Health Hazard Studies
1. McDiarmid M, Oliver M et al. Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. JOEM. 2010; 52: 1028-1034.
To determine the frequency of “signature” chromosomal abnormalities in oncology workers handling anticancer drugs.
Peripheral blood from health care personnel (N = 109) was examined with probes for targets on chromosomes 5, 7, and 11. The effect of drug-handling frequency on chromosome abnormalities was assessed.
An excess of structural (0.18 vs 0.02; P = 0.04) and total abnormalities (0.29 vs 0.04; P = 0.01) of chromosome 5 was observed in the high-exposure group compared with the unexposed. Increased incidence rate ratios (IRRs) for abnormalities of chromosome 5 (IRR = 1.24; P = 0.01) and for either chromosome 5 or 7 (IRR = 1.20; P = 0.01) were obtained at 100 handling events. Effect sizes were augmented 2- to 4-fold when alkylating agent handling alone was considered.
Biologically important exposure to genotoxic drugs is apparently occurring in oncology work settings despite reported use of safety practices.
2. Peelen S, Roeleveld N et al. Toxic effects on reproduction in hospital personnel. Netherlands: Elsevier; 1999. (Translation by Interverbum, Gothenburg Sweden from original Dutch)
On the basis of the literature, operating-theatre staff and oncology nurses have been distinguished as the most significant potential at-risk groups with regard to the occurrence of toxic effects on reproduction among hospital personnel in the Netherlands. In previous research, increased risks have been found among them particularly for spontaneous abortion and congenital abnormalities in the offspring.
Evidence was also found in this study of an increased risk of spontaneous abortion in operating-theatre staff, particularly if they have been present at inductions of anaesthesia and Sluder operations, and of an increased risk of congenital abnormalities associated with exposure to anaesthetic gases. There is also found to be an increased risk of premature birth for operating-theatre staff present at the induction of anaesthesia for operations. Evidence was additionally found of a lowered sex ratio among children of theatre staff.
For oncology nurses, this study suggests increased risks of spontaneous abortion and low birth weight of the child which are associated with exposure to cytotoxic agents.
An increased risk of low birth weight of the child is found particularly in nurses working in outpatient clinics and/or involved in the preparation of cytotoxic agents and in cleaning activities. An increased risk of congenital abnormalities in the offspring is also found to exist for oncology nurses who prepare cytotoxic agents.
It is found from the exposure study on the anaesthetic gases nitrous oxide, halothane, isoflurane and sevoflurane in the operating theatres of the hospitals where measurements were performed that the average exposure levels during operations are relatively low and generally below the 8-hour TW A limit values or recommended values for the anaesthetic gases concerned. Evidence nevertheless emerged from the epidemiological study that occupational exposure to anaesthetic gases can result in toxic effects on reproduction in operating-theatre staff. These effects on reproduction are possibly due to high exposures for a short period to anaesthetic gases, which can occur particularly in the induction of anaesthesia for operations and in Sluder operations. However, it must be borne in mind in interpreting the results of this epidemiological study using the data from the industrial hygiene study that the exposure measurements were only carried out for a limited number of anaesthetic gases and cytotoxic agents in a small number of hospitals, which may possibly not be representative of all hospitals in the Netherlands. The effects on reproduction also relate to the period 1990-1997, whereas the exposure data were collected in 1997. The levels of exposure at the start of the nineties may possibly have been substantially higher than the present-day levels of exposure, particularly in hospitals which have taken control measures in the meantime.
It has been demonstrated in the exposure study among oncology nurses that despite protective measures internal exposure to cytotoxic agents takes place. Cytotoxic agents are found more often in the urine of nurses in wards than among nurses in outpatient clinics. Contamination of gloves and of the working environment with cytotoxic agents is also found to occur during various activities. The results of the epidemiological study suggest that exposure to cytotoxic agents plays a role in the risk of toxic effects on reproduction for oncology nurses. The increased risks for nurses who prepare cytotoxic agents in particular can be substantiated by exposure data. The present study also suggests that contamination of the working environment takes place, but the exposure mechanisms are as yet unclear. In order to obtain greater insight into the exposure of oncology nurses to cytotoxic agents, it is important to make source detection more sophisticated, so that specific action can be taken.
3. Sessink PJM, Bos RP. Drugs hazardous to healthcare workers (evaluation of methods for monitoring occupational exposure to cytostatic drugs). A Review Article. Drug Safety. 1999; 20(4): 347-359.
