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Potency ranking of methemoglobin‐forming agents

This study represents the first systematic attempt to rank methemoglobin‐forming agents. It is a quantitative potency ranking study utilizing linear regression analysis of dose‐response data for comparative purposes. Six agents that are direct‐acting and eight that require bioactivation were tested for their ability to induce methemoglobin formation in Dorset sheep erythrocytes under defined in vitro conditions. The agents were then ranked according to three complementary methods based on the slope of the linear regression, the calculated dose expected to induce a given amount of methemoglobin formation and the calculated percentage methemoglobin response induced by 1 mmol 1−1 of the agent. The direct‐acting agents, ranked from most to least potent inducers of methemoglobin formation, are: p‐dinitrobenzene > o‐dinitrobenzene > copper = nitrite > chlorite > chlorate. The ranking from most to least potent inducers of the bioactivated agents are: α‐naphthol > p‐nitroaniline > m‐nitroaniline, o‐nitroaniline > p‐nitrotoluene = aniline > m‐nitrotoluene = o‐nitrotoluene. The ranking procedures are discussed and issues of interindividual variation and agent‐specific sensitivities are addressed.