1 Clinique Pasteur Saint-Esprit, Brest, 2 INSERM U-292, Le Kremlin-Bicêtre, 3 Centre Hospitalier Universitaire Augustin Morvan, Brest, 4 Human Fertility Research Group, Toulouse University, Toulouse, France
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Abstract |
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Key words: heat exposure/low dose radiation/male infertility/occupational hazards
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Introduction |
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For women, there is consensus concerning the major medical infertility risk factors, the list of which includes pelvic and tubal inflammatory diseases, endometriosis, cervico-uterine malformations, and ovulation disorders. For men, a few infertility risk factors, such as infections (orchitis, epididymitis and prostatitis), varicocele, and cryptorchidism are well documented (Healy et al., 1994; Templeton, 1995
).
During the last decade, our knowledge about the impact of certain occupational hazards on reproductive health, particularly on male and female fertility, has increased. For example, studies have shown that exposure to pesticides (De Cock et al., 1994) or to heavy metals (Lancranjan et al., 1975
; Rowland et al., 1992
) may have deleterious effects on human fertility.
Very few studies have investigated the possible effects of environmental radiation on male reproductive function (Hoyes and Morris, 1996). However, it is well established that the testis is one of the most radiation-sensitive organs (Meistrich and Van Beek, 1990
). Most of the available data concerning the sensitivity to radiation of the human testis are necessarily associated with the treatment of cancer (Ash, 1980
; Goldman and Johnson, 1993
). Data have been obtained in various other situations, including accidental exposure, and radioactive contamination after atomic bomb testing and nuclear accidents (Kitabatake et al., 1974
; Fischbein et al., 1997
; Goncharov et al., 1998
). We know that the biological response to radiation differs between tissues and between organs, according to the duration of exposure and whether the total dose is received in one or several instalments (Littley et al., 1991
; Ogilvy-Stuart and Shalet, 1993
).
In 1996, we were asked by gynaecologists and biologists working in Brest (a French town with a large military naval base housing nuclear submarines) to investigate an apparent increase in the number of couples undergoing medical investigations for infertility in the military population working in submarines.
We thus conducted a population-based case-control study to evaluate the various infertility risk factors in the military population of Brest.
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Materials and methods |
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Cases and controls were recruited between March and September 1996.
Cases
All couples who had sought medical advice, during the 7 months of the study, for infertility lasting more than 12 months and in which the man was employed by the military at the time of the study were eligible for inclusion (n = 75). According to World Health Organization (WHO, 1992) criteria for infertility, we excluded 11 couples for whom the duration of infertility was less than 12 months at the time of the medical examination. We also excluded one couple for whom the length of the period of infertility was unknown, one couple in which the woman had undergone tubal ligation, one couple in which the man had undergone a vasectomy, and one couple already enrolled in an IVF programme. We finally included 60 cases.
Controls
All couples who had had a child during the 7 months of the study and in which the man was employed by the military at the time of the study were eligible for inclusion (n = 179). We excluded 13 couples who had taken more than 12 months to conceive this child, and one couple who had received IVF treatment. We thus included 165 controls.
Questionnaire
A standardized and pre-tested questionnaire was completed (self-administered) by all cases and controls, during infertility investigation for the cases, and during the post-delivery stay of the mother at the maternity unit (during the husband's visits) for the controls. The main questions concerned the age of both partners, how long it took for the woman to become pregnant (for the controls) and the duration of infertility (for the cases), the dates and outcomes of all previous pregnancies, the most recent contraceptive method and the date on which it was stopped, the woman's medical (genital infection, endometriosis) and surgical (ectopic pregnancy, appendicitis, tubo-ovarian surgery) history, the man's medical (genital infection, varicocele, cryptorchidism) history, and tobacco and alcohol use (over the last 6 years).
To take into account the recent occupations of both partners, we asked them what job they did and to describe possible occupational exposures over the last 6 years. Based on previous studies, we focused this section on several possible exposures: having worked in a nuclear environment, having used solvents or pesticides, having been in contact with electromagnetic fields or radar waves (for both partners), having worked in hot conditions (for men only), and having been exposed to antimitotic drugs (for women only). The question concerning exposure to nuclear radiation was expressed as follows: `Do you consider yourself to have been professionally exposed to nuclear radiation during any of the last 6 years? If yes, would you please provide details of the conditions in which this exposure may have occurred'.
