NTP monograph on the systematic review of occupational exposure to cancer chemotherapy agents and adverse health outcomes.

Introduction: 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.

Objectives: 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.

Methods: 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.

Results and evidence synthesis: 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).

Discussion and conclusions: 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).