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OSHA Hazard Information Bulletins
Dimethylformamide and Testicular Cancer


February 17, 1988

MEMORANDUM FOR:

REGIONAL ADMINISTRATORS

THRU:

  • LEO CAREY
  • Director
  • Office of Field Programs

FROM:

  • EDWARD BAIER
  • Director
  • Directorate of Technical Support

SUBJECT:

  • Health Hazard Information Bulletin: Dimethylformamide and Testicular Cancer

Information sent to the Occupational Safety and Health Administration from the Almalgamated Clothing and Textile Workers Union (ACTWU) indicated that germinal cell testicular cancer has now been identified in leather tanning and aircraft workers exposed to dimethylformamide (DMF).

Incidence of germ cell tumors has been reported among aircraft repairmen in the Journal of Urology as well as leather tanners in the Lancet. Potential Worker exposure may occur through skin absorption and/or inhalation. CSHO's should be on the look-out for possible DMF exposures involving aircraft repair and leather tanning as well as other operations where DMF may be used.

Attached are the following (2) references:

  1. Ducatman, A.M., Conwill, D.E., and Crawl, J., Germ Cell Tumors of the Testicle Among Aircraft Repairmen, The Journal of Urology, Vol. 136, October 86, p.p. 834-836.
  2. Levin, S.M., et. al., Testicular Cancer in Leather Tanners Exposed to Dimethylformamide, The Lancet, No. 8568, Vol. II, November 14, 1987, p. 1154.

Attachments

GERM CELL TUMORS OF THE TESTICLE AMONG AIRCRAFT REPAIRMEN

Alan M. Ducatman, David E. Conwill* and James Crawl From the Departments of Occupational Health and Preventive Medicine, Navy Environmental Health Center, Norfolk, Virginia

ABSTRACT

A cluster of testicular germ cell tumors occurred among 3 of 153 white men who worked in a shop engaged in repair of exterior surfaces and electrical components of the airframes of F4 Phantom Jet aircraft. Evaluation of an occupationally identical shop at a second F4 rework facility at which there had been no previous reports of excess neoplasms revealed 4 additional men with a history of testicular germ cell tumors (p less than 0.01, Poison, compared to the expected number of cases based on national incidence rates). Our investigation raises but does not prove a hypothesis of association between subsequent development of testicular germ cell cancer and history of extensive exposure to a mixture containing dimethylformamide, which had been used in F4 repair work at these facilities in the 1960s and 1970s. This represents the first report of 2 corresponding mini-epidemics of testicular tumors among workers in occupationally identical industrial settings.

A report of several men with testicular germ cell tumors at a Navy aircraft exterior surface repair workplace triggered an onsite health hazard evaluation. This investigation led, in turn, to surveys of 2 additional airframe repair shops at different geographic locations -1 at which the same type of aircraft (F4 Phantom Jets) was repaired and 1 at which such repair had never been done. At neither of the latter 2 facilities had any questions of excess neoplasms been raised.

The average annual age-adjusted incidence of testicular germ cell tumors in the United States is approximately 5 in 100,000 white men of working age (20 to 64 years), with a peak incidence of about 10 in 100,000 white men 20 to 29 years old. (1) Of concern, the incidence among young men in the United States and other developed countries has been suggested to have been increasing for the last few decades. (1,2)

Risk factors for testicular germ cell tumors include cryptorchidism, testicular atrophy, other urogenital developmental abnormalities, family history of urogenital abnormalities, and history of inguinal hernia, mumps orchitis and, possibly, prenatal diethylstilbestrol exposure. (2-5) Black men appear far less likely to have testicular germ cell tumors than white men. (1,2) Other hypothesized risk factors include maternal hyperemesis gravidarum, prenatal ionizing radiation exposure, rural residence, exposure to pesticides or unrefined petroleum products, testicular trauma and elevated testicular temperature that might result from wearing jockey-type undershorts, or traumatic and heat-generating activities, such as bicycle or horseback riding. (6-10)

Only 2 time-and-space clusters of testicular germ cell tumors have been reported previously in the medical literature: 1 among students and graduates of a podiatry school and the other among a group of 52 neighbors in a small town. (11,12) Neither cluster had an evident etiology. No industrial cluster has been identified previously and no cluster of testicular germ cell tumors has been investigated by further sampling of similarly employed populations elsewhere.

