Gerhard Zbinden, 1924–1993

Hanspeter Witschi1

ITEH, University of California, Davis, One Shields Avenue, Davis, California 95616

Received September 3, 1999; accepted September 7, 1999

"Significance of the LD50 Test for the Toxicological Evaluation of Chemical Substances." Such was the title of a paper published in 1981 in the Archives of Toxicology. The senior author was Gerhard Zbinden. The paper was written as a response to increasing numbers of government regulations in many countries. Determination of the LD50 for an ever-expanding number of chemicals became part of routine toxicity-testing requirements, which often necessitated the use of large numbers of laboratory animals, including higher species such as dogs or monkeys. A critical analysis of this development was called for, particularly as to what extent the LD50 test really was warranted or useful.

According to Zbinden, the LD50 test was first introduced in 1927, when it was used for the standardization of important, but also highly toxic and possibly fatal drugs such as insulin, digitalis extracts, and diphtheria toxins. Because the potency of these drugs might vary among different sources or batches, it was essential to have precise measurements. Chemical methods were, at this time, not yet available. Eventually, determination of the LD50 was used to assess the acute toxicity of chemicals other than just drugs. However, it came to be forgotten as the method designed for the biological standardization of highly active pharmacological agents for which no chemical analytical method was available. Many countries required an LD50 test for a multitude of chemical substances: food additives, cosmetics, pesticides, and industrial chemicals. In one particular country, new drugs required acute LD50 data in rats, mice, dogs, and occasionally also in monkeys by the oral, subcutaneous, and intravenous routes. This produced a waste of animals and, understandably, advocates of decreasing the use of animals in biomedical research strongly and vocally objected to what they considered to be a needless and cruel practice.

In his paper, Zbinden thoroughly analyzed and documented, with numerous citations, the use of the LD50 test. He emphasized that, in most cases, the test could be performed with far fewer animals than was customary at the time, and in many instances the test was actually of no practical value whatever. It did not predict the human lethal dose of a drug or the symptomatology of acute poisoning after overdose. LD50 data were essentially meaningless to the emergency physician. Zbinden stressed that the concept of acute toxicity testing (harmful effects of single doses) was not identical with the classical LD50 test. He strongly recommended the acquisition of additional information in acute term toxicity studies such as clinical chemistry, hematology, histopathology, as well as special tests, for example, functional analyses of subtle neurological changes. These data would yield much more useful information on the toxicity of a drug than simple lethality. Furthermore, he thought that no LD50 test should be done with pharmacologically inert substances. It should suffice to determine that a single parenteral dose of about 2 g/kg or a single oral dose of about 5 g/kg caused no acute symptoms or death of the animals—information that can be obtained with very few animals. The use of large animals (dogs, monkeys) was to be discouraged.

With this well-researched and documented paper, Gerhard Zbinden made an efficient plea for responsible toxicology. He clearly advocated reduction of the use of animals in toxicology, although he never called for complete abolition of animal research; his background in medicine and pathology had taught him that in order to understand disease processes, experiments in integrated biological systems were necessary. However, he strongly advocated the use of intelligent experimental design. Modern methods and concepts in pathology, biochemistry, immunology, and other related disciplines should be used to advantage in order to obtain as much information as possible on pathogenesis and underlying mechanisms in the study of toxicity. As a former colleague of his eloquently pointed out: "Another major goal in Gerhard Zbinden's professional life is also worth mentioning. With great efforts he pleaded for a more meaningful approach in toxicology. Instead of often-meaningless routine experiments, he proposed to design, at every time, suitable experiments. With it went a genuine interest in saving experimental animals, which does not mean that he wanted to completely replace their use with new `alternative' methods. However, this position did not always make him friends, but Gerhard could be a tough discussion partner, who did not avoid argumentation when he was convinced of his goal."

