Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
NTP Monogr. 2019 Mar(5). doi: 10.22427/NTP-MGRAPH-5.
Many cancer chemotherapy agents are known carcinogens, genetic toxicants, and developmental toxicants. Secondary malignancies, such as therapy-related acute myeloid leukemia, are caused by cancer chemotherapy agents administered to patients for the treatment of cancer. Occupational exposure to these agents was first documented in the 1970s and continues to occur, despite the issuance of safe handling guidelines in 1980s.
Based on the evidence of carcinogenicity and genetic toxicity associated with direct administration of cancer chemotherapy agents and current evidence of occupational exposure, the National Toxicology Program (NTP) conducted a systematic review to: (1) evaluate whether occupational exposure (e.g., medical, manufacturing, research, and veterinary) is associated with any adverse health outcomes in humans, and (2) summarize the prevalence and levels of chemotherapy agents in the workplace as measured by environmental monitoring and biomonitoring for possible worker exposures.
The evaluation was conducted following the Office of Health Assessment and Translation (OHAT) method. A literature search was performed up to February 23, 2017, using PubMed, Embase, Scopus, Toxline, and Web of Science. Relevant human studies were data extracted and assessed for risk of bias. Bodies of evidence were assessed to develop confidence ratings and level-of-evidence conclusions that reflect the certainty in the evidence that occupational exposure to cancer chemotherapy agents are associated with health effects on a per outcome basis.
The literature search and screening process identified 110 epidemiological studies relevant to assessing possible adverse health outcomes. Most studies addressing health outcomes evaluated potential DNA damage (n = 66; specifically, structural chromosomal aberrations (CA) and micronucleus (MN) induction and comet assay endpoints) and spontaneous abortion (n = 16). In addition to DNA damage, groups of studies were identified to evaluate the potential association between occupational exposure to cancer chemotherapy agents and adverse health outcomes, including cancer (three studies) and adverse effects on reproduction (30 studies). Additional health outcomes included acute effects, immune effects, and liver and kidney toxicity. One hundred seventy-one studies were identified to assess workplace exposure based on reporting of environmental contamination (107 studies) and urine and/or blood monitoring of these agents (82 studies).
NTP concluded that there is a moderate level of evidence that occupational exposure to chemotherapy agents is associated with increased incidence of spontaneous abortion, particularly when evaluating studies of nursing and pharmacy personnel. NTP also concluded that there is a moderate level of evidence that exposure to chemotherapy agents in the workplace is associated with genetic toxicity in humans based on consistent reports significantly higher levels of structural CA (% of cells with CA and number of CA), MN induction (number of cells with MN and number of MN) and DNA damage measured by comet assay (% tail DNA, tail length, tail moment, and DNA damage index) in exposed personnel. There was inadequate evidence for NTP to reach level-of-evidence conclusions on the remaining health outcomes, including cancer, primarily due to few studies per outcome and heterogeneity in the data. Despite current safety guidelines, cancer chemotherapy agents were commonly detected in environmental samples of the workplace (e.g., surface wipes and air sampling) and biosamples (e.g., urine or blood) of workers handling these agents, including data collected as recently as 2014 to 2016. Considering the potential for occupational exposure to these agents and the association between exposure and DNA damage and spontaneous abortions, there is a continued need to reduce exposures through training in safe handling procedures and provision and use of personal protective equipment and associated safety containment equipment. Health surveillance of occupationally exposed personnel would also benefit from improved exposure characterization methods, such as use of daily diaries that are assessed and validated to estimate exposure levels and additional environmental monitoring and biomonitoring data that include analytical chemistry approaches to assess multiple agents. There is also a need to better understand the sources (i.e., activities or physical locations) of worker exposure, especially in settings that have not been adequately studied (e.g., home care, veterinary clinics).
许多癌症化疗药物是已知的致癌物、遗传毒物和发育毒物。继发性恶性肿瘤，如治疗相关的急性髓系白血病，是由用于治疗癌症的癌症化疗药物引起的。职业接触这些药物最早记录于20世纪70年代，尽管在20世纪80年代发布了安全处理指南，但此类接触仍在继续发生。
基于与直接使用癌症化疗药物相关的致癌性和遗传毒性证据以及当前职业接触的证据，美国国家毒理学计划（NTP）进行了一项系统评价，以：（1）评估职业接触（如医疗、制造、研究和兽医领域）是否与人类的任何不良健康结果相关，以及（2）总结通过环境监测和生物监测测量的工作场所化疗药物的流行情况和水平，以确定可能的工人接触情况。
按照健康评估与转化办公室（OHAT）的方法进行评估。截至2017年2月23日，使用PubMed、Embase、Scopus、Toxline和Web of Science进行文献检索。提取相关人体研究的数据并评估偏倚风险。评估证据主体以得出置信度评级和证据水平结论，这些结论反映了职业接触癌症化疗药物与每种结果的健康影响相关的证据的确定性。
文献检索和筛选过程确定了110项与评估可能的不良健康结果相关的流行病学研究。大多数涉及健康结果的研究评估了潜在的DNA损伤（n = 66；具体而言，结构染色体畸变（CA）和微核（MN）诱导以及彗星试验终点）和自然流产（n = 16）。除了DNA损伤外，还确定了几组研究来评估职业接触癌症化疗药物与不良健康结果之间的潜在关联，包括癌症（三项研究）和对生殖的不良影响（30项研究）。其他健康结果包括急性影响、免疫影响以及肝脏和肾脏毒性。确定了171项研究，基于环境污染报告（107项研究）以及对这些药物的尿液和/或血液监测（82项研究）来评估工作场所接触情况。
NTP得出结论，有中等水平的证据表明职业接触化疗药物与自然流产发生率增加有关，特别是在评估护理和药房人员的研究时。NTP还得出结论，有中等水平的证据表明工作场所接触化疗药物与人类遗传毒性有关，这基于一致的报告，即接触人员中结构CA（有CA的细胞百分比和CA数量）、MN诱导（有MN的细胞数量和MN数量）以及通过彗星试验测量的DNA损伤（尾DNA百分比、尾长、尾矩和DNA损伤指数）的水平显著更高。NTP没有足够的证据就包括癌症在内的其余健康结果得出证据水平结论，主要原因是每个结果的研究较少且数据存在异质性。尽管有当前的安全指南，但在工作场所的环境样本（如表面擦拭物和空气采样）以及处理这些药物的工人的生物样本（如尿液或血液）中仍普遍检测到癌症化疗药物，包括2014年至2016年最近收集的数据。考虑到职业接触这些药物的可能性以及接触与DNA损伤和自然流产之间的关联，持续需要通过安全处理程序培训以及提供和使用个人防护设备及相关安全防护设备来减少接触。职业接触人员的健康监测也将受益于改进的接触特征描述方法，例如使用经过评估和验证以估计接触水平的每日日记以及包括分析化学方法以评估多种药物的额外环境监测和生物监测数据。还需要更好地了解工人接触的来源（即活动或物理位置），特别是在尚未充分研究的环境中（如家庭护理、兽医诊所）。
