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NOV ^08 ' 96 04:34PM ADMIN 1803 BLDG 517 636 1875 P.1/28 'riately icneral asured ely re;k with for co0.99. levels on two adients rimary further aternal SPH :er & liology ilina sure and itancous vm J Ind 95-100. cpatlonal American Journal of Industrial Medicine 27t61I-613 (1993) LETTER TO THE EDITOR Paternal Occupational Exposure and Spontaneous Abortions: A Closer Look at Paternal Recall and Vinyl Chloride Key words: paternal exposure, recall bias, spontaneous abortion, vinyl chloride We commend Savitz et al. [1994] for their effort at summarizing the epidemi ology literature regarding paternal occupational exposure and spontaneous abortion, especially as it pertains to methodological issues. They identified three major meth odological issues: (1) accurate ascertainment of the occurrence of a spontaneous abortion, (2) validity of the father's exposure assignment, and (3) potential confound ing by parental lifestyle factors that may be correlated with paternal occupation. Concerning the first issue, it should be noted that an article was recently published by Fikrcc ct al. [1993] that assessed the recall agreement of pregnancy outcomes among 857 couples. Using the wives' reports as the standard, Ftkree et al. [1993] found 71,2% sensitivity and 98.8% specificity for husbands' recall of spontaneous abor tions. We have also observed differences in recall of spontaneous abortions by male employees. These observations showed that 20 spontaneous abortions were recalled among 96 (20.8%) lifetime pregnancy outcomes (live births, still births, and spon taneous abortions) by'male employees who had their spouses/partners assist with a reproductive health survey. There were only six spontaneous abortions among 114 (5.3%) lifetime pregnancy outcomes recalled by male employees who chose not to involve a spouse/partner. These data support the opinion of Savitz et al. [1994] that paternal occupational exposure studies "should routinely seek reproductive outcome information from the woman, whenever possible." Based on the Infante et al. [1976a] data collected from male employees only, Savitz et al. [1994] suggested that further epidemiologic research be initiated on paternal occupational exposure to vinyl chloride and spontaneous abortion. Infante et al. [1976a] reported an age-adjusted fetal death loss of 15.8%, as recalled by male workers (N = 95) who had potential exposure to vinyl chloride, compared to 8.8% recalled by rubber and polyvinyl chloride fabrication male workers (N = 158). When the analysis was restricted to men under age 30, they reported 20.0% fetal death loss for the vinyl chloride group compared to 5.3% for the nonexposed group. Although they alluded to the fact that the risks reported by Infante et al. [1976a] Address reprint requests to Dr. G. W. Olsen. Epidemiology, H&ES, Dow Chemical Co., 1801 Building, Midland, MI 43674. Accepted for publication June 27. 1994. 1995 WUey-Liss, Inc. Poat-lt* Fax Note 7671 T 'SVctail/ i/c-w Phono # ' Fraocr s--ozy pnon##?r^-6i Fax* f CMA 118987 )V 38 '96 B4 3SPM ADTIIIN ife rii nd: M 636 lM) 6X2 Olsen et al. "P.c/ Palemal Age Fig. 1. Fetal deaths by paternal age and potential exposure 10 vinyl Chloride monomer as defined by Infante el al. Note: the rubber and polyvinylchloride fabrication group was considered not exposed to vinyl chloride monomer. The ratios in the graph are the number of fetsl deaths divided by pregnancies per each age group {adapted from Infante et al., 1976a,b; Stallones, 1987]. were observed primarily among the younger male employees, Savitz et al, [ 1994] were apparently unaware of additional paternal age-specific fetal death loss data requested by Paddle [1976] and subsequently published by Infante et al. [1976b], These addi tional data demonstrated that the difference in the overall age-adjusted risks (15.8% vs. 8.8% in the original published work) was the result of divergent age-spccific fetal death loss percentage in only one of the four 5-year age strata (Fig. 1). The late Reuel Stallones, in a commentary on the use and abuse of subgroup analyses in epidemiology [1987], asked the following questions concerning the In fante etal. [1976a] data: "Why was the harm limited to the 25-to 29-year age group? r Why was the rate higher in the exposed 25-29-year age group than in cither of the two older exposed age groups? Wiry was the rate lower in the nonexposed 25-29-year age group than in the younger, nonexposed age group?'* Stallones' conclusion was "No answers to these questions are evident; a sensible conclusion is that something went wrong in the study, resulting in aberrant findings, and tbat the study therefore should be discarded. If published at all, the data should appear in a textbook of epidemiology as a most pertinent example of the value of a subgroup analysis in discovering a problem, internal to the research, which renders invalid the results obtained for the total group and which might have been accepted had the subgroup analysis not been done." Hatch et al. (1981] have also raised other concerns about the analyses in Infante et al. [1976a], Savitz et al. [1994] suggested that the dominant lethal test may be the animal study most relevant to human spontaneous abortion. In this regard we note that Short et al. [1977] reported a negative result for vinyl chloride in the dominant lethal assay CMA 118988 NOV 08 '96 04:35PM ADMIN 1803 BLDG 517 636 1875 Paternal Exposure and Spontaneous Abortion 613 in male rats exposed to vinyl chloride levels as high as 1,000 ppm for 6 hours daily over an 11-week period. Anderson et al. [1976] found no response to vinyl chloride in the dominant lethal assay in male mice exposed briefly to levels as high as 30,000 ppm. In summary, we again commend Savitz et al. [1994] for their ambitious and comprehensive review of the literature concerning paternal occupational exposures and spontaneous abortion. However, we concur with Stallones' [1987] conclusions. Wc believe there is no justification for continuing to use the data of Infante et aJ. [1976a] to support the suggestion in the epidemiology literature of a positive asso ciation between paternal occupational exposure to vinyl chloride and spontaneous abortion. If other epidemiology reviewers do Find the conclusions of Infante et al. to be credible, then wc believe they should at least offer the reader their answers to Stallones' three questions. Geary W. Olsen Jonathan M. Ramlow Susan Hearn Epidemiology Department Health & Environmental Sciences Dow Chemical Company Midland, MI 48674. REFERENCES Anderson D, Hodge MCE, Purchase IFH (1976): Vinyl chloride: Dominant lethal studies in male CD*1 mice. Mtitat Res 40:339--370. Fikree FF, Gray RH, Shah F (1993): Can men be trusted? A comparison of pregnancy histories reported by husbands and wives. Am J Epidemiol 138:137-242, Hatch M, Kline J, Slain Z (1981): Power considerations in studies of reproductive effects of vinyl chloride and some structural analogs. Environ Health Perspect 41:195-201, Infante PF, Wagoner JK. MeMichacI AJ, WaxweilerRJ, Falk H (1976a): Generic risks of vinyl chloride. Lancet 1:734-735. Infante PF, Wagoner JK, McMichacI AJ, Wsxweiler RJ, Falk H (1976b): Genetic risks of vinyl chloride. Lancet 1:1289-1290. Paddle CM (1976): Genetic risks of vinyl chloride. Lancet 1:1079. SiVitz DA, SoAnenfeld NL, Olshan AF (1994): Review of epidbipiologic studies of paternal occupational exposure and spontaneous abortion. Am J Ind Med 25:361-363. Short RO, Minor JL, Winston JM. Lee C-C (1977): A dominant lethal study in male rats after repeated exposures to vinyl chloride or vioylidene chloride. J Toxicol Env Health 3:965-968. SuJloncs RA (1987): The use and abuse of subgroup analysis in epidemiological research. Prev Med 16:183-194 7 "* NOV 08 '96 04:35PM ADMIN 1803 BLDG 517 636 1375 American Journal of Industrial Medicine 27:415-41$ (1995) LETTER TO THE EDITOR Reply to Olsen, Ramlow, and Hearn Key words: occupational exposure, vinyl chloride, spontaneous abortion, paternal risks Dr. Olsen and colleagues [1994] share our concerns with the quality of paternal reports of reproductive events, particularly spontaneous abortion, and cite evidence for their fallibility Reliance on paternal reports constitutes one of the deficiencies in the study by Infante et al. [1976a], although Olsen et al.'s main concern is with the pattern of results and their interpretation. The constellation of results presented by Infante ec al. [1976a,b] yield evidence of a positive association between paternal exposure to vinyl chloride and spontaneous abortion in their wives that should be viewed as tentative for a number of reasons. In favor of a causal interpretation is the pattern of similar risk between exposed and unexposed populations prior to employment. A sizable increase in risk was seen only among the wives of exposed men subsequent to employment. A notable reduction in excess risk among exposed men when restricted to couples that experienced fewer than three spontaneous abortions [Infante et al., 1976b; Hatch et al., 1981] diminishes the support for that association, presuming that repeat spontaneous abortions are more likely to be due to intrinsic maternal factors than to a persistent adverse effect of paternal vinyl chloride exposure. In the case of vinyl chloride, animal data such as the dominant lethal results cited by Olsen et al. [1994] are of limited value in ruling out human effects [Hatch et al., 1981]. The pattern of age-specific results appears to be most troubling to Olsen et al. [1994], Infante et al. [1976a] reported an overall increase in risk which appeared to be concentrated in younger workers, as we noted In our review [Savitz et al., 1994], In spite of the apparent heterogeneity in risk as a (Unction of paternal age, a summary measure for the total population remains a useful description of the average effect of vinyl chloride [Pearce, 1989], The principal strength of that summary is that it is less vulnerable to fluctuations due to small numbers, in contrast to the age-specific re sults. The pattern presented by Stallones [1987] taken from Infante et al. [1976b] is clearly quite erratic since it is based on such small numbers. Conclusions about any of the age-speeifie risk ratios are thus of limited value. The study tells us very little about the effect of vinyl chloride on reproductive risks among 25-29-ycar-old men or any other specific age group, including those for which no apparent elevation in risk was found. The three questions raised by Stal- Addtest reprint requests to Dr. David A. Savitz, Department of Epidemiology, CB #7400, University of North Carolina, Chapel Hill, NC 27599. Accepted for publication June 27, 1994. 