Male Reproductive Toxicity - SQU Home

TABLE 8Case-Control Studies of Paternal EffectsType of Exposure/OccupationAssociation withExposure a Effect Ref.Printing industry (+) Cleft lip 144Paint (+) Cleft palate 144Paint + Damage to CNS b 145Solvents (+) Damage to CNS b 145Low-level radiation + Neural tube defects 146Organic solvents + Spontaneous abortion 147Aromatic hydrocarbons + Spontaneous abortion 147Dusts + Spontaneous abortion 147Radiation + Childhood leukemia 148Welding + Time to conception 149Agriculture (+) Child brain tumor 150Construction (+) Child brain tumor 150Food/tobacco processing (+) Child brain tumor 150Metal + Child brain tumor 150Lead (+) Spontaneous abortion 151Lead (+) Congenital defects 152Ethylene glycol ether + Abnormal spermiogram 153Metals + Cadmium in semen 154a(+): marginally significant association; +: significant association.bCNS = central nervous system.Source: Modified from Taskinen, H., Scand. J. Work Environ. Health, 16, 297, 1990.and other data sources. Like population-based studies, case-control studies provide thestatistics needed to detect a rare event; however, in this type of study individual bias mayyield misleading results. A person who has experienced an adverse outcome may report anexposure more readily than one with no history of reproductive dysfunction. As Levindescribes, 81 a couple that has recently experienced a stillbirth or congenitally malformed childwill be more inclined to search for a previous toxic exposure as the source. Another potentialsource of bias in these studies exists with the interviewer, who should be “blind” to thereproductive status and the exposure classification of the respondent.2.3.4 Standardized Fertility RatioThe standardized fertility or birth ratio (SFR) (Table 9) provides a comparison of thenumber of observed births within a population to the number of expected births. The lattervalue is obtained using the birth rate of an external population. To monitor a specific workforcegroup, Wong 82 uses a simple standardization method that provides noninvasive, readilyavailable data. His method uses a couple’s reproductive history to measure male fecundity.The number of expected births is obtained from the birth rate for U.S. women of the sameage group. There are some problems with this simplified approach. Because the U.S. birthrate as collected by the National Center for Health Statistics does not take into accountmarital status, birth control, or frequency of intercourse, 83 the potential exists for a positiveor negative bias in making such comparisons. Wong’s method erroneously assumes all womento be equally libidinous and fecund. Additionally, because only married men are evaluated inSFR studies, there are age-related restrictions in the data as well as a likely underestimate ofthe number of children born out of wedlock. Some researchers have tried to correct for thesevariations in the population using different models. 83,84 It appears that the SFR overestimatesbirth rate in both control and exposed populations, even when a reduction in semen quality© 1999 by CRC Press LLC

TABLE 9Standarized Birth Ratio Studies of Male Fertility EffectsType of Exposure/OccupationAssociation withExposure aRef.Ethylene dibromide (+) 82DBCP + 83TDA and DNT – 78Mercury – 155Manganese + 155Ethylene glycol ether – 85Chemical-contaminated sewage – 156a–: no significant association; (+): marginally significantassociation; +: significant association.Source: Modified from Taskinen, H., Scand. J. Work Environ.Health, 16, 297, 1990.exists. 85 Levine 84 suggests SFR would be a reliable indicator in a cohort study in which bothcontrol and comparison population are selected on the same basis.2.3.5 Cohort StudiesCohort studies (Table 10) evaluate the frequency of adverse reproductive outcomebetween exposed and unexposed groups. Cross-sectional cohort studies evaluate the groupsas they currently exist, whereas historical cohort studies are conducted on previously exposedand unexposed groups. An example of the latter is the 1989 Vietnam experience study inwhich military veterans were grouped according to whether or not they had served in Vietnamfrom 1967 to 1972. 86 This study was able to detect subsequent differences between thegroups in semen quality and time to pregnancy but revealed little about the reproductivehealth of the individuals at the time of exposure.A cohort study may be longitudinal (prospective). In such a study, baseline data arecollected, and individuals are studied over time for a specific reproductive outcome. Alongitudinal study is exemplified by the study of “summer hire” pesticide applicators. 41Individuals were evaluated at the beginning of the season before they started working withpesticides and at the conclusion of the spraying season 2 months later. This report illustratesthe importance of selecting appropriate variables for a study design. If semen analyses areconducted to predict reproductive outcome, the correct time frame is needed. Since the timefor spermatogenesis and delivery of mature sperm to the ejaculate is approximately 72 days,if primary spermatogonia were affected by exposure, this would not be observed in a timeframe covering less than 80 to 90 days. Thus, the study of “summer hire” workers could notmake valid conclusions regarding the effects of a 2-month exposure to pesticide applicationon spermatogenesis.Cohort studies may involve questionnaires, neuroendocrine measurements, and semenanalyses or a combination of these. Questionnaire studies are advantageous in that they arethe least expensive and least invasive. As with case control studies, however, inherent problemsexist, such as possible interviewer bias and the selective memory of respondents who haveexperienced an adverse outcome. Additionally, many cohort studies lack the number ofpregnancies needed to detect differences between groups. 87 Studies evaluating the neuroendocrinesystem measure male hormones in blood samples. Although blood sampling is awidely accepted medical practice, it is an invasive procedure, and the endocrine profile doesnot necessarily reflect the status of the male reproductive system. 88 Semen analysis provides© 1999 by CRC Press LLC

