Environmental Toxins Associated with Recurrent Pregnancy Loss

ABSTRACT

Couples experiencing recurrent pregnancy loss are often concerned that toxins within the environment have contributed to their reproductive difficulty. Questions posed by these couples to their health care providers are difficult to answer because scientifically accurate information regarding the reproductive impact of potential environmental toxins and other teratogens is not readily available. Heavy metals such as lead and mercury, organic solvents, alcohol, and ionizing radiation are confirmed environmental teratogens, and exposure could contribute to pregnancy loss. Caffeine, cigarette smoking, and hyperthermia are suspected teratogens, and the teratogenic impact of pesticides remains unknown. The teratogenic potential of multiple other environmental factors has been studied and is reviewed. Before definitive conclusions can be drawn regarding the teratogenicity of environmental exposures, several clinical factors need to be addressed, including gestational age at the time of exposure, the amount of toxin reaching the conceptus, the duration of exposure, the impact of other factors or agents to which the mother or her conceptus is simultaneously exposed, and the physiological status of the mother and conceptus. In addition, in a given population, the interrelationship between frequency of exposures, frequency of effects, and recognizability of adverse outcomes, such as spontaneous abortion, should be considered.

KEYWORD

Environment - toxins - teratogens

REFERENCES

• 1 Carson R. Silent Spring.  Boston: Houghton Mifflin; 1962
• 2 Shepard T. Catalog of Teratogenic Agents.  8th ed. Baltimore: Johns Hopkins University Press; 1995
• 3 Koren G. Maternal-Fetal Toxicology: A Clinician's guide New York: Marcel Dekker; 1990
• 4 Shepard T H. Human teratogenicity.  Adv Pediatr . 1986;  33 225
• 5 Brent R L. The effects of embryonic and fetal exposure to x-ray, microwaves, and ultrasound.  Clin Perinatol . 1986;  13 615
• 6 Friedman J, Polifka J. Teratogenic Effects of Drugs: A Resource for Clinicians (TERIS).  Baltimore: Johns Hopkins University Press; 1994
• 7 James W. Environmental toxicants and sex ratios: effects?.  <~>[letter]. Fertil Steril . 1999;  71 775
• 8 Wilson J G. Embryotoxicity of drugs in man. In: Wilson JG, Fraser FC, eds. Handbook of Teratology Vol. 1. New York: Plenum 1977: 309-355
• 9 Brent R L. Editor's note.  Teratology . 1978;  17 183-184
• 10 Beckman D A, Brent R L. Mechanisms of teratogenesis.  Annu Rev Pharmacol Toxicol . 1984;  24 483-500
• 11 Karnofsky C A. Mechanisms of action of certain growth-inhibiting drugs. In: Wilson JG, Warkany J, eds. Teratology: Principles and Techniques Chicago: University of Chicago Press 1965: 185-213
• 12 Gregg N M. Congenital cataract following German measles in the mother.  Trans Ophthalmol Soc Aust . 1941;  3 35
• 13 Koren G, Pastuszak M, Ito S. Drugs in pregnancy.  N Engl J Med . 1998;  338 1128-1137
• 14 Miller R W. Effects of ionizing radiation from the atomic bomb on Japanese children.  Pediatrics . 1968;  41 257
• 15 Wood J W, Johnson K G, Omori Y. Mental retardation in children exposed in utero to the atomic bombs in Hiroshima and Nagasaki.  Am J Public Health . 1967;  57 1381
• 16 Yamazaki J N, Schull W H. Perinatal loss and neurological abnormalities among children of the atomic bomb: Nagasaki and Hiroshima revisited, 1949 to 1989.  JAMA . 1990;  264 605
• 17 Dekaban A S. Abnormalities in children exposed to x-radiation during various stages of gestation: tentative timetable of radiation injury to the human fetus, part I.  J Nucl Med . 1968;  9 471
• 18 Creasy R K, Resnick R. Maternal-Fetal Medicine: Principles and Practice 3rd ed. Philadelphia: WB Saunders; 1994
• 19 Archer V E. Anencephalus, drinking water, geomagnetism and cosmic radiation.  Am J Epidemiol . 1979;  109 88