1993 Wiley-Llss, Inc. . 4/28 ! CMA118990 jv'W "36 tMUbHI hMn IdtrJ BLK-'Sl'TfcSBTSW P.5/23 T 614 Savitz et al, lones [1987] concerning why the harm was limited to 25-29-year-olds, why the rate was higher in exposed 25-29-year-olds than in older exposed groups, and why the rate was lower In the nonexposed 25-29-year-olds than In younger, nonexposed groups are, of course, not answerable. The only candidate explanation is a statistical aberration due to small numbers (synonymous with "unknown"). Concluding that "something went wrong" more generally in the study ignores the myriad unexplained sources of variability in small studies, and is neither informative nor testable. In spite of the erratic pattern in relation to paternal age. neither Stallones (1987] nor Olsen et al. [1994] have proposed a methodologic bias that might have produced it. Legitimate concerns with the deficiencies in the study by Infante et al. [1976a] render the results far from conclusive, yet wc noted that there have been no attempts at replication. A study of the same topic that is free from the principal deficiencies of Infante et al. [1976a], namely reliance on paternal report and limited study size, is the only way to evaluate whether ``something went wrong." DAVID A. SAV1T2. PhD NANCY L. SONNENFELD. MSPH ANDREW F. OLSHAN. PhD Carolina Population Center & Department of Epidemiology University of North Carolina Chapel Hill, North Carolina REFERENCES Hatch M, Kline J, Stein Z (1981): Pouter considerations in studies or reproductive effects of vinyl chloride, and some structural analogs. Environ Health Perspect 41:195--201. Infante PF, Wagoner IK', MeMichael AJ, Waxweiler RJ, Falk H (1976a); Genetic risk* of vinyl chloride. Lancet 1:734-735. Infante PF, Wagoner JK, MeMichael AJ. Waxweiler RJ, Falk H (1976b): Genetic riski of vinyl chloride (Letter). Lancet 1:1289--1290. Oisen GW, Ramlow JM, Hearn S (1994): Paternal occupational exposure and spontaneous abortions: A closer look at paternal recall and vinyl cloride (Letter). Am J Ind Med 27:611-613, Paddle CM (1976): Genetic risks of vinyl chloride. Lancet 1:1079. Pearce N (1989): Analytical implications of epidemiologic concepts of interaction, lot J Epidemiol 18.976-980. Savita DA, Sonnenfeld NL, Olshan AF (1994): Review of epidemiologic studies of paternal occupational exposure and spontaneous abortion. Am J Ind Med 25.361-383. Stallones RA (1987): The use and abuse of subgroup analysis in epidemiological research. Prev Med 16:183-194. it I i CMA 118991 'a yi$tM#'iWsri9rS` MKlUiaftUM BUSTS 17 i w/mW w;ViA` `*i,7 O k VAvVyl American Journal of Industrial Mcdkte* 2JJ41-383 (1994) Review of Epidemiologic Studies of Paternal Occupational Exposure and Spontaneous Abortion David A. Savitz, PhO, Nanoy L Sonnenfeld, mcph, and Andrew P. Otshan, PhD The question of whether paternal exposures influence risk of spontaneous abortion is of f great public interest, with the possibility supported by laboretory invesdgatiom. Thirty- nine studies of male occupational exposure and risk of spontaneous abortion were examined, with the methods and results tabulated. Many of there reports were limited by exposure data based on maternal report of the father's jab title or by potentially inaccurate paternal repons of spontaneous abortion, though the quality of more recent studies Is markedly enhanced. Mercury has been implicated most strongly based on recent studies that included quantitative exposure estimates; a number of studies show ing associations for exposure to anesthetic gases. Suggestive associations have also been found inconsistently for exposure to lead, rubber manufacturing, selected solvents, and some pesticides. Further study is encouraged, but with more Intensive effort to measure accurately both spontaneous abortion and occupational exposures. O IMA Wilty-U*!, Inc. Key words; fathers, occupational exposure, mercury, pesticides, solvents, spontaneous abortion, paternal reproduction risk INTRODUCTION Over the past decade, there has been a growing interest in the potential roie of male occupational exposures in reproductive health. A male contribution to infertility is now well accepted, with at least one agent (dibromochloropropane) an established cause of male infertility [Whorton et ai.. 1977]. The phenomenon of concern In this review is the possible impact of paternal workplace exposures on the risk of spon taneous abonion. Such an association might be mediated by maternal exposure through contamination of the home environment [Knishkowy and Baker, 1986], concentration of the agent in semen (Stachei et al.. 1989], and passage through sexual intercourse, or transmission of the agent directly on the sperm [Yazigi et al., 1991], Of particular interest here is a more direct paternal effect on the fetus. Genet ically damaged sperm that remain capable of fertilization might produce an impaired conceptus that is more likely to result in a pregnancy loss. Paternally mediated ab normalities in development are the presumed phenomenon underlying such concerns Department of Epidemiology, School of Public Health, and Carolina Population Center, University of North Carolina, Chapel Hill, NC. Address reprint requests to David A. Savin. Ph.D., Department of Epidemiology, CB #7400. School of Public Health, University of North Carolina, Chapel Hill. NC 27599. Accepted for publication February 24, 1993. D 1994 WlJey-Usi, Inc. CMA 118992 ''96 04:37PM ADMIN 1303 BLDG 517 636 1375 P.7^20 362 Strife at al. as male exposure to Agent Orange and birth defects in their offspring [Erickson et al., 1984], and ionizing radiation and childhood leukemia [Gardner et al,, 1990], Al though there is not yet a well-established male exposure proven to influence post conception reproductive events m general, or spontaneous abortion in particular, there are several lines of evidence that strongly support the possibility, including the sizable body of epidemiologic data reviewed here. Experimental studies of male laboratory animals (mostly rodents) have clearly indicated the potential for developmental toxicity following paternal exposure to ionizing radiation and mutagenic chemicals. These studies have shown that the full spectrum of developmental endpoints appear to be responsive to paternal exposure, including gene mutations, chromosomal aberrations, lethality, congenital anomalies, tumors, neurobehavioral deficits, and growth retardation [Olshan and Fausunan, 1993]. In vivo assays used to assess paternal genetic effects include the specific locus test, dominant skeletal, dominant cataract, and dominant lethal tests, and the heritable translocation test [Russell and Shelby, 1985]. The most relevant test to human spontaneous abortion is probably the dominant lethal test [Green et al., 1985]. A dominant lethal mutation U defined as a genetic defect occurring in the gamete that permits fertilization but results in embryonic death. The genetic basis for these deaths is believed to be structural or numerical chromosome abnormalities in the germ cell of the treated male, with death occurring before or after Implantation. An EPA-Genetox working group summarized the pub lished studies using this assay [Green et al., 1985] and found that, of the 140 chemicals tested, 65 (46%) were determined to be positive. Although the dominant lethal test is not a direct analog of human spontaneous abortion, it does demonstrate that the agent affects the paternal genetic material. For the sizable fraction of human spontaneous abortions that are due to chromosomal abnormalities (estimated at 40% by Kline et al. [1989]), the assay is more directly applicable. Litter size reduction in laboratory animal studies is also relevant to human spontaneous abortion. Reduced litter size has been found following male exposure to ionizing radiation and ethylni* trosurea [Russell and Hunsicker, 1988: Selby and Russell, 1985]. Occupational exposures are dearly capable of adversely influencing human semen [Wyrobek et al.. 1983a.b], yet lew .studies have attempted to evaluate whether abnormal semen characteristics are associated with spontaneous abortion. Case-con trol studies from the 1960s [Furuhjelm et ai., 1962; Joel, 1966] found that concep tions ending in spontaneous abortion were more likely to bcJhc product of `iflbnormal" semen than pregnancies that were successful. The semen abnormalities linked to poor pregnancy outcome were reduced sperm concentration, increased proportion with abnormal morphology, elevated sperm concentration, and reduced DNA content of the sperm. Given the era in which these studies were conducted, the lack of technological sophistication in semen evaluation, as well as methodological deficien cies concerning confounding, analytic methods, and selection of control groups are expected. The question of whether agents that influence sperm grossly may adversely affect the health of the resulting conceptus remains largely unexamined. In this review, we will summarize the epidemiologic evidence concerning as sociations between paternal exposures and the risk of spontaneous abortion. The methodologic strategies of the past studies will be critically examined to note the key limitations and to recommend specific improvements needed to extend knowledge on this topic. Of particular concern in this research area is the challenge m accurately % i CMA 118993 * Paternal Exposure end Spontaneous Abortoo 363 ascertaining-the occurrence of spontaneous abortion, the validity of exposure assign ment based on job title, and the potential for confounding by lifestyle factors of the mother or father that are correlated with paternal occupation, all discussed in more detail after the presentation of the results. Finally, given the array of studies to date, the most promising avenues for further research will be noted. METHODS OF REVIEW We attempted to identify all studies in which the father's occupation was ex amined in relation to the risk of spomaneous abortion in his partner. Literature searches, cross-checking reference lists, and consultation with experts were used to make this compilation of evidence as complete as possible. In many