The significance of the Druckrey-Kiipfmiiller equation for risk assessment-The toxicity of neonicotinoid insecticides to arthropods is reinforced by exposure time: Responding to a Letter to the Editor by Drs. C. Maus and R. Nauen of Bayer Crop-Science AG

摘要

In 1948, Druckrey and Kupfmuller provided a theoretical explanation for Haber's rule (Haber, 1924). Haber had noted that exposure to a low concentration of a poisonous gas for a long time often had the same effect (death) as exposure to a high concentration for a short time. Haber's rule (for a review, see Witschi, 1999) states that the product of exposure concentration (c) and exposure duration (r) produces a constant toxic effect (ct = constant). The results of Druckrey's ground-breaking study on the carcinogenic-ity of 4-dimethylaminoazobenzene (4-DAB) in BDIII rats (Druckrey, 1943) were strikingly similar to Haber's rule: doubling the daily 4-DAB dose (d), and thereby presumably doubling the concentration of the carcinogen at the site of action (c), halved the time up to the appearance of liver cancer (t). However, the extended latency periods at lower 4-DAB dose levels had never before been observed in an experimental study, and were highly intriguing. As described in detail in my paper (Tennekes, 2010a), Druckrey and Kupfmuller reasoned that Haber's rule was, in theory, consistent with irreversible receptor binding. Many years later Warwick and Roberts confirmed the theorem of Druckrey and Kupfmuller by demonstrating covalent binding of a 4-DAB metabolite to DNA (Warwick and Roberts, 1967).