Getting the dose-response wrong: why hormesis became marginalized and the threshold model accepted.

The dose-response relationship is central to the biological and biomedical sciences. During the early decades of the twentieth century consensus emerged that the most fundamental dose-response relationship was the threshold model, upon which scientific, health and medical research/clinical practices have been based. This paper documents that the scientific community made a fundamental error on the nature of the dose response in accepting the threshold model and in rejecting the hormetic-biphasic model, principally due to conflicts with homeopathy. Not only does this paper detail the underlying factors leading to this dose response decision, but it reveals that the scientific community never validated the threshold model throughout the twentieth century. Recent findings indicate that the threshold model poorly predicts responses in the low dose zone whereas its dose response "rival", the hormesis model, has performed very well. This analysis challenges a key foundation upon which biological, biomedical and clinical science rest.

Historical blunders: how toxicology got the dose-response relationship half right.

Substantial evidence indicates that reliable examples of hormetic dose responses in the toxicological literature are common and generalizable across biological model, endpoint measured and chemical class. Further evaluation revealed that the hormetic dose response model is more common than the threshold dose response model in objective, head-to-head comparisons. Nonetheless, the field of toxicology made a profound error by rejecting the use of the hormetic dose response model in its teaching, research, risk assessment and regulatory activities over nearly the past century. This paper argues that the hormetic dose response model (formerly called the Arndt-Schulz Law) was rejected principally because of its close historical association with the medical practice of homeopathy as a result of the prolonged and bitter feud between traditional medicine and homeopathy. Opponents of the concept of hormesis, making use of strong appeals to authority, were successful in their misrepresentation of the scientific foundations of hormesis and in their unfair association of it with segments of the homeopathic movement with extreme and discreditable views. These misrepresentations became established and integrated within the pharmacology and toxicology communities as a result of their origins in and continuities with traditional medicine and subsequently profoundly impacted a broad range of governmental risk assessment activities further consolidating the rejection of hormesis. This error of judgment was reinforced by toxicological hazard assessment methods using only high and few doses that were unable to assess hormetic responses, statistical modeling processes that were constrained to deny the possibility of hormetic dose response relationships and by the modest nature of the hormetic stimulatory response itself, which required more rigorous study designs to evaluate possible hormetic responses.

[Gutiérrez Bueno (1745-1822), textbooks and a new public for chemistry in the last third of the 18th century]. / Pedro Gutiérrez Bueno (1745-1822), los libros de texto y los nuevos pùblicos de la química en el último tercio del siglo XVIII.

This paper is a part of a general research project on the role that chemistry played in the transition of materia medica to experimental pharmacology during 19th century Spain. Within this general framework, the paper deals with the main characteristics of Spanish textbooks aimed at pharmaceutical and medical students. In a former study, published in this journal, we outlined the institutional context in which these books were read, written and published. Some of these issues are developed in the present paper through analysis of the "Curso de química" written by Pedro Gutiérrez Bueno. New light is shed on the public for chemistry during the late XVIII century Spain and their role in shaping the contents and organisation of chemistry textbooks.

[Laqueur and Organon. The university laboratory and the pharmaceutical industry in the Netherlands]. / Laqueur en Organon. Het universitaire laboratorium en de farmaceutische industrie in Nederland.

Since the 1970s cooperation between universities and pharmaceutical firms is business as usual. This has not always been the case. The first alliances between academic scientists and the pharmaceutical industry can be traced back to the 1920s. Compared to the U.S. and most other European countries, the creation of networks between the Dutch academy and industry shows a rather peculiar pattern that is illustrative in clarifying how the relationships between scientists and the pharmaceutical companies were built. Dutch scientists could not ally themselves with the pharmaceutical industry, simply because no Dutch pharmaceutical company specialized in organpreparations existed prior to the 1920s. This situation forced scientists to opt for the strongest form of alliance they could create, namely to take part in the founding of a pharmaceutical company. Ernst Laqueur, a professor in pharmacology at the University of Amsterdam, was one of the three founders of Organon, the Dutch pharmaceutical firm that was founded in 1923. Based on an analysis of the early history of sex endocrinology, this paper examines the creation of networks between Laqueur and Organon. The paper concludes that the university laboratory played a crucial role in the development of Organon. Organon was dependent on Laqueurs laboratory for the provision of the required biological essay techniques in order to manufacture standardized hormone products, Moreover, Laqueur mediated all the contacts between Organon and the clinic, required for the clinical testing of hormones and the provision of raw materials for the making of hormones into chemicals and drugs.