We review the literature concerning possible health risks for individuals (e.g. healthcare workers and pharmaceutical plant employees) occupationally exposed to cytostatic drugs. Cytostatic drugs possess toxic properties and may therefore cause mutagenic, carcinogenic and teratogenic effects. Hence, individuals handling these drugs in the course of their employment may face health risks. For this reason, it is important to monitor occupational exposure to these drugs. An overview of exposure monitoring methods is presented and their value is discussed. Most studies involve nonselective methods for biological monitoring and biological effect monitoring, such as the urinary mutagenicity assay and analysis of chromosomal aberrations and sister-chromatid exchanges in peripheral blood lymphocytes. The disadvantages of these biological methods are that their sensitivity is low and it cannot be proved beyond any doubt that the results found were caused by occupational exposure to cytostatic drugs. For occupational health services it is important to have sensitive and specific methods for monitoring exposure to cytostatic drugs. One of the most promising methods seems to be the determination of cyclophosphamide in urine using gas chromatography-tandem mass spectrometry. Several studies have demonstrated exposure to cyclophosphamide and other cytostatic drugs, even when protective measures were taken and safety guidelines were followed. To estimate the magnitude of any health effects arising from this exposure, we calculated the risk of cancer due to occupational exposure to cyclophosphamide on the basis of available human and animal dose-response data and the amounts of cyclophosphamide found in urine. The initial results show an extra cancer risk for pharmacy technicians and nurses.
4. Valanis B, Vollmer WM, Steele P. Occupational exposure to antineoplastic agents: self-reported miscarriages and stillbirths among nurses and pharmacists. J Occup Environ Med. 1999; 41(8): 632-638.
Insult to the germ cells of an ovum or sperm prior to pregnancy as well as exposures to a fetus during pregnancy can affect the outcome of a pregnancy. Antineoplastic agents are mutagenic and teratogenic, so the potential effects of exposure on reproduction are of concern to the workers who handle them. This study investigates pregnancy loss associated with occupational exposures to antineoplastic drugs by comparing rates of spontaneous abortion and stillbirths for pregnancies without antineoplastic exposure and exposed pregnancies in which the pregnant woman or the father handled antineoplastic agents either before or during the pregnancy. A total of 7094 pregnancies of 2976 pharmacy and nursing staff were examined. After age during pregnancy, prior gravidity, maternal smoking during the pregnancy, and occurrence of a spontaneous abortion or stillbirth in a prior pregnancy were controlled for, exposure of the mother to or the handling of antineoplastic agents during the pregnancy was associated with a significantly increased risk of spontaneous abortion (odds ratio = 1.5; 95% confidence interval, 1.2 to 1.8) and combined risk of spontaneous abortion and stillbirth (odds ratio = 1.4; 95% confidence interval, 1.2 to 1.7) but not stillbirth alone. Among the wives of exposed men, too few stillbirths occurred to allow analysis. However, for spontaneous abortion and any loss, the patterns of increased risk were similar to those seen for women, although the odds ratios were not statistically significant.
5. Labuhn K, Valanis B, Loveday K et al. Nurses´ and pharmacists´ exposure to antineoplastic drugs: findings from industrial hygiene scans and urine mutagenicity tests. Cancer Nurs. 1998; 21(2): 79-89.
Data from 83 nurses and pharmacists handling antineoplastic drugs and 35 nurse/pharmacist controls who participated in a national study of antineoplastic drug-handling risks were examined to investigate antineoplastic drug exposure. Measures of external exposure included self-completion drug logs and industrial hygiene scans conducted in clinical settings. Internal exposure was measured by urine mutagenicity tests on end-of-week 24-hour urine specimens. To control for potential confounders, the staff was asked to complete food and hobby diaries and to avoid identified mutagenic substances for 1 week before collection of 24-hour urine samples. On the scans of the drug handlers, 13% showed one or more spots of drug contamination on gloved and ungloved hands, gowns, or shoes. Of the 24-hour urine samples, 15% were mutagenic for Salmonella typhimurium: Rates did not differ significantly for drug handlers and controls. Among nurses who both prepared and administered antineoplastics, those with positive mutagenicity tests handled more doses of the drugs, used less skin protection, and had more skin contact with the drugs than those with negative tests. Nurses who only administered the drugs and had positive mutagenicity tests handled fewer doses of drugs than those with negative tests, but they also reported less use of protection and more skin contact. For both groups of nurses, skin contact with antineoplastics was associated with positive mutagenicity test results (p < 0.01).
6. Sessink PJM, Kroese ED, van Kranen HJ et al. Cancer risk assessment for healthcare workers occupationally exposed to cyclophosphamide.Int Arch Occup Environ Health. 1995; 67: 317-323.