• 20 Segall A, MacMahon D, Hannigan M. Congenital malformations and background radiation in northern New England.  J Chronic Dis . 1964;  17 915
• 21 Elliot J P, Trujillo F. Fetal monitoring during emergency obstetric transport.  Am J Obstet Gynecol . 1987;  157 245-247
• 22 Huch R, Baumann H, Fallenstein F, Schneider K T, Holdener F, Huch A. Physiologic changes in pregnant women and their fetuses during jet air travel.  Am J Obstet Gynecol . 1986;  154 996-1000
• 23 Cruikshank J M, Gorlin R, Jennett B. Air travel and thrombotic episodes: the economy class syndrome.  Lancet . 1988;  2 498
• 24 Michaelson S M. Biological effects of microwave exposure. In: Cleary SF, ed. Biological Effects and Implications of Microwave Radiation. Symposium Proceedings, Richmond, VA. September 17-19 Richmond, VA: U.S. Public Health Service 1969: 35-58
• 25 Brent R L. Radiations and other physical agents. In: Wilson JG, Frasier FC, eds. Handbook of Teratology Vol. 1. New York: Plenum 1977: 153-223
• 26 Lary J M, Conover D L. Teratogenic effects of radio frequency radiation. IEEE Eng Med Biol Mag 1987 March: 26-42
• 27 Rubin A, Erdman W J. Microwave exposure of the human female pelvis during early pregnancy and prior to conception: case report.  Am J Phys Med . 1959;  38 219-220
• 28 Ouellet-Hellstrom R, Stewart W F. Miscarriages among female physical therapists who report using radio- and microwave-frequency electromagnetic radiation.  Am J Epidemiol . 1993;  138 775-786
• 29 Mannor S M, Serr D M, Tamari I, Meshorer A, Frei E H. The safety of ultrasound in fetal monitoring.  Am J Obstet Gynecol . 1972;  133 653-661
• 30 Lary J M, Conover D L, Fole E D, Hanser P L. Teratogenicity of 27.12 MHz radiofrequency radiation in rats.  Teratology . 1982;  26 299-309
• 31 Brown-Woodman P DC, Hadley J A, Waterhouse J, Webster W S. Teratogenic effects of exposure to radiofrequency radiation (27.12 MHz) from a shortwave diathermy unit.  Ind Health . 1988;  26 1-10
• 32 Nyborg W L. Physical Mechanisms for Biologic Effects of Ultrasound. HEW Publication (FDA) 78-8062, 1977
• 33 Repacholi M H. Ultrasound: Characteristics and Biological Action. National Research Council of Canada, Publication NRCC 19244, Ottawa, 1981
• 34 Stewart H F, Stratmeyer M E. An Overview of Ultrasound: Theory, Measurement, Medical Applications and Biological Effects. HHS Publication FDA 82-8290 Washington, DC: U.S. Government Printing Office; 1982
• 35 World Health Organization (WHO). Environmental Health Criteria 22 for Ultrasound. Geneva, Switzerland, 1982
• 36 National Institute of Health. Diagnostic Ultrasound Imaging in Pregnancy: Report of a Consensus.  NIH Publication 84-667. Washington, DC: U.S. Government Printing Office; 1984
• 37 Reece E A, Assimakipoulos E, Zheng X, Hagay Z, Hobbins J C. The safety of obstetric ultrasonography: concern for the fetus.  Obstet Gynecol Rev . 1990;  76 139-145
• 38 Meyer R E, Aldrich T E, Easterly C E. Effects of noise and electromagnetic fields on reproductive outcomes.  Environ Health Perspect . 1989;  81 193-200
• 39 Chernoff J, Rogers J M, Kavet R. A review of the literature on potential reproductive and developmental toxicity of electric and magnetic fields.  Toxicology . 1992;  74 91-126
• 40 Robert E. Birth defects and high voltage power lines: an exploratory study based on registry data.  Reprod Toxicol . 1993;  7 283-287
• 41 Kowalczuk C I, Robbins L, Thomas J M, Butland B K, Saunders R D. Effects of prenatal exposure to 50 Hz magnetic fields on development in mice: I. Implantation rate and fetal development.  Bioelectromagnetics . 1994;  15 349-361
• 42 Mevissen M, Buntenkotter S, Loscher W. Effects of static and time-varying (50 Hz) magnetic fields on reproduction and fetal development in rats.  Teratology . 1994;  50 229-237
