" DISCLAIMER: The ILO does not take responsibility for content presented on this web portal that is presented in any language other than English, which is the language used for the initial production and peer-review of original content. Certain statistics have not been updated since the production of the 4th edition of the Encyclopaedia (1998)."

Saturday, 19 February 2011 00:08

Structure of the Female Reproductive System and Target Organ Vulnerability

Written by
Rate this item
(0 votes)

Figure 1. The female reproductive system.


The female reproductive system is controlled by components of the central nervous system, including the hypothalamus and pituitary. It consists of the ovaries, the fallopian tubes, the uterus and the vagina (Figure 1). The ovaries, the female gonads, are the source of oocytes and also synthesize and secrete oestrogens and progestogens, the major female sex hormones. The fallopian tubes transport oocytes to and sperm from the uterus. The uterus is a pear-shaped muscular organ, the upper part of which communicates through the fallopian tubes to the abdominal cavity, while the lower part is contiguous through the narrow canal of the cervix with the vagina, which passes to the exterior. Table 1 summarizes compounds, clinical manifestations, site and mechanisms of action of potential reproductive toxicants.






Table 1. Potential female reproductive toxicants

Compound Clinical manifestation Site Mechanism/target
Chemical reactivity
Altered menses
Ovarian atrophy

Decreased fertility
Premature menopause

Granulosa cell cytotoxicity
Oocyte cytotoxicity
Endometrial cell cytotoxicity
Lead Abnormal menses
Ovarian atrophy
Decreased fertility
Decreased FSH
Decreased progesterone
Mercury Abnormal menses Hypothalamus

Altered gonadotrophin production and secretion
Follicle toxicity
Granulosa cell proliferation
Cadmium Follicular atresia
Persistent diestrus
Vascular toxicity
Granulosa cell cytotoxicity
Structural similarity
Azathioprine Reduced follicle numbers Ovary

Purine analog

Disruption of DNA/RNA synthesis
Chlordecone Impaired fertility Hypothalamus Oestrogen agonist
DDT Altered menses Pituitary FSH, LH disruption
2,4-D Infertility    
Lindane Amenorrhoea    
Toxaphene Hypermenorrhoea    
PCBs, PBBs Abnormal menses   FSH, LH disruption

Source: From Plowchalk, Meadows and Mattison 1992. These compounds are suggested to be direct-acting reproductive toxicants based primarily on toxicity testing in experimental animals.

The Hypothalamus and Pituitary

The hypothalamus is located in the diencephalon, which sits on top of the brainstem and is surrounded by the cerebral hemispheres. The hypothalamus is the principal intermediary between the nervous and the endocrine systems, the two major control systems of the body. The hypothalamus regulates the pituitary gland and hormone production.

The mechanisms by which a chemical might disrupt the reproductive function of the hypothalamus generally include any event that could modify the pulsatile release of gonadotrophin releasing hormone (GnRH). This may involve an alteration in either the frequency or the amplitude of GnRH pulses. The processes susceptible to chemical injury are those involved in the synthesis and secretion of GnRH—more specifically, transcription or translation, packaging or axonal transport, and secretory mechanisms. These processes represent sites where direct-acting chemically reactive compounds might interfere with hypothalmic synthesis or release of GnRH. An altered frequency or amplitude of GnRH pulses could result from disruptions in stimulatory or inhibitory pathways that regulate the release of GnRH. Investigations of the regulation of the GnRH pulse generator have shown that catecholamines, dopamine, serotonin, γ-aminobutyric acid, and endorphins all have some potential for altering the release of GnRH. Therefore, xenobiotics that are agonists or antagonists of these compounds could modify GnRH release, thus interfering with communication with the pituitary.

Prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are three protein hormones secreted by the anterior pituitary that are essential for reproduction. These play a critical role in maintaining the ovarian cycle, governing follicle recruitment and maturation, steroidogenesis, completion of ova maturation, ovulation and luteinization.

The precise, finely tuned control of the reproductive system is accomplished by the anterior pituitary in response to positive and negative feedback signals from the gonads. The appropriate release of FSH and LH during the ovarian cycle controls normal follicular development, and the absence of these hormones is followed by amenorrhoea and gonadal atrophy. The gonadotrophins play a critical role in initiating changes in the morphology of ovarian follicles and in their steroidal microenvironments through the stimulation of steroid production and the induction of receptor populations. Timely and adequate release of these gonadotrophins is also essential for ovulatory events and a functional luteal phase. Because gonadotrophins are essential for ovarian function, altered synthesis, storage or secretion may seriously disrupt reproductive capacity. Interference with gene expression—whether in transcription or translation, post-translational events or packaging, or secretory mechanisms—may modify the level of gonadotrophins reaching the gonads. Chemicals that act by means of structural similarity or altered endocrine homeostasis might produce effects by interference with normal feedback mechanisms. Steroid-receptor agonists and antagonists might initiate an inappropriate release of gonadotrophins from the pituitary, thereby inducing steroid-metabolizing enzymes, reducing steroid half-life and subsequently the circulating level of steroids reaching the pituitary.