In the present study a cancer risk assessment of occupational exposure to cyclophosphamide (CP), a genotoxic carcinogenic antineoplastic agent, was carried out following two approaches based on (1) data from an animal study and (2) data on primary and secondary tumors in CP-treated patients. Data on the urinary excretion of CP in health care workers were used to estimate the uptake of CP, which ranged from 3.6 to 18 micrograms/day. Based on data from an animal study, cancer risks were calculated for a health care worker with a body weight of 70 kg and a working period of 40 years, 200 days a year (linear extrapolation). The life-time risks (70 years) of urinary bladder cancer in men and leukemias in men and women were found to be nearly the same and ranged from 95 to 600 per million. Based on the patient studies, cancer risks were calculated by multiplication of the 10-year cumulative incidence per gram of CP in patients by the estimated mean total uptake in health care workers over 10 years, 200 days a year. The risk of leukemias in women over 10 years ranged from 17 to 100 per million using the secondary tumor data (linear extrapolation). Comparable results were obtained for the risk of urinary bladder tumors and leukemias in men and women when primary tumor data were used. Thus, on an annual basis, cancer risks obtained from both the animal and the patient study were nearly the same and ranged from about 1.4 to 10 per million. In The Netherlands it is proposed that, for workers, a cancer risk per compound of one extra cancer case per million a year should be striven for (“target risk”) and that no risk higher than 100 per million a year (“prohibitory risk”) should be tolerated. From the animal and the patient study it appears that the target risk is exceeded but that the risk is still below the prohibitory risk.
7. Hansen J, Olsen JH. Cancer morbidity among Danish female pharmacy technicians. Scand J Work Environ Health. 1994; 20: 22-26.
Pharmacy technicians maintain a substantial production and packing of pharmaceuticals and other chemicals, many of which are carcinogens. This study reports on cancer incidence among Danish female pharmacy assistants and dispensers.
Altogether, 8499 compulsory members were identified in the archives of the Association of Danish Pharmacy Technicians and followed through the files of the Danish Cancer Registry (1970-1990); observed figures were compared with those expected on the basis of national cancer incidence rates.
The overall standardized incidence ratio [SIR] for cancer was 1.0 [N = 219, 95% confidence interval (95% CI) 0.8-1.1]. A 1.5-fold (N = 34; 95% CI 1.1-2.1) elevated risk of nonmelanoma skin cancer was found, especially for long-term pharmacy assistants (N = 15, SIR 2.8, 95% CI 1.6-4.6). An increased risk for non-Hodgkin’s lymphoma appeared among long-term pharmacy dispensers (N = 5, SIR 3.7, 95% CI 1.2-8.9). In the entire group, the risk of tobacco-related tumors was significantly reduced (N = 8, SIRW 0.4, 95% CI 0.2-0.9), together with the probably socioeconomic-associated cervical cancer risk (N = 18, SIR 0.6, 95% CI 0.4-0.9).
Sunlight is usually the dominant cause of nonmelanoma and melanoma skin cancer, but occupational factors may have contributed in this study in view of the uncommon localization observed for many of these cancers and the unelevated melanoma risk. In addition to the increased risk of non-Hodgkin’s lymphomas, which may have been associated with exposure to organic solvents, the results do not indicate any other notable cancer risks during the follow-up.
8. Sessink PJM, Cerna M, Rossner P et al. Urinary cyclophosphamide excretion and chromosomal aberrations in peripheral blood lymphocytes after occupational exposure to antineoplastic agents.Mutat Res. 1994; 309: 193-199.
In this study we have compared the results of a method for the detection of cyclophosphamide in urine and the results of analysis of chromosomal aberrations in peripheral blood lymphocytes of ofur groups of subjects with various exposure statuses. These groups are 17 Dutch and 11 Czech exposed workers (maily hospital nurses and pharmacy technicians) handling antineoplastic agents and 35 Dutch and 23 Czech controls (nurses, medical doctors, pharmacy and lab technicians) not handling these drugs. The groups were subdivided into smokers and non-smokers because of a confounding effect of smoking.
Within the Dutch groups, the percentage of aberrant cells and the number of breaks per cell were increased for smokers compared to non-smokers. The percentage of aberrant cells was increased in Dutch exposed workers in comparison with Dutch control workers. Within the Czech groups the percentage of aberrant cells and the number of break per cell were increased in exposed wotkers in comparison with control workers. However, both Dutch and Czech smokers mainly contributed to the increase. The results suggest an additive effect of exposure and smoking in the Dutch subjects and a more than additive effect in the Czech subjects.