• 43 Goldhaber M K, Polen M R, Hiatt R A. The risk of miscarriage and birth defects among women who use video display terminals during pregnancy.  Am J Ind Med . 1988;  13 695-706
• 44 Windham G C, Fenster L, Swan S H, Neutra R R. Use of video display terminals during pregnancy and the risk of spontaneous abortion, low birthweight, or intrauterine growth retardation.  Am J Ind Med . 1990;  18 675-688
• 45 McDonald A D, Cherry N M, Delorme C, McDonald J C. Visual display units and pregnancy: evidence from the Montreal survey.  J Occup Med . 1986;  8 1226-1231
• 46 Schnorr T M, Grajewski B A, Hornung R W. Video display terminals and the risk of spontaneous abortion.  N Engl J Med . 1991;  325 811-813
• 47 McAnulty P A, Collier M J, Enticott J. Absence of developmental effects in cf-1 mice exposed to aspartame in utero.  Fundam Appl Toxicol . 1989;  13 296-302
• 48 Lederer J, Bodin J, Colson A. L'Aspartame et son effect sur la gestation chez le rat.  J Toxicol Clin Exp . 1985;  7-14
• 49 Stegnik L D, Filer L J, Baker G L, McDonnell J E. Effect of an abuse dose of aspartame upon plasma and erythrocyte levels of amino acids in phenylketonuria heterozygous and normal adults.  J Nutr . 1980;  110 2216-2224
• 50 Cranmer M F. Saccharin: A Report.  Park Forest South, IL: American Drug Institute and Pathotox Publishers; 1980
• 51 Fritz H, Hess R. Prenatal development in the rat following administration of cyclamate, saccharin, and sucrose.  Experientia . 1968;  24 1140-1141
• 52 Kline J, Stein Z A, Susser M, Warburton D. Spontaneous abortion and the use of sugar substitutes.  Am J Obstet Gynecol . 1978;  130 708-711
• 53 Kroes R, Peters P WJ, Berkvens J M, Verschuuren T D, Van Esch J G. Long term toxicity and reproduction study (including a teratogenicity study) with cyclamate, saccharin, and cyclohexylamine.  Toxicology . 1977;  8 285-300
• 54 Taylor J M, Weinberger M A, Friedman L. Chronic toxicity and carcinogenicity to the urinary bladder of sodium saccharin in the in utero-exposed rat.  Toxicol Appl Pharmacol . 1980;  54 57-75
• 55 Nelig A, Debry G. Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review on human and animal data.  Neurotoxicol Teratol . 1994;  16 531-543
• 56 Bertrand M, Schwam E, Frandon A, Vagne A, Alary J. Sur un effet teratogene systematique et specifique de la cafeine chez les rongeurs.  C R Soc Biol (Paris) . 1965;  159 2199-2202
• 57 Linn S, Schoenbaum S C, Monson R R, Rosner B, Stabblefield P G, Ryan K J. No association between coffee consumption and adverse outcomes of pregnancy.  N Engl J Med . 1982;  306 141-145
• 58 Rosenberg L, Mitchell A A, Shapiro S, Slone D. Selected birth defects in relation to caffeine containing beverages.  JAMA . 1982;  247 1429-1432
• 59 Srisuphan W, Bracken M B. Caffeine consumption during pregnancy and association with late spontaneous abortion.  Am J Obstet Gynecol . 1986;  154 14-20
• 60 Kline J, Levin B, Silverman J. Caffeine and spontaneous abortion of known karyotype.  Epidemiology . 1991;  2 409-417
• 61 Infante-Rivard C, Fernandez A, Gauthier F, David M, Rivard G. Fetal loss associated with caffeine intake before and during pregnancy.  JAMA . 1993;  270 2940-2943
• 62 Mills J L, Holmes L B, Aarons J H. Moderate caffeine use and the risk of spontaneous abortion and intrauterine growth retardation.  JAMA . 1993;  269 593-597
• 63 Stein Z, Susser M. Miscarriage, caffeine, and the epiphenomena of pregnancy: the causal model.  Epidemiology . 1991;  2 163-167
• 64 Tarka Jr M S, Applebaum R S, Borzelleca J F. Evaluation of the perinatal, postnatal, and teratogenic effects of cocoa powder and theobromine in Sprague-Dawley CD rats.  Food Chem Toxicol . 1986;  24 375-382
• 65 Deane M, Swan S H, Harris J A. Adverse pregnancy outcomes in relation to water contamination, Santa Clara County, California 1980-1981.  Am J Epidemiol . 1989;  129 894
