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Effect of pesticides on testicular function
STERILITY-FERTILITY
EFFECT OF PESTICIDES ON TESTICULAR FUNCTION SUMNER
MARSHALL,
M.D.
DONALD
WHORTON,
M.D.
RONALD
M. KRAUSS,
M.D.
WILLIAM
S. PALMER,
M.D.
From the Department of Urology, University of California School of Medicine, San Francisco; the Department of Industrial Medicine, University of California, Berkeley; and the Departments of Urology, Endocrinology, and Pathology, Alta Bates Hospital, Berkeley, California
- Marked impairment of spermatogenesis was found in a group of men exposed to the pesticide 1,2-dibromo&chloropropane (DBCP), demonstrated by semen analyses, testicular biopsies, and hormone studies. The ramifications of the use of this pesticide are discussed.
ABSTRACT
The spermatogenic tubules are vulnerable to the effects of heat, temporary devascularization (as in torsion of the testes), radiation, mumps virus, and to many drugs.l Laboratory animal experiments have demonstrated the toxic effects of certain pesticides on the spermatogenic tubules.2 However, the possible relevance of this toxicity to humans was not brought to light until recently when the workers in the pesticide section of a chemical plant in Northern California became aware that very few of them had sired children during their employment. When these men were initially examined by one of the authors (D. W.), moderate to marked depression of their fertility status was found. At that time, the plant was manufacturing many different chemical compounds. As a result of epidemiologic investigations carried out in this chemical plant and others in the country, 1,2-dibromo-3-chloropropane (DBCP) was believed to be the compound most likely causing the impairment in testicular function. 3
In an attempt to correlate exposure time to DBCP with measurable aberrations in testicular anatomy and function, serum levels of follicle-
/ MARCH 1978 / VOLUME
XI, NUMBER
3
l-3 YRS
<3MO
NO OF CASES sp$f,R~&
Material and Methods
UROLOGY
stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were determined in the 38 male and 3 female workers exposed to the chemicals. The semen of the 27 nonvasectomized men was analyzed. Ten of the men (including both vasectomized and nonvasectomized men) underwent testicular biopsies. The results of endocrine evaluation, semen analyses, and testicular biopsies showed that the longer the subjects studied were exposed to the chemical DBCP, the greater was the impairment in testicular function. No measurable
13 8?ZMILLION/ml
>3YRS
2 ZOMILLION/ml
11
O-1
MILLION/ml
FIGURE 1. Progressive decrease in sperm count in men with longer exposure to DBCP is shown. After three years most had complete absence of sperm in ejaculate.
FIGURE 2. Testicular biopsies illustrate decreased spermatogenic activity with prolonged chemical exposure. Note near total absence of spet-matogonia in testis after three years of exposure.
abnormalities were found in the 3 women studied. The men working in the laboratory, using appropriate precautions against risk of exposure, had no apparent change in their fertility status. Those who worked less than three months in the pesticide section had no apparent depression in their sperm count. However, marked spermatogenic impairment was present in all of the men tested who had had at least three years of direct exposure to DBCP (11 cases). This was reflected by sperm counts of less than 1 million per cc. of ejaculate. Indeed, in 9 of them, there was complete absence of sperm (Fig. 1). Results of the testicular biopsies also showed a close correlation between exposure time and degree of impaired spermatogenesis. No obvious damage was seen in the biopsied testicular tissue of men having been exposed to DBCP three months or less. Decreased spermatogenic activity was seen in those samples from men exposed to the chemical for more than
30
500
[IIz1 >3YRS 20
0 FSH
LH
TESTOSTERONE
0
FIGURE 3. Comparison of mean values of FSH, LH, and testosterone in men with exposure time under three months and over three years. Note prominent increase in FSH levels, with marked, though appreciable increase in LH levels in men exposed to DBCP for more than three years.
