The replacement of Druckrey’s model of dose-time-response by the ‘acceptable daily intake’ concept has invalidated risk assessment

In the 1950s the commission on food coloring of the German Research Society (DFG), headed by the biochemist Adolf Butenandt and the pharmacologist Hermann Druckrey, represented a policy of preventive risk management in regard to food additives. Druckrey had conducted animal tests with butter yellow, an azo compound used to give butter an attractive yellow colour. These experiments demonstrated that the production of tumours required a certain total dose, regardless of how this was distributed over 35 to 365 days. The latency period, Druckrey stated, was inversely related to the daily dose. If experiments were extended over the life span of the animals, a smaller dose was necessary to produce an effect. Druckrey concluded that the carcinogenic effect of butter yellow was therefore, even at the smallest doses, irreversible from the beginning of the experiment during the entire life span of the animals, and was additive with further exposure without any modiication, until, after a critical total dose has been exceeded, tumours would develop. It was thereby recapitulating a discourse on “food poisoning” and a critique on an inner nexus being constructed by our civilization between foreign substances and carcinogenesis. Such a connection had already been expressed in the early 1930s. Discourses on purity and contamination were translated into mathematical models (the dose-time-response) and legislative measures (new German food law in 1958). With the organisation EUROTOX and within the scope of JECFA, Druckrey tried to implement this pharmacology of cancer on a global scale. At the end of the 1950s these purist and preventive risk policies were forced back by the primacy of economics. With the replacement of Druckrey’s model of dose-time-response by the much more flexible concept of ‘acceptable daily intake,’ industry- and trade-friendly policy of calculable risk prevailed over the policy of preventive risk management, which in West Germany was represented from then on by a rising consumer movement. However, regulatory decisions based on current risk approaches are flawed simply because the science underpinning the risk of chemicals is inappropriate in many cases. A fundamental problem is to use one methodology for all compounds, irrespective of their toxic mode of action in organisms. According to the theories of Druckrey and Küpfmüller, the character of a poison is primarily determined by the reversibility of critical receptor binding. Chemicals showing irreversible or slowly reversible binding to specific receptors will produce cumulative effects with time of exposure, and whenever the effects are also irreversible (e.g. death) they are reinforced over time; these chemicals have time-cumulative toxicity.This concept was validated by Druckrey and co-workers with genotoxic carcinogens, the action of which is described by what is now known as the Druckrey-Küpfmüller equation: c x t˄n = constant, where c = exposure concentration, t = median time to effect, and n is an exponent > 1, which reflects reinforcement of the effect over time. Using data generated by Sanchez-Bayo, Tennekes demonstrated that the Druckrey-Küpfmüller equation also described the toxicity of (non-genotoxic) neonicotinoid insecticides to arthropods. This discovery showed that the theories of Druckrey and Küpfmüller were generally applicable in toxicology and, perhaps even more importantly, that risk assessment procedures needed to be revised, because the risks of time-cumulative toxins had been seriously underestimated.

While most toxicants with a generic mode of action can be evaluated by the traditional concentration–effect approaches, a certain number of chemicals, including carcinogens, methylmercury, rodenticides, neonicotinoids and cartap insecticides have toxic effects that are reinforced with time of exposure (time-cumulative effects). Therefore, the traditional risk approach cannot predict the impacts of the latter chemicals in the environment. New assessment procedures are needed to evaluate the risk that the latter chemicals pose on humans and the environment.
Sources:
Heiko Stoff, Zur Kritik der Chemisierung und Technisierung der Umwelt. Risiko- und Präventionspolitik von Lebensmittelzusatzstoffen in den 1950er Jahren in: TG Technikgeschichte, Seite 229 - 250 TG, Jahrgang 81 (2014), Heft 3, ISSN print: 0040-117X, ISSN online: 0040-117X, DOI: 10.5771/0040-117X-2014-3-229 (in German)
Heiko Stoff, Oestrogens and Butter Yellow: Gendered Policies of Contamination in Germany, 1930-1970. In: Gendered Drugs and Medicine, Historical and Socio-Cultural Perspectives, Eds. Teresa Ortiz-Gómez & María Jesús Santesmases, Ashgate Publishing Limited, Farnham, Surrey GU9 7PT, UK.
H. A. Tennekes and F. Sánchez-Bayo (2013) The molecular basis of simple relationships between exposure concentration and toxic effects with time. Toxicology 309, 39– 51