• 66 Deane M, Swan S H, Harris J A. Adverse pregnancy outcomes in relation to water contamination: a reanalysis of data from the original Santa Clara County Study, California, 1980-1981.  Epidemiology . 1992;  3 94-97
• 67 Hertz-Picciotto I, Swan S H, Neutra R R. Tap or bottled water consumption and spontaneous abortion: a 1986 case-control study in California.  Epidemiology . 1992;  3 113-119
• 68 Wrensch M, Swan S H, Lipscomb J. Spontaneous abortions and birth defects related to tap and bottled water use, San Jose, California, 1980-1985.  Epidemiology . 1992;  3 113-119
• 69 Swan S H, Neutra R R, Wrensch M. Is drinking water related to spontaneous abortion?.  <~>Reviewing the evidence from the California Department of Health Services studies. Epidemiology . 1992;  3 83-93
• 70 Swan S H, Waller K, Hopkins B. A prospective study of spontaneous abortion: relation to amount and source of drinking water consumed in early pregnancy.  Epidemiology . 1998;  9 126-133
• 71 Waller K, Swan S H, DeLorenze G, Hopkins B. Trihalomethanes in drinking water and spontaneous abortion.  Epidemiology . 1998;  9 134-140
• 72 Savitz D A, Andrews K W, Pastore L M. Drinking water and pregnancy outcome in central North Carolina: source, amount, and trihalomethane levels.  Environ Health Perspect . 1995;  103 592-596
• 73 Urir-Hare J Y, Swan S H, Bui L M, Neutra R R, Keen C L. Drinking water source and reproductive outcomes in Sprague-Dawley rats.  Reprod Toxicol . 1995;  9 549-561
• 74 Chernoff N, Rogers E H, Carver B, Kavlock R, Gray E. The fetotoxic potential of municipal drinking water in the mouse.  Teratology . 1979;  19 165-170
• 75 Staples R E, Worthy W C, Marks T A. Influence of drinking water: tap versus purified on embryo and fetal development in mice.  Teratology . 1979;  19 237-244
• 76 Ruddick J A, Villeneuve D C, Chu I, Valli V E. A teratological assessment of four trihalomethanes in the rat.  J Environ Sci Health . 1983;  B18 333-349
• 77 Eppard P J, Bentle L A, Violand B N. Comparison of the galactopoietic response to pituitary-derived and recombinant-derived variants of bovine growth hormone.  J Endocrinol . 1992;  132 47-56
• 78 Jorgensen K D, Svendsen O, Agergaard N, Skydsgaard K. Effect of human growth hormone on the reproduction of female rats.  Pharmacol Toxicol . 1991;  68 14-20
• 79 Prosser C G, Fleet I R, Corps A N. Increased secretion of insulin-like growth factor 1 into milk of cows treated with recombinantly derived bovine growth hormone.  J Dairy Res . 1989;  56 17-26
• 80 Witkamp R F, Korstanje C, van Miert S A. (Toxicological and pharmacological effects of the use of bovine somatotropin in dairy farming).  Tijdschr Diergeneeskd . 1990;  115 780-788
• 81 Pleet H B, Graham J M, Smith D W. Central nervous system and facial defects associated with maternal hyperthermia at four to 14 weeks gestation.  Pediatrics . 1981;  67 785-795
• 82 Warkany J. Teratogen update: hyperthermia.  Teratology . 1986;  33 365-371
• 83 Chance P F, Smith D W. Hyperthermia and meningomyelocele and anencephaly.  Lancet . 1978;  1 769-770
• 84 Miller P, Smith D W, Shepard T H. Hyperthermia as one possible etiology of anencephaly.  Lancet . 1978;  1 519-521
• 85 Layde P M, Edmonds L D, Ericksen J D. Maternal fever and neural tube defects.  Teratology . 1980;  21 105-108
• 86 Christo G C, Urala M S, Duvvi H V, Venkatesh A. Maternal hyperthermia as a teratogenic agent.  Indian Pediatr . 1987;  24 597-600
• 87 Pleet H B, Graham J H, Harvey M A, Smith D W. Patterns of malformations resulting from the teratogenic effects of first trimester hyperthermia.  Pediatr Res . 1980;  14 587
• 88 Milunsky A, Ulcickas M, Rothman K J, Willett W, Jick S S, Jick J. Maternal heat exposure and neural tube defects.  JAMA . 1992;  268 882-885
• 89 Kline J, Stein Z A, Susser M, Warburton D. Fever during pregnancy and spontaneous abortion.  Am J Epidemiol . 1985;  121 832-842
