*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.).
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.
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.
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.
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-