The Ovary

The ovary in primates is responsible for the control of reproduction through its principal products, oocytes and steroid and protein hormones. Folliculogenesis, which involves both intraovarian and extraovarian regulatory mechanisms, is the process by which oocytes and hormones are produced. The ovary itself has three functional subunits: the follicle, the oocyte and the corpus luteum. During the normal menstrual cycle, these components, under the influence of FSH and LH, function in concert to produce a viable ovum for fertilization and a suitable environment for implantation and subsequent gestation.

During the preovulatory period of the menstrual cycle, follicle recruitment and development occur under the influence of FSH and LH. The latter stimulates the production of androgens by thecal cells, whereas the former stimulates the aromatization of androgens into oestrogens by the granulosa cells and the production of inhibin, a protein hormone. Inhibin acts at the anterior pituitary to decrease the release of FSH. This prevents excess stimulation of follicular development and allows continuing development of the dominant follicle—the follicle destined to ovulate. Oestrogen production increases, stimulating both the LH surge (resulting in ovulation) and the cellular and secretory changes in the vagina, cervix, uterus and oviduct that enhance spermatozoa viability and transport.

In the postovulatory phase, thecal and granulosa cells remaining in the follicular cavity of the ovulated ovum, form the corpus luteum and secrete progesterone. This hormone stimulates the uterus to provide a proper environment for implantation of the embryo if fertilization occurs. Unlike the male gonad, the female gonad has a finite number of germ cells at birth and is therefore uniquely sensitive to reproductive toxicants. Such exposure of the female can lead to decreased fecundity, increased pregnancy wastage, early menopause or infertility.

As the basic reproductive unit of the ovary, the follicle maintains the delicate hormonal environment necessary to support the growth and maturation of an oocyte. As previously noted, this complex process is known as folliculogenesis and involves both intraovarian and extraovarian regulation. Numerous morphological and biochemical changes occur as a primordial follicle progresses to a pre-ovulatory follicle (which contains a developing oocyte), and each stage of follicular growth exhibits unique patterns of gonadotrophin sensitivity, steroid production and feedback pathways. These characteristics suggest that a number of sites are available for xenobiotic interaction. Also, there are different follicle populations within the ovary, which further complicates the situation by allowing for differential follicle toxicity. This creates a situation in which the patterns of infertility induced by a chemical agent would depend on the follicle type affected. For example, toxicity to primordial follicles would not produce immediate signs of infertility but would ultimately shorten the reproductive lifespan. On the other hand, toxicity to antral or preovulatory follicles would result in an immediate loss of reproductive function. The follicle complex is composed of three basic components: granulosa cells, thecal cells and the oocyte. Each of these components has characteristics that may make it uniquely susceptible to chemical injury.

Several investigators have explored methodology for screening xenobiotics for granulosa cell toxicity by measuring the effects on progesterone production by granulosa cells in culture. Oestradiol suppression of progesterone production by granulosa cells has been utilized to verify granulosa cell responsiveness. The pesticide p,p’-DDT and its o,p’-DDT isomer produce supression of progesterone production apparently with potencies equal to that of oestradiol. By contrast, the pesticides malathion, arathion and dieldrin and the fungicide hexachlorobenzene are without effect. Further detailed analysis of isolated granulosa cell responses to xenobiotics is needed to define the utility of this assay system. The attractiveness of isolated systems such as this is economy and ease of use; however, it is important to remember that granulosa cells represent only one component of the reproductive system.

Thecal cells provide precursors for steroids synthesized by granulosa cells. Thecal cells are believed to be recruited from ovarian stroma cells during follicle formation and growth. Recruitment may involve stromal cellular proliferation as well as migration to regions around the follicle. Xenobiotics that impair cell proliferation, migration and communication will impact on thecal cell function. Xenobiotics that alter thecal androgen production may also impair follicle function. For example, the androgens metabolized to oestrogens by granulosa cells are provided by thecal cells. Alterations in thecal cell androgen production, either increases or decreases, are expected to have a significant effect on follicle function. For example, it is believed that excess production of androgens by thecal cells will lead to follicle atresia. In addition, impaired production of androgens by thecal cells may lead to decreased poestrogen production by granulosa cells. Either circumstance will clearly impact on reproductive performance. At resent, little is known about thecal cell vulnerability to xenobiotics.

Although there is a acuity of information defining the vulnerability of ovarian cells to xenobiotics, there are data clearly demonstrating that oocytes can be damaged or destroyed by such agents. Alkylating agents destroy oocytes in humans and experimental animals. Lead produces ovarian toxicity. Mercury and cadmium also produce ovarian damage that may be mediated through oocyte toxicity.

Fertilization to Implantation

Gametogenesis, release and union of male and female germ cells are all preliminary events leading to a zygote. Sperm cells deposited in the vagina must enter the cervix and move through the uterus and into the fallopian tube to meet the ovum. penetration of ovum by sperm and the merging of their respective DNA comprise the process of fertilization. After fertilization cell division is initiated and continues during the next three or four days, forming a solid mass of cells called a morula. The cells of the morula continue to divide, and by the time the developing embryo reaches the uterus it is a hollow ball called a blastocyst.

