Introduction - Uppsala Monitoring Centre

see Hart PW in ‘Blood dyscrasias due to drugs and other agents.’ Girdwood RH,
1973. The term ‘agranulocytosis was proposed by Schultz in 1922 and has been
defined as a neutrophil count of less than 0.2 x 109/1. ‘It appears unlikely that
agranulocytosis occurred in any considerable numbers before the year 1922, for, if it
had, expert clinicians of the preceding period would certainly have described it.’
(Kracke & Parker, 1935). Aplastic anaemia was first described by Paul Ehrlich in
1888. It is defined as peripheral pancytopenia occurring in the presence of a
hypoplastic bone marrow with replacement of normal haemopoiesis by fat cells.
Haematological ADRs account for 10% of worldwide withdrawals (Smith, 2006).
Carcinogenicity (Drug introduced–found to be carcinogenic): thorium (1928–
1933), diethylstilboestrol (1938–1938), urethane (1894–1943), Phenacetin (1902 -
1974), chloroform (1831–1976), methapyrilene (1947–1980), danthron (1959–
1985), chloral hydrate (1869–1986) and phenolphthalein (1902–1997).
Carcinogenicity testing in animals started about 1918 when Yamagiva and
Ichikawa applied coal tar experimentally to rabbits’ ears and produced skin
carcinomas (Yamagiva & Ichikawa, 1918). In the 1920s it was proposed that cancer
might be the result of a somatic mutation and from this the study of classical
carcinogens through in vitro and in vivo approaches showed that they yielded
mutants in certain organisms. In 1961 at the National Cancer Institute, the Bioassay
Program started to test chemicals for carcinogenicity. These bioassays lasted for 24
months in rats and approximately 20 months in mice, the results of which were
published over the next 10 years (Weisburger, 1999). Some drugs bind covalently
with DNA resulting in mutagenicity and Dr Ames developed a short–term
mutagenicity test using Salmonella typhimurium in 1970. In Japan over 700
chemicals were tested for mutagenicity and there was a good correlation between
mutagenicity and carcinogenicity, e.g. among 167 kinds of compounds with
mutagenic activity 146 (87%) were carcinogens. Phenacetin was shown to be
mutagenic in 1974 and carcinogenic in 1978 illustrating the longer time needed to
show carcinogenicity (Kawachi, 1980). As evidence that already in the 1930’s
experimental evidence of carcinogenicity obtained in long-term animal tests was
held as predictive of a similar effects in humans (Tomatis, 2006). ‘Most of the early
withdrawals, i.e., before 1970, were related to reports of side-effects in patients.
Since 1970, however, a number of drugs have been discontinued in light of benign
or malignant tumours that appear after chronic exposure in animals. After 1980 all
drug discontinuations have been in association with data from clinical use.’ (Bakke
et al., 1984). The National Cancer Institute’s Bioassay program in 1961 either did
not test or tested but not found a problem with: Phenacetin, chloroform,
methapyrilene, danthron, chloral hydrate and phenolpthalein. The knowledge that
diethylstilboestrol was carcinogenic did not stop its development.
The IARC has placed drugs into four groups:
Group 1 Carcinogenic to humans, e.g. arsenic, thorium and