instances, spon taneous abortion was only one among many outcomes considered, or paternal occu pational exposures were one among many potenuai risk factors considered, raising questions about whether our search was completely successful. Studies that contained fewer than five exposed cases in all the associations they reported [e.g.. Goldsmith et al., 1984) were excluded from the review. Studies were not excluded on the basis of qualitative criteria, but we attempted to provide sufficient mcthodoiogic informa tion for the reader to make independent evaluations of the quality of the evidence. Information abstracted for this review is presented in nine text tables and an appendix, with the studies arranged in chronological order within the tables. Table I presents key methodological data on the studies, including the source population, I sources of exposure and outcome data, number of spontaneous abortions, and re sponse proportion, in order to provide some insight into the potenuai biases and limitations of the various studies. The final column in Table I reports the categories of exposure examined in each study, serving as an index to the following seven tables, which are organized to present results for a specific category of exposure. The source population, delineated as "general population" or "occupational cohort" was noted since, in general, occupational cohorts provide the opportunity for more refined exposure assessments than studies of the general population, but may be less gcneralizable. The number of spontaneous abortions reported in Table I includes all observations of spontaneous abortion used in any relevant analysis within the paper, even though the number of spontaneous abortions included in any specific analysis was often smaller. The response proportion noted in Table 1 is that repotted by the original author for the total study population, including both the exposed and unexposed. In a number of studies, the reported response proportion provides a rather favorable assessment of the representativeness of the sample population, since indi viduals who were excluded because of migration or incomplete records were omitted from the denominator. The response proportion typically reports only the proportion who had complete data in records or agreed to the interview, and does not take into account unusable data or missing values on specific items of Interest- Tables II--VIII present the results from the studies that were reviewed, divided into seven broad categories of exposure: metals, solvents, anesthetic gases, pesti cides, physical agents, hydrocarbons and automobile exhaust, and miscellaneous industries, occupations, and agents. The heterogeneity within some of these catego ries should be noted, with solvents including a variety of exposures in the plastics and rubber industry, and pesticides broadened to include sterilizing agents and wood preservatives The results tables include the exposed group used in each analysis and CMA 118994 38PM ADMIN 1803 BLDG 517 536 1875 P.9/28 364 Savttz et aL TABLE L Reports on Ptarq*l Occupational Exposure and Spontaneous Abortion: Study Deeigm and Methods____________________ ___________ RafcreM* 0often tL 11974} tu*a*dn!. |197J| Cohan et *J. (I9T5I KmlWO*e*ti *1. (1975} IrlpAH h. JJ97*) VaiwoUi (1976) ftounbery and Vanmneri (I97K Tomlin 11979) COfWIKiil. I19W) Kfturui di a). (|9p0| Cannfill t a). (19*1) Ltu<vtni rt il. 119411 tatawi M Nordsuem (19521 Htmill tl Bt. 119521 KIMeU1953) Smith at !, (1952) Townsend et tl. J1982) Cm rt II. (IWp Hnw(A4i eiil. (19151 Noraioom <( if. ((9521 Lindbohm cl ll. |lH4| Morgan er il. (1914) Roan dll. (19*4) SlTHE Cl ll. (I9ii| Siskind k HefltbcTK II94) it. IIWJI Dvuall k VmMMA H9II1 `vielimio cl il. | (9H81 Cl>C (IMDI AlrWtra) (1919) A<ft4ndfau k MutHW 1(9*9) MeDroM l <1. [19891 Tuiuacji * *1 (19191 Guirguittt(. (1990! Rtslrepo r *1- (I990| Cor<Wvii. [1991] UMbohm ti il. |J99U) 5wt* population Owupoootu) ehhort Omcrvi pepuM** Occupation*! cohort Gctapuional cohort Owupaiiottal cdhotr Occupational h>KWt OcEopatt9**l cohort Occupytn*i cohort OtditpftiloMl cohort Occupational co*9rt 5<reN* o/ upnurt d PitfRAl report Maternal upon Parental report Piremt repnrt Carnpanr rccocdl Wortflioce moniion.il ftnomai report preanul report PiiarM report Paternal ftpon I>ifnipmww4 **M Occupational cohort OctupUfOMl cohort Parental 'pn Paternal report Parental report Octopaiwl whort Ooiwoi papal*** Worttpheo ftwnwrutf CtunuJ report Miwmi repon Qaiupailomi cohere QcgoptiOftoi hmt Gmril pppuimau General jwpyhMim Occupational cohort Oencret population Occupational whon Paiemif npAR KfnplOTict ftMOMt, ContpMy iiiohe NA Cmmii nedt Company rpcoedi, ftauntil report Cenwy reoortlt Company recorth Ritcriu) report Occupational cohort Occupational 3Short OccopMtonil cohort OeetipWKwi cohort <7iiril population (.fceupiUoaal cohort Occopatiortvi cohon Occupational cohort OonofU populMHIP Opnerei population Pltofiul ropon ynifM reerd> Ptimil report Work localyin C ompany records J'ufmj) ipm Birth itrtihcito Patemaf repun Miluary reCoCtli fffOrt Company reei*Ji HmUifical nwntiiirtnf' Medical reronh Miiiiary retonh MaicrtMl repon OxiipMraniti oohort Owupthontf omor OccnpmenV cohort Occupational cohort CcM/U (lupilitofi talvtfM repwrrv InMptMi moohonnp Ruarnat report EoeWtr uVaniuuon rmnii report wortpuoc mreutomt Company mortis 9r04sf>cal nrnutort*C Cmsui record* 8umaa of oyieiioadau rawreM report Karyotype Pstfrtuf report Plcnil report raiarul report recnulntm Piicmal report Paienrel repon Parental repon Pkuntai report Hmptrel records Mattrtval report Paiomal report Piwreai report Noeprlaf reerem PueittM repan Karyotype of fans PtOhim nliaio mop Mwemat report Midrcu reeerPi Mjaaraal ^on Morenial report lloiprm rejtfpy HcrepftaJ recordf PaierMl report H96pnal retpehy Mffrena( report PaiarMl report Hwpftai recoiPi Marentai repent MalarnalfpOKmai report* Paternal repnrt I'tHfA-l report htrtn ceniftciic P*i<rnjl report ymernai rep.m Paemal report He>mbel record* KfeprtAi record MoMrtkU report Mptpfrar registry CVlpahear rmrdh Pfzenioi report farerna) report Manrnal report Hmsl Rtuvy Number of ippruiOMqs ponMM KS3 446* 1 452 73 NA' 62 M 6*0 ! t>4 93 IM 4* m n m 9.419 HO 6* 3,599 12 (03 220 no 671 N/S 417 1.75* >70 2U1 I0.593 120 411 II TO 8.731 Undbohm at H, |l99lb| Riipoaat. 11991) dewsaaenil tehM Occupohonot u(ion Piumal report Bmloyaai rmeeisnop NA ttciPlUJ reamry Clin* ruffid* NA ID 1.555 Respect* prupimiyn <5*1 $% Jl ?0 61-77 NA <i9 91 74 61 W 47 19 13 79 W <a Ha 83 *9 91 0 # 35 53* 73 91 NA *4-87 81 94 NA 7.7 *1 48 T7 NA 74 NA Studref A Pa A A 3 S A A A P 9 A M S MPaNMj P P f MM* Pt M S KM Mi ? 5 f M s P P M P MSPPa KM* SMj A P M MS PR* H M* MSPiH P M = metals. S * solvents; A * inesthetic gases; P a pesticides; Pa = physical agents; H = hydrocarbons and automobile exhaust: Ms = miscellaneous Industries, occupations, and agents. "Karyotypicelly abnormal case-control. 'NA = not available. ``Cited in Sterling and Arundel (19861. 'Excludes losiea because of modality. fltenui Exposure and Spontaneous Abortion 365 an estimate of the risk ratio with 95% confidence interval (Cl) contrasting exposed to unexposed men. The desired 95% CIs were often not provided and had to be derived from the data using test-based methods [Rothman, 1986] for risk ratios or odds ratios as required [Alcser et al., 1989; Beckman arid Nordstrom, 1982; Boue et al., 1975; Brodsky etal., 1985; Cohen etal., 1974, 1975; Hamill etal., 1982; Hemminki et al., 1983; Infante et al., 1976; Khairazi et al., 1980; Knill-Jones et al.. 1975; Lauwerys et al,, 1981; Morganet al,, 1984; Nordstrom et al., 1983; Rosenberg and. Vanttlnen, 1978; Roan et al., 1984; Rupa ct al., 1991; Savitz ct al., 1984; Smith M al,, 1982; Sterling and Arundel, 1986; Suskind and Hertzberg, 1984], Exposure classification was often based on a combination of job title or em ployment setting and an inference regarding the specific agents of interest. The author's terminology and intentions were retained in describing the exposures. When a broad array of exposures were analyzed, only exposures for which there were five or more exposed cases were tabulated. Papers frequently inciuded.multiple analyses of closely related groups. To restrict the size of the tables and to retain clarity, it was necessary to present these results selectively. When multiple unexposed groups were analyzed and all comparisons produced similar results, results were presented for the largest unexposed group or the one thought least likely to introduce bias. When multiple unexposed groups produced different results and none was clearly superior to the others, all analyses were tabulated. Adjusted results were provided when confounding was present and the adjusted results were available. Indications of effect modification by age or other factors were not routinely included in the results tables but are discussed in the text where relevant. The Appendix table presents additional information on study location, study type, confounders addressed, definition of cases, and baseline risk of spontaneous abortion. The potential confounders listed for a given study include all confounders addressed in any exposure examined within that study but not all results provided statistical adjustments for the entire list of factors. Footnotes are used in the results tables to indicate potentially important discrepancies between the confounders listed for a given study and the confounders addressed for a given exposure. Included among the confounders addressed are those risk factors which the authors claimed to have accounted for, sometimes based on inappropriate methods such as statistical testing of differences between study groups or relying only on an impression that the groups were not notably different. The baseline risk of spontaneous abortion was computed for the unexposed when possible, but in some studies only the overall rate of spontaneous abortion among exposed plus unexposed was available. RESULTS OF REVIEW As summarized in Table I, 39 studies published over the last >8 years have provided data to evaluate the potential link between paternal occupation and spon taneous abortion. Only 8 appeared in the 1970s, with notable growth to the present and 4 appearing in 1991 alone. The attributes of those studies vary markedly and are noted as relevant in discussing the agents which they address. Most studies have relied on matemaJ or paternal self-report for both exposure and pregnancy outcome data. Study sizes vary markedly, from around 20 to nearly 10,000 spontaneous abortions. Response proportions range from under 50% to around 90%, with an obvious potential for influencing the study's validity. '96 04:39PM ADMIN 1803 BLDG 517 636 1875 P.11/23 366 Saritz et al. TABLE II. Itoeulta of SimHb Reference Beckman A Nordstrom [1982] Kline et al. [1982] Hemminki et al. [1983] Lindbohm et al. |I98) Brodsky et al, [198S] Alcseret al. [1989] McDonald et al. [1989] Cordier et al. [1991] Lindbohm et al. [1991a] Lindbohm el al. [1991b) PKtml Evpaanraa to Heavy Metoli and Spootoneotu Abortion Agent, industry, or occupation RR 93% Cl Copper smelter (lead, arsenic, mercury. 