Following fertilization, the developing embryo migrates through the fallopian tube into the uterus. The blastocyst enters the uterus and implants in the endometrium approximately seven days after ovulation. At this time the endometrium is in the postovulatory phase. Implantation enables the blastocyst to absorb nutrients or toxicants from the glands and blood vessels of the endometrium.



Read 15375 times Last modified on Tuesday, 11 October 2011 20:45


Part I. The Body
Cardiovascular System
Digestive System
Mental Health
Musculoskeletal System
Nervous System
Renal-Urinary System
Reproductive System
Respiratory System
Sensory Systems
Skin Diseases
Systematic Conditions
Part II. Health Care
Part III. Management & Policy
Part IV. Tools and Approaches
Part V. Psychosocial and Organizational Factors
Part VI. General Hazards
Part VII. The Environment
Part VIII. Accidents and Safety Management
Part IX. Chemicals
Part X. Industries Based on Biological Resources
Part XI. Industries Based on Natural Resources
Part XII. Chemical Industries
Part XIII. Manufacturing Industries
Part XIV. Textile and Apparel Industries
Part XV. Transport Industries
Part XVI. Construction
Part XVII. Services and Trade
Part XVIII. Guides

Reproductive System Additional Resources

Click the Button below to view additional resources for this topic.


Reproductive System References

Agency for Toxic Substance and Disease Registry. 1992. Mercury toxicity. Am Fam Phys 46(6):1731-1741.

Ahlborg, JR, L Bodin, and C Hogstedt. 1990. Heavy lifting during pregnancy–A hazard to the fetus? A prospective study. Int J Epidemiol 19:90-97.

Alderson, M. 1986. Occupational Cancer. London: Butterworths.
Anderson, HA, R Lilis, SM Daum, AS Fischbein, and IJ Selikoff. 1976. Household contact asbestos neoplastic risk. Ann NY Acad Sci 271:311-332.

Apostoli, P, L Romeo, E Peroni, A Ferioli, S Ferrari, F Pasini, and F Aprili. 1989. Steroid hormone sulphation in lead workers. Br J Ind Med 46:204-208.

Assennato, G, C Paci, ME Baser, R Molinini, RG Candela, BM Altmura, and R Giogino. 1986. Sperm count suppression with endocrine dysfunction in lead-exposed men. Arch Environ Health 41:387-390.

Awumbila, B and E Bokuma. 1994. Survey of pesticides used in the control of ectoparasites on farm animals in Ghana. Tropic Animal Health Prod 26(1):7-12.

Baker, HWG, TJ Worgul, RJ Santen, LS Jefferson, and CW Bardin. 1977. Effect of prolactin on nuclear androgens in perifused male accessory sex organs. In The Testis in Normal and Infertile Men, edited by P and HN Troen. New York: Raven Press.

Bakir, F, SF Damluji, L Amin-Zaki, M Murtadha, A Khalidi, NY Al-Rawi, S Tikriti, HT Dhahir, TW Clarkson, JC Smith, and RA Doherty. 1973. Methyl mercury poisoning in Iraq. Science 181:230-241.

Bardin, CW. 1986. Pituitary-testicular axis. In Reproductive Endocrinology, edited by SSC Yen and RB Jaffe. Philadelphia: WB Saunders.

Bellinger, D, A Leviton, C Waternaux, H Needleman, and M Rabinowitz. 1987. Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. New Engl J Med 316:1037-1043.

Bellinger, D, A Leviton, E Allred, and M Rabinowitz. 1994. Pre- and postnatal lead exposure and behavior problems in school-aged children. Environ Res 66:12-30.

Berkowitz, GS. 1981. An epidemiologic study of preterm delivery. Am J Epidemiol 113:81-92.

Bertucat, I, N Mamelle, and F Munoz. 1987. Conditions de travail des femmes enceintes–étude dans cinq secteurs d’activité de la région Rhône-Alpes. Arch mal prof méd trav secur soc 48:375-385.

Bianchi, C, A Brollo, and C Zuch. 1993. Asbestos-related familial mesothelioma. Eur J Cancer 2(3) (May):247-250.

Bonde, JPE. 1992. Subfertility in relation to welding–A case referent study among male welders. Danish Med Bull 37:105-108.

Bornschein, RL, J Grote, and T Mitchell. 1989. Effects of prenatal lead exposure on infant size at birth. In Lead Exposure and Child Development, edited by M Smith and L Grant. Boston: Kluwer Academic.

Brody, DJ, JL Pirkle, RA Kramer, KM Flegal, TD Matte, EW Gunter, and DC Pashal. 1994. Blood lead levels in the US population: Phase one of the Third National Health and Nutrition Examination survey (NHANES III, 1988 to 1991). J Am Med Assoc 272:277-283.

Casey, PB, JP Thompson, and JA Vale. 1994. Suspected paediatric poisoning in the UK; I-Home accident surveillance system 1982-1988. Hum Exp Toxicol 13:529-533.

Chapin, RE, SL Dutton, MD Ross, BM Sumrell, and JC Lamb IV. 1984. The effects of ethylene glycol monomethyl ether on testicular histology in F344 rats. J Androl 5:369-380.

Chapin, RE, SL Dutton, MD Ross, and JC Lamb IV. 1985. Effects of ethylene glycol monomethyl ether (EGME) on mating performance and epididymal sperm parameters in F344 rats. Fund Appl Toxicol 5:182-189.