Gerhard Zbinden had a remarkable career in toxicology. He was born close to Bern, Switzerland, where he attended medical school. He obtained further training at the Institute of Pathology and the Children's Hospital at the University of Bern. In 1954, he went to the research laboratories of Hoffmann-La Roche in Basel and in 1959 he was given the opportunity to move to its Research Division in Nutley, New Jersey, where he was to be director of research and vice-president. He became heavily involved there in the development of new, exciting, and important drugs such as librium, valium, and bactrim. It may be assumed that much of what he described in his book, The Source of the River PoWinning, Losing and High Living in Drug Research, reflects his experiences while staying in the highly competitive field of drug development in the U.S. Or, as he states in the preface to the book:

To make a new drug, you need chemists, exceptionally good ones, pharmacologists, microbiologists, and many other "...ists," and lots of luck. But the most precious commodity is time, the only thing that money cannot buy. You hear the clock ticking constantly, reminding you that the life of your drug's patent is getting short, the patience of your management is running out, the money is becoming scarce, and the competitors are catching up. But there are few corners you can cut, and ugly surprises may hit you at any time. You meet lots of people in this business, some brilliant and full of enthusiasm, dedicated friends and clever operators, but also scoundrels of all shapes and colors. The book is about them, the men and women involved in developing and selling new drugs, beginning with Andy Zoller, whose job is similar to the one I once struggled to fill as hard as he does.

And then, of course, comes the usual disclaimer that all is fiction and that any resemblance to real people is unintended and purely coincidental. The book makes delightful reading for its description of good science, human intrigues, idiosyncrasies of managers and lawyers, and also of the wines and other culinary delights of France.

In 1967, Zbinden moved back to Europe, first to the University of Cambridge, England and then, in 1970, to the University of Zurich, Switzerland. At first, his laboratories were in a remodeled apartment, a somewhat unconventional setting. Nevertheless, he assembled a group of enthusiastic collaborators and started an exciting and productive program in experimental toxicology. He was a master in recognizing new important trends in toxicology and developed them long before they became popular. His interests were in the cardiotoxicity of chemotherapeutic agents, the toxicity of food additives, subtle neurological damage that might affect behavior, including exposure occurring during in utero development. He recognized early on the importance of immunotoxicology. In all his research he always was deeply concerned with how to apply laboratory work to the human situation. During this time, he also published a small two-volume work called Progress in ToxicologySpecial Topics, in which he discussed, in an informal yet highly informative way, "everything you always wanted to know about toxicology but were afraid to ask." A later book Menschen, Tiere und Chemie (Man, Animals and Chemicals) dealt more in depth with the problems of toxicology. The book discusses more than 100 chemicals and gives their effects and their toxicological evaluation as examples.

In 1975 he became Director of the Institute of Toxicology in Schwerzenbach, a joint venture between the University of Zurich and the Swiss Federal Institute of Technology. Together with his collaborators, he created a thriving research environment. He was an excellent teacher. He also recognized that the results of basic medical research should be explained and made available to a larger audience than just scientists, and he strived hard to accomplish this goal. He continuously advocated replacing animal experimentation, where feasible, with in vitro techniques. In 1985, he became president of the H. Doerenkamp–G. Zbinden Foundation, which provides stipends to researchers dedicated to the development of alternative experimental methods, particularly in the domain of large animals. As Alan M. Goldberg, Director of the Center for Alternatives to Animal Testing at Johns Hopkins University, said: "He translated the 3R's (reduction, refinement, replacement) of Russell and Burch into the language of the toxicologist."

Gerhard Zbinden died in 1993. He is remembered for his humanity, his professional visions and expertise, and his dedication to contributing to public life and public affairs, as a scientist and as a citizen. A close friend of his for 40 years, Professor Peter G. Waser from the University of Zurich, wrote his obituary.

NOTES

1 For correspondence via fax: (30) 752-5300. E-mail:hrwitschi{at}ucdavis.edu Back

Further Reading

Waser, P. G. (1993). In memory of Gerhard Zbinden (1924–1993), toxicologist (1995). Toxicology 96, 167–171.[ISI][Medline]

Zbinden, G., and Flury-Roversi, M. (1981). Significance of the LD50 test for the toxicological evaluation of chemical substances. Arch. Toxicol. 47, 77–99.[ISI][Medline]

Zbinden, G. (1993). The Source of the River PoWinning, Losing, and High Living in Drug Research, 2nd ed. Haag and Herrchen, Frankfurt, Germany.





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