MATERIALS AND METHODS

Preliminary evaluation of the reported cluster of cases at facility A and inquiries about the occurrence of other types of tumors were done before our investigation by personnel from the Naval Hospital serving the facility. Populations at 2 additional facilities, designated facilities B and C, with no initial reports of any excess cancer then were surveyed to identify potential cases. Facility B was selected for comparison because it is the only Navy facility other than facility A at which exterior airframe repair on F4 Phantom Jet aircraft has been done. In contrast, major airframe structural repair of F4 Phantom Jet aircraft has been done at facility C. Interviews with workers (including all identified cases), supervisors and medical personnel at the facilities covered medical and occupational histories, possible independent risk factors, and potential workplace and life-style exposures. Present and historical worksite practices at all facilities were investigated with site visits and reviews of industrial hygiene data.

A case was defined as any employee working at an airframe repair facility at least 3 years before the onset of signs or symptoms leading to a documented histopathological diagnosis of testicular germ cell cancer. Three years were chosen as the shortest reasonable latency for a hypothesized environmental cancer, as in other reports. (11) Medical records and histopathological documentation were reviewed for all cases. Questionnaire and interview attempts also were made to identify any historical cases in retired or deceased workers. Denominator/employee census data during the years of interest were provided by management at the facilities. Of particular interest in the analysis are denominator data concerning white male workers because all cases identified were among these groups and because black subjects appear far less likely to have germ cell tumors of the testes. (1,2)

RESULTS

Tables 1 to 3 reveal case findings for the facilities surveyed. At facility A, 3 of 153 white men employed in the F4 airframe repair shop were confirmed to have had testicular germ cell tumors from 1981 to 1983. All 3 men met our case definition. Only 1 other man with a confirmed history of testicular germ cell tumor was found from the remainder of the entire facility (a total of 3,200 employees, with 2,450 white men of working age). This individual, a 46 year-old sheet metal, worker, had noticed symptoms of embryonal carcinoma within 1 year of his (Missing pages 835-836.)

THE LANCET TESTICULAR CANCER IN LEATHER TANNERS EXPOSED TO DIMETHYLFORMAMIDE

Sir, - We describe here three cases of testicular malignancy in leather tanner workers who did essentially the same job in the same plant during the same period. Testicular cancer is the most common malignancy among white men aged 15-44.(1) Age-adjusted mortality in the United States has not varied in the past 40 years, but the incidence in whites has almost doubled.(2) These three men worked as swabbers on the spray lines in the leather finishing process and, after latency periods of 8, 13, and 14 years, testicular cancers developed with common histological features. Dimethylformamide (DMF) may have been responsible.

Case 1.- At 32 years of age this man developed a painful, nodular swelling of the right testis in May, 1982, 13 years after his first exposure as a swabber. He underwent testicular biopsy and orchiectomy, and histological analysis revealed an embryonal cell carcinoma. Retroperitoneal dissection revealed evidence of metastatic disease, histologically identical with the testicular tumor, in two of thirteen excised lymph-nodes. There have been no signs of further metastatic disease. This man worked as a swabber at three other tanneries from 1969 to 1975, before his employment at the plant from 1975 to 1979. His job entailed spreading liquid dyes onto leather hides on a conveyer belt. The dyes were applied by three spray guns about 60 cm "upstream" of the swabbers and about 45 cm above the belt.

The hides passed under an exhaust hood before reaching the swabbers, who used felt-bottomed paddles to spread the dyes over the leather. The men had to lean over the hide, with their faces close to the leather. They wore no gloves and contamination of skin and clothing by liquid dye was virtually continuous. During spray-line operations at the plant in question, a fine mist was present in the air, accompanied by a strong, solvent-like odor which was said to be detectable up to 200 meters from the tannery. General ventilation was provided only by windows; these were usually kept open, except in winter. This man had not had mumps and he had no history of testicular abnormalities at birth, inguinal hernia, or unusual testicular trauma. His mother denied having received X-ray examinations or taking diethylstilboestrol (DES) during pregnancy.