In urine samples of three out of 11 Dutch exposed workers cyclophosphamide was found in a range of View the MathML source. Higher levels were detected in the urine of eight out of 11 Czech exposed workers, a range of View the MathML source. No correlation was observed between the amounts of cyclophosphamide excreted in urine on the one hand and the percentage of aberrat cells and the number of breaks per cell on the other hand.
The present study is the first study showing that hospital workers having an increase in chromosome aberrations related to their work are exposed to at least one antineoplastic agent.
9. Sauere-Cubizolles MJ, Job-Spira N, Estryn-Behar M. Ectopic pregnancy and occupational exposure to antineoplastic drugs. Lancet. 1993; 341: 1169-1171.
The incidence of ectopic pregnancy has risen substantially during the past two decades, but the aetiology of a third of cases remains unknown. We have used data from a survey of nurses in Paris, France, to examine the relation between ectopic pregnancy and various occupational exposures. We studied two groups of women–operating-theatre staff and nurses from other departments. The women were asked about outcomes of all pregnancies and occupational exposure to anaesthetic gases, formol, ionising radiation, and antineoplastic drugs during the first trimester of pregnancy. Of 734 pregnancies reported, 15 (2%) had been ectopic. In chi-square analysis, there were significant associations (p < 0.02) between ectopic pregnancy and exposure to antineoplastic drugs, the woman’s age, and the number of previous pregnancies. Other occupational exposures and working in an operating theatre did not show significant associations. In logistic regression analysis with adjustment for gravidity, the odds ratio (by the exact method) for ectopic pregnancy associated with occupational exposure to antineoplastic drugs was 10.0 (95% CI 2.1-56.2). Because we had only small numbers of ectopic pregnancies, the odds ratios we estimated have wide confidence intervals. Our findings should be confirmed by a larger study specifically designed to investigate the relation between antineoplastic exposure and ectopic pregnancy.
Stucker I, Caillard J-F, Collin R et al. Risk of spontaneous abortion among nurses handling antineoplastic drugs. Scand J Work Environ Health. 1990; 16: 102-107.
Selevan SG, Lindbohm M-L, Hornug RW et al. A study of occupational exposure to antineoplastic drugs and fetal loss in nurses. N Engl J Med. 1985; 313: 1173-1178.
10. Sessink PJM, Scholtes MM, Anzion RBM et al. Determination of cyclophosphamide in urine by gas chromatography-mass spectometry. J Chromatogr B Biomed Appl. 1993; 616: 333-337.
A sensitive gas chromatographic method for the determination of cyclophosphamide in urine is presented. After liquid-liquid extraction with diethyl ether and derivatization with trifluoroacetic anhydride, cyclophosphamide was identified and quantified with mass spectrometry. The method is suitable for the determination of cyclophosphamide at concentrations of more than 0.25 ng/ml, which enables the uptake of cyclophosphamide during occupational activities, such as the preparation and administration of antineoplastic agents in hospitals, to be measured. Simple preparation makes the method appropriate for routine analysis.
11. Valanis B, Vollmer W, Glass A. Acute symptoms associated with antineoplastic drug handling among nurses. Cancer Nurs. 1993; 16(4): 288-295.
Antineoplastic drug handling in the absence of adequate protective measures has been associated with biological uptake of the drugs among pharmacists and nurses. This study investigated the association between occupational exposure to antineoplastics and the presence of acute symptoms in a nationwide sample of 2,048 nurses and nurses’ aides. Reported skin contact with the drugs was associated with a small but statistically significant increase in reported symptoms. Although number of doses handled and extent of protection used were significantly associated with number of symptoms, their effect was not independent of skin contact.
12. Valanis BG, Vollmer WM, Labuhn KT et al. Association of antineoplastic drug handling with acute adverse effects in pharmacy personnel. Am J Health-System Pharm. 1993; 50: 455-462.
The relationship between occupational exposure to antineoplastic drugs and the presence of acute symptoms of exposure was investigated by questionnaire. Data were derived from a questionnaire distributed to 8566 pharmacists, pharmacy technicians, nurses and nurse aides at 57 member institutions of the National Surgical Adjuvant Breast and Bowel Project nationwide. Of the 4659 respondents (54%), 1057 were pharmacists or pharmacy technicians; after exclusions, the sample size was 738. Data were collected on four handling activities: mixing of antineoplastic drugs, administering these drugs, cleaning up spills, and handling patient excreta. Information on mixing was divided into dose, duration, use of protection, and reported skin contact. Respondents indicated which of 27 acute symptoms they had experienced during the past three months.