• 90 Edwards M J. Hyperthermia as a teratogen: a review of experimental studies and their clinical significance.  Teratog Carcinog Mutagen . 1986;  6 563-582
• 91 Skreb N, Frank Z. Developmental abnormalities in the rat induced by heat shock.  J Embryol Exp Morphol . 1963;  11 445-457
• 92 Edwards M J. Congenital defects in guinea pigs: fetal resorptions, abortions, and malformations following induced hyperthermia during early gestation.  Teratology . 1969;  2 313-328
• 93 Adlercreutz H. Phytoestrogens: epidemiology and a possible role in cancer protection.  Environ Health Perspect . 1995;  103 103-112
• 94 Fredriks G R, Kincaid R L, Boniiloi K R, Wright Jr W R. Ovulation rates and embryo degeneracy in female mice fed the phytoestrogen coumestrol.  Proc Soc Exp Biol Med . 1981;  167 237-241
• 95 Whitten P L, Russel D, Naftolin F. Influence of phytoestrogen diets on estradiol action in the rat uterus.  Steroids . 1994;  59 443-449
• 96 Adams N R. Detection of the effects of phytoestrogens on sheep and cattle.  J Anim Sci . 1995;  73 1509-1515
• 97 Baird D D, Umbach D M, Lansdel L. Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women.  J Clin Endocrinol Metab . 1995;  80 1685-1690
• 98 Whitten P L, Lewis C, Russel E, Naftolin F. Potential adverse effects of phytoestrogens.  J Nutr . 1995;  125 771S-776S
• 99 Heindel J J, Gulati D K, Mounce R C, Russel S R, Lamb J C. Reproductive toxicity of three phthalic esters in a continuous breeding protocol.  Fundam Appl Toxicol . 1989;  12 508-518
• 100 Safe S H. Environmental and dietary estrogens and human health: is there a problem?.  Environ Health Perspect . 1995;  103 784-785
• 101 Courtney K D, Gaylor D W, Hogan M D. Teratogenic evaluation of 2,4,5-T.  Science . 1970;  168 864
• 102 Birnbaum L S. Health effects of dioxins.  Environ Health Perspect . 1995;  103 89-94
• 103 Erickson J D, Mulinare J, McClain P W, et al Vietnam veterans' risk for fathering babies with birth defects. JAMA .  1984;  252 903-912
• 104 Mocarelli P, Marocchi A, Branbilla P. Effects of dioxin exposure in humans at Seveso, Italy.  Banbury Report 35: Biological Basis for Risk Assessment of Dioxins and Related Compounds, 1991: 95-110
• 105 Hersh J H, Podruch P E, Rogers R, Weisskopf B. Toluene embryopathy.  J Pediatr . 1985;  106 922
• 106 Goodwin T M. Toluene abuse and renal tubular acidosis in pregnancy.  Obstet Gynecol . 1988;  71 715
• 107 Toutant C, Lippmann S. Fetal solvents syndrome.  Lancet . 1979;  1 1356
• 108 Ahlborg G. Pregnancy outcome among women working in laundries and dry cleaning shops using tetrachloroethylene.  Am J Ind Med . 1990;  17 567-575
• 109 Donald J M, Hooper K, Hopenhayn-Rich C. Reproductive and developmental toxicity of toluene: a review.  Environ Health Perspect . 1991;  94 237-244
• 110 Ungvary G, Tatrai E. Studies on the embryotoxic effects of ortho-, meta- and para-xylene.  Toxicology. 1980;  18 61-74
• 111 Lipscomb J A, Fenster L, Wrensch M, Shusterman D, Swan S. Pregnancy outcomes in women potentially exposed to occupational solvents and women working in the electronics industry.  J Med . 1991;  33 597-604
• 112 Lindbohm M L, Taskinen H, Sallmen M, Hemminiki K. Spontaneous abortions among women exposed to organic solvents.  Am J Ind Med . 1990;  17 449-463
• 113 Sharara F I, Seifer D B, Flaws J A. Environmental toxicants and female reproduction: modern trends.  Fertil Steril . 1998;  70 613-622
• 114 Heidam L Z. Spontaneous abortions among dental assistants, factory workers, painters, and gardening workers: a follow-up study.  J Epidemiol Community Health . 1984;  38 149
• 115 Pastides J, Calabrese E J, Hosmer D W, Harris D R. Spontaneous abortion and general illness symptoms among semiconductor manufacturers.  J Occup Med . 1988;  30 543
• 116 McMartin K I, Chu M, Kopecky E, Einarson T R, Koren G. Pregnancy outcome following maternal organic solvent exposure: a metaanalysis of epidemiologic studies.  Am J Ind Med . 1998;  34 288-292