Charlton, A. 1994. Children and passive smoking. J Fam Pract 38(3)(March):267-277.

Chia, SE, CN Ong, ST Lee, and FHM Tsakok. 1992. Blood concentrations of lead, cadmium, mercury, zinc, and copper and human semen parameters. Arch Androl 29(2):177-183.

Chisholm, JJ Jr. 1978. Fouling one’s nest. Pediatrics 62:614-617.

Chilmonczyk, BA, LM Salmun, KN Megathlin, LM Neveux, GE Palomaki, GJ Knight, AJ Pulkkinen, and JE Haddow. 1993. Association between exposure to environmental tobacco smoke and exacerbations of asthma in children. New Engl J Med 328:1665-1669.

Clarkson, TW, GF Nordberg, and PR Sager. 1985. Reproductive and developmental toxicity of metals. Scand J Work Environ Health 11:145-154.
Clement International Corporation. 1991. Toxicological Profile for Lead. Washington, DC: US Department of Health and Human Services, Public Health Service Agency for Toxic Substances and Disease Registry.

——. 1992. Toxicological Profile for A-, B-, G-, and D-Hexachlorocyclohexane. Washington, DC: US Department of Health and Human Services, Public Health Service Agency for Toxic Substances and Disease Registry.

Culler, MD and A Negro-Vilar. 1986. Evidence that pulsatile follicle-stimulating hormone secretion is independent of endogenous luteinizing hormone-releasing hormone. Endocrinology 118:609-612.

Dabeka, RW, KF Karpinski, AD McKenzie, and CD Bajdik. 1986. Survey of lead, cadmium and flouride in human milk and correlation of levels with environmental and food factors. Food Chem Toxicol 24:913-921.

Daniell, WE and TL Vaughn. 1988. Paternal employment in solvent related occupations and adverse pregnancy outcomes. Br J Ind Med 45:193-197.
Davies, JE, HV Dedhia, C Morgade, A Barquet, and HI Maibach. 1983. Lindane poisonings. Arch Dermatol 119 (Feb):142-144.

Davis, JR, RC Bronson, and R Garcia. 1992. Family pesticide use in the home, garden, orchard, and yard. Arch Environ Contam Toxicol 22(3):260-266.

Dawson, A, A Gibbs, K Browne, F Pooley, and M Griffiths. 1992. Familial mesothelioma. Details of seventeen cases with histopathologic findings and mineral analysis. Cancer 70(5):1183-1187.

D’Ercole, JA, RD Arthur, JD Cain, and BF Barrentine. 1976. Insecticide exposure of mothers and newborns in a rural agricultural area. Pediatrics 57(6):869-874.

Ehling, UH, L Machemer, W Buselmaier, J Dycka, H Froomberg, J Dratochvilova, R Lang, D Lorke, D Muller, J Peh, G Rohrborn, R Roll, M Schulze-Schencking, and H Wiemann. 1978. Standard protocol for the dominant lethal test on male mice. Arch Toxicol 39:173-185.

Evenson, DP. 1986. Flow cytometry of acridine orange stained sperm is a rapid and practical method for monitoring occupational exposure to genotoxicants. In Monitoring of Occupational Genotoxicants, edited by M Sorsa and H Norppa. New York: Alan R Liss.

Fabro, S. 1985. Drugs and male sexual function. Rep Toxicol Med Lettr 4:1-4.

Farfel, MR, JJ Chisholm Jr, and CA Rohde. 1994. The long-term effectiveness of residential lead paint abatement. Environ Res 66:217-221.

Fein, G, JL Jacobson, SL Jacobson, PM Schwartz, and JK Dowler. 1984. Prenatal exposure to polychlorinated biphenyls: effects on birth size and gestational age. J Pediat 105:315-320.

Fenske, RA, KG Black, KP Elkner, C Lee, MM Methner, and R Soto. 1994. Potential exposure and health risks of infants following indoor residential pesticide applications. Am J Public Health 80(6):689-693.

Fischbein, A and MS Wolff. 1987. Conjugal exposure to polychlorinated biphenyls (PCBs). Br J Ind Med 44:284-286.

Florentine, MJ and DJ II Sanfilippo. 1991. Elemental mercury poisoning. Clin Pharmacol 10(3):213-221.

Frischer, T, J Kuehr, R Meinert, W Karmaus, R Barth, E Hermann-Kunz, and R Urbanek. 1992. Maternal smoking in early childhood: A risk factor for bronchial responsiveness to exercise in primary-school children. J Pediat 121 (Jul):17-22.

Gardner, MJ, AJ Hall, and MP Snee. 1990. Methods and basic design of case-control study of leukemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. Br Med J 300:429-434.

Gold, EB and LE Sever. 1994. Childhood cancers associated with parental occupational exposures. Occup Med .

Goldman, LR and J Carra. 1994. Childhood lead poisoning in 1994. J Am Med Assoc 272(4):315-316.

Grandjean, P and E Bach. 1986. Indirect exposures: the significance of bystanders at work and at home. Am Ind Hyg Assoc J 47(12):819-824.
Hansen, J, NH de-Klerk, JL Eccles, AW Musk, and MS Hobbs. 1993. Malignant mesothelioma after environmental exposure to blue asbestos. Int J Cancer 54(4):578-581.

