Anilinas vs. organofosforados: la implicación de la empresa Bayer en las polémicas en torno al Síndrome del Aceite Tóxico / Anilines vs. organophosphates: the involvement of the Bayer company in the controversies surrounding the Toxic Oil Syndrome

La aparición de la intoxicación alimentaria en España en el año 1981, causante del Síndrome del Aceite Tóxico, unido a la imposibilidad de encontrar la toxina responsable de la enfermedad, potenció la posibilidad de señalar otros agentes causales, en particular un pesticida organofosforado de la casa Bayer, Nemacur. Se desarrolló así una línea alternativa a la decisión oficial, liderada por los médicos Antonio Muro y Luís Frontela, particularmente defendida, en España, por la empresa editorial Grupo 16. La polémica traspasó las fronteras españolas y se difundió a través de los medios de comunicación alemanes; los miembros del grupo político Los Verdes/Die Grünen tuvieron especial interés en servir de amplificador a estas suposiciones. La llegada de esta ola de acusaciones a Alemania, a principios de febrero de 1985, fue el detonante que alarmó a la empresa Bayer y le obligó a dar explicaciones para evitar poner en peligro la imagen corporativa de la multinacional química de Leverkusen. La documentación conservada en los archivos de la empresa alemana aporta nueva luz sobre esta polémica (AU)

Organophosphorus Compounds at 80: Some Old and New Issues.

One of the major classes of pesticides is that of the organophosphates (OPs). Initial developments date back almost 2 centuries but it was only in the mid-1940s that OPs reached a prominent status as insecticides, a status that, albeit declining, is still ongoing. OPs are highly toxic to nontarget species including humans, the primary effects being an acute cholinergic toxicity (responsible for thousands of poisoning each year) and a delayed polyneuropathy. Several issues of current debate and investigation on the toxicology of OPs are discussed in this brief review. These include (1) possible additional targets of OPs, (2) OPs as developmental neurotoxicants, (3) OPs and neurodegenerative diseases, (4) OPs and the "aerotoxic syndrome," (5) OPs and the microbiome, and (6) OPs and cancer. Some of these issues have been debated and studied for some time, while others are newer, suggesting that the study of the toxicology of OPs will remain an important scientific and public health issue for years to come.

Synthesis of tetraethyl pyrophosphate (TEPP): from physician Abbot and pharmacist Riegel to chemist Nylen.

Tetraethyl pyrophosphate (TEPP) made history not only as the first man-made organophosphate cholinesterase inhibitor but also as a most successful commercial product traded under a good number of names. The substance was first synthesized by a Russian chemist, Wladimir Petrovich Moshnin, while studying in Paris as an eleve (student) of Wurtz. The synthesis was soon thereafter repeated and reported to the Academy of Sciences by Philippe de Clermont, another student of Wurtz, who acknowledged the earlier work of Moshnin. Holmstedt in his chapter dealing with the beginnings of organophosphate chemistry in Koelle's Textbook Cholinesterases and Anticholinesterase Agents concluded his remarks by noting that after the initial synthesis by Moshnin and de Clermont, over the years, a good half-a-dozen of other pharmacists and chemists also managed the feat (of synthesizing TEPP). This led to my attempts at identifying those involved in the synthesis of TEPP. The compiled list turned out to be quite long: Abbot (1879), Riegel (1896), Cavalier (1906), Rosenheim A, Stadler & Jacobsohn (1906), Rosenheim & Pritze (1908), Balareff (1914), Nylen (1930), Arbusow & Arbusow (1931), Schrader (1938), Woodstock (1946) and Toy (1948). This report while summarizing the synthetic approach used in obtaining TEPP by the respective scientists mainly attempts to shed light on the life of the less known pharmacists and chemists involved in the synthesis of TEPP. The focus is on the pre-industrial synthesis period ending with Nylen largely because details on the Arbusow family, as well as on Schrader and Toy are fairly well known or have recently been described.

Anticholinesterase insecticide retrospective.