• 117 Fielding J E. Smoking and women: tragedy of the majority.  N Engl J Med . 1987;  317 1343-1345
• 118 McIntosh I D. Smoking and pregnancy: attributable risks and public health implications.  Can J Public Health . 1984;  75 141-148
• 119 Hughes E G, Brennen B G. Does cigarette smoking impair natural or assisted fecundity?.  Fertil Steril . 1996;  66 679-689
• 120 Boue J, Boue A, Lasar P. Retrospective and prospective epidemiological studies of 1500 karyotyped spontaneous human abortions.  Teratology . 1975;  12 11-26
• 121 Harlap S, Shiono P H. Alcohol, smoking, and incidence of spontaneous abortions in the first and second trimester.  Lancet . 1980;  2 173-178
• 122 Armstrong B G, McDonald A D, Sloan B A. Cigarette, alcohol, and coffee consumption and spontaneous abortion.  Am J Public Health . 1992;  82 85-87
• 123 Himmelberger D U, Brown B W, Cohen E N. Cigarette smoking during pregnancy and the occurrence of spontaneous abortion and congenital abnormality.  Am J Epidemiol . 1978;  108 470
• 124 Hemminki K, Mutanen P, Saloniemi I. Smoking and the occurrence of malformations and spontaneous abortions: multivariate analysis.  Am J Obstet Gynecol . 1983;  145 61
• 125 Windham G C, Swan S H, Fenster L. Parental cigarette smoking and the risk of spontaneous abortion.  Am J Epidemiol . 1992;  135 1394-1403
• 126 Kline J, Stein Z A, Susser M, Warburton D. Smoking: a risk factor for spontaneous abortion.  N Engl J Med . 1977;  297 793-796
• 127 Coste J, Job-Spira N, Fernandez H. Risk factors for spontaneous abortion: a case-control study in France.  Hum Reprod . 1991;  6 1332-1337
• 128 Centers for Disease Control and Prevention. Fetal alcohol syndrome in the U.S., 1979-1992.  MMWR Morb Mortal Wkly Rep . 1993;  42 339-341
• 129 Stratton K, Howe C, Battaglia F, eds. Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment. Institute of Medicine Committee to Study Fetal Alcohol Syndrome.  Washington, DC: National Academy Press; 1996
• 130 Jones K L, Smith D W, Ulleland C N, Streissguth A P. Pattern of malformation in offspring of chronic alcoholic mothers.  Lancet . 1973;  1 1267-1271
• 131 Streissguth A P, LaDue R A. Fetal alcohol: teratogenic causes of developmental disabilities. In: Schroeder S, ed. Toxic Substances and Mental Retardation Washington, DC: American Association on Mental Deficiency; 1987
• 132 Jacobsen J L, Jacobsen S W, Sokol R J. Effects of alcohol use, smoking, and illicit drug use on fetal growth in black infants.  J Pediatr . 1994;  124 757-764
• 133 Streissguth A P, Samson P D, Barr H M. I.Q. at age 4 in relation to maternal alcohol use and smoking during pregnancy.  Dev Psychol . 1989;  25 3-11
• 134 Larroque B, Kaminski M, Dehaene P. Moderate prenatal alcohol exposure and psychomotor development at preschool age.  Am J Public Health . 1995;  85 1654-1661
• 135 Streissguth A P, Barr H M, Sampson P D. Moderate prenatal alcohol exposure. Effects on child I.Q. and learning problems at age 7-1/2 years.  Alcohol Clin Exp Res . 1990;  14 662-669
• 136 Harlap S, Shiono P H. Alcohol, smoking, and incidence of spontaneous abortions in the first and second trimester.  Lancet . 1980;  2 173-178
• 137 Kline J, Shroat P, Stein Z A, Susser M, Warburton D. Drinking during pregnancy and spontaneous abortion.  Lancet . 1980;  2 176-180
• 138 Streissguth A P, Martin D C, Martin J C, Barr H M. The Seattle longitudinal prospective study on alcohol and pregnancy.  Neurobehav Toxicol Teratol . 1981;  3 223-233
• 139 Narzullaeva M S, Nikiten A I, Slozina N M. The influence of alcohol on the female reproductive function and the fetus.  Zdravookhr Tajikistana (USSR) . 1987;  6 14-18
• 140 Clarren S K, Bowden D M, Astley S J. Pregnancy outcomes after weekly oral administration of ethanol during gestation in the pig-tailed macaque.  Teratology . 1987;  35 345-354