Hecht, NB. 1987. Detecting the effects of toxic agents on spermatogenesis using DNA probes. Environ Health Persp 74:31-40.
Holly, EA, DA Aston, DK Ahn, and JJ Kristiansen. 1992. Ewing’s bone sarcoma, paternal occupational exposure and other factors. Am J Epidemiol 135:122-129.

Homer, CJ, SA Beredford, and SA James. 1990. Work-related physical exertion and risk of preterm, low birthweight delivery. Paediat Perin Epidemiol 4:161-174.

International Agency for Research on Cancer (IARC). 1987. Monographs On the Evaluation of Carcinogenic Risks to Humans, Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs. Vol. 1-42, Suppl. 7. Lyon: IARC.

International Labour Organization (ILO). 1965. Maternity Protection: A World Survey of National Law and Practice. Extract from the Report of the Thirty-fifth Session of the Committee of Experts on the Application of Conventions and Recommendations, para. 199, note 1, p.235. Geneva:ILO.

——. 1988. Equality in Employment and Occupation, Report III (4B). International Labour Conference, 75th Session. Geneva: ILO.

Isenman, AW and LJ Warshaw. 1977. Guidelines On Pregnancy and Work. Chicago: American College of Obstetricians and Gynecologists.

Jacobson, SW, G Fein, JL Jacobson, PM Schwartz, and JK Dowler. 1985. The effect of intrauterine PCB exposure on visual recognition memory. Child Development 56:853-860.

Jensen, NE, IB Sneddon, and AE Walker. 1972. Tetrachlorobenzodioxin and chloracne. Trans St Johns Hosp Dermatol Soc 58:172-177.

Källén, B. 1988. Epidemiology of Human Reproduction. Boca Raton:CRC Press

Kaminski, M, C Rumeau, and D Schwartz. 1978. Alcohol consumption in pregnant women and the outcome of pregnancy. Alcohol, Clin Exp Res 2:155-163.

Kaye, WE, TE Novotny, and M Tucker. 1987. New ceramics-related industry implicated in elevated blood lead levels in children. Arch Environ Health 42:161-164.

Klebanoff, MA, PH Shiono, and JC Carey. 1990. The effect of physical activity during pregnancy on preterm delivery and birthweight. Am J Obstet Gynecol 163:1450-1456.

Kline, J, Z Stein, and M Susser. 1989. Conception to birth-epidemiology of prenatal development. Vol. 14. Monograph in Epidemiology and Biostatistics. New York: Oxford Univ. Press.

Kotsugi, F, SJ Winters, HS Keeping, B Attardi, H Oshima, and P Troen. 1988. Effects of inhibin from primate sertoli cells on follicle-stimulating hormone and luteinizing hormone release by perifused rat pituitary cells. Endocrinology 122:2796-2802.

Kramer, MS, TA Hutchinson, SA Rudnick, JM Leventhal, and AR Feinstein. 1990. Operational criteria for adverse drug reactions in evaluating suspected toxicity of a popular scabicide. Clin Pharmacol Ther 27(2):149-155.

Kristensen, P, LM Irgens, AK Daltveit, and A Andersen. 1993. Perinatal outcome among children of men exposed to lead and organic solvents in the printing industry. Am J Epidemiol 137:134-144.

Kucera, J. 1968. Exposure to fat solvents: A possible cause of sacral agenesis in man. J Pediat 72:857-859.

Landrigan, PJ and CC Campbell. 1991. Chemical and physical agents. Chap. 17 in Fetal and Neonatal Effects of Maternal Disease, edited by AY Sweet and EG Brown. St. Louis: Mosby Year Book.

Launer, LJ, J Villar, E Kestler, and M de Onis. 1990. The effect of maternal work on fetal growth and duration of pregnancy: a prospective study. Br J Obstet Gynaec 97:62-70.

Lewis, RG, RC Fortmann, and DE Camann. 1994. Evaluation of methods for monitoring the potential exposure of small children to pesticides in the residential environment. Arch Environ Contam Toxicol 26:37-46.

Li, FP, MG Dreyfus, and KH Antman. 1989. Asbestos-contaminated nappies and familial mesothelioma. Lancet 1:909-910.

Lindbohm, ML, K Hemminki, and P Kyyronen. 1984. Parental occupational exposure and spontaneous abortions in Finland. Am J Epidemiol 120:370-378.

Lindbohm, ML, K Hemminki, MG Bonhomme, A Anttila, K Rantala, P Heikkila, and MJ Rosenberg. 1991a. Effects of paternal occupational exposure on spontaneous abortions. Am J Public Health 81:1029-1033.

Lindbohm, ML, M Sallmen, A Antilla, H Taskinen, and K Hemminki. 1991b. Paternal occupational lead exposure and spontaneous abortion. Scand J Work Environ Health 17:95-103.

Luke, B, N Mamelle, L Keith, and F Munoz. 1995. The association between occupational factors and preterm birth in US nurses’ survey. Obstet Gynecol Ann 173(3):849-862.