258
twelve months. Spermatocytes and spermatogonia were almost totally absent in the men who had been exposed to it for three years or longer. No obvious changes were noted in the histology of the Sertoli or Leydig cells (Fig. 2). One man who had worked for a three-year period in the pesticide formulations section of the plant but had been assigned to another section in the plant for the most recent three years had a normal sperm count, although his testicular biopsy showed some peritubular fibrosis as well as decrease in the number of spermatogonia. FSH and LH levels were increased in the men with marked spermatogenic impairment secondary to the long-standing exposure. Testosterone levels were not changed appreciably (Fig. 3). Comment Male fertility status is difficult to establish objectively since conception is dependent on both male and female fertility. Semen analysis provides the most objective method to determine fertility level in the male; nevertheless, much discrepancy exists in the literature regarding what constitutes a normal semen.4’5 However, it is generally agreed that true oligospermia exists when the count is below 20 million per cc. But as long as any amount of normal motile sperm is present, impregnation can theoretically be achieved. The function of the testes is twofold: endocrine and spermatogenic. The sources of hormones, the interstitial or Leydig cells, are more resistant to the effect of toxic substances than the spermatogenic tubules. As a result, germinal aplasia may exist, without any apparent disturbance to the interstitial cells. In the cases reported herein, the degree of disruption of testicular anatomy was closely correlated with the length of exposure to the suspect chemical DBCP. From the testicular
UROLOGY
/ MARCH1978
/ VOLUMEXI,
NUMBER3
tissue biopsy it is difficult to be certain about the degree of recoverability of the spermatogenie function; yet, as noted, one man had a normal sperm count three years after having left the area of exposure (although his testicular biopsy did show some impairment of spermatogenie activity). The results of testicular biopsies done on the men who had recent exposure to DBCP showed evident impairment in sperm production. The workers also underwent extensive multisystem evaluations: no consistent aberration was noted except in the effect of the toxic substance on the spermatogenic tubules. Possible ramifications of the pesticide exposure are open to speculation. Questions must be raised as to the possible effect of the suspect chemical not only on the workers in this chemical plant but also on farm workers. Also, could residual levels in produce have a perceptible effect on the consumer? Late effects of DBCP in man are unknown. A mechanism is being set up by the chemical industry and certain
UROLOGY
I
MARCH 1978
/
VOLUME XI. NUMBER 3
governmental agencies for a long-term follow-up of the people exposed to the chemical. The final answers will have to await many years of close observation. M-553, University of California San Francisco, California 94143 (DR. MARSHALL) References 1. Dubin L, and Amelar RD: Etiologic factors in 1,294 consecutive cases of male infertility, Fertil. Steril. 22: 469 (1971). 2. Torkelson TR, et al.: Toxicologic investigations of 1,2dibromo-3-chloropropane, Toxicol. Appl. Pharmacol. 3: 545 (1961). 3. Whorton D, Krauss R, Marshall S, and Milby T: Infertility in male pesticide workers, Lancet 2: 1259 (1977). . 4. McCleod I. and Gold RA: The male factor in fertility and infertility. II. Spermatazoon counts in 1,000 men of known fertility and in 1,006 cases of infertile marriage, J. Urol. 66: 436 (1951). 5. Nelson CMK, and Bunge RC: Semen analysis: evidence for changing parameters of male fertility potential, Fertil. Steril. 25: 563 (1974).
259
EFFECT OF PESTICIDES ON TESTICULAR FUNCTION SUMNER
MARSHALL,
M.D.
DONALD
WHORTON,
M.D.
RONALD
M. KRAUSS,
M.D.
WILLIAM
S. PALMER,
M.D.
From the Department of Urology, University of California School of Medicine, San Francisco; the Department of Industrial Medicine, University of California, Berkeley; and the Departments of Urology, Endocrinology, and Pathology, Alta Bates Hospital, Berkeley, California
- Marked impairment of spermatogenesis was found in a group of men exposed to the pesticide 1,2-dibromo&chloropropane (DBCP), demonstrated by semen analyses, testicular biopsies, and hormone studies. The ramifications of the use of this pesticide are discussed.
ABSTRACT
The spermatogenic tubules are vulnerable to the effects of heat, temporary devascularization (as in torsion of the testes), radiation, mumps virus, and to many drugs.l Laboratory animal experiments have demonstrated the toxic effects of certain pesticides on the spermatogenic tubules.2 However, the possible relevance of this toxicity to humans was not brought to light until recently when the workers in the pesticide section of a chemical plant in Northern California became aware that very few of them had sired children during their employment. When these men were initially examined by one of the authors (D. W.), moderate to marked depression of their fertility status was found. At that time, the plant was manufacturing many different chemical compounds. As a result of epidemiologic investigations carried out in this chemical plant and others in the country, 1,2-dibromo-3-chloropropane (DBCP) was believed to be the compound most likely causing the impairment in testicular function. 3
In an attempt to correlate exposure time to DBCP with measurable aberrations in testicular anatomy and function, serum levels of follicle-
/ MARCH 1978 / VOLUME
XI, NUMBER
3
l-3 YRS
<3MO
NO OF CASES sp$f,R~&
Material and Methods
UROLOGY
stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were determined in the 38 male and 3 female workers exposed to the chemicals. The semen of the 27 nonvasectomized men was analyzed. Ten of the men (including both vasectomized and nonvasectomized men) underwent testicular biopsies. The results of endocrine evaluation, semen analyses, and testicular biopsies showed that the longer the subjects studied were exposed to the chemical DBCP, the greater was the impairment in testicular function. No measurable
13 8?ZMILLION/ml
>3YRS
2 ZOMILLION/ml
11
O-1
MILLION/ml
FIGURE 1. Progressive decrease in sperm count in men with longer exposure to DBCP is shown. After three years most had complete absence of sperm in ejaculate.