1.5 0.9-2.3 cadmium) Metals Metallurgical industry [zinc, cobalt) Metal industry Metals manufacturing Metal-plate and construction steel Dentistry (mercury) Urinary mercury levels 2.000-3.999 M-g/1 Urinary mercury level* 4.000-9.000 ug/l Ore. metal, stone processing Metal machining Metal fabricating Urinary mercury levels 1-19 i*g/l Urinary mercury levels 20-49 p.g/1 Unnary mercury levels >49 *g/l Lead Nickel and nickel oxides Chromiuxn/chronuuizi eompemnds Metals Wire & pipe drawers Blood lead levels 1.0-1.4 p,molyl Blood lead levels 1.5-1.8 |imol/l Blood lead levels >1 $ timol/l Blood lead level* 1 0-1 4 ^mol/l during tvpcrmaioceneMs Blood lead levels >1.4 iuriol/1 during spcrmatogenesi'. Cadmium Chromium Nickel Zinc Copper 0.5* 1 0" 1.1 0.7 0.9 1,4 0.9 1.1 1.7 l.: 1.0 0.9 1.3 1.7 2.3 0.9 1.0 1.0 1.0 1.2 1.0 1.3 1.6 0.7 3.8 1.4 0.9 1.1 2.2 2.8 0.2-1.1 0.4-2.2 0,8-1.5 0.4-1.5 O.S-I.O 1.0-1.9 0.7-1.1 0.8-1.6 1.1-2.5 0.9-1.3 0.9-1.2 0.7-1.2 1.0-1.7 1.0-3.0 1.0--5.2 0.8-1.0 0.9-1.1 0.9-1.1 0.8-1.1 0.5-3.1 0.6-1.7 0.5-3.4 0.6-4,0 0.3-1.9 1.2-12.0 0.6-3,4 0.5-1,6 0.6-1.9 0.8-J.5 1.1-7.0 Public clinic patient*, norma) karyotype. ''Public clinic patient*, abnormal karyotype. Exposure to Heavy Metals Occupational agents ns potential causes of spontaneous abortion have been examined in a number of mostly recent studies (Table 1). Ten studies oontain infor mation that address paternal exposure to lead, mercury, and other metals in relation to spontaneous abortion (Table I and 11). Many are community-based surveys, with exposure defined by inferences based on employment sector or job title rather than direct measurement. However, four studies focused directly on cohorts exposed to the metals of interest, namely, lead (Lindbohm et al., 1991b] and mercury (Brodsky et al., 1985; AlcSer et al., 1989; Cordier et al., 1991]. With these exceptions, the Paternal Exposure tod $ponuneoarAbortion 347 magnitude of metal exposure is not known and may not even be present for some of the "exposed" groups (e.g., work in the "metal industry"). Also, many of these exposure sources (e.g., copper smelter) contain a range of potentially hazardous agents, in addition to metals. A number of studies provide evidence of positive associations, including smelter workers (RR ~ 1.5) (Beckman and Nordstrom, 1932), metal-plate and steel industry workers (RR 1.4) [Lindbohm et al., 1984], men with elevated estimated lead exposure (RRs - 1,0, 1.3, and 1.6 for low, moderate, and high levels, respec tively), zinc exposure (RR " 2.2), and copper exposure (RR * 2.8) [Lindbohm et al., 1991b], Most notable is the association for high measured mercury exposure (RR 1.7) [Alcseret al., 1989] and estimated mercury exposure (RRs - 1.3, 1,7, and 2.3 for low, moderate, and high levels, respectively) (Cordieretal., 1991] (Table II). Unique among the studies was Lindbohm et al.'s [l99lb] evaluation of lead exposures around the time of spermatogenesis, which yielded a markedly elevated but imprecise risk ratio. Contradictory null results or even inverse associations are also present In Table IL including the absence of an increased risk for dentists preparing mercury amal gams [Brodsky et al.. 1985] and workers with job titles thought to indicate exposure to lead (Lindbohm et al., 1991a]. However, the most methodologically sophisticated in terms of exposure assessment [Alcseret al.. 1989: Lindbohm et al.. 199 lb: Cordier et al., 1991] provide strong suggestions of a link between exposure to heavy metals, especially mercury, and spontaneous abortion. Exposure to Rubber, Plastics, and Solvents The array of agents under this rubnc is quite broad, with a number of studies related to rubber, plastics, and related industries, as well as specific solvents and other agents often encountered in those work settings (Table III). In addition to the community studies that contribute results on a wide range of exposures [Lindbohm et al.. 1984; McDonald et al., 1989; Lindbohm et al.. 1991a], a number of studies have targeted particular exposures in this category, most notably vinyl chloride (Infante ct al., 1976], toluene diamine and dinitrotoluene [Hamill et ai., 1982], several specific solvents such as toluene and trichloroethylene [Taskinen et al., 1989], and perchloroethylene [Eskenazi et al., 1991]. Regardless of the results, the effort to design studies capable of implicating or exonerating specific agents is commendable. The initial study of Infante et al. [1976] provided the first suggested link between males' occupational chemical exposures and reproductive outcome. An overall elevation in risk of spontaneous abortion was found among spouses of men working with vinyl chloride (RR l .8), pronounced among younger (but not older) fathers (RR - 3.7) (Table III). Maternal age was not ascertained so that it could be examined only indirectly through the closely correlated father's age. Sanotskii [1976] reported a strong association of spontaneous abortion with chloroprene exposure, but insufficient methodological details are available to criti cally evaluate that observation. Risk ratios of i .5 or greater were reported for organic solvents in general (RR = 2.3), toluene fRR = 1.5), and xylene (RR = 1.8) by Taskinen et al. [1989], in a study with unusual precision in exposure classification to specific solvents in specific industrial settings. Lindbohm et al.'s [1991a] survey found sizable associations with gasoline or benzene exposure in petroleum refineries (RR - 2.2), trichloroethane and methylene chloride (RR - 1.9) in rubber manu- CMA 118998 '96 04:40PM ADMIN 1B03 BLDG 517 636 1875 P.13/28 368 Savitx at al. TABLE III. Uvula in Stadia of Paternal fiqmgn to Rubber, Plastics, or Satan* and Reference Infante et 4. [1976] Sanotskii (1976) Hamill et a). 11982] Undbohm et al. I19W] Savitz et al. (1984) Daniell & Vaughan [1988] MeConald et al. f 1989] Taskinen et al. (1989) Undbohm et #1. (1991a) Lindbohm et al. (1991b] Agent, industry, or occupation Vinyl chloride, polyvinyl chloride Chloroprene and manufacturing Toluene diamine, dinitrotoluene Solvents HaJogenated hydrocarbon* Autobody workers Painteia in maintenance, construction Fiberglass, bathtub, boat, plastics workers Printers, pressmen, lithographers LaundtyMry cleaning Rubber, plastic fabricating Printing operations Organic solvents Aromatic hydrocarbon! Styrene Toluene Xylene HaJogenated hydrocarbons Trichloroethylene 2,1.1-Tnchioroethine Aliphatic hydrocarbons Acetone Miscellaneous solvents Petroleum refinery solvents (gasoline, benzene) Benzene Trichloroethylene Rubber manufacturing solvents (trichloroethylene. methylene chloride; Rubber chemicals Styrene Plastic manulaetunng solvents (styrene) Plastic monomers Rubber product workers Organic solvent exposure 'Poiwmployment risk for esposod vs, unexposed. sNot available. RR 14* >3.0 1.0 0.9 1.2 1.0 0,9 0.9 l.t 0.9 1.0 0.9 2.3 1.6 1.3 1.5 1.8 1.1 1.0 0.9 1.5 1.0 1.7 2.2 1.0 0,9 1.9 1,5 0.9 1.0 0.8 1.5 1.1 95% Cl 1.0-3.1 NA* 0.6-1.8 0.7-1.1 0.8-1.8 0.8-1.2 04-1.i 0.7-1.2 04-13 0,6-I.J 04-1 5 04-1.2 1.1-5.0 1.0-2.4 04-2.1 0.9-2.5 1.1-3.2 04-1,8 0.6-2.0 0.3-2.3 0.9-2.5 04-1.7 1.1-24 1.3-34 0.7-1 3 0.3-2.1 1.2-24 1.1-2.2 0.5-14 0.7-1,5 0.4-I.4 1,1-2.2 0 7-1.5 factoring, and tnchloroethane in general (RR - 1.5). It is difficult to juxtapose results given the diversity of agents of interest, but there are replicated positive associations present for rubber workers, and to a lesser extent for petroleum refinery products and individual solvents. No attempts to replicate the observations for vinyl Chloride [Infante et al., 1976], chloroprene (Sanotskii, 1976], end^speciflo solvents implicated by Taskinen et al. [1989] have been reported. Many of the negative studies are limited in their ability to exonerate any ex posures given the weak methods of exposure classification combined -with poor re sponse proportions [Savitz et al., 1984] or questionably high rates of spontaneous abortion [Daniell and Vaughan, 1988], However, some of the'negttive results are more credible. Hamill et al.'s [1982] study was small but Included a strong effort to CMA 118999 Paternal Exposure and Spontaneous Abortion 369 TABLE IV. Results in Studies of Patent*! Exposure to Anesthetic Gases and Spontaneous Abortion ____________________________ Reference Agent, industry, or occupation RR 93% a Cohen et *1. [19741 Cohen ei al. (1973) Anesthesiologists Anesthetic nurtus Operation room technicians Dentists working with anesthetics >3 hr/week 0.9 0.8-1.1 1.2 0.3-2.6 1.8 0.8-4,1 1.3 1.4-2.2 Kmll-Jones et al. [1973] Rosenberg ft Vanttinen (19781 Physicians working in operating room Anesthesiologists 1.1* 0.7-1.7 0.8 0.3--1.4 Tomlin [1979] Cohen et al. [1980] Lauwerys et al. [1981] Guirguis et al. [1990] Anesthesiologists working in operating room 20 or more hours per week Dcnti&iS working with anesthesia 1*8 hr/week Dentists working with anastftesU 8* hr/wk Physician*, nurse* working in OR Physicians, nurses, other staff in OR 1.6 1.1 1.3 1.1 2,3 0.9-3.0 1.0-1.4 1.3-1.8 0.7-1.8 1.7-3,1 OR operating room. Father exposed but mother not exposed. accurately classify workplace exposure. McDonald et ai.'s [1989] study did not identify associations for laundry/dry cleaning or rubber workers, and a number of solvents, including benzene and carbon disulfide, were not associated with sponta neous abortion in Undbohm et ai.'s [1991a] study. The most promising leads to pursue would be exposures in the rubber industry and exposures to vinyl chloride and specific solvents associated with spontaneous abortion (Table III). Exposure to Anesthetic Gases Given the observation that maternal exposure to anesthetic gases could increase the risk of spontaneous abortion [Tannenbaum and Goldberg, 1985], a