactive electrophilic compounds produced brisk yields of nasal cancer even when the animals were exposed for only 30 days (6 hr/day×5 day/wk). In addition, carcinogenic potencies of the compounds appeared to relate to their chemical reactivities as measured by hydrolysis rates. For a further study of this phenomenon, inhalation exposures were conducted with five additional water-reactive compounds: β-propiolactone [(BPL) CAS: 57-57-8], methylmethane sulfonate [(MMS) CAS: 66-27-3], ethylchloroformate [(ECF) CAS: 541-41-3], dichloroacetyl chloride [(DCAC) CAS: 79-36-7], and propylene oxide [(PO) CAS: 75-56-9] on male Sprague-Dawley rats. The hydrolysis rates of these compounds span 6 orders of magnitude. The compounds were administered for 30 days (6 hr/day×5 days/wk) with the use of exposure concentrations that were inversely proportional to the respective hydrolysis rates. With this protocol, all compounds except PO (the slowest reacting compound) produced nasal cancer in rats. The concentrations of MMS and BPL employed in the studies produced similar nasal cancer yields, indicating that the carcinogenic potencies of these compounds in rat nasal mucosa were proportional to their hydrolysis rates. The nasal cancer yields of DCAC and ECF were less than expected. DCAC hydrolyzes so rapidly at in vivo temperatures (half-life 0.01 min) that it may not reach target DNA in reactive form. Why the exposures to ECF produced yields of nasal cancer not predicted by its reactivity is currently under investigation. These results combined with our earlier results demonstrate that the carcinogenic potencies of some inhaled reactive electrophilic compounds are related to their hydrolysis rates.