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Preliminary Communication

INFERTILITY IN MALE PESTICIDE WORKERS

DONALD WHORTON

University of California, Berkeley

RONALD M.KRAUSS

Endocrinology Service, Alta Bates Hospital, Berkeley

SUMNER MARSHALL

Department of Urology, Alta Bates Hospital, Berkeley, and University of California, San Francisco

THOMAS H.MILBY

Environmental Health Associates, Berkeley, California, U.S.A.

Summary A number of cases of infertility were discovered among men working in a California pesticide factory. The suspected cause was exposure to the chemical 1,2-dibromo-3-chloropropane (D.B.C.P.). The major effects, seen in 14 of 25 non-vasectomised men, were azoospermia or oligospermia and raised serum-levels of follicle-stimulating hormone and luteinising hormone. No other major abnormalities were detected, and testosterone levels were normal. Although a quantitative estimation of exposure could not be obtained, the observed effects appeared to be related to duration of exposure to D.B.C.P.

INTRODUCTION

MALE infertility can result from pathological pro-

Reprinted with permission from Lancet 2(8051):1259–61, Copyright 1977, The Lancet Ltd.



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Environmental Medicine: Integrating a Missing Element into Medical Education Preliminary Communication INFERTILITY IN MALE PESTICIDE WORKERS DONALD WHORTON University of California, Berkeley RONALD M.KRAUSS Endocrinology Service, Alta Bates Hospital, Berkeley SUMNER MARSHALL Department of Urology, Alta Bates Hospital, Berkeley, and University of California, San Francisco THOMAS H.MILBY Environmental Health Associates, Berkeley, California, U.S.A. Summary A number of cases of infertility were discovered among men working in a California pesticide factory. The suspected cause was exposure to the chemical 1,2-dibromo-3-chloropropane (D.B.C.P.). The major effects, seen in 14 of 25 non-vasectomised men, were azoospermia or oligospermia and raised serum-levels of follicle-stimulating hormone and luteinising hormone. No other major abnormalities were detected, and testosterone levels were normal. Although a quantitative estimation of exposure could not be obtained, the observed effects appeared to be related to duration of exposure to D.B.C.P. INTRODUCTION MALE infertility can result from pathological pro- Reprinted with permission from Lancet 2(8051):1259–61, Copyright 1977, The Lancet Ltd.

