Anti-diphtheria immunization combining Schick testing and active immunization with Toxin-Antitoxin Mixture commenced in Britain in 1920. However, the practice was restricted to residential institutions in London, Birmingham, Bristol, Manchester, Edinburgh, Glasgow, and Aberdeen, and supervised by local medical authorities, the Ministry of Health, and personnel attached to the Wellcome Research Laboratories. From 1922 to 1925, active immunization with antitoxin extended to include elementary schools in Edinburgh, Aberdeen, Birmingham, and Cardiff, and to infant welfare centres in the London boroughs of Holborn, Westminster, and Camberwell. However, antitoxin mixtures never found a commercial outlet in Britain as health authorities there considered the serums ‘potentially unsafe’. Reticence to adopt antitoxin on a mass scale in Britain lay with the fact that the safety, or otherwise, of antitoxin, relied heavily on the production of a neutralized toxin. Failure to adhere to this formula at the production stage, or indeed any subsequent mishandling of toxin-antitoxin, could and had proved to have lethal consequences.

In 1919, an error during the production of toxin-antitoxin in a Dallas laboratory resulted in the production of a toxic mixture. Whether due to inexperience or accident, the addition of toxin to the toxoid in two stages, rather than the recommended one stage process, resulted in a Danyze phenomenon, and the production of an unequal, un-neutralized mixture. When the toxic mixture was utilized in an immunization scheme, 45 children experienced severe reactions, and five fatalities ensued. In 1924, in the towns of Concord and Bridgewater, Massachusetts, a single bottle of toxin- antitoxin caused severe reactions in 40 children. Although many hundreds of children received treatment with serum from the same batch, health authorities discovered that the affected children all received serum from the same bottle. Subsequently, William Park, found that the suspect bottle was stored below freezing point: thereby altering its chemical composition. Alternate freezing and thawing gave rise to a local concentration of the preservative Phenol, causing a destruction of the antitoxin, resulting in an unbalanced toxic mixture.

In Europe, the administration of a local preparation, issued as toxinantitoxin, resulted in six infant fatalities at a children's home in Baden, near Vienna, in 1925. In this case, an investigation conducted by the Hygienic Institute found that due to a laboratory error, technicians omitted to add the necessary antitoxin control, and the serum issued contained pure toxin only.