The anticholinesterase (antiChE) organophosphorus (OP) and methylcarbamate (MC) insecticides have been used very effectively as contact and systemic plant protectants for seven decades. About 90 of these compounds are still in use - the largest number for any insecticide chemotype or mode of action. In both insects and mammals, AChE inhibition and acetylcholine accumulation leads to excitation and death. The cholinergic system of insects is located centrally (where it is protected from ionized OPs and MCs) but not at the neuromuscular junction. Structural differences between insect and mammalian AChE are also evident in their genomics, amino acid sequences and active site conformations. Species selectivity is determined in part by inhibitor and target site specificity. Pest population selection with OPs and MCs has resulted in a multitude of modified AChEs of altered inhibitor specificity some conferring insecticide resistance and others enhancing sensitivity. Much of the success of antiChE insecticides results from a suitable balance of bioactivation and detoxification by families of CYP450 oxidases, hydrolases, glutathione S-transferases and others. Known inhibitors for these enzymes block detoxification and enhance potency which is particularly important in resistant strains. The current market for OPs and MCs of 19% of worldwide insecticide sales is only half of that of 10 years ago for several reasons: there have been no major new compounds for 30 years; resistance has eroded their effectiveness; human toxicity problems are still encountered; the patents have expired reducing the incentive to update registration packages; alternative chemotypes or control methods have been developed. Despite this decline, they still play a major role in pest control and the increasing knowledge on their target sites and metabolism may make it possible to redesign the inhibitors for insensitive AChEs and to target new sites in the cholinergic system. The OPs and MCs are down but not out.

[From metabolism to comparative biochemistry of toxic organophosphorus compounds. To the 100th anniversary from the birth of V. I. Rozengart].

The main stages of the scientific biography of Professor Victor losifovich Rozengart are exposed: his works on muscle bioenergetics, discovery of the pathway of creatinine synthesis, his development of novel concepts of pathways of metabolism of organophosphorus xenobiotics, creation of biochemical grounds of selective toxicity as well as studies in the new field whose one of its founders he is--comparative biochemistry of toxic organophosphorus compounds.

Diagnóstico de intoxicação por organofosforados baseado em quadro clínico / Organophosphate intoxication diagnosis based on clinical present

Os organofosforados são compostos agrotóxicos, de ampla comercialização no Brasil, que inibem a enzima acetilcolinesterase, levando a sintomas muscarínicos e nicotínicos, além de possíveis manifestações do sistema nervoso central (SNC). Na rotina de atendimento em Toxicologia, preconiza-se a identificação do agente para tomada de medidas específicas. Contudo, em casos de intoxicações por organofosforados, a peculiaridade do quadro clínico pode ser suficiente para o diagnóstico correto.Apresentamos revisão bibliográfica e relato de caso como ilustração do quadro clínico e levantamento dos casos atendidos no Ceatox-79 (Centro de Atendimento Toxicológico de Marília/SP) no ano de 2007.No caso atendido foi possível realizar o diagnóstico com base no quadro clínico da paciente, que se iniciou com sinais inespecíficos e evoluiu com a apresentação de sinais nicotínicos, possibilitando a conduta adequada. As intoxicações por agrotóxicos, principalmente por anticolinesterásicos, como os organofosforados, apresentam alta incidência. Apesar disso, ainda é escassa a quantidade de referências bibliográficas sobre o assunto, que também não é enfatizado em níveis acadêmico e profissional.

History of organophosphate synthesis: the very early days.

The early days of ether chemistry can be divided into two periods: before and after Williamson serendipitous discovery (1851) of a new and efficient way to produce ethers using ethyl iodide and potassium salts. In the early part of the 19th century however, before Williamson, the direct reaction between the "spirit of wine" (ethanol) and acids was the only method of generating the elusive "ethers". This brief report looks at the pharmacists-chemists involved in the quest to produce phosphoric acid ether in the pre-Williamson period (Boudet, Boullay, Lassaigne, Pelouze), paving the way for Voegeli's synthesis of triethyl phosphate (TEP) in 1848.

The synthesis of phosphor ethers: who was Franz Anton Voegeli?

The synthesis of the first organophosphate cholinesterase inhibitor (tetraethyl pyrophosphate, TEPP) is credited to the French organic chemist Philippe de Clermont (1831-1921) and to the Russian chemist Wladimir P. Moshnin from Moscow, both working in the laboratories of Adolphe Wurtz in Paris. In his publications de Clermont describes however not only the TEPP synthesis but also that of the related compound triethyl phosphate (TEP). TEP was previously synthesized by the Swiss chemist Franz Anton Voegeli (1825-1874), working in the laboratory of Gustav Magnus in Berlin. While TEPP is a potent organophosphate cholinesterase inhibitor with an IC50 in the low nanomolar range, TEP has no anticholinesterase activity up to millimolar concentrations. Therefore de Clermont and Moschnin are indeed the fathers of the first organophosphate cholinesterase inhibitor (TEPP), but are not entitled to claim paternity of the first compound in the class of phosphoric acid esters (TEP), an honor which belongs to Franz Anton Voegeli.