La Vecchia Carlo, Turati Federica, Negri Eva
Department of Clinical Sciences and Community Health, University of Milan.
Unit of Medical Statistics and Biometry, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano.
Eur J Cancer Prev. 2022 Jan 1;31(1):64-72. doi: 10.1097/CEJ.0000000000000658.
The thyroid peroxidase inhibiting compounds methimazole, methylthiouracil, propylthiouracil, thiouracil (i.e. 'antithyroid' drugs) and ethylenethiourea have been associated to thyroid tumours in rodents. According to a systematic review by the International Agency for Research on Cancer (IARC) published in 2000, evidence for the human carcinogenicity was inadequate.
We performed an up-to-date systematic review of human epidemiological studies on the association between such compounds and thyroid cancer incidence or mortality.
The literature research (1999-March 2020) identified four relevant articles. Considering also reports from the previous IARC review, this systematic review considered seven reports (five distinct studies) on antithyroid drugs and two on ethylenethiourea. As for antithyroid drugs, three reports based on different follow-ups gave results from a cohort of patients treated for hyperthyroidism in 1946-1964. In the earlier report, thyroid cancer incidence was higher in patients primarily treated with antithyroid drugs (3.2/1000) than in those originally treated with thyroidectomy (0.34/1000) or radioactive iodine (0.88/1000), which can be explained by the higher frequency of subsequent thyroidectomy, and hence the higher chance of cancer detection, in that group (30 vs. 0.5 and 1.2%). The two subsequent reports found no deaths from thyroid cancer among patients treated exclusively with antithyroid drugs through 1990 and 2014. A nested case-control study found an odds ratio (OR) of thyroid cancer of 2.79 [95% confidence interval (CI), 0.78-10.02, from a 2-year lag analysis] for ≥3 vs. no propylthiouracil prescriptions. The increased risk can be attributed to advanced diagnosis of an underlying cancer, as suggested by the stronger association observed in a no-lag analysis (OR, 8.03). In a historical cohort of newly diagnosed hyperthyroid patients, the hazard ratio for treatment with radioactive iodine vs. thionamides only was 0.45 (95% CI, 0.21-0.99), possibly due to the closer surveillance of patients receiving thionamides only. Two case-control studies did not find any association with the use of antithyroid drugs. As for ethylenethiourea, no thyroid cancer cases were found in a historical cohort of 1929 workers occupationally exposed in a 15-year period and no association with proxies of mancozeb exposure (a fungicide whose main metabolite is ethylenethiourea) was detected in a cohort of >236 000 farmers.
There is no evidence for a relevant role of either antithyroid drugs or ethylenethiourea on thyroid cancer.
甲状腺过氧化物酶抑制化合物甲巯咪唑、甲基硫氧嘧啶、丙基硫氧嘧啶、硫氧嘧啶（即“抗甲状腺”药物）和乙撑硫脲已被证实与啮齿动物的甲状腺肿瘤有关。根据国际癌症研究机构（IARC）2000年发表的一项系统评价，关于这些化合物对人类致癌性的证据并不充分。
我们对关于此类化合物与甲状腺癌发病率或死亡率之间关联的人类流行病学研究进行了最新的系统评价。
文献研究（1999年至2020年3月）共识别出4篇相关文章。结合IARC之前综述中的报告，本系统评价共纳入了7篇关于抗甲状腺药物的报告（5项不同研究）和2篇关于乙撑硫脲的报告。对于抗甲状腺药物，3篇基于不同随访的报告给出了1946年至1964年接受甲亢治疗患者队列的结果。在较早的报告中，主要接受抗甲状腺药物治疗的患者甲状腺癌发病率（3.2/1000）高于最初接受甲状腺切除术（0.34/1000）或放射性碘治疗（0.88/1000）的患者，这可能是因为该组随后进行甲状腺切除术的频率较高，因此癌症检测的机会也更高（分别为30%、0.5%和1.2%）。随后的两篇报告发现，在1990年至2014年期间，仅接受抗甲状腺药物治疗的患者中没有甲状腺癌死亡病例。一项巢式病例对照研究发现，≥3次与未开具丙基硫氧嘧啶处方相比，甲状腺癌的比值比（OR）为2.79[95%置信区间（CI），0.78 - 10.02，来自2年滞后分析]。风险增加可能归因于潜在癌症的早期诊断，无滞后分析中观察到的更强关联（OR，8.03）表明了这一点。在一组新诊断的甲亢患者的历史队列中，放射性碘治疗与仅使用硫代酰胺类药物治疗的风险比为0.45（95%CI，0.21 - 0.99），这可能是因为仅接受硫代酰胺类药物治疗的患者受到了更密切的监测。两项病例对照研究未发现与使用抗甲状腺药物有任何关联。对于乙撑硫脲，在一个15年期间职业暴露的1929名工人的历史队列中未发现甲状腺癌病例，并且在一个超过236,000名农民的队列中未检测到与代森锰锌暴露指标（一种主要代谢产物为乙撑硫脲的杀菌剂）的关联。
没有证据表明抗甲状腺药物或乙撑硫脲在甲状腺癌中起相关作用。