Statistical analysis
We used the 2-test to compare cases and controls. We calculated the odds ratio (OR) for each potential risk factor and its estimated 95% confidence interval (CI). To take the age difference between cases and controls into account (cases were older than controls) we adjusted the OR for age (the variable `age' was used as a dichotomous variable, <30 or
30 years; we also performed the analysis with age as a continuous variable).
We also performed logistic regression analysis, taking into account the various risk factors evaluated by the questionnaire (age, tobacco and alcohol use, medical histories, and various occupational exposures of both partners were all included in the model).
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Results |
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To take into account the possible effects of the various exposures, we performed a logistic regression analysis. We included in the logistic model the variables with the highest OR in univariate analysis: age of each partner as a dichotomous variable (under or over 30 years), female and male smoking, history of tubo-ovarian surgery, history of salpingitis and ectopic pregnancy, varicocele, cryptorchidism, and male exposure to heat and solvents or having worked in a nuclear submarine. We obtained an adjusted odds ratio of 2.9 (95% CI: 1.36.3) for men having worked in a nuclear submarine, and an adjusted odds ratio of 5.4 (95% CI: 1.816.4) for men exposed to hot conditions [similar results were obtained with age used as a continuous variable (OR: 2.8; 95% CI: 1.36.0) for having worked in a nuclear submarine (OR: 5.1; 95% CI: 1.715.4) for exposure to high temperatures] (Table IV).
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We also performed a regression analysis focusing on job title and occupational exposures in the last year only. We obtained an OR for having worked in a nuclear submarine of 2.9 (95% CI: 1.36.7), and an OR for heat exposure of 2.5 (95% CI: 0.88.4).
To ensure that the military occupations of the men were as similar as possible for cases and controls, we performed a comparison for submariners only. Table V shows the data for submariners only (n = 67): nuclear submariners (n = 56), diesel submariners (n = 6) and those having worked in both diesel and nuclear submarines (n = 5). All of the 22 submariners consulting for infertility (cases) were working in nuclear submarines, and none were working in diesel submarines; for controls, 34 of the 45 fertile submariners were working in nuclear submarines, six worked in diesel submarines and five had worked in both nuclear and diesel submarines. If we excluded submariners who had worked in both types (nuclear and diesel) of submarine (n = 5), we observed a significant difference (P = 0.05) between those who had worked in nuclear-powered submarines and those who had worked in diesel-powered submarines.
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Discussion |
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In a study of healthy volunteers from a prison population (Oregon and Washington State Penitentiary), Rowley et al. showed that direct exposure to low-dose radiation (0.15 Gy) causes a significant reduction in sperm count, with temporary azoospermia occurring after exposure to doses of 0.3 Gy (Rowley et al., 1974). Spermatogonia in men seem to be more susceptible than spermatocytes to radiation-induced cell damage. In the 2 months following low-dose irradiation, sperm production is 50% that of controls. The surviving spermatogonia recover and complete recovery occurs within 9-18 months after exposure to 1 Gy, and within around 30 months for exposure to 23 Gy (Clifton et al., 1983; Pinon-Lataillade et al., 1988
; Ogilvy-Stuart and Bremmer, 1993).
For nuclear workers (including nuclear submariners) the annual maximum allowable radiation dose in the United States is 50 mSV, a dose lower than those used by Rowley for prison volunteers. It is also difficult to compare our results with those obtained in patients receiving abdominal, inguinal or pelvic radiotherapy for cancer (Hodgkin's lymphoma, seminoma). Deleterious effects (decreases in sperm count, azoospermia) were observed in these studies, but doses were probably much higher than 150 mSV.