Hormesis: Toxicological foundations and role in aging research.

The field of toxicology adopted the threshold dose response in the early decades of the 20th century. The model was rapidly incorporated into governmental regulatory assessment procedures and became a central feature of chemical evaluation and assessment. The toxicological community never validated the capacity of this model to make accurate predictions throughout the remainder of the 20th century. A series of recent investigations have demonstrated that the threshold and linear dose response model failed to make accurate predictions in the low dose zone. Such findings demonstrate a profound failure by the toxicology community on the central pillar of its discipline and one with profound public health, medical and economic implications. Ironically, the hormetic dose response, which was rejected by the toxicology community during the early decades of the 20th century, accurately predicted responses in the low dose zone in the same three large-scale validation assessments. Within the past two decades hormetic dose responses have been frequently reported in the experimental biogerontology literature, associated with endpoints associated enhancing healthy aging and longevity. The low dose stimulatory response of the hormetic dose response model represents the quantification of enhanced biological performance in the experimental facilitation of aging quality via multiple endpoints and mechanisms and in the extension of lifespan in such animal models research.

[Protomedicato and pharmacy in Castile at the end of the sixteenth century: "Catálogo de las Cosas que los Boticarios han de tener en sus Boticas" (Catalogue of the things that apothecaries must have in their shops), by Andrés Zamudio de Alfaro, Protomédico General (1592-1599)]. / Protomedicato y farmacia en Castilla a finales del siglo XVI: edición crítica del "Catálogo de las Cosas que los Boticarios han de tener en sus Boticas," de Andrés Zamudio de Alfaro, Protomédico General (1592-1599).

In this article we present a catalogue of medicinal products preserved in a manuscript copy among the papers of a druggist who died in Madrid in 1599. This catalogue, whose title expresses its normative character, contains 423 entries and is signed by Andrés Zamudio de Alfaro, Protomédico General of Castile from 1592 until his death in 1599. It was presumably issued by the Real Tribunal del Protomedicato during the last decade of the sixteenth century for the use of the protomédicos and examiners who carried out official visits to apothecaries under the aegis of the Tribunal, in accordance with the royal decrees of 1588 and 1593, and was also distributed among the apothecaries themselves and their suppliers, such as the druggist who possessed the copy edited here. The document offers valuable evidence of the policy of normalization of medical, and specifically pharmaceutical, practice imposed during this period by the State through the Protomedicato.

[History of opium poppy and morphine]. / Opiumsvalmuen og morfin gennem tiderne.

Opium has been known for millennia to relieve pain and its use for surgical analgesia has been recorded for several centuries. The Sumerian clay tablet (about 2100 BC) is considered to be the world's oldest recorded list of medical prescriptions. It is believed by some scholars that the opium poppy is referred to on the tablet. Some objects from the ancient Greek Minoan culture may also suggest the knowledge of the poppy. A goddess from about 1500 BC shows her hair adorned probably with poppy-capsules and her closed eyes disclose sedation. Also juglets probably imitating the poppy-capsules were found in that period in both Cyprus and Egypt. The first authentic reference to the milky juice of the poppy we find by Theophrastus at the beginning of the third century BC. In the first century the opium poppy and opium was known by Dioscorides, Pliny and Celsus and later on by Galen. Celsus suggests the use of opium before surgery and Dioscorides recommended patients should take mandrake (contains scopolamine and atropine) mixed with wine, before limb amputation. The Arabic physicians used opium very extensively and about 1000 AD it was recommended by Avicenna especially in diarrhoea and diseases of the eye. Polypharmacy, including a mixture of nonsensical medications were often used. Fortunately for both patients and physicians many of the preparations contained opium. The goal was a panacea for all diseases. A famous and expensive panacea was theriaca containing up to sixty drugs including opium. Simplified preparations of opium such as tinctura opii were used up to about 2000 in Denmark. In the early 1800s sciences developed and Sertürner isolated morphine from opium and was the founder of alkaloid research. A more safe and standardized effect was obtained by the pure opium. Several morphine-like drugs have been synthesized to minimize adverse effects and abuse potential. Opioid receptors were identified and characterized in binding assays and their localization examined. However, the complexity of the system including interaction with several neurons and transmitters indicate the goal of nonaddictive opiates to be elusive. Combination therapy, innovative delivery systems and long-acting formulations may improve clinical utility.