• 141 Clarren S K, Astley S J. Pregnancy outcomes after weekly oral administration of ethanol during gestation in the pig-tailed macaque: comparing early gestational exposure to full gestational exposure.  Teratology . 1992;  45 1-9
• 142 Sandor S, Amels D. The action of aethanol on the prenatal development of albino rats.  Rev Roum Embryol Cytol Ser Embryol . 1971;  8 105-118
• 143 Jacobson J L, Jacobson S W, Sokol R J. Effects of alcohol use, smoking and illicit drug use on fetal growth in black infants.  J Pediatr . 1994;  124 757-764
• 144 Koos B J, Longo L D. Mercury toxicity in the pregnant woman, fetus, and newborn infant.  Am J Obstet Gynecol . 1976;  126 390
• 145 Choi B H. Effects of prenatal methylmercury poisoning upon growth and development of fetal central nervous system. In: Clarkson TW, Nordberg GF, Sager PR, eds. Reproductive and Developmental Toxicology of Metals New York: Plenum; 1983
• 146 Nishimura H, Tanamura T. Clinical Aspects of the Teratogenicity of Drugs.  New York: American Elsevier; 1976
• 147 Bakir F, DamluJi S F, Amin-Zaki M. Methylmercury poisoning in Iraq.  Science . 1973;  181 230
• 148 Clarkson T W. The pharmacology of mercury compounds.  Annu Rev Pharmacol . 1972;  12 348
• 149 Burbacher T M, Monnett C, Grant K S, Mottet N K. Methylmercury exposure and reproductive dysfunction in the non human primate.  Toxicol Appl Pharmacol . 1984;  75 18
• 150 Sikorski R, Juszkiewicz R, Paszkowski T. Women in dental surgeries: reproductive hazards in occupational exposure to metallic mercury.  Int Arch Occup Environ Health . 1987;  59 551
• 151 Heidam L Z. Spontaneous abortions among dental assistants, factory workers, painters, gardening workers: a follow-up study.  J Epidemiol Community Health . 1984;  38 149
• 152 Brodsky J B, Cohen E N, Whitcher C. Occupational exposure to mercury in dentistry and pregnancy outcome.  J Am Dent Assoc . 1985;  111 779
• 153 Myers G J, Marsh D O, Davidson P W. Main neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fish diet: outcome at six months.  Neurotoxicology . 1995;  16 653-664
• 154 Rom W M. Effects of lead on the female and reproduction: a review.  Mount Sinai J Med . 1976;  43 542
• 155 Constan A A, Yang R SH, Baker D C. A unique pattern of hepatocyte proliferation in F344 rats following long-term exposures to low levels of a chemical mixture of groundwater contaminants.  Carcinogenesis . 1995;  16 303-310
• 156 Scanlon J W. Dangers to the human fetus from certain heavy metals in the environment.  Rev Environ Health . 1975;  2 39-64
• 157 Hall A. The increasing use of lead as an abortifacient.  Br Med J . 1905;  1 584
• 158 Schardein. unpublished data 1993
• 159 Centers for Disease Control. Preventing lead poisoning in young children in the United States.  MMWR Morb Mortal Wkly Rep . 1985;  34 66
• 160 CDC. Preventing Lead Poisoning in Young Children. A Statement by the Centers for Disease Control, Atlanta, GA, October, 1991
• 161 Ecobichon D J, Joy R M. Pesticides and Neurological Diseases Boca Raton, FL: CRC Press; 1982
• 162 Nurminen T. Maternal pesticide exposure and pregnancy outcome.  J Occup Environ Med . 1995;  37 935-940
• 163 Hayes Jr W J, Laws Jr E R. Handbook of Pesticide Toxicology, Vols. 1-3 San Diego: Academic Press; 1991
• 164 Heindel J J, Chapin R E, Gulati D K. Assessment of the reproductive developmental toxicity of pesticide/fertilizer mixtures based on confirmed pesticide contamination in California and Iowa groundwater.  Fundam Appl Toxicol . 1994;  22 605-621
• 165 Roan C C, Matanoski G E, McIlnay C Q. Spontaneous abortions, still births and birth defects in families of agricultural pilots.  Arch Environ Health . 1984;  39 46-60
• 166 Restrepo M, Munoz N, Day N E. Prevalence of adverse reproductive outcomes in a population occupationally exposed to pesticides in Colombia.  Scand J Work Environ Health . 1990;  16 232-238