number of studies in the 1970s addressed the possibility that paternal exposure to anesthetic gases could produce a similar effect (Table IV). All but one of the eight studies of this issue were published between 1974 and 1981. and all were based on surveys of male health professionals, generally dentists or physicians. All were questionnaire surveys of self-reported exposure and pregnancy outcome, yet the reported risk of spontane ous abortion varied rather markedly from 5.1% [Guirguis et al.. 1990] to 13.2% [Rosenberg and Vanttinen, 1978] in spite of the similar methods (Appendix table). Such variation may be due to true heterogeneity in the populations, selection bias due to nonresponse patterns, or erroneous reporting. Response proportions did, in fact, vary quite markedly (41-92.4%), but there was not an obvious association between response proportion and reported risk of spontaneous abortion. The comparability of exposed and unexposed groups is unusually favorable, in that subgroups of poten tially exposed health professionals (physicians, dentists, or technicians) were com pared to other (presumably sociologically similar) subgroups from the same profes sion who were not likely to be exposed. Most of these studies have found increased risks for the partners of anestheticexposed men (Table IV). Risk ratios of 1.5 or greater have been reported for operating room technicians (RR 1.8) [Cohen ct al.. 1974], dentists working with anesthesia over 3 hours per week (RR = 1.8) [Cohen et al., 1975], anesthesiologists working CMA 119000 half-time or more in the operating room (RR = 1,6) [Tomlin, 1979], dentists working with anesthetics 8 or more hours per week (RR ^ 1.5) [Cohen et al., 1980], and hospital workers exposed to the operating room (RR " 2.3) [Guirguis et al., 1990], Other studies of physicians in particular, including those with briefer exposure peri ods. have not found increased risk [Knill-Jones et al., 1975; Rosenberg and Vanttinen, 1978]. The suggestive evidence for dentists is noteworthy, although the domi nance of the literature by a single group of investigators (with a particular approach to study methods, questionnaire design, etc.) diminishes the value of the independent replications. The traditionally intensive and uncontrolled use of anesthetics, espe cially nitrous oxide, in dental practice (Cohen et al.. 1980] warrants further exami nation. Exposure to Pesticides end Related Products Fifteen studies have provided data to assess risks of spontaneous abortion from male exposure to pesticides, antimicrobials and related products encountered in chem ical manufacturing, agricultural application, and from herbicide use in the war in Vietnam (Tables I and V). The diversity of agents and exposure settings i$ apparent. Nearly all studies established exposure through paternal report, sometimes sup plemented by company records [Smith et al., 1982; Townsend et al., 1982; Suskind and Hertzberg, 1984] or military records [Steilman et al,, 1968; Aschengrau and Monson, 1989] Overall, substantial attention was given to specific exposures m these studies, with most studies explicitly designed to address the agent(s) of interest. However, the degree of success in pinpointing actual exposures to Agent Orange, for example, or pesticides in agricultural applications is still quite limited. Reproductive outcomes were typically ascertained through maternal or paternal report. In reviewing the methodological details (Table 1 and Appendix table), notable outliers are the baseline risk of spontaneous abortion of 1.9% in Resirepo et al.'s (1990) study and the response of only 26% in the survey of Roan et al, [1984], seriously diminishing the credibiliiy of their results. Usually, but not always, major potential confounders such as maternal age and cigarette smoking were addressed. Even without the clearly invalid result of Kestrepo et al. [1990], a twofold range in spontaneous abortion risks (5-8-11.9%) was observed across studies. Results of pesticide studies were mixed (Table V), but again it is difficult to define which results address truly analogous exposures. DBCP exposure was found to increase spontaneous abortion risk in one study (RR = 3.0) [Kharrazi et al., 1980]. The results for 2,4-D, 2.4,5-T, dioxin, and Agent Orange show sporadic increases in risk, for example, among forestry workers (RR = 1.6) [Carmelli etal., 1981]andmen potentially exposed to herbicides in Vietnam based on self-perception [CDC, 1988] or imputed potential exposure [Steilman et al., 1988]. Other studies of related expo sures, equal or superior In quality, found no increased risk [Smith et al., 1982; Townsend etal.. 1982; Suskind and Hertzberg, 1984; Aschengrau and Monson, 1989]. Rupa et al. [ 1991] found an increased nsk of spontaneous abortion in the wives of male cotton workers in India. Although the study lacked some methodological details, the agents and exposure conditions may be worthy of closer examination. The notable associations reported by Restrepo et al. [1990] are greatly tempered by the anomalous spontaneous abortion risk of 1.9%, which suggests serious error in re porting accuracy or completeness, and the report of marked elevations in risk, even for jobs thought to-involve no exposure to pesticides. Similarly, Roan et al.'s [1984] Paternal Exposure and Spontaneous Abortion 371 TABLE V. Results iir Studies ef Paternal Expoaurc to Pesticide*, Antf-Mierebiafa, and Related Products and Spontaneous Abortion_____________________ Reference Kharrazi et al. (19801 Carmelli et al. (1981] Smith et al. (1982) Townsend ct al. (19821 Can et al. [ 1983) Goldsmith et nl. (1984] Roan ct al. (1984) Suskind A- Members (1984) CDC (1989] Slellman ct al, (19881 Aschengrau & Moriscm (1989) McDonald et al. (19891 Resirepo et al. (1990) Lindbohm et al. (1991a) Rupa et al. (1991] Agent, industry, or occupation RR Dibromochloropropane (DBCP) 3.0 2.4-dichlorophcnoxyaeetic acid (2.4-D) Farming Forestry/cgmmerciai applicator* 1.0 1.6 2,4,5-trichlorophenoxyecetic acid (2.4,5*T) 0.9 2,3,7,8-recrachlorodibenzo-p-dioxin (TCDD) Any dioxin Agent Orange 1.0 1.0 1.2 DBCP Agricultural pesticides 1.1 1.2 2.4.5-T and dloxun 0.9* Herbicide* lany perceived exposure) Low .Moderate High Agent Orange Handle! herbicide* Luw exposure Moderate exposure High exposure 1.3 1.2 1.4 17 1.6 I-.3 1.5 1.7 Service in Vietnam Agncuiture/homculiuie Floncultuml industry No pesticide job Low pesticide job Moderate pesticide job High peitieide job 0.9 1.0 2.4 1.6 Z.O 0.7 Ethylene oxide Impregrams' of wood formaldehyde (low exposure) Formaldehyde (high exposure) 4,7 1.9 1.1 1.0 Pesticide* used in cotton production .............. ,, ,1.7 o 4>> k to 95* a 1.3-7.0 0.5-2.0 0.8-3.1 0.6-1.3 0.7-1.4 0.8-1.4 1.2-1.3 0.3-4.0 1.0-2.1 0.6--1.2 1.2-1.4 1 0-1,4 1.2-1.6 1,3-2.1 0.8-2.9 1.0-1.6 1-1-2.0 1.3-2.3 0.8-1.4 1.1-5.0 0.7-3.7 1.2-3.3 0.1-5.3 1.2-18.4 0 7-5.0 0.9-1.4' 0.8-1.4 .1.6-1.9 JNot adjusted despite- differences between' exposed and utiexposed in age, education, and duration of smoking. report of a i .5-fold increased risk for agricultural pilots is diminished in its impor tance by the poor response proportion. Among the diverse results that were repotted, the observations most deserving of attempted replication (given study quality and biologic plausibility) are the increased risk for DBCP (Khanazi et at.. 1980], the association of spontaneous abortion with cotton pesticides (RR 1.7) [Rupa et aJ., 1991], and the isolated observation of an increased risk from ethylene oxide (RR 4,7) (Lindbohm et al.. 1991a]. Exposure to Physical Agents Of the six studies providing data on male exposure to physical agents (ionizing and non-ionizing radiation, heat), only one (Nordstrom et ai., 1983] was focused on CMA 119002 '96 04:42PM ADMIN 1803 BLDG 517 636 1875 P.17/2a 372 Savitt t al. TABLE VI, Results ! Studio of Paternal Expoeare to Phyafcai Agents ami Reference Boue el al. [1975] Kline ci 4. [I9S2J Nordstrom al. [1983] McDonald et ai. [I989J Lindbohm et al. [1991a] Lindbohm et al. [1991b] Agent, industry, or occupation lontiinp radiation Electrical Heat Nonionizing radiation Electromagnetic Helds Other job* (lowest voltase! Switchyard/line construction imodenie) Switchyard workers (high voltage) Ionizing radiation Radon exposure X-rays RR 1.3 1.2* 2.0* 0.7-1,8" 0.6 0,6 1.0 0.9 1.2 i.S 'Public patients. normal karyotype. "Range of risk ratios across normal/abnormal karyotype, public/private clinic. 93% Cl 1.1-1.3 0.6-2.3 0.9-4.9 -- 0.3-1.1 0.3-1.1 0-3-1.7 0.6-1.3 0.8-1.8 0.6-36 this particular topic, so thru the quality of exposure assessment was generally limited (Table VI). Suggestive associations were found for ionizing radiation in two studies [Boue et al.. 1975; Lindbohm et al., 1991b], with modestly elevated risk ratios of 1.3-1.5. Nonionizing radiation, a ubiquitous but poorly defined exposure, was found by Kline et al. [1982] to be associated with spontaneous abortions of both normal and abnormal karyotype but only among private patients. Nordstrom et al. [ 1983] did not find power-frequency electromagnetic fields to be associated with increased risk. Given clear evidence that ionizing radiation causes mutations [BEIR, 1990] and that heat can impair sperm function |Levine e< al., 1990]. this avenue appears to be worthy of pursuit in spite of the results currently available. The only data on heat exposure provided a suggestively positive result |Kline et al., 1982). Exposure to Hydrocarbons and Exhaust Several studies provided data on miscellaneous hydrocarbon and motor vehicle exhaust exposures, all as components of broader surveys (Table Vll). Nonetheless, perhaps because of the literature linking such agents to childhood cancer in the offspring [Savitz and Chen. 1990), several investigators had considerable interest in these exposures [Kline etal., 1982; Lindbohm et al., 1984; Lindbohm eta!., 1991a). These studies address diverse exposures that are highly prevalent, such that a number of studies provide evidence of small but statistically precise elevations in risk [Lind bohm et ai., 1984; McDonald et al.. 1989]. Consideration of the magnitude of increase found across studies yields rather consistently close to the null. Only the risk ratios of 1.4 and 1.5 found for chimney sweeps and refinery workers, respectively [Lindbohm et al., 1991a], would constitute positive results worthy of replication. However, the presence of known mutagenic agents within these exposure groups provides a greater impetus for further study than can be derived from these results. Exposure to Miscellaneous Industries, Occupations, and Agents In addition to the results that fall into the above categories, many reported associations did not fall into any of the specific categories. For example, one prom- t CMa 119003 Paternal Exposure and Spontaneous Abortion 373 TABLE VII. Results in Studies of Paternal Exposure to Exhaust and Hydrocarbons and Spontaneous Abortion Reference Agent. industiy, or occupation RR 95% ci Kline ei si. [1982] Auto fume* (narrow) Auto fumes (narrow) Auto fumes (narrow) Hydrocarbons (narrow) Hydrocarbons (narrow) 1.2* 0.8-1.7 1,3* 0.4-3.7 1,0* 0.6-1.5 1.2* 0.7-2.3 1,2' 0.6-2.6 Lindbohm cl si, [ 198*1 Polycyclic aromatic hydrocarbons Automobile exhaust and fumea Service station attendants 1.0 0,9-1. i 1.0 0.9-1,1 1.2 1.0-1.6 McDonald et al. [19891 Mechanics and repairers Transport operations/materials handling 1.1 1.0-1.2 1.0 0.9-1.1 Lindbohm el al. [1991a] Limibuhm ei jl Polycyclic aromatic hydrocarbons (modCTOU/high) Polycyclic aromatic hydrocarbons (low) Gasoline Chimney sweeps Refinery workers Carbon mnnomdc 1.0 1.0 0.9 1.5 1.4 i.i 0.9-1.2 0.9-1 0 0.3-1.1 0.9-2.4 0.8-2.5 0.8-1.7 'Normal karyotype, public clinic patients. ''Normal karyotype, private clinic patients. 