Handling of antineoplastics was associated with a small but significant increase in the number of symptoms compared with controls; reported skin contact was the most important predictor of symptoms. The number of doses handled and the extent of protection were significantly associated with the number of symptoms, but their effect was not independent of that of skin contact. Body mass was significantly associated with the number of symptoms in women but not men.
Pharmacists and technicians who handle antineoplastic drugs reported more symptoms associated with exposure than did those who do not handle such agents. All available protective measures should be used.
13. Skov T, Maarup B, Olsen J et al. Leukemia and reproductive outcome among nurses handling antineoplastic drugs. Br J Ind Med. 1992; 49: 855-861.
During the past decades conclusive evidence has accumulated that alkylating antineoplastic drugs (ADs) can cause cancer, most notably acute non-lymphocytic leukaemia, and that most ADs are reprotoxic. Studies on health workers handling ADs have shown significantly increased risks for miscarriages (two studies) and malformations (two studies). The present study monitored the risk for cancer and adverse reproductive outcome among Danish nurses handling ADs. No increased risks were found for miscarriages, malformations, low birth weight, or preterm birth among the offspring of nurses handling ADs during pregnancy. The sex ratio was normal. The relative risk (RR) for leukaemia was significantly increased (10.65) but based on only two cases, one of acute myeloblastic and one of chronic myeloid leukaemia. From the available exposure data occupational exposures to ADs were apparently higher in the studies that have reported increased risks for miscarriages and malformations than in the present one. Regarding reproductive outcome the study gives some confidence that the safety measures which were implemented in the oncology departments around 1980 can protect the health personnel against adverse effects of ADs on reproduction. As the study is as yet the only negative one in a well protected setting, it should be followed up by other studies of well protected health personnel handling ADs. The findings concerning the leukaemia risk, although based on small numbers, encourage larger studies.
14. McDonald AD, McDonald JC, Armstrong B et al. Congenital defects and work in pregnancy. Br J Ind Med. 1988; 45: 581-588.
The risk of congenital defect was examined in 47,913 pregnancies of women employed for 15 hours a week or more at time of conception. The rate of defects of all types per 1000 births in this series was 25.0; 1.8 from defects classified as chromosomal (group A), 10.8 as developmental (group B), and 12.5 as musculoskeletal (group C). Some evidence of an excess in the risk ratio (p less than 0.05) was found in the services sector and in four occupations–agriculture and horticulture (2.61), telephone and postal clerks (1.74), a miscellaneous group of service jobs (1.68), and receptionists and information clerks (1.47); excesses of lower statistical significance (p less than 0.1) were found in those engaged in plastics and rubber manufacture (2.02) and in child minders (1.84). There were two cases of tracheo-oesophageal fistula–a rare defect–among eight defects (1.32 expected) in agriculture and horticulture. Overall, the distribution of risk ratios in the 60 occupations examined was not significantly heterogeneous. Analysis of chemical exposure profiles for each occupational group showed no evidence of any increased risk, perhaps due to lack of sensitivity and discrimination in this method of exposure estimation. In 152 pregnancies of doctors and nurses who had administered antineoplastic drugs in the first month eight defects, miscellaneous in type, were observed compared with 4.05 expected (p = 0.05). Special study of musculoskeletal defects and work demands showed some evidence of an association with a long working week (greater than or equal to 46 hours) but no other ergonomic factor. With these few exceptions the survey failed to identify appreciable risk of congenital defect related to occupation.
Hemminki K Kyyronen P, Lindlohm ML. Spontaneous abortions and malformations in the offspring of nurses exposed to anaesthetic gases, cytostatic drugs, and other potential hazards in hospitals, based on registered information of outcome. J Epidemiol Community Health. 1985; 39: 141-147.
15. Sotaniemi EA, Sutinen S, Arranto AJ et al. Liver damage in nurses handling cytostatic agents. Acta Med Scand. 1983; 214: 181-189.
Three consecutive head nurses developed liver injury after years of handling cytostatic drugs. They had neurological symptoms associated with elevated serum alanine amino-transferase (ALAT) and alkaline phosphatase (ALP) levels. Liver histology showed portal hepatitis with piecemeal necrosis in one of them, the others had hepatic fibrosis and fat accumulation. The subjects’ livers were metabolically active as reflected by adaptive and toxic changes in cellular ultrastructure. After withdrawal of the drugs, serum ALAT and ALP values fluctuated between normal and 2-3 times elevated. Follow-up biopsies demonstrated an increase in collagen fibres and a decrease in microsomal enzyme activity, as reflected by arylhydrocarbon hydroxylase activity in vitro. The findings suggest that handling of cytostatic drugs may insidiously damage the liver, which, with time, seems to lead to irreversible fibrosis.