TABLE 11Clinical/Case Studies of Male Reproductive Effects withPositive Association with ExposureType of Study Type of Exposure Effect Ref.Cluster DBCP Semen, endocrine 181Case report Kepone Semen 93Medical monitor Lead Semen 182Case report Methylene chloride Semen 183Case report Lead Semen 92Accident Bromine vapor Semen 76Accident Radiation Semen, endocrine 77therapy. His sperm count increased as his blood levels decreased, and he subsequently fatheredanother child after the level of lead decreased below 30 mg/dl. Similarly, after men exposedto high levels of kepone in the work environment were treated with cholestyramine to offsetthe toxic action of kepone, their sperm count and sperm motility increased accordingly. 93Work-related accidents may provide case study data on high-level exposures. These inturn may indicate the parameters to be studied at lower exposures.3 SURVEILLANCE OF MALE REPRODUCTIONA surveillance strategy for evaluating men working with known male reproductive toxicantswas proposed and conducted by a team from the University of California; 94 however,this program had many problems and was eventually discontinued. 95 While this first attemptwas discouraging, chemicals such as lead and ethylene glycol ethers remain in the U.S.workplace, posing a hazard to the reproductive health of the male worker. A surveillanceprogram is required to monitor those working with these and other occupational toxicants.3.1 SUSCEPTIBILITY OF SUBGROUPSThere is a concern that there may be a subgroup of individuals that may be moresusceptible to a toxicant than others in the population. While for male reproductive toxicantsin humans this has not been tested, there are some indications that it may in fact happen insome cases. Chapin et al. 96 have shown that different strains of mice respond differently dothe same toxicant. Their data indicate that a strain of mice known to be “poor breeders”were more sensitive to the toxicant 2-methoxyethanol than strains of “good breeders”. Asimilar response was noted by Welch et al., 97 who reported on a study in which workers wereexposed to a related compound, 2-ethoxyethanol. In this human study, the exposed workershad a median sperm count similar to the unexposed comparison group; however, when thedistribution of sperm counts was evaluated, it appeared that the number of sperm of menwith low sperm counts was much lower. This suggested that a man with a lower sperm countsuffered a severe decrement compared to others in the population with exposure.3.2 DECLINING SPERM COUNTSMuch has been written about declining male fecundity in recent years. 68,98,99 The reporteddecline in sperm numbers has received the most attention. Such reports are not necessarilynew, as this controversy has been debated before. 63-67 What appears different is that the© 1999 by CRC Press LLC