FIGURE 2. Testicular biopsies illustrate decreased spermatogenic activity with prolonged chemical exposure. Note near total absence of spet-matogonia in testis after three years of exposure.
abnormalities were found in the 3 women studied. The men working in the laboratory, using appropriate precautions against risk of exposure, had no apparent change in their fertility status. Those who worked less than three months in the pesticide section had no apparent depression in their sperm count. However, marked spermatogenic impairment was present in all of the men tested who had had at least three years of direct exposure to DBCP (11 cases). This was reflected by sperm counts of less than 1 million per cc. of ejaculate. Indeed, in 9 of them, there was complete absence of sperm (Fig. 1). Results of the testicular biopsies also showed a close correlation between exposure time and degree of impaired spermatogenesis. No obvious damage was seen in the biopsied testicular tissue of men having been exposed to DBCP three months or less. Decreased spermatogenic activity was seen in those samples from men exposed to the chemical for more than
30
500
[IIz1 >3YRS 20
0 FSH
LH
TESTOSTERONE
0
FIGURE 3. Comparison of mean values of FSH, LH, and testosterone in men with exposure time under three months and over three years. Note prominent increase in FSH levels, with marked, though appreciable increase in LH levels in men exposed to DBCP for more than three years.
258
twelve months. Spermatocytes and spermatogonia were almost totally absent in the men who had been exposed to it for three years or longer. No obvious changes were noted in the histology of the Sertoli or Leydig cells (Fig. 2). One man who had worked for a three-year period in the pesticide formulations section of the plant but had been assigned to another section in the plant for the most recent three years had a normal sperm count, although his testicular biopsy showed some peritubular fibrosis as well as decrease in the number of spermatogonia. FSH and LH levels were increased in the men with marked spermatogenic impairment secondary to the long-standing exposure. Testosterone levels were not changed appreciably (Fig. 3). Comment Male fertility status is difficult to establish objectively since conception is dependent on both male and female fertility. Semen analysis provides the most objective method to determine fertility level in the male; nevertheless, much discrepancy exists in the literature regarding what constitutes a normal semen.4’5 However, it is generally agreed that true oligospermia exists when the count is below 20 million per cc. But as long as any amount of normal motile sperm is present, impregnation can theoretically be achieved. The function of the testes is twofold: endocrine and spermatogenic. The sources of hormones, the interstitial or Leydig cells, are more resistant to the effect of toxic substances than the spermatogenic tubules. As a result, germinal aplasia may exist, without any apparent disturbance to the interstitial cells. In the cases reported herein, the degree of disruption of testicular anatomy was closely correlated with the length of exposure to the suspect chemical DBCP. From the testicular
UROLOGY
/ MARCH1978
/ VOLUMEXI,
NUMBER3
tissue biopsy it is difficult to be certain about the degree of recoverability of the spermatogenie function; yet, as noted, one man had a normal sperm count three years after having left the area of exposure (although his testicular biopsy did show some impairment of spermatogenie activity). The results of testicular biopsies done on the men who had recent exposure to DBCP showed evident impairment in sperm production. The workers also underwent extensive multisystem evaluations: no consistent aberration was noted except in the effect of the toxic substance on the spermatogenic tubules. Possible ramifications of the pesticide exposure are open to speculation. Questions must be raised as to the possible effect of the suspect chemical not only on the workers in this chemical plant but also on farm workers. Also, could residual levels in produce have a perceptible effect on the consumer? Late effects of DBCP in man are unknown. A mechanism is being set up by the chemical industry and certain
UROLOGY
I
MARCH 1978
/
VOLUME XI. NUMBER 3
governmental agencies for a long-term follow-up of the people exposed to the chemical. The final answers will have to await many years of close observation. M-553, University of California San Francisco, California 94143 (DR. MARSHALL) References 1. Dubin L, and Amelar RD: Etiologic factors in 1,294 consecutive cases of male infertility, Fertil. Steril. 22: 469 (1971). 2. Torkelson TR, et al.: Toxicologic investigations of 1,2dibromo-3-chloropropane, Toxicol. Appl. Pharmacol. 3: 545 (1961). 3. Whorton D, Krauss R, Marshall S, and Milby T: Infertility in male pesticide workers, Lancet 2: 1259 (1977). . 4. McCleod I. and Gold RA: The male factor in fertility and infertility. II. Spermatazoon counts in 1,000 men of known fertility and in 1,006 cases of infertile marriage, J. Urol. 66: 436 (1951). 5. Nelson CMK, and Bunge RC: Semen analysis: evidence for changing parameters of male fertility potential, Fertil. Steril. 25: 563 (1974).
259