'Abnormal karyotypes, public clinic patienu. inent study [Morgan et al,, 1984) addressed wastewater treatment plant workers who are not easily classified elsewhere (Table VJII), Notably elevated risk ratios (2.0 or greater) have been found for chemical crushers (RR *=* 2.2), cloth sewers (RR m 2.5), caretakers of fur*bcaring animals (RR = 2.3) [Lindbohm et al., 1984], all wastewater treatment plant workers (RR * 2.1), and mechanical, instrument, and electrical workers in the wastewater treatment plant (RR = 4.9) [Morgan et al., 1984). Associations between 1.5 and 2.0 have been reported for leather industry workers (RR * 1.8) [Hemminki et al., 1983] and for watchmakers (RR = 1.5) [Lindbohm et al., 1991a], A number of specific agents that could plausibly be linked to spontaneous abortion (e.g.. mutagens, miscellaneous industrial chemicals) were queried or im puted by investigators in a number of studies but did not yield any notably positive associations (Table VIID. None of the reported risk ratios reached 1.5. providing little basis for directing future study efforts. The explicit goal of studies such as these is to suggest agents more worthy of detailed examination, and leads from the above results are rather nonspecific in their suggestions for further study of hazardous chemicals in industry and health care. DISCUSSION Summary of Results The literature providing data to evaluate possible associations between paternal occupational exposures and spontaneous abortion is large but, at least until recently, not of high quality. Most studies examining the issue did so without having focused on this particular topic, with limited effort to measure exposure or outcome or both CMA119004 '96 04=43PM ADMIN 1803 BLDG 517 636 1875 374 Saviti t al. TABLE V1Q. Rnalta In Studies of Mbc*Uan*oiu Paitraal Exponmi/Occppatlons and Spontaneous Abortion Reference Kilns ci il. [19521 Hemminki c< al 119*31 Undbohm cm. |I984] Morgan el al, 119841 McDonald et ill, 119891 Ttokintn et a), H989] Lindbohm si ji. ||99|a] tnduwy, or occupation Chemical! Food Chemical industry Textile industry Uaiher industry Chemical crushers Cloth sewer* Caretakers of lur-bearing animats Textile ditti Animal microorganiama Other chemical* W|i water treatment plant worker* Ail job mk* Proceaa operators Mechanical. instrument, electrical Physical sciential* Physicians/dentin* Techniciana/art Chemical processing Food, beverage. wood, textile* Wood, stone machining Electrical fabricating Wood, textile, leather I'lbncaiins Construction trades Stationary equipment/miscellaneous mnnu/nctuftag C*ttlrtWgnA Dusts Watchmaker. Textile machine i-cuervopcran'r' Textile HnwheTS ,m0 [Jryvrs Mutagens thigh exposure t MuUfien* (low exposure' RR 0.7-0.5* 0 7-1. : 0.B 0.8 1,6 2.2 2.3 2.4 1,0 1.3 0.9 95a Cl -- 0.4-1 6 0,4-1.8 0.5-3. M-4J 1.3-3.0 1.3-4.4 o.e-i.5 0.9-1 9 0.7-1.2 2.1 0.9-4.3 0.9 o, i-s.a 4.9 1.3-15 1.2 0.9-1 0 1.0 0.7-1.2 1.1 O.S-I-I 0,9 0.6-1,4 1 0 0.9-1.2 1.2 0.8-1,8 0.9 0.7-1,0 1.0 0.8-1.1 i.a 0.9-1,1 M 0,9-1.4 1.3 Q.9-2 l 1,4 0.7-3 6 1.5 0 8-2 7 1.2 0,0-1,9 1.3 0 8-2,4 1.0 0.9-1.: 1,0 0.9-1 0 `Range of risk ratios across normal/abnonnal karyotype, public/private clinic. in the detail that would be desired. Nonetheless, some suggestions emerge from the literature regarding specific agents that are worthy of further evaluation. Given the imprecision in exposure assessment which plagues most of this literature, the ability of negative studies to persuasively exonerate agents is quite limited. A summary of the evidence for several agents of particular interest is provided in Table IX. The recent studies suggesting positive associations of occupational exposure to metals (mercury and lead) to Spontaneous abortion [Alcscr et al., 1989; Lindbohm et al., 1991b; Cordieret al., 1991] are of potential importance, especially given the evidence that lead [Lancranjan et al., 1975] and mercury [Lee and Dixon, 1975] may be disruptive to spermatogenesis. Although these agents are not thought to be mutagenic, developmental alterations through other processes such as epigenetic mechanisms may be involved. Mercury, in particular, has been found to be associated with increased risk in two high-quality studies. Solvents would be among the agents of greatest interest based on their wide- ;1 CMA 119005 Paternal Exposure and Spontaneous Abortion TABLE IX. Summary of Strength of Evidence Linking Selected Paternal Expoaurw to Spontaneous Abortion Agent Elevated RR Evidence from in >i Study RK>I,5 high quality studies Overall Laid Mercury Solvents Anesthetic gases Pesticides Pbenoxy herbicides Ionizing radiation Hydrocarbons No Vet Yes Yes Yea Yes No No Yet res Yea Ye* Yes Mixed Y Mixed Yet No YC5 No No No No No Moderare Strong Moderate Strong Weak Weak Very weak Very weak 375 spread use and potential for mutagenicity, and there are sporadic indications of increased risk associated with such exposures in the rubber and petrochemical indus tries. However, there has been little or no replication of the positive associations reported by infante et al. [19761 for vinyl chloride. Sanolsku [1976] for chloroprene, or Taskinen at al. [1989] for a number of different solvents used in specific industrial settings. Known adverse effects of these agents have resulted in reductions in expo sure, so that replication is not feasible. Anesthetic gases have long been of interest as reproductive hazards given the link between exposure during pregnancy and risk of spontaneous abortion [Tannenbaum and Goldberg, 1985]. Studies of demists and other health care workers con sistently suggest an association between male exposure and spontaneous abortion, but these are all based on mail surveys and many are from the same investigators. Refinements in exposure and outcome assessment are needed in future studies, but the reduction in anesthetic gas exposures in most settings may limit the informativeness of such efforts. Pesticides, especially Agent Orange, have been the focus of much effort but there are at most sporadic indications of positive associations. The diversity of agents and exposure circumstances that have been studied makes it particularly difficult to identify comparable studies, but there are few observations suggestive of an adverse effect of piCV.CldC wlpwUrC. Ur.lCoo jv<uv uiCiTiS of wiiuijg uic luiuuuubitf ciiailenges of exposure assessment can be identified (e.g, biological monitoring), addi tional simplistic efforts hold little promise. Exposure to Agent Orange, in particular, has been difficult to evaluate [Boyle et al., 1989; Lilicnfeld and Gallo, 1989], Ionizing radiation and hydrocarbons have produced limited support for an as sociation with spontaneous abortion. However, the theoretical basis for interest in these highly mutagenic agents to which many people are exposed is strong enough to warrant further study, in spice of the limited epidemiologic support. Ionizing radiation, in particular, may be amenable to studies that take advantage of the unique individual monitoring programs of large numbers of workers in place at many industries. Methodological issues The difficulties in conducting studies of paternal exposure and spontaneous abortion are substantial, including the challenge of isolating a paternal exposure from maternal influences, determining whether an association reflects indirect exposure to the mother rather than a direct sperm-mediated process, heterogeneity in the causes CMA 119006 '96 04:44PM ADMIN 1803 BLDG 517 636 1875 P.21/28 376 Savtfcr t al. of spontaneous abortion, and the difficulty of accurately measuring the occurrence of spontaneous abortion. Assessment of spontaneous abortion, regardless of the exposure of interest, is challenging. Reports of clinically recognized spontaneous abortions are known to incompletely reflect the total number of conceptions that are lost (Wilcox et al.. 1988) . Although valid results may still be obtained for the category of "clinically recognized spontaneous abortions," at the early gestational ages at which recognition is ambiguous the reporting may be both incomplete [Wilcox and Horney, 1984] and biased in relation to exposure status. The limited public perception of a paternal role in the etiology of spontaneous abortion makes differential reporting by exposure status somewhat less likely than for such highly publicized maternal exposures as anesthetic gases or use of video display terminals. Males are known to be particularly unreliable informants regarding reproductive history [Selcvan, 1985). Regarding spontaneous abortions, it is not only more likely that men would forget their wife's experience but even possible that they would be unaware that an early spontaneous abortion had occurred at all. Studies should rou tinely seek reproductive outcome information from the woman, whenever possible, contending with the logistical difficulties that can arise in locating and interviewing spouses no longer living with the male worker of interest- Research in which both the male (for exposure information) and female (for reproductive outcome information) are interviewed is needed in spite of the additional