Mamelle, N, I Bertucat, and F Munoz. 1989. Pregnant women at work: Rest periods to prevent preterm birth? Paediat Perin Epidemiol 3:19-28.

Mamelle, N, B Laumon, and PH Lazar. 1984. Prematurity and occupational activity during pregnancy. Am J Epidemiol 119:309-322.

Mamelle, N and F Munoz. 1987. Occupational working conditions and preterm birth: A reliable scoring system. Am J Epidemiol 126:150-152.

Mamelle, N, J Dreyfus, M Van Lierde, and R Renaud. 1982. Mode de vie et grossesse. J Gynecol Obstet Biol Reprod 11:55-63.

Mamelle, N, I Bertucat, JP Auray, and G Duru. 1986. Quelles mesures de la prevention de la prématurité en milieu professionel? Rev Epidemiol Santé Publ 34:286-293.

Marbury, MC, SK Hammon, and NJ Haley. 1993. Measuring exposure to environmental tobacco smoke in studies of acute health effects. Am J Epidemiol 137(10):1089-1097.

Marks, R. 1988. Role of childhood in the development of skin cancer. Aust Paediat J 24:337-338.

Martin, RH. 1983. A detailed method for obtaining preparations of human sperm chromosomes. Cytogenet Cell Genet 35:252-256.

Matsumoto, AM. 1989. Hormonal control of human spermatogenesis. In The Testis, edited by H Burger and D de Kretser. New York: Raven Press.

Mattison, DR, DR Plowchalk, MJ Meadows, AZ Al-Juburi, J Gandy, and A Malek. 1990. Reproductive toxicity: male and female reproductive systems as targets for chemical injury. Med Clin N Am 74:391-411.

Maxcy Rosenau-Last. 1994. Public Health and Preventive Medicine. New York: Appleton-Century-Crofts.

McConnell, R. 1986. Pesticides and related compounds. In Clinical Occupational Medicine, edited by L Rosenstock and MR Cullen. Philadelphia: WB Saunders.

McDonald, AD, JC McDonald, B Armstrong, NM Cherry, AD Nolin, and D Robert. 1988. Prematurity and work in pregnancy. Br J Ind Med 45:56-62.

——. 1989. Fathers’ occupation and pregnancy outcome. Br J Ind Med 46:329-333.

McLachlan, RL, AM Matsumoto, HG Burger, DM de Kretzer, and WJ Bremner. 1988. Relative roles of follicle-stimulating hormone and luteinizing hormone in the control of inhibin secretion in normal men. J Clin Invest 82:880-884.

Meeks, A, PR Keith, and MS Tanner. 1990. Nephrotic syndrome in two members of a family with mercury poisoning. J Trace Elements Electrol Health Dis 4(4):237-239.

National Reasearch Council. 1986. Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects. Washington, DC: National Academy Press.

——. 1993. Pesticides in the Diets of Infants and Children. Washington, DC: National Academy Press.

Needleman, HL and D Bellinger. 1984. The developmental consequences of childhood exposure to lead. Adv Clin Child Psychol 7:195-220.

Nelson, K and LB Holmes. 1989. Malformations due to presumed spontaneous mutations in newborn infants. New Engl J Med 320(1):19-23.

Nicholson, WJ. 1986. Airborne Asbestos Health Assessment Update. Document No. EPS/600/8084/003F. Washington, DC: Environmental Criteria and Assessment.

O’Leary, LM, AM Hicks, JM Peters, and S London. 1991. Parental occupational exposures and risk of childhood cancer: a review. Am J Ind Med 20:17-35.

Olsen, J. 1983. Risk of exposure to teratogens amongst laboratory staff and painters. Danish Med Bull 30:24-28.

Olsen, JH, PDN Brown, G Schulgen, and OM Jensen. 1991. Parental employment at time of conception and risk of cancer in offspring. Eur J Cancer 27:958-965.

Otte, KE, TI Sigsgaard, and J Kjaerulff. 1990. Malignant mesothelioma clustering in a family producing asbestos cement in their home. Br J Ind Med 47:10-13.

Paul, M. 1993. Occupational and Environmental Reproductive Hazards: A Guide for Clinicians. Baltimore: Williams & Wilkins.

Peoples-Sheps, MD, E Siegel, CM Suchindran, H Origasa, A Ware, and A Barakat. 1991. Characteristics of maternal employment during pregnancy: Effects on low birthweight. Am J Public Health 81:1007-1012.

Pirkle, JL, DJ Brody, EW Gunter, RA Kramer, DC Paschal, KM Flegal, and TD Matte. 1994. The decline in blood lead levels in the United States. J Am Med Assoc 272 (Jul):284-291.

Plant, TM. 1988. Puberty in primates. In The Physiology of Reproduction, edited by E Knobil and JD Neill. New York: Raven Press.

Plowchalk, DR, MJ Meadows, and DR Mattison. 1992. Female reproductive toxicity. In Occupational and Environmental Reproductive Hazards: A Guide for Clinicians, edited by M Paul. Baltimore: Williams and Wilkins.

Potashnik, G and D Abeliovich. 1985. Chromosomal analysis and health status of children conceived to men during or following dibromochloropropane-induced spermatogenic suppression. Andrologia 17:291-296.