• 167 Parron T, Hernandez A F, Pla A. Clinical and biochemical changes in greenhouse sprayers chronically exposed to pesticides.  Hum Exp Toxicol . 1996;  15 957-963
• 168 Le Marchand L, Kolonel L N, Siegel B Z, Dendle III H W. Trends in birth defects for a Hawaiian population exposed to heptachlor and for the United States.  Arch Environ Health . 1986;  41 145
• 169 Clifton D K, Bremmer W J. The effect of testicular x-irradiation on spermatogenesis in man: a comparison with the mouse.  J Androl . 1983;  4 387
• 170 Cowan D N, DeFraites R F, Gray G C, Goldenbaum M B, Wishik S M. The risk of birth defects among children of Persian Gulf War veterans.  N Engl J Med . 1997;  336 1650-1656
• 171 Assennato G, Paci C, Baser M E. Sperm count suppression without endocrine dysfunction in lead-exposed men.  Arch Environ Health . 1987;  42 124-127
• 172 Alexander B H, Checkoway H, Vannetten C. Semen quality of men employed at a lead smelter.  Occup Environ Med . 1996;  53 411-416
• 173 Lindbohm M-L, Sallmen M, Anttila A. Paternal occupational lead exposure and spontaneous abortion.  Scand J Work Environ Health . 1991;  17 95-103
• 174 Pearn J H. Teratogens and the male: an analysis with special reference to herbicide exposure.  Med J Aust . 1983;  2 16-20
• 175 Tuohimma P, Wichmann L. In: Hemminki, K et al, eds. Occupational Hazards and Reproduction Washington, DC: Hemisphere 1981: 73-79
• 176 Passaro K T, Little R E, Savitz D A, Noss J, The Alspac Study Team. Effect of paternal alcohol consumption before conception on infant birth weight.  Teratology . 1998;  57 294-301
• 177 Savitz D A, Zhang J, Schwingl P, John E M. Association of paternal alcohol use with gestational age and birth weight.  Teratology . 1992;  46 465-471
• 178 Heinonen O P, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: John Wright-PSG 1977 410-411 444 449
• 179 Wernick U, Lanman B M, Fraux J L. Chronic toxicity, teratologic, and reproductive studies with hair dyes.  Toxicol Appl Pharmacol . 1975;  32 450-460
• 180 DiNardo J C, Picciano J C, Schnetzinger R W. Teratologic assessment of five oxidative hair dyes in the rat.  Toxicol Appl Pharmacol . 1985;  78 163-166
• 181 Marks T A, Gupta B N, Ledoux T A, Staples R E. Teratogenic evaluation of 4-nitro-p-phenylenediamine, 4-nitro-o-phenlyenediamine and 2,5-toluenediamine sulfate in the mouse.  Teratology . 1981;  24 253-265
• 182 McDonald A D, McDonald J C, Armstrong B. Congenital defects and work in pregnancy.  Br J Ind Med . 1988;  45 581-588
• 183 John E M, Savitz D A, Shy C M. Spontaneous abortion among cosmetologists.  Epidemiology . 1994;  5 147-155
• 184 Paul M, Kurtz S. Reproductive hazards in the work place. Worcester, MA: University of Massachusetts Medical Center, Occupational and Environmental Reproductive Hazards Center 1990
• 185 Polifka J E, Friedman J M. Environmental toxins and recurrent pregnancy loss.  Infertil Reprod Med Clin North Am . 1991;  2 175-213
• 186 Harlop S, Shiono P H. Alcohol, smoking, and the incidence of spontaneous abortions in the first and second trimester.  Lancet . 1980;  2 173-176
• 187 Cavallo F, Russo F, Zotti C, Camerlengo A, Ruggenini A M. Moderate alcohol consumption and spontaneous abortion.  Alcohol . 1995;  30 195-201
• 188 Kline J, Stein Z, Susser M. Environmental influences in early reproductive loss in a current New York City study. In: Porter IHM and Hook HD, eds. Human Embryonic and Fetal Death New York: Academic Press; 1980
• 189 Ferguson D M, Horwood L J, Shannon F T. Smoking during pregnancy.  N Z Med J . 1979;  89 41-43
• 190 Dlugosz L, Bracken M B. Reproductive effects of caffeine: a review and theoretical analysis.  Epidemiol Rev . 1992;  4 83-100
• 191 Mattison D R. Minimizing toxic hazards to fetal health.  Contemp Obstet Gynecol . 1992;  8 81-100