costs. Perhaps the most critical issue with regard to identification and classification of spontaneous abortions is the heterogeneity in the causes of spontaneous abortion. Isolation of the subset of all spontaneous abortions that are plausibly attributable to the paternal genome would markedly strengthen any true etiologic associations. One approach that has been taken in epidemiologic studies is to distinguish chromosomally normal and abnormal abortuses based on karyotyping the conceptus [Kline et al., 1989) . Some karyotypic abnormalities are attributable to the father, whereas others are clearly contributed by the mother, such that identification of the paternally derived subset of karyotypically abnormal abortuses could, in theory, be made. In practice, however, the logistical challenges of even obtaining information on the karyotype of the abortus are daunting, and the additional requirement to identify the source of the abnormality poses an additional challenge. For karyotypically normal abortuses, a potential role for paternal factors cannot be discounted, in that there may still be genetic determinants that do not act at the chromosomal level. It may be possible to identify more simplistic indicators of spontaneous abortions most likely to be influenced by paternal exposures by strati fying cases on gestational age to determine whether early or later losses are more affected, or to restrict the analysis to mothers at low risk (young mothers, nonsmok ers, etc.). Clinical and laboratory studies aimed at identifying the determining pa rental origin of spontaneous abortion would dramatically accelerate the development of this literature. Until recently, exposure classification has been rather poor, often based on the wife's report of her husband's job title or the male's employment in a broad industrial category. The limitations inherent in a job title as a marker of exposure are well known [Siemiatyckl, 1991), with imperfect sensitivity and specificity as an indicator of actual exposure to any particular agent, The design of these studies would gener ally lead to a prediction of nondifferential misclassification, i.c., the uncertainty in j -Wr * " ErSaTTI Paternal Exposure and Spontaneous Abortion 377 going from a job title to an exposure assignment would be similar for men who had fathered conceptions resulting in spontaneous abortion as in those who had fathered conceptions resulting in live bom children. Under those circumstances, the resulting risk estimates are diluted, understating the magnitude of any etiologic association [Copeland et al., 19771. This is the principal reason that "negative" studies should not be viewed as persuasive evidence chat the agents of interest do not produce increased risks. Instead, it would be safe to infer that the job categories do not have a widespread, extremely strong adverse influence on spontaneous abortion. Confounding is always a concern, with speculation limited only by the limited knowledge of risk factors for spontaneous abortion. Paternal occupation is undoubt edly correlated with such lifestyle factors as smoking [Sterling and Weinkftm, 197$; Siemiatycki et ai., 1988], yet there is little evidence to suggest that paternal lifestyle factors such as smoking [Beckman and Nordstrom, 1982; Taskinen et a]., 1989] or alcohol use [Halmesmaki et al., 1989; Parazzini et al., 1990] influence risk of spontaneous abortion.. Confounding by other workplace agents Is always possible, given that jobs with an environmental hazard rarely involve only one such agent. At present, however, with no paternal exposure that constitutes a proven etiologic agent, such concerns are highly speculative. Even among maternal factors, the only proven determinants are history of spontaneous abortion (which may reflect persistent ex posure or inherent characteristics of the woman), advanced maternal age, and pos sibly cigarette smoking or alcohol use (Kline et al.. 1989]. Since paternal occupation is a determinant of social class, and social class is closely related to maternal smoking during pregnancy [Williamson et al.. 19891. maternal smoking should be considered as a potential confounding factor, yet only about half of the studies we reviewed did so (Appendix table). A number of study design issues need to be considered in evaluating this literature and making recommendations for future research. Some studies have com pared preemployment and postemployment outcomes in the same individuals [Townsend et al., 1982; Restrepo et al.. 1990], Although such a design offers the advantage of controlling for any intrinsic factors to the couple, the potential for confounding by maternal and paternal age is substantial. Induced abortions have the potential for biasing comparisons of spontaneous abortion risks in comparisons of populations with differing induced aboition occur rence. Specifically, induced abortions remove pregnancies from being at risk of spontaneous abortion, and failure to consider them as "pregnancies at risk" artifi cially inflates the risk of spontaneous abortions relative to what would be found in a life table analysis [Olsen, 1984]. Alternatively, if induced abortions are counted as pregnancies at risk without noting that they ended prior to the end of the risk period for spontaneous abortion, the risk of spontaneous abortion wilt be artificially reduced relative to what would be found in a life table analysis [Modvig et al., 1990]. The ideal approach is to determine precise timing of all induced and spontaneous abortions and to conduct an analysis of spontaneous abortion incidence by week of gestation. However, the accuracy of reported induced abortions (especially by males) and the precision of the timing of induced and spontaneous abortions makes this strategy difficult to implement in practice. The size and resulting statistical power of these studies should also be consid ered. Starting with a large work force, the number of informative events (pregnancies among spouses) is limited by the proportion of men who are married and have CMA 119008 f 45PM ADMIN 1803 BLDG 517 636 1875 P.23/29 378 Savin et #1- reproductive experiences in the time period of employment, often resulting in highly imprecise risk estimates. Many of the most interesting groups, for example, workers exposed to DBCP, are too small to generate reliable risk estimates. Accepting the inherent constraints in addressing the topic of paternal exposure and spontaneous abortion, there are a number of opportunities for advancing knowl edge through improved study methods. Opportunistic studies in which paternal ex posures are included in studies focused on other issues (e.g., maternal exposures) can still add valuable information. In the context of a well-designed study of spontaneous abortion (including registry-based studies), addition of a modest series of quesiions about the father's exposures to potentially harmful agents through habits (tobacco, alcohol, illicit drugs), at home (hobbies, home repairs), and at work (querying work activities and locations as well as specific agents) would be contributory. A more ambitious step would be the detailed ascertainment of occupational exposure histories as developed by Siemiatycki and colleagues for a community-based study of occu pational carcinogens [Siemiatycld, 1991]. Their two-stage approach involves an ini tial interview followed by an interview with an industrial hygienist focusing in detail on activities and agents associated with the individual's work setting. In addition to opportunistic studies, sufficient evidence has accrued to justify development of targeted studies of paternal exposures. Populations of men with potentially harmful exposures could be studied in retrospective cohort designs with attention to accurate classification of exposure presence and riming based on industryspecific job-exposure matrices. In addition to industrial exposures, men exposed to medications or men with identified sperm characteristics could be studied to assess the reproductive outcomes in their spouses. Carefully designed case-control studies in the community could obtain data on lifestyle factors as well as retrospective reports of occupational exposures. In parallel with the evolving epidemiologic evidence, the need for additional laboratory studies should be emphasized. Insofar as the toxicologists can pinpoint exposures or suggest subsets of paternally derived spontaneous abortions, the epide miologic literature would benefit markedly. In the absence of a clearly demonstrated example of paternally caused spontaneous abortions in humans, skepticism about the potential for this process to operate will remain. However, the absence of such clear-cut evidence is not a result of a scries of carefully designed negative studies. In contrast, the present literature consists of studies of improving quality that contain a number of suggestively positive results. In combination with laboratory evidence and public concern, this research avenue deserves to be pursued to evaluate thoroughly the possibility that paternal exposures constitute an important, preventable cause of spontaneous abortions. REFERENCES Aldaer KM, Brlx KA. fine U. Kallcnluch LR. Wolfe RA (1989): Occupational mercury exposure and male reproductive health- Am J lnd Med 1:5:317-529. Ascbengmu A, Monson RR (1989): Paternal military tcroce in Vietnam and risk of tpomaneous abor tion. ) Occup Med 31:619-623. Beckman L, Nordstrom S (1982): Occupational and environmental risks m and around a smelter in northern Sweden. Hertditas 97:1-7. BBJR (1990): "Health Effects of Exposure to Low Levels of Ionizing Radiation: BE1R V." Committee on the Biological Effects of Ionizing Radiations, National Research Council. Washington, DC: National Aeadtmy Press. Paternal Exposure and Spontancwi Abortion 379 Boue J, Boue A. Lizar P (1975): Retrospective and prospective epidemiological studies of 1300 kary otyped spontaneous human abortions. Teratology 12:11-26. Boyle CA, Decoufli P, O'Brien TR (1989): Long-term health consequences of military service in Vietnam. Epidemiol Rev 11:1-27. Brodsky JB. Cohen N, Whitchar C, Brown BW Wu ML (1983): Occupational exposure to mercury in dentistry snd pregnancy outcome. JaDA 11:779-780. Carmelli D, Hofherr L. Tomsk J. Morgan RW (1981): "A Case-Control Study of the Relationship Between Exposure to 2,4-D and Spontaneous Abortions in Humans." Final report to the Nations! Forest