Several studies have assessed the effects on reproductive health of the Chernobyl catastrophe. Fischbein and Bartoov compared the ultramorphological sperm characteristics of 18 liquidators (individuals involved in clean-up operations) and 18 control men (Fischbein et al., 1997). Ten years after the catastrophe, they observed a higher percentage of certain ultrastructural characteristics of the sperm head in liquidators, with no difference in sperm density and viability (Fischbein et al., 1997
). Goncharov compared hormonal and semen characteristics in 416 liquidators and 88 healthy age-matched controls and found that the percentage of normal forms of spermatozoa in liquidators (35%) was significantly lower than that in the control group (43%) (Goncharov et al., 1998
). Although not statistically significant, they also observed a higher percentage of cases with teratozoospermia (26 verses 10%), oligozoospermia (23% versus 10%), and asthenozoospermia (16 versus 5%) among the liquidators. The dose of radiation to which the liquidators was exposed was estimated at 0.001-0.33 Gy (assessed using personal dosimeters). In these two studies, men were examined 79 years after radiation exposure. This is a long period of time, possibly dissipating the effect and facilitating a recovery in spermatogenesis, as suggested by the preliminary results of a study by Gorpinchenko and Boyko, who analysed semen parameters in liquidators in the first few years after the Chernobyl accident. They observed higher percentages of quantitative and qualitative abnormalities in the clean-up group of men exposed to nuclear radiation than in a control group of healthy individuals (Gorpinchenko and Boyko, 1997
).
In this study, we also observed a relationship between infertility and the reported exposure of the man to heat (no interaction was found between exposure to heat and potential nuclear exposure from having worked in a nuclear submarine; Wald test: P = 0.68). We checked the job title of the men who said they had been exposed to heat. Most of these men were mechanics, cooks, and submariners (the temperature at the rear of the submarine, particularly in the area close to the motor, is high, between 40 and 60°C). Our results are consistent with several recent studies showing that occupational exposure to heat may cause male infertility (Rachootin and Olsen, 1983; Bonde, 1992
; Mieusset and Bujan, 1995
; Thonneau et al., 1997
). In Italy, it was shown that the female partners of Italian pottery workers (repeatedly exposed to high temperatures) take longer to conceive than control women whose partners are not exposed to such high temperatures (Figa-Talamanca et al., 1992
). In a retrospective survey of 402 fertile French couples, it was found that it took longer to conceive a child if the man was exposed to heat (baker, welder) than if he was not (Thonneau et al., 1996
).
In this retrospective study, we were unable to compare the sperm characteristics of cases and controls (lack of semen from the control group). As stated (Chatterjee et al., 2000), it would be interesting in further studies to analyse semen and DNA damage in men exposed to potentially deleterious environments.
It is well established that varicocele and crytorchidism may increase testis temperature, impairing spermatogenesis. Except for varicocele [significant only in univariate analysis, and probably linked to recall bias in fertile patients (WHO, 1992)], we found no relationship between medical history and male infertility. Nevertheless, the number of men and women who reported such medical or surgical risk factors was small (<10 for each type of exposure), giving OR with very large confidence intervals.
Bias
Limited exposure assessment
One major limitation of this study is the lack of exposure measurements. Unfortunately, for these submariners, it was not possible to obtain more information about job description, for example, about the type of reactor used in these nuclear-powered submarines and the possible risks associated with this form of energy. We were also unable to obtain the personal dosimeters worn by military personnel working in nuclear submarines. Even if the total annual dose for each individual were within the usual norms, it would be interesting to determine and to study the distribution of the dose over time for cases and controls, and as a function of the type of nuclear reactor. Assuming that submariners working in nuclear-powered submarines may have been exposed to chronic low-dose nuclear radiation due to contamination from the nuclear-powered propulsion system, such exposure may have had deleterious effects on male reproductive function. We hope that this study will help to stimulate scientific collaboration (including access to all relevant information) with the military sector, to evaluate the impact of hazardous low-dose radiation on human fertility.
For some types of exposure, such as exposure to solvents, pesticides and, to a lesser extent, heat, the responses may have resulted in under- or overestimation. However, it is unlikely that men working in a nuclear-powered submarine would deliberately not answer the question or underreport reproductive information (Coughlin et al., 1998).
