Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 3) Radiation Marrow aplasia is a major acute sequela of radiation. Radiation damages DNA; tissues dependent on active mitosis are particularly susceptible. Nuclear accidents can involve not only power plant workers but also employees of hospitals, laboratories, and industry (food sterilization, metal radiography, etc.), as well as innocents exposed to stolen, misplaced, or misused sources. While the radiation dose can be approximated from the rate and degree of decline in blood counts, dosimetry by reconstruction of the exposure can help to estimate the patient's prognosis and also to protect medical personnel from contact with radioactive tissue and excreta. MDS and leukemia, but probably not aplastic anemia, are late effects of radiation. Chemicals Benzene is a notorious cause of bone marrow failure. Vast quantities of epidemiologic, clinical, and laboratory data link benzene to aplastic anemia, acute leukemia, and blood and marrow abnormalities. The occurrence of leukemia is roughly correlated with cumulative exposure, but susceptibility must also be important, as only a minority of even heavily exposed workers develop benzene myelotoxicity. The employment history is important, especially in industries where benzene is used for a secondary purpose, usually as a solvent. Benzene- related blood diseases have declined with regulation of industrial exposure. Although benzene is no longer generally available as a household solvent, exposure to its metabolites occurs in the normal diet and in the environment. The association between marrow failure and other chemicals is much less well substantiated. Drugs (Table 102-3) Many chemotherapeutic drugs have marrow suppression as a major toxicity; effects are dose-dependent and will occur in all recipients. In contrast, idiosyncratic reactions to a large and diverse group of drugs may lead to aplastic anemia without a clear dose-response relationship. These associations rested largely on accumulated case reports until a large international study in Europe in the 1980s quantitated drug relationships, especially for nonsteroidal analgesics, sulfonamides, thyrostatic drugs, some psychotropics, penicillamine, allopurinol, and gold. Not all associations necessarily reflect causation: a drug may have been used to treat the first symptoms of bone marrow failure (antibiotics for fever or the preceding viral illness) or provoked the first symptom of a preexisting disease (petechiae by nonsteroidal anti-inflammatory agents administered to the thrombocytopenic patient). In the context of total drug use, idiosyncratic reactions, while individually devastating, are rare events. Chloramphenicol, the most infamous culprit, reportedly produced aplasia in only about 1/60,000 therapy courses, and even this number is almost certainly an overestimate (risks are almost invariably exaggerated when based on collections of cases; although the introduction of chloramphenicol was perceived to have created an epidemic of aplastic anemia, its diminished use was not followed by a changed frequency of marrow failure). Risk estimates are usually lower when determined in population-based studies; furthermore, the low absolute risk is also made more obvious: even a ten- or twentyfold increase in risk translates, in a rare disease, to but a handful of drug-induced aplastic anemia cases among hundreds of thousands of exposed persons. Table 102- 3 Some Drugs and Chemicals Associated with Aplastic Anemia Agents that regu larly produce marrow depression as major toxicity in commonly employed doses or normal exposures: Cytotoxic drugs used in cancer chemotherapy: alkylating agents , antimetabolites, antimitotics, some antibiotics Agents that frequently but not inevitably produce marrow aplasia: Benzene Agents associated with aplastic anemia but with a relatively low probability: Chloramphenicol Insecticides Antiprotozoals: quinacrine and chloroquine, mepacrine Nonsteroidal anti-inflammatory drugs (including phenylbutazone , indomethacin, ibuprofen, sulindac, aspirin) Anticonvulsants (hydantoins, carbamazapine, phenacemide, felbamate) Heavy metals (gold, arsenic, bismuth, mercury) Sulfonamides: some antibiotics, antithyroid drugs (methimazole, met hylthiouracil, propylthiouracil), antidiabetes drugs (tolbutamide, chlorpropamide), carbonic anhydrase inhibitors (acetazolamide and methazolamide) Antihistamines (cimetidine, chlorpheniramine) D-Penicillamine Estrogens (in pregnancy and in high doses in animals) Agents whose association with aplastic anemia is more tenuous: Other antibiotics (streptomycin, tetracycline, methicillin, mebendazole, trimethoprim/sulfamethoxazole, flucytosine) Sedatives and tranquilizers (chlorpromazine, prochlo rperazine, piperacetazine, chlordiazepoxide, meprobamate, methyprylon) Allopurinol Methyldopa Quinidine Lithium Guanidine Potassium perchlorate Thiocyanate Carbimazole Note: Terms set in italic show the most consistent associatio n with aplastic anemia. . Chapter 102. Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes (Part 3) Radiation Marrow aplasia is a major acute sequela. radioactive tissue and excreta. MDS and leukemia, but probably not aplastic anemia, are late effects of radiation. Chemicals Benzene is a notorious cause of bone marrow failure. Vast quantities. epidemiologic, clinical, and laboratory data link benzene to aplastic anemia, acute leukemia, and blood and marrow abnormalities. The occurrence of leukemia is roughly correlated with cumulative