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Environmental Medicine: Integrating a Missing Element into Medical Education COMPARISON OF NON-VASECTOMISED D.B.C.P. WORKERS WITH VERY LOW (GROUP A) AND NORMAL (GROUP B) SPERM-COUNTS* Group No. of subjects Age (yr) Exposure (yr) Sperm-count (×106/ml) F.S.H. (mI.U./ml) L.H. (mI.U./ml) Testosterone (ng/dl) A 11 32·7±1·6† 8·0±1·2‡ 0·2±0·1§ 11·3±1·8‡ 28·4±3·3† 459±35 B 11 26·7±1·2† 0·08±0·02‡ 93±18 2·6±0·4‡ 14·0±2·8† 463±31 *All results given as mean±standard error of mean. ‡Difference between groups A and B significant at P<0·001. †Difference between groups A and B significant at P<0·01. §9 workers with 0 sperm/ml, 2 with 1×106/ml. cesses affecting production or transport of sperm. Infection, trauma, varicocele, cryptorchidism, exposure to toxic agents, and autoimmunity have all been cited as causes of male infertility, but in many cases the cause is unknown.1 We have investigated infertility observed in a group of men working in a California pesticide factory. Although the connection has not been proved beyond doubt, the cause in these cases seems to be exposure to the nematocide, 1,2-dibromo-3-chloropropane (D.B.C.P.). BACKGROUND The company employing the affected men manufactures fertilisers and ammonia, and it formulates pesticides for agricultural and household use. In the latter process, workers mix, dilute, and repackage technical-grade pesticides obtained from primary chemical manufacturers. Some 100 different chemicals are used in the formulation of approximately 200 different products, including organophosphorus compounds, halogenated hydrocarbons, and carbamates. The products manufactured or formulated vary with market demand. Since 1962 the company has regularly formulated D.B.C.P. in a special agricultural chemical division (A.C.D.). For several years before the infertility was brought to our attention men working in the A.C.D. had become increasingly aware that few of them had recently fathered children. After a preliminary evaluation of 5 men had revealed oligospermia or azoospermia, other male employees were studied in more detail. METHOD Subjects All 39 employees in the A.C.D. took part in the study. There were 3 supervisors, 24 production workers, 4 maintenance mechanics, 2 clerks, and 6 laboratory workers. 36 of the group were men, 11 of whom had had vasectomies. There was no way of determining exact differences in chemical exposure received by the production workers, since they were assigned interchangeably to different tasks. Thus, only the length of time they had worked in the A.C.D. could be used as a measure of exposure. Procedure Each of the 39 employees was asked to complete a medical-history questionnaire, and one of us (D.W.) then asked each subject specific questions about his or her reproductive system. All participants were also examined thoroughly. Semen samples were obtained from all non-vasectomised men and were promptly taken to the laboratory for determination of sperm-count, motility, and morphology. Other laboratory tests done on all 39 subjects included urinalysis, complete and differential blood counts, blood chemistry, T3-resin uptake, and assays for serum-levels of thyroxine, testosterone, follicle stimulating hormone (F.S.H.), and luteinising hormone (L.H.). The last four tests were done by radioimmunoassay. All the analyses were performed by the clinical and endocrine laboratories of Alta Bates Hospital. Early in the investigation it became apparent that infertility was associated with length of time worked in the A.C.D. To examine the relationship between exposure duration and sperm-count, we first excluded from our original group 3 women, 11 vasectomised men, and 3 men with sperm-counts between 10 million and 30 million. This left 11 men with indisputably low sperm-counts (≤1 million, group A) and 11 men with normal sperm-counts (≥40 million, group B). We then compared these two groups by age, time worked in the A.C.D., and serum L.H., F.S.H., and testosterone levels. After the preliminary evaluations, bilateral open testicular biopsies were performed on 9 volunteers representing a spectrum of chemical-exposure times and sperm-counts within the A.C.D. RESULTS None of the 3 women had had abnormal menstrual cycles, and all had borne children. None of the men had loss of libido, difficulty with erection or ejaculation, loss or altered distribution of facial or body hair, testicular atrophy, epididymal abnormalities, gynæcomastia, or abnormalities of the prostate. 3 had varicoceles, but all 3 had previously fathered children. 7 of the 36 men had never fathered children. Some of the production workers had occasional symptoms, such as mild headache, nausea, light-headedness, and weakness, when formulating some organophosphorus pesticides. Symptoms due to irritation of the upper respiratory tract were also mentioned by some as being associated with their work in the manufacture of certain thiocarbamate compounds. No other important information was brought to light by the history or physical examination of any of the subjects. The few hepatic, renal, hæmopoietic, and thyroid abnormalities revealed by laboratory studies were consistent with previous medical problems. The relationship of length of chemical exposure (time of employment) to sperm-count was striking (see table). Workers with sperm counts ≤1 million had been exposed at least three years. None with sperm-counts above 40 million had been exposed for more than three months. The 2 men in group A (see table) who were not azoospermic showed great reduction of sperm motility and increases in abnormal forms. Sperm motility and morphology were normal in all the men in group B. The mean age in group A was slightly higher than in group B, but differences in testicular function would not be expected to result from this small age difference. The mean level of F.S.H. was significantly higher in group A—a finding consistent with the severe impairment in spermatogenesis in these individuals.1,2 F.S.H. levels in group B were in a range comparable with those in a larger, unexposed population of male employees from elsewhere in the company who are now being studied. Group A also had a higher mean L.H. level. This also probably represents a response to testicular damage, although serum-testosterone levels were comparable in the two groups. Thus, the stimulus for the increase in L.H. is not known. Studies are planned to evaluate testi-