Selection bias (Schlesselman and Stolley, 1992)
We cannot exclude the possibility of effects of stress and psychological difficulties linked to working in such conditions (very restricted area, artificial light, psychological pressure related to the transport of nuclear weapons) (McGrady et al., 1984; Schenker et al., 1992). We thus reanalysed the data for submariners only (nuclear submariners versus diesel submariners). Our results, with small numbers in each group, showed a slightly higher risk of infertility in men who had worked in nuclear submarines than in men who had worked only in diesel submarines (Table V
).
All the deliveries (for military and non-military populations) took place in the four maternity units in Brest in which we conducted this study. All private and public units dealing with male and female infertility investigation and treatment were involved in the study. There is no specific clinic for military personnel in the town of Brest (military personnel use the same medical, maternity and infertility services as the rest of the population of Brest), and we did not recruit infertile military personnel outside Brest. Nevertheless, we cannot exclude the possibility that some infertile couples chose to consult only general practitioners and not the specialists involved in our study.
Brest is located far from other large cities (the nearest towns with maternity and infertility facilities are about 150 km away). No couples from Brest were reported to be seeking infertility exploration or maternity services elsewhere by doctors from other cities near Brest. This phenomenon should certainly be considered very rare.
Selection bias in the identification of controls and cases is always possible. In particular, members of the public are well aware that radiation may affect fertility, and couples in which one of the partners is a nuclear submariner may therefore seek help very early if they fail to conceive. To limit this possibility, we adopted a strict threshold of 12 months: fertile couples who took more than 12 months to conceive a child were excluded from the control group, and infertile couples who sought medical advice for conception difficulties within 1 year were excluded from the case group. We thus excluded 11 infertile couples from the case group for whom the duration of infertility was less than 12 months at the time of the medical examination, and one couple for whom the period of infertility was unknown. Even for infertile couples who sought help very early, only those with infertility of more than 12 months duration were included as cases.
In conclusion, this study suggests that in this specific military population, having worked as a submariner in a nuclear-powered submarine and having worked in very hot conditions should be considered as risk factors for infertility. As the number of subjects in our study was small and as other male infertility risk factors (stress) may also be involved, further studies in military and other populations, including analysis of sperm and DNA damage, are required to confirm these results.
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Acknowledgments |
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Notes |
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References |
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Bonde, J.P. (1992) Semen quality in welders exposed to radiant heat. Br. J. Indust. Med., 49, 510.[ISI][Medline]
Chatterjee, R., Haines, G.A., Perera, D.M.D. et al. (2000) Testicular and sperm DNA damage after treatment with fludarabine for chronic lymphocytic leukaemia. Hum. Reprod., 15, 762766.
Clifton, D.K. and Bremmer, W.J. (1983) The effect of testicular X-irradiation on spermatogenesis in man: a comparison with the mouse. J. Androl., 4, 387392.
Coughlin, M.T., Laporte, R.E., O'Leary, L.A. and Lee, P.A. (1998) How accurate is male recall of reproductive information? Am. J. Epidemiol., 148, 806809.[Abstract]
De Cock, J., Westveer, K., Heederik, D. et al. (1994) Time to pregancy and occupational exposure to pesticides in fruit growers in the Netherlands. Occup. Environ. Med., 51, 693699.[Abstract]
Figa-Talamanca, I., DellOrco, V., Pupi, A et al. (1992) Fertility and semen quality of workers exposed to high temperatures in the ceramics industry. Reprod. Toxicol., 6, 51723.[ISI][Medline]
Fischbein, A., Zabludovsky, N., Eltes, F. et al. (1997) Ultramorphological sperm characteristics in the risk assessment of health effects after radiation exposure among salvage workers in Chernobyl. Environ. Health Perspect., 105((Suppl. 6), 14451449.[ISI][Medline]
Goldman, S. and Johnson, F.L. (1993) Effects of chemotherapy and irradiation on the gonads. Endocrinol. Metab. Clin., 22, 6172920.[ISI]
Goncharov, N.P., Katsiya, G.V., Kolesnikova, G.S. et al. (1998) Endocrine and reproductive health status of men who had experienced short-term radiation exposure at Chernobyl. Int. J. Androl., 21, 271276.[ISI][Medline]
Gorpinchenko, I.I. and Boyko, N.I. (1997) Semen parameters of clean-up workers of Chernobyl accident. Int. J. Androl., 20 (Suppl. 1), Abstract 250, p. 63.
