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attribution in man has finally to be based on epidemiological studies. The principal mechanisms are:

• Alteration ofDNA (genotoxicity, mutagenicity). Many chemicals or their metabolites act by causing mutations, activating oncogenes; those substances that are used as medicines include griseofulvin and alkylating cytotoxics. Leukaemias and lymphomas are the most common malignancies.

• Immunosuppression.The immune system has a role in suppressing cancers (immune surveillance). A wide range of cancers develop in immunosuppressed patients, e.g after organ transplantation and cancer chemotherapy.

• Hormonal. Long-term use of oestrogen replacement in postmenopausal women induces endometrial cancer.

Combined oestrogen/progestogen oral contraceptives may both suppress and enhance cancers (see pp. 719, 723).

Diethylstilbestrol caused vaginal adenosis and cancer in the offspring of mothers who took it during pregnancy in the hope of preventing miscarriage. It was used for this purpose for decades after its introduction in the 1940s, on purely theoretical grounds. Controlled therapeutic trials were not done and there is no valid evidence of therapeutic efficacy. Male fetuses developed nonmalignant genital abnormalities.

Carcinogenesis due to medicines requires that drug exposure be prolonged,13 i.e. months or years; the cancers develop most commonly over 3-5 years and often years after treatment has ceased.

Incidence of second cancers in patients treated for primary cancer can be as high as 15 times the normal rate. The use of immunosuppression in, e.g. rheumatoid arthritis and organ transplants, also increases the incidence of cancers.

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