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Environmental Medicine: Integrating a Missing Element into Medical Education cular and pituitary hormone production in these workers. The 2 women workers not currently using oral contraceptives had normal F.S.H. and L.H. results. Preliminary evaluation of the testicular-biopsy results of the severely affected men indicated loss of spermatogonia, with no evidence of inflammation or severe fibrosis. The 3 men not included in the comparison who had sperm-counts of 10 million–30 million had exposures between one and three years—an observation that supports the notion of a direct relationship between length of exposure and degree of oligospermia. DISCUSSION Chemically reduced male infertility related to occupation has seldom been reported. Lancranjan et al.3 reported that lead-poisoned workers had lowered sperm-counts, decreased sperm motility, and a higher propertion of abnormal forms. Diminished libido and difficulty in erection and ejaculation were also found. Kepone, an organochlorine insecticide, severely poisoned workers in Virginia in 1975. Most of the affected workers had severe neurological abnormalities, and some were also reported to be infertile.4 The chemical suspected in the present investigation to be the cause of infertility had previously been shown to produce sterility in animals. D.B.C.P. was shown by Torkelson et al.5 to be toxic to the testes of rats, guineapigs, and rabbits. In the rat testis it caused degeneration of the seminiferous tubules, increase in Sertoli cells, reduced sperm-count, and abnormal sperm morphology. Rats with these effects also showed hepatic and renal degeneration. D.B.C.P. was found to produce these changes through skin absorption as well as ingestion or inhalation. Faidysh et al.6 showed that D.B.C.P. damaged the testes, liver, and kidneys of rats, but these organs regenerated in the survivors. Airborne concentrations of D.B.C.P. in the factory we investigated are believed to be lower than the 1 p.p.m. limit recommended by Torkelson et al.5 D.B.C.P. levels measured in early 1977 in the A.C.D. were 0·4 p.p.m. (averaged for an eight-hour day). These measurements were made with personal air-sampling devices.7 Research is being continued at this plant, together with studies in other areas. Follow-up studies of the affected workers are being planned. Our findings have raised a number of important issues. One is the significance of duration and intensity of exposure. Although all severely affected workers (group A) were, or had been, production workers for at least three years, the shortest time of exposure associated with oligospermia was only one year. Another question is whether the observed sterility is reversible in man as it has been shown to be in animals. Finally, since D.B.C.P. is carcinogenic in animals8 and mutagenic in bacterial systems,9 the possibility of such damage in man must also be considered seriously. How big a problem D.B.C.P.-induced infertility is we do not yet know, but our communications with medical officers of other companies manufacturing D.B.C.P. clearly indicate that it extends beyond the formulating plant described here. This study would not have been possible without the support and cooperation of the Occidental Chemical Company, Western Division, and the Oil, Chemical, and Atomic Workers Union, Local 1–5. We thank Dr William Palmer, Dr Louis Brahen, and Dr Edward Smuckler for advice on pathology, Dr John Linfoot for assistance with endocrine assays, and Dr Ken Dod, Claire Lalor, and Mary Ann Gustavson for administrative support. Requests for reprints should be addressed to D.W., 2521 Channing Way, University of California, Berkeley, California 94720, U.S.A. REFERENCES 1. Amelar, R.D., Dubin, L., Walsh, P.C. Male Infertility. Philadelphia, 1977. 2. Odell, W.D., Swerdloff, R.S. West. F. Med. 1976, 124, 446. 3. Lancranjan, I., Popescu, H.I., Gavanescu, O., Klepsch, I., Servanescu, M. Archs envir. Hlth, 1975, 30, 396. 4. Zavon, M. Personal communication. 5. Torkelson, T.R., Sadek, S.E., Rowe, V.K., Kodama, J.K., Anderson, H.H., Loquvam, G.S., Hine, C.H. Toxicol. appl. Pharmac. 1961, 3, 545. 6. Faidysh, E.V., Rakhmatullaev, N.N., Varshavskii, V.A. Medskii Zh. Uzbek. 1970, 1, 64. 7. Rappaport, S., Spear, R. Personal communication. 9. Olson, W.A., Habermann, R.T., Weisburger, E.K., Ward, J.M., Weisburger, J.H. F. natn. Cancer Inst. 1973, 51, 1993. 9. Rosenkranz, H.S. Bull envir. Contam. Toxicol. 1975, 14, 18. 10. Scharnweber, C., Joyner, R. Personal communication.