Rabinowitz, M, A Leviton, and H Needleman. 1985. Lead in milk and infant blood: A dose-response model. Arch Environ Health 40:283-286.

Ratcliffe, JM, SM Schrader, K Steenland, DE Clapp, T Turner, and RW Hornung. 1987. Semen quality in papaya workers with long term exposure to ethylene dibromide. Br J Ind Med 44:317-326.

Referee (The). 1994. J Assoc Anal Chem 18(8):1-16.

Rinehart, RD and Y Yanagisawa. 1993. Paraoccupational exposures to lead and tin carried by electric-cable splicers. Am Ind Hyg Assoc J 54(10):593-599.

Rodamilans, M, MJM Osaba, J To-Figueras, F Rivera Fillat, JM Marques, P Perez, and J Corbella. 1988. Lead toxicity on endocrine testicular function in an occupationally exposed population. Hum Toxicol 7:125-128.

Rogan, WJ, BC Gladen, JD McKinney, N Carreras, P Hardy, J Thullen, J Tingelstad, and M Tully. 1986. Neonatal effects of transplacental exposure to PCBs and DDE. J Pediat 109:335-341.

Roggli, VL and WE Longo. 1991. Mineral fiber content of lung tissue in patients with environmental exposures: household contacts vs. building occupants. Ann NY Acad Sci 643 (31 Dec):511-518.

Roper, WL. 1991. Preventing Lead Poisoning in Young Children: A Statement by the Centers for Disease Control. Washington, DC: US Department of Health and Human Services.

Rowens, B, D Guerrero-Betancourt, CA Gottlieb, RJ Boyes, and MS Eichenhorn. 1991. Respiratory failure and death following acute inhalation of mercury vapor. A clinical and histologic perspective. Chest 99(1):185-190.

Rylander, E, G Pershagen, M Eriksson, and L Nordvall. 1993. Parental smoking and other risk factors for wheezing bronchitis in children. Eur J Epidemiol 9(5):516-526.

Ryu, JE, EE Ziegler, and JS Fomon. 1978. Maternal lead exposure and blood lead concentration in infancy. J Pediat 93:476-478.

Ryu, JE, EE Ziegler, SE Nelson, and JS Fomon. 1983. Dietary intake of lead and blood lead concentration in early infancy. Am J Dis Child 137:886-891.

Sager, DB and DM Girard. 1994. Long term effects on reproductive parameters in female rats after translactional exposure to PCBs. Environ Res 66:52-76.

Sallmen, M, ML Lindbohm, A Anttila, H Taskinen, and K Hemminki. 1992. Paternal occupational lead exposure and congenital malformations. J Epidemiol Community Health 46(5):519-522.

Saurel-Cubizolles, MJ and M Kaminski. 1987. Pregnant women’s working conditions and their changes during pregnancy: A national study in France. Br J Ind Med 44:236-243.

Savitz, DA, NL Sonnerfeld, and AF Olshaw. 1994. Review of epidemiologic studies of paternal occupational exposure and spontaneous abortion. Am J Ind Med 25:361-383.

Savy-Moore, RJ and NB Schwartz. 1980. Differential control of FSH and LH secretion. Int Rev Physiol 22:203-248.

Schaefer, M. 1994. Children and toxic substances: Confronting a major public health challenge. Environ Health Persp 102 Suppl. 2:155-156.

Schenker, MB, SJ Samuels, RS Green, and P Wiggins. 1990. Adverse reproductive outcomes among female veterinarians. Am J Epidemiol 132 (January):96-106.

Schreiber, JS. 1993. Predicted infant exposure to tetrachloroethene in human breastmilk. Risk Anal 13(5):515-524.

Segal, S, H Yaffe, N Laufer, and M Ben-David. 1979. Male hyperprolactinemia: Effects on fertility. Fert Steril 32:556-561.

Selevan, SG. 1985. Design of pregnancy outcome studies of industrial exposures. In Occupational Hazards and Reproduction, edited by K Hemminki, M Sorsa, and H Vainio. Washington, DC: Hemisphere.

Sever, LE, ES Gilbert, NA Hessol, and JM McIntyre. 1988. A case-control study of congenital malformations and occupational exposure to low-level radiation. Am J Epidemiol 127:226-242.

Shannon, MW and JW Graef. 1992. Lead intoxication in infancy. Pediatrics 89:87-90.

Sharpe, RM. 1989. Follicle-stimulating hormone and spermatogenesis in the adult male. J Endocrinol 121:405-407.

Shepard, T, AG Fantel, and J Fitsimmons. 1989. Congenital defect abortuses: Twenty years of monitoring. Teratology 39:325-331.

Shilon, M, GF Paz, and ZT Homonnai. 1984. The use of phenoxybenzamine treatment in premature ejaculation. Fert Steril 42:659-661.

Smith, AG. 1991. Chlorinated hydrocarbon insecticides. In Handbook of Pesticide Toxicology, edited by WJ Hayes and ER Laws. New York: Acedemic Press.

Sockrider, MM and DB Coultras. 1994. Environmental tobacco smoke: a real and present danger. J Resp Dis 15(8):715-733.