Case 2.- In April, 1984, at the age of 36 this man was admitted to the hospital with a small, painful nodular growth on the right testis, 14 years after beginning work on the spray line. After radical orchiectomy the tumour was found to be a combined embryonal cell carcinoma and seminoma. Excision of retroperitoneal lymph-nodes found no evidence of metastasis, and he has shown no evidence of disseminated disease since surgery. He was a working forman on the same spray line at the plant, filling in from about 2 hours a day while the swabbers took breaks, but he supervised the line throughout the working day. He maintained and cleaned the spray guns every day and repaired them when they became clogged. He began spray-line work at the plant in 1970 and has been a supervisor since 1974. He could recall no testicular injury and had not had mumps. There was not history of maternal DES use. His mother could not recall whether she had received diagnostic X-rays during pregnancy.

Case 3.- In March, 1984, at the age of 25 this man had an occasionally tender lump on his left testicle. A radical left orchiectomy was performed; the tumour was an embryonal cell carcinoma with foci of choriocarcinoma. One of six excised nodes was positive for metastasis, and the clinical course has been marked by metastasis to lungs and mediastinum, treated with chemotherapy and radiotherapy. He had begun spray-line work at another plant in 1976, and in 1978 he began employment in the plant where all three cases worked. He had had his right kidney removed in 1979 after a motorcycle accident. He denied trauma to the testes. He had had mumps at age 8, without clinically evident orchitis. His mother denied DES use and could not recall receiving diagnostic X-rays while pregnant.

The health and safety staff of the Amalgamated Clothing and Textile Workers Union identified a wide range of dyes and solvents in the plant and in the other tanneries. All the tanneries used DMF, which became the focus of concern in light of the report by Ducatman et al (3) in 1986, who found clusters of embryonal cell carcinoma of the testis in two aircraft repair facilities among mechanics who had worked extensively with DMF.

DMF and its metabolite monomethylformamide cause testicular damage in laboratory animals, (4,5) and workplace exposure to DMF had been reported to be associated with increased chromosomal aberrations.(6) Kommineni (7) reported one embryonal cell carcinoma of the testis in nine mice exposed to DMF.

1983 National Occupational Exposure Survey data suggest that there are over 100,000 workers in the United States exposed to DMF currently or in the past decade in the production of paint, fibers, and pharmaceuticals and as a solvent for pesticides and other materials. The identification of clusters of testicular cancers of the same cell type in two separate populations working with DMF in different industrial settings may represent a sentinel health event.(8) Worker (and consumer) exposure to DMF-containing materials should be reduced to the extent technically feasible until further epidemiological and toxicological investigation of its carcinogenic potential is completed.

STEPHEN M. LEVIN DEAN B. BAKER PHILIP J. LANDRIGAN SUSAN V. MONAGHAN

Division of Environmental and Occupational Medicine, Department of community Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA

ERIC FRUMIN MITCHELL BRAITHWAITE WILLIAM TOWNE

Amalgamated Clothing and Textile Workers Union, New York

  1. Young JL, Percey CL, Asire AJ. Surveillance, epidemiology, and end results: Incidence and mortality data, 1973-1977. Nat Cancer Inst Manager 1981; no. 57.
  2. Schottenfeld D, Warshauer ME, Sherlock S, et al. The epidemiology of testicular cancer in young adults. Am J Epidemal 1980; 112:232-46.
  3. Ducatman AM, Conwill D, Crawl J. Germ cell tumors of the testicle among aircraft repairmen. J Urol 1986; 136:834-836.
  4. Barlow SM, Sullivan FM. Reproductive hazards of industrial chemicals. London: Academic Press, 1982:346-54.
  5. Pham HC, Nguyen X, Azum-Gelade MC. Toxicological study of formamide and its derivatives N-methyl and N-ethyl. Therapie 1971;26:409-24.
  6. Berger H, Haber I, Wunscher G, Bittersohl G. Epidemiologische Untersuchungen zur Dimethylformamidexposition. Z Gesamte Hyg 1985;31:366-69.
  7. Kommineni C. Pathologic studies of aflatoxin fractions and dimethyl-formamide in MRC rats. Dissertation thesis. Lincoln: University of Nebraska, 1972.
  8. Rutstein DD, Mullan RJ, Frazier TM, et al. Sentinel health events (occupational): a basis for physician recognition and public health surveillance. Am J Publ Health 1983;73:1054-62.
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