popular press has sensationalized these reports. While there is evidence that sperm numbershave changed, one must be cautious, remembering that both andrology and laboratorymethodology have changed over the last half century. Are the observed changes a reflectionof study participants and/or methodology, and are they real? 100-102 Related to this currentcontroversy are reports that this decline is due to male offspring being exposed in utero toestrogenic compounds from our environment. While exposure to estrogenic (and otherhormonal) compounds in utero can have negative effects on sperm production, 103 a directcause and effect have not been shown between estrogenic compounds and a decline of spermnumbers in the human race. This is an interesting hypothesis that needs much more research.4 SUMMARYThe male reproductive system is susceptible to toxic insult that results in decreasedfecundity and/or an increase in adverse pregnancy. Each year, several hundred new compoundsare added to the 70 thousand compounds and 4 million mixtures already in commercialuse, 104 suggesting that there is a need to evaluate the effects that a man’s workplaceand environment has on his fecundity. There are several methods for evaluating male fecundity,often requiring a large research team and complex laboratory assessments. While the problemsin conducting such a study may seem unsurmountable, a team approach has allowed thisresearch to be successful. 91REFERENCES1. Sokol, R. Z., Endocrine evaluations in the assessment of male reproductive hazards, Reprod. Toxicol., 2,217–222, 1988.2. Schrader, S. M., Turner, T. W., Breitenstein, M. J., and Simon, S. D., Measurement of male reproductivehormones for field studies, J. Occup. Med., 35, 574–576, 1993.3. Bardin, C. W., Pituitary-testicular axis, in Reproductive Endocrinology, Yen, S. S. C. and Jaffe, R. B., Eds.,W.B. Saunders, Philadelphia, 1986, pp. 177–199.4. Raid-Fahmy, D., Read, G. F., Walker, R. F., and Griffiths, K., Steroids in saliva for assessing endocrinefunction, Endocrinol. Rev., 3, 367–395, 1982.5. Apostoli, P., Romeo, L., Peroni, E., Ferioli, A., Ferrari, S., Pasini, F., and Aprili, F., Steroid hormone sulphationin lead workers, Br. J. Ind. Med., 46, 204–208, 1989.6. Plant, T. M., Puberty in primates, in The Physiology of Reproduction, Knobil, E. and Neill, J. D., Eds., RavenPress, New York, 1988, pp. 1763–1788.7. NIOSH, Collecting a Semen Sample, National Institute for Occupational Safety and Health, Cincinnati, OH,1986.8. Eliasson, R. and Treichl, L., Supravital staining of human spermatozoa, Fertil. Steril., 22, 134–137, 1971.9. Jeyendran, R. S., Van den Ven, H. H., Perez-Palaez, M., Crabo, B. G., and Zaneveld, L. J. D., Developmentof an assay to assess the functional integrity of the human sperm membrane and its relationship to othersemen characteristics, J. Reprod. Fertil., 70, 219–228, 1984.10. Schrader, S. M., Platek, S. F., Zaneveld, L. J. D., Perez-Palaez, M., and Jeyendran, R. S., Sperm viability: acomparison of analytical methods, Andrologia, 18, 530–538, 1986.11. MacLeod, J., Semen quality in 1000 men of known fertility and in 800 cases of infertile marriage, Fertil.Steril., 2, 115–139, 1951.12. Freund, M., Standards for the rating of human sperm morphology, Int. J. Fertil., 11, 97–180, 1966.13. Fredricson, B., Morphologic evaluation of spermatozoa in different laboratories, Andrologia, 11, 57–61, 1979.14. Hanke, L. J., Comparison of Laboratories Conducting Sperm Morphology, Report TA78-28, National Institutefor Occupational Safety and Health, Cincinnati, OH, 1981.15. Schmassmann, A., Mikuz, G., Bartsch, G., and Rohr, H., Quantification of human sperm morphology andmotility by means of semi-automatic image analysis systems, Microscopica Acta, 82, 163–178, 1979.16. Katz, D. F., Overstreet, J. W., and Pelprey, R. J., Integrated assessment of the motility, morphology andmorphometry of human spermatozoa, INSERM, 103, 97–100, 1981.© 1999 by CRC Press LLC

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U., Detection of sex chromosomalaneuploidies X-X, Y-Y, and X-Y in human sperm using two-chromosome fluorescence in situ hybridization,Am. J. Med. Genet., 53, 1–7, 1994.37. Bischoff, F. Z., Nguyen, D. D., Burt, K. J., and Shaffer, L. G., Estimates of aneuploidy using multicolorfluorescence in situ hybridization on human sperm, Cytogenet. Cell Genet., 66, 237–243, 1994.38. Stachel, B., Dougherty, R. C., Lahl, U., Schlosser, M., and Zeschmar, B., Toxic environmental chemicals inhuman semen: analytical method and case studies, Andrologia, 21, 282–291, 1989.39. Zikarge, A., Cross-Sectional Study of Ethylene Dibromide-Induced Alterations of Seminal Plasma Biochemistryas a Function of Post-Testicular Toxicity with Relationships to Some Indices of Semen Analysis andEndocrine Profile, Dissertation to the University of Texas Health Science Center, Houston, TX, 1986.40. Mann, T. and Lutwak-Mann, C., Passage of chemicals into human and animal semen: mechanisms andsignificance, CRC Crit. Rev. 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78. Hamill, P. V. V., Steinberger, E., Levine, R. J., Rodriguez-Rigau, L. J., Lemeshow, S., and Avrunin, J. S.,The epidemiologic assessment of male reproductive hazard from occupational exposure to TDA and DNT,J. Occup. Med., 24, 985–993, 1982.79. Colie, C. F., Male-mediated teratogenesis, Reprod. Toxicol., 7, 3–9, 1993.80. Davis, D. L., Friedler, G., Mattison, D., and Morris, R., Male-mediated teratogenesis and other reproductiveeffects — biologic and epidemiologic findings and a plea for clinical research, Reprod. Toxicol., 6, 289–292,1992.81. Levin, S. M., Problems and pitfalls in conducting epidemiological research in the area of reproductivetoxicology, Am. J. Ind. Med., 4, 349–364, 1983.82. Wong, O., Utidijian, H. M. D., and Karten, V. S., Retrospective evaluation of reproductive performance ofworkers exposed to ethylene dibromide (EDB), J. Occup. Med., 21, 98–102, 1979.83. Levine, R. J., Blunden, P. B., Dalcorso, D., Starr, L. B., and Ross, C. 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