Eula Bingham PhD John Zapp PhD deceased

2 Experimental Toxicology

Experimental toxicology, as we know, it followed the rise of organic chemistry, which is usually dated at around 1800. The rise was very rapid, and it is estimated that by 1880 some 12,000 compounds had been synthesized, and of these some turned out to be very toxic, in some cases proving fatal to the chemists who prepared them. Two of the war gases employed on a large scale in World War I, that is, phosgene (COCl2) and mustard gas, bis(b-chloroethyl) sulfide, had been prepared in 1812 and 1822, respectively.

Early organic chemists were not deliberately looking for poisons, but for dyes, solvents, or pharmaceuticals. For example, toxicity was an unwanted side effect, but if it was there, it had to be recognized. The sheer number of new organic compounds synthesized in the laboratory, along with a growing public disapproval of the practice of letting toxicity be discovered by its effects on people, led to a more extensive use of convenient and available animals such as dogs, cats, or rabbits as surrogates for human beings, much as some of the ancient kings used dogs instead of slaves to test their food before they dined.

Loomis (5) credits M. J. B. Orfila (6) with being the father of modern toxicology. A Spaniard by birth, Orfila studied medicine in Paris. According to Loomis:

He is said to be the father of modern toxicology because his interests centered on the harmful effects of chemicals as well as therapy of chemical effects, and because he introduced quantitative methodology into the study of the action of chemicals on animals. He was the author of the first book devoted entirely to studies of the harmful effects of chemicals (6). He was the first to point out the valuable use of chemical analyses for proof that existing symptomatology was related to the presence of the chemical in the body. He criticized and demonstrated the inefficiency of many of the antidotes that were recommended for therapy in those days. Many of his concepts regarding the treatment of poisoning by chemicals remain valid today, for he recognized the value of such procedures as artificial respiration, and he understood some of the principles involved in the elimination of the drug or chemical from the body. Like many of his immediate followers, he was concerned primarily with naturally occurring substances for which considerable folklore existed with respect to the harmfulness of such compounds.

A reading of some of the earlier nineteenth century reports indicates a lack of recognition of and concern with either intraspecies or interspecies variation. Sometimes it is not possible to determine from the report which species of animal was tested. Some reports were based on dosage of only one animal, it being assumed that all others would react similarly. In reports of inhalation toxicity, a lethal concentration might be identified without designating the length of the exposure time.

The initial recognition of biological variability comes from the study of the action of drugs rather than from the study of the action of chemicals as such. The increased interest in the action of drugs resulted from the availability of so many new organic compounds that could be explored for possible therapeutic activity.

In the second half of the nineteenth century, the phenomenon of biological variability was recognized by pharmacologists, as was also the necessity for establishing the margin of safety between a therapeutically effective dose and a toxic dose of a drug. Clinical trials of new drugs with adequate controls began to be accepted as good science. The traditional wisdom and beliefs about therapeutic practice were reexamined by pharmacologists.

Early European efforts are credited by Warren Cook to Gruber (7) who used animals and himself in 1883 to set the boundaries for carbon monoxide poisoning. Lehmann and his colleagues (8) performed toxicity testing on numerous compounds using animals, and these provided the basis for establishing many exposure limits. Korbert (9) provided dose response data on acute exposures for twenty substances that gave information on levels that produced minimal symptoms after several hours, / to 1 hour exposures without serious disturbances, and / to 1 hour exposures that range from dangerous to rapidly fatal to man and animals. Many of these evaluations are still valid today.

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