Healy, D.L., Trounson, A.O. and Andersen, A.N. (1994) Female infertility: causes and treatment [Review]. Lancet, 343, 15391544.[ISI][Medline]
Hoyes, K.P. and Morris, I.D. (1996) Environmental radiation and male reproduction. Int. J. Androl., 19, 199204.[ISI][Medline]
Hull, M.G., Glazener, C.M., Kelly, N.J. et al. (1985) Population study of causes, treatment and outcome of infertility. Br. Med. J., 291, 169397.[ISI][Medline]
Kitabatake, T., Watanabe, T. and Sato, T. (1974) Sterility in Japanese radiological technicians. Tohoku J. Exp. Med., 112, 209212.[ISI][Medline]
Lancranjan, I., Popescu, H.I., Gavanescu, O. et al. (1975) Reproductive ability of workmen occupationally exposed to lead. Arch. Environ. Health., 30, 396401.[ISI][Medline]
Littley, M.D., Shalet, S.M., Morgenstern, G.R. and Deakin, D.P. (1991) Endocrine and reproductive dysfunction following fractionated total body irradiation in adults. Q. J. Med., 78, 265274.[Medline]
Meistrich, M.L. and Van Beek, M. (1990) Radiation sensitivity of the human testis. Adv. Radiat. Biol., 14, 227268.
McGrady, A.V. (1984) Effects of psychological stress on male reproduction: a review. Arch. Androl., 13, 17.[ISI][Medline]
Mieusset, R. and Bujan, L. (1995) Testicular heating and its possible contributions to male infertility: a review. Int. J. Androl., 18, 169184.[ISI][Medline]
Ogilvy-Stuart, A.L. and Shalet, S.M. (1993) Effects of radiation on the human reproductive system. Environ. Health Perspect., 101(Suppl. 2) , 109116.
Pinon-Lataillade, G., Velez De La Calle, J.-F., Viguier-Martinez, M.C. et al. (1988) Influence of germ cells upon Sertoli cells during continuous low-dose rate gamma-irradiation of adult rats. Mol. Cell. Endocrinol., 58, 5163.[ISI][Medline]
Rachootin, P. and Olsen, J. (1983) The risk of infertility and delayed conception associated with exposures in the Danish workplace. J. Occupat. Med., 25, 394402.[ISI][Medline]
Rowland, A.S., Baird, D.D., Weinberg, C.R. et al. (1992) Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N. Engl. J. Med., 327, 993997.[Abstract]
Rowley, M.J., Leach, D., Warner, G. and Heller, C.G. (1974) Effects of graded doses of ionizing radiation on the human testis. Radiat. Res., 59, 665678.[ISI][Medline]
Schenker, J.G., Meirow, D. and Schenker, E. (1992) Stress and human reproduction. Eur. J. Obstet. Gynecol. Biol., 45, 18.[ISI][Medline]
Schlesselman, J.J. and Stolley, P.D. (1982) Sources of bias. In Schlesselman J.J. (ed.), Case-Control Studies. Oxford University Press, Oxford, pp. 124143.
Templeton, A. (1995) Infertility|epidemiology, etiology and effective management. Health Bull., 53, 294298.
Thonneau, P., Ducot, B., Bujan, L. et al. (1996) Heat exposure as a hazard to male fertility. Lancet, 347, 204205.[ISI][Medline]
Thonneau, P., Ducot, B., Bujan, L. et al. (1997) Effect of male occupational heat exposure on time to pregnancy. Int. J. Androl., 20, 274278.[ISI]
Thonneau, P., Marchand, S., Tallec, A. et al. (1991) Incidence and main causes of infertility in a resident population (1 850 000) of three French regions (19881989). Hum. Reprod., 6, 811816.[Abstract]
WHO (1992) The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil. Steril., 57, 12891293.[ISI][Medline]
Submitted on June 19, 2000; accepted on November 27, 2000.