Stachel, B, RC Dougherty, U Lahl, M Schlosser, and B Zeschmar. 1989. Toxic environmental chemicals in human semen: analytical method and case studies. Andrologia 21:282-291.

Starr, HG, FD Aldrich, WD McDougall III, and LM Mounce. 1974. Contribution of household dust to the human exposure to pesticides. Pest Monit J 8:209-212.

Stein, ZA, MW Susser, and G Saenger. 1975. Famine and Human Development. The Dutch Hunger Winter of 1944/45. New York: Oxford Univ. Press.

Taguchi, S and T Yakushiji. 1988. Influence of termite treatment in the home on the chlordane concentration in human milk. Arch Environ Contam Toxicol 17:65-71.

Taskinen, HK. 1993. Epidemiological studies in monitoring reproductive effects. Environ Health Persp 101 Suppl. 3:279-283.

Taskinen, H, A Antilla, ML Lindbohm, M Sallmen, and K Hemminki. 1989. Spontaneous abortions and congenital malformations among the wives of men occupationally exposed to organic solvents. Scand J Work Environ Health 15:345-352.

Teitelman, AM, LS Welch, KG Hellenbrand, and MB Bracken. 1990. The effects of maternal work activity on preterm birth and low birth weight. Am J Epidemiol 131:104-113.

Thorner, MO, CRW Edwards, JP Hanker, G Abraham, and GM Besser. 1977. Prolactin and gonadotropin interaction in the male. In The Testis in Normal and Infertile Men, edited by P Troen and H Nankin. New York :Raven Press.

US Environmental Protection Agency (US EPA). 1992. Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders. Publication No. EPA/600/6-90/006F. Washington, DC: US EPA.

Veulemans, H, O Steeno, R Masschelein, and D Groesneken. 1993. Exposure to ethylene glycol ethers and spermatogenic disorders in man: A case-control study. Br J Ind Med 50:71-78.

Villar, J and JM Belizan. 1982. The relative contribution of prematurity and fetal growth retardation to low birth weight in developing and developed societies. Am J Obstet Gynecol 143(7):793-798.

Welch, LS, SM Schrader, TW Turner, and MR Cullen. 1988. Effects of exposure to ethylene glycol ethers on shipyard painters: ii. male reproduction. Am J Ind Med 14:509-526.

Whorton, D, TH Milby, RM Krauss, and HA Stubbs. 1979. Testicular function in DBCP exposed pesticide workers. J Occup Med 21:161-166.

Wilcox, AJ, CR Weinberg, JF O’Connor, DD BBaird, JP Schlatterer, RE Canfield, EG Armstrong, and BC Nisula. 1988. Incidence of early loss of pregnancy. New Engl J Med 319:189-194.

Wilkins, JR and T Sinks. 1990. Parental occupation and intracranial neoplasms of childhood: Results of a case-control interview study. Am J Epidemiol 132:275-292.

Wilson, JG. 1973. Environment and Birth Defects. New York: Academic Press.

——. 1977. current status of teratology-general principles and mechanisms derived from animal studies. In Handbook of Teratology, Volume 1, General Principles and Etiology, edited by JG Fraser and FC Wilson. New York: Plenum.

Winters, SJ. 1990. Inhibin is released together with testosterone by the human testis. J Clin Endocrinol Metabol 70:548-550.

Wolff, MS. 1985. Occupational exposure to polychlorinated biphenyls. Environ Health Persp 60:133-138.

——. 1993. Lactation. In Occupational and Environmental Reproductive Hazards: A Guide for Clinicians, edited by M Paul. Baltimore: Williams & Wilkins.

Wolff, MS and A Schecter. 1991. Accidental exposure of children to polychlorinated biphenyls. Arch Environ Contam Toxicol 20:449-453.

World Health Organization (WHO). 1969. Prevention of perinatal morbidity and mortality. Public Health Papers, No. 42. Geneva: WHO.

——. 1977. Modification Recommended by FIGO. WHO recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal death. Acta Obstet Gynecol Scand 56:247-253.

Zaneveld, LJD. 1978. The biology of human spermatozoa. Obstet Gynecol Ann 7:15-40.

Ziegler, EE, BB Edwards, RL Jensen, KR Mahaffey, and JS Fomon. 1978. Absorption and retention of lead by infants. Pediat Res 12:29-34.

Zikarge, A. 1986. Cross-Sectional Study of Ethylene Dibromide-Induced Alterations of Seminal Plasma Biochemistry as a Function of Post-Testicular Toxicity with Relationships to Some Indices of Semen Analysis and Endocrine Profile. Dissertation, Houston, Texas: Univ.of Texas Health Science Center.

Zirschky, J and L Wetherell. 1987. Cleanup of mercury contamination of thermometer workers’ homes. Am Ind Hyg Assoc J 48:82-84.

Zukerman, Z, LJ Rodriguez-Rigau, DB Weiss, AK Chowdhury, KD Smith, and E Steinberger. 1978. Quantitative analysis of the seminiferous epithelium in human testicular biopsies, and the relation of spermatogenesis to sperm density. Fert Steril 30:448-455.

Zwiener, RJ and CM Ginsburg. 1988. Organophosphate and carbamate poisoning in infants and children. Pediatrics 81(1):121-126