Studies on the toxicity of chlorinated p-nitrobiphenyl ether : I—Methemoglobin formation in vitro and in vivo induced by nitroso and amino derivatives of chlorinated biphenyl ether

Abstract

Methemoglobin formation by nitroso and amino derivatives of chlorinated biphenyl ether was investigated. All the nitroso derivatives used induced methemoglubin formation in suspensions of human erythrocytes. Ability to induce methemoglobin formation among the nitroso derivatives was the highest for nitrosobenzene, followed by p-nitrosobiphenyl ether, 4-chloro p-nitrosobiphenyl ether, 2,4-dichloro p-nitrosobiphenyl ether and then 2,4,6-trichloro p-nitrosobiphenyl ether. The monochloro p-nitrosobiphenyl ethers showed all the same activity. Therefore, the ability to induced methemoglobin formation depended on the number of chlorines rather than on the position of chlorine substitution on the phenoxy group in the molecule. Since lactate decreased but glucose and xylitol increased the methemoglobin level produced by the nitroso compounds, this reaction would appear to require an NADPH-dependent enzyme system in erythrocytes. All of the amino derivatives used induced methemoglobin formation in suspensions of human erythrocytes with rat liver homogenates. Ability to induced methemoglobin formation among the amino derivatives was the highest for p-aminobiphenyl ether, followed by 4-chloro p-aminobiphenyl ether, 2,4,-dichloro p-aminobiphenyl ether, 2,4,6-trichloro p-aminobiphenyl ether, and then aniline. Methemoglobin formation bychlorinated p-aminobiphenyl ether was examined by intraperitoneal and oral administration to rats. After i.p. injection, methemoglobinemia was induced by p-aminobiphenyl ether, aniline, and 2,4-dichloro p-aminobiphenyl ether but not by 2,4,6-trichloro p-aminobiphenyl ether over the period tested. The order of methemoglobin formation was p- aminobiphenyl ether ≧ 4- chloro p- aminobiphenyl ether > aniline ≧ 2,4- dichloro p-aminobiphenyl ether. Oral administration gave almost the same result as i.p. injection. The maximum methemoglobin levels produced by the amino derivatives were highest for 4-chloro p-aminobiphenyl ether, followed by p-aminobiphenyl ether, 2,4-dichloro p-aminobiphenyl ether, aniline, and then 2,4,6-trichloro p-aminobiphenyl ether. However, the methemoglobin level produced by 2,4,6-trichloro p-aminobiphenyl ether was very low and not significantly greater than the background level.