Haloacetonitriles: Metabolism, Genotoxicity, and Tumor-Initiating Activity

Abstract

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org. . The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives. Haloacetonitriles (HAN) are drinking water contaminants produced during chlorine disinfection. This paper evaluates metabolism, genotoxicity, and tumor-initiating activity of these chemicals. The alkylating potential of the HAN to react with the electrophile-trapping agent, 4-(p-nitrobenzyl)pyridine, followed the order dibromoacetonitrile (DBAN) > bromochloroacetonitrile (BCAN) > chloroacetonitrile (CAN) > dich? loroacetonitrile (DCAN) > trichloroacetonitrile (TCAN). When administered orally to rats, the HAN were metabolized to cyanide and excreted in the urine as thiocyanate. The extent of thiocyanate excretion was CAN > BCAN > DCAN > DBAN ? TCAN. Haloacetonitriles inhibited in vitro microsomal dimethyl? nitrosamine demethylase (DMN-DM) activity. The most potent inhibitors were DBAN and BCAN, with Kt = 3-4 x 10"5 M; the next potent were DCAN and TCAN, with Kt = 2 x 10"4 M; and the least potent inhibitor was CAN, with K{ = 9 x 10~2 M. When administered orally, TCAN, but not DBAN, inhibited hepatic DMN-DM activity.The HAN produced DNA strand breaks in cultured human lymphoblastic (CCRF-CEM) cells. TCAN was the most potent DNA strand breaker, and BCAN > DBAN > DCAN > CAN, which was only marginally active. DCAN reacted with polyadenylic acid and DNA to form adducts in a cell-free system; however, the oral administration of DBAN or DCAN to rats did not result in detectable adduct formation in liver DNA. None of the HAN initiated 7-glutamyltranspeptidase (GGT) foci when assayed for tumor-initiating activity in rat liver foci bioassay. In summary, the HAN were demonstrated to possess alkylating activity and genotoxicity in vitro and appeared after oral administration to possess biological activity as indicated by the inhibition of DMN-DM by TCAN but appeared to lack genotoxic and tumor-initiating activity in rat liver. It is proposed that if the HAN found in drinking water pose a carcinogenic hazard it would be limited to the gastrointestinal tract.

Potential of the NBP Method for the Study of Alkylation Mechanisms: NBP as a DNA-Model

“…For instance, competing hydrolysis and isomerization reactions have often been completely overlooked in the study of epoxides, especially those of polycyclic aromatic hydrocarbons. 26,27,69,191−193 Such assumptions are not unique to oxiranes, and they have also appeared in the study of nitrogen mustards and aziridines, 23 chloroethylene, 31 cyclophosphamide, 194 3-methyl-1-phenyltriazenes, 38 S-(2-haloethyl)-1-cysteine analogues, 83 antineoplastic agents, 195 haloacetonitriles, 196 N-methyl-N′-aryl-N-nitrosoureas, 175 and phosphoraziridines. 25 The NBP test has obvious limitations: the lack of selectivity and applicability only to S N 2 alkylating agents, in addition to the fact that correlating the results of the NBP assay with in vivo results is sometimes oversimplistic and neglects important processes such as metabolism or DNA-repair systems.…”

“…Choice of the appropriate approach is of importance, and abundant instances of poor mechanistic perspective in the kinetic application of the NBP test can be found in the literature. For instance, competing hydrolysis and isomerization reactions have often been completely overlooked in the study of epoxides, especially those of polycyclic aromatic hydrocarbons. ,,,− Such assumptions are not unique to oxiranes, and they have also appeared in the study of nitrogen mustards and aziridines, chloroethylene, cyclophosphamide, 3-methyl-1-phenyltriazenes, S -(2-haloethyl)-1-cysteine analogues, antineoplastic agents, haloacetonitriles, N -methyl- N′ -aryl- N -nitrosoureas, and phosphoraziridines …”

Occurrence, Synthesis, and Mammalian Cell Cytotoxicity and Genotoxicity of Haloacetamides: An Emerging Class of Nitrogenous Drinking Water Disinfection Byproducts

“…Although the acute benefits of drinking water disinfection are universally acknowledged, there is concern about adverse health risks due to long-term DBP exposure , . Epidemiology studies provide moderate evidence for DBP associations with adverse pregnancy outcomes – ; specific DBPs are mutagens, carcinogens, teratogens, or developmental toxicants – . In 2006, the U.S. Environmental Protection Agency (EPA) promulgated the Stage 2 Disinfectants/Disinfection Byproducts Rule .…”

Investigation of the inhibition effect of the environmentally friendly inhibitor sodium alginate on magnesium alloy in sodium chloride solution

“…Magnesium alloys are extensively used in automobile manufacture, spacecraft engineering, and the electronics industry owing to their low density, high strength‐to‐weight ratio, good weldability, excellent electrical conductivity, and exceptional recyclability characteristics . Unfortunately, in many fields, their applications are still limited by their high chemical reactivity and poor corrosion resistance . Hence, a number of approaches have been utilized to enhance the corrosion resistance of magnesium alloys, such as changing and optimizing alloy microstructure , surface coating , and the addition of inhibitors to service media .…”