Products Association and U S. Department of Agriculture--Forest Service. Menlo Piric, CA: SRI International, August 14, 1981. Centers for Disease Control Vietnam Experience Study (CDO (1988): Health status of Vietnam veterans, III. Reproductive outcomes and child health. JAMA 259:2713-2719. Cohen EN, for the Ad Hoc Committee on the Effect of Tract Anesthetics on the Health of Operating Room Personnel. American Society of Anesthesiologists (1974): Occupational diaease among operating room personnel: A national study. Anesthesiology 41:321-340. Cohen EN, Brown BW, Bruce DL, Cascorbi HF. Corbett TH. lonei TW, Whitcher CE (1975)' a survey of anesthetic health hazards among dentists. JADA 90:1291-1290. Cohen EN, Brown BW. Wu ML, Whitcher CE. Bredsky JB. Gift HC, Greenfield W, Jones TW, Driscoll El (1980): Occupational disease in dentistry snd chronic exposure to trace anesthetic gases. JADA 101:21-31. Copeland KT, Checkoway H. McMichael Ai. Holbrook RH (1977): Bias due to misctassification in the estimation of relative risk- Am J Epidemiol 105:488-495. Curdier S. Deplan F. Mandereau L. Henioft IP I 1991); Paternal exposure to mercury and spontaneous abortions. Br J Ind Med 48:375-381. Daniell W, Vaughan TL (1988): Paternal employment in solvent related occupations and adverse preg nancy outcomes. Br 1 Ind Med 45:193-197, Enckson JD, Mulinire J. McClain PW, Fitch TG. James LM. McClearn AB, Adams MJ Jr. (1984): Vietnam veterans' risks for fathering babies with blnh defects. JAMA 232:903-912. Eskenazi B, Fenster L. Hudes M. Wyrobck AJ. Katz DF. Gerson J. Rempel DM (1991): A study of the effect of perchloroeihylene exposure on the reproductive outcomes of wives of dry-cleaning workers. Am J Ind Med 20:393-600. Eurahjelm M, Jonson B. Lagerjren C-G (1962): The quality of human semen in spontaneous abortion. Int J FertU 7:17-21. Gardner MJ, Snee MP. Hall AJ, Powell CA. Downes S. Terrell JD (1990): Results of ease-control study of leukaemii and lymphoma among young people near Sellafield nuclear plant in West Cumbria. Br Med J 300:423-434. Goldsmith JR, Potashnik Q. Israeli R (1984): Reproductive outcomes in families of DBCP-exposod men. Arch Envir Health 39:83 -89 Green S, Aulctta A, Fabricant J, Kapp R. ManandharM. Shtu C, Springer J, Whitfield B (1983): CuiTtm status of bioassays in genetic toxicology--the dominant lethal assay: A report of the U.S. Envi ronmental Protection Agency Gene-Tox Program. Mutst Res 134:49-67. Guirguis SS. Pslmesr PL. Roy ML, Wong L (1990): Health effects associatid with exposure io anaes thetic gases in Ontario hospital personnel. Br 1 Ind Med 47:490-497. Halmesmakt E. Valimaki M, Roine R. Yllkahri R. YlikorkaJa O (1989): Maternal and paternal alcohol consumption and miscarriage. Br J Obitet Gynecol %:188-I9l. Hamiil pvy, Steinbcrgcr E. Levine RJ. Rodriguez-Rigau Lf. Lemeshow S, Avrunin JS (1982): The epidemiologic assessment of male reproductive hazard from occupational exposure to TDA and DNT. 1 Oceup Med 24:985-994. Hemminki K. Kyyronen P, Hlemi M-L. Koskinen K. Ssllmen M, Vuinio H (19831: SpontSMOUS abor tions in an industrialized community in Finland. Am J Publ Health 73:32-37. Infante PF. Wagoner JK. McMichael AJ, Wsxweiler RJ. Falk H (1976): Genetic risks of vinyl chloride. Lancet 1:734. Joel CA (1986): New etiologic aspects of habitual abortion and Infertility, with special reference to the male (actor. Fcitil Steril 17:374-380. Kharrazt M. Potashnik G, Goldsmith JR (1980): Reproductive effects of dlbromochloropropine. lured J Med 5cl 16:403 -406, Kline J, Stem Z, Hatch M, Hutzler M, Lai A, Pintel-Silverman J (1982): "Surveillance of Parental CMA 119010 HOV 38 '96 04:46PM ADMIN 1803 BLDG 517 S36 1875 P.25/29 380 Snvita et *1. Employment end Spontaneous Abortion." Final Report to the National Institute for Occupational Safety and Health. Contract No. 210813002. Cincinnati. OH: National lnititutc for Occupational Safety and Health. Kline J. Stein Z. Sutler M (1989): "Conception to Birth. Epidemiology of Prenatal Development." New York: Oxford University Preai. Knill-Jones RP. Newman BJ, Spence AA (1975): Anaesthetic practice and pregnancy. Lancet 2:807-809, Knithkowy B. Baker EL (19861: Transmission of occupational disease to family member;. Am ] Ind Med 9:545-550. Laneranjan 1. Popcscu HI. Gavanescu O. Klcpsch I. Serbanescu M (1975): Reproductive ability of workmen occupationally exposed to lead. Arch Environ Health 30:396-401. Lauwerys R. Siddoni M. Misson CB. Borlee I. Bouckaert A. Lechat MF. Temmentian PD (198)1: Anaesthetic health hazards among Belgian nurses and physicians, lnt Arch Occup Environ Health 48:195-203. Lee IP, Dixon RL (1975): Effects of mercury on spermatogenesis studied by velocity sedimentation cell separation and serial mating. J Pharmacol Exp Ther 194:171-181. Levine RJ. Mathew RM, Chenaull CB. Brown MH. Hunt ME, Bentley KS, Mohr KL. Working PK (1990): Differences in the quality of semen in outdoor workers during summer and winter. N Engl J Med 323:12-16. Ulienfeld DE, Gallo MA (1989): 2,4*0, 2.4,J-T, und 2,3,7,8-TCDD: An overview. Epidemiol Rev 11:28-58. Undbohm M-L, Hemminki K. Bonhomme MG. Annile A. Rantala K, Heikkila P. Rosenberg MJ (1991a): Effects of paternal occupational exposure on spontaneous abortions. Am J Pub Health 81:1029-1033. Undbohm M-L. Sallmen M, Anitila A. Tukinen H. Hemminki K (1991b): Paternal occupational lead exposure and spontaneous abortion, Scand J Work Environ Health 17:95-103. Lindbohm M-L, Hemminki K, Hyyronen P (1984); Parental occupational exposure and spontaneous abortions in Finland, Am J Epidemiol 120:370-378. McDonald AD, McDonald JC, Armstrong B. Cherry N. Delorme C, Nolin AD. Robert D (1987): Occupation and pregnancy outcome. Br J ind Med 44:521-526. McDonald AD, McDonald JC, Armstrong B. Cherry NM, Nolin AD. Robert D (1989): Father's occu pation and pregnancy outcome. Br J Inti Med 46:329-333. Modvig !. Schmidt L. Damsgaard MT (1990): Measurement Of lire total risk of spontaneous abortion: The virtu* of conditional risk estimation. Am J Epidemiol 132:1021-1038. Morgan RW, Kheifets L. Obnnxky DL, whorton ML), Foiiart DE (|984): Fetal loss and work in s wasic water treatment plant. Am J PUbl Health 74 499-501. Nordstrom S. Birke E. Gusiavsson L (1983): Reproductive hazards among workers at high voltage substations. 8ioclcctromaneiK.s 4:91-101 Olsen J (1984): Calculating risk ratios for spontaneous abortions: The problem of induced abortions. Ini J Epidemiol 13-347--30. Olahan AF, Faustmen E (1993): Male-mediated developmental toxicity, Ann Rev Public Health, (4: 159-181, Panzzini F, Boeeiolon* L, La Vecchta C, Negri E, Fedele L (1990): Maternal and paternal moderate daily alcohol consumption and unexplained miscarriages, Br J Obsttt Gynaecol 97:618-622. Restrepo M. Munoz N, Day NE. Pam JE. de Romero L, Nguycn-Dinh X (1990): Prevalence of adverse reproductive outcomes in a population occupationally exposed to pcsticidei in Colombia. Scand J Work Environ Health 16:232-238. Roan CC, Matanoski GE. Mcllnay CQ, Olds KL, Pylant F. Trout JR, Wheeler P. Morgan DP (1984): Spontaneous abortions, stillbirths, and birth deftels in families ef agricultural pilots. Arch Env Health 3936-60. Rosenberg PH, Vanttinen H (1978): Occupational hazards to reproduction and health in anaesthetists and paediatricians. Acta Anacstb Scand 22:202-207, Rothman KJ (1986): "Modam Epidemiology." Boston: Litila, Brown and Company. Rupa DS, Reddy PP, Reddi OS (1991): Reproductive performance in population exposed to pesticides in cotton fields in India. Environ Res 55:123 -128. Russell LB, Shelby MD (1985): Tests for heritable genetic damage and far evidence of gonedeJ exposure in mammals. Mutat Res 154:69-84, ` i a g a 4 , | f t i % f t Paternal Exposure and Spontaneous Abortion 391 Russell WL, Hunsieker PR (1988): Dominant mutagenic effect of ENU on fint-gcntrttioa litter size in mice following treatment of spermatogonia! stem cells. Environ Mol Muuy ll(Suppl 11)30. Sanotskii IV (1976): Aspects of the toxicology of chlofopme: Immediate and long-term effect*. Environ Health Perspect 17:83-93. 5avua DA. Chen J (1990): Parental occupation and childhood cancer Review of epidemiologic studies. Environ Health Pcrspect 88:323-37. Savitz DA, Harley B, Krekel S, Marshall J. Bondy 1. Orleans M (1984): Survey of reproductive hazards among Oil, Chemical, and Atomic Workers exposed to haiogenated hydrocarbons. Am J Ind Med 6:253-264. Selby PB, Russell WL (1985): First-generation litter size reduction following irradiation of tpermatogomat stem cells in mice and its use in risk estimation. Environ Mutag 7:451-69. Selevan SO (1985): Design of pregnancy outcome studies of industrial exposure. In Hcmminki K, Sons M. Vainio H (ed): "Occupational Hazards and Reproduction." Washington, DC: Hemisphere Publishing Compeny. Siemiatyeki J (1991): "Risk Factors for Cancer in the Workplace." Boca Raton. FL: CRC Pres*. Sienuatyckl J, Wecholder S. Dewar R, Wald L, Begin 0. Richardson L, Rosenman JC, GOrin M (1988): Smoking and degree of occupational exposure: Are internal analyses in cohort stadias likely to ha confounded by smoking sutus7 Am J Ind Med 13:59-69. Smith AH. Fisher DO. Pearce N. Chapman CJ (1982): Congenital defects and miscimages among New Zealand 2,4.5-T sprayers Arch Environ Health 37 197-200. Stachel B. Dougherty rc. Lahl U. Schlosser M. Zcxehmar B (19H9V. Toxic environmental chemicals in human semen: Anulyncil method and case studies Andrologia 21:282-91. SteUmtin 3D. Stellman JM. Sommer JF ildHH)- Health and reproductive outcomes among Americin Legionnaires m relation to combat and herbicide exposure in Vietnam. Environ Res 47:130-174, Sterling TD. Arundel A (1986): Review of recent Vietnamese studies on the carcinogenic and teratogenic effects of phenoxy herbicide exposure Ini J Health Scrv 16:265-278. Sterling TD. Wcinkam JJ (1976): Smoking characteristics by type of employment. J ObCup Med 18: 743-754 Suskind RR. Hcnzberg VS (1984): Human health effects oi 2,4,5-T and its toxic contaminants. JAMA 251:2372-2380. Tanncnbaum TN. Goldberg RJ (1985): Exposure to anesthetic gases and reproductive outcome J Occup Med 27:659-668, Taskincn H. Anttila A. Lindbohm M-L. Sailmen M. Hemmmk! K (1989); Spontaneous abortions and congenital malformations among the wives of men occupationally exposed to organic solvents. Scand J Work Environ Health 15:345-352. Tomlin PJ (1979): Health problems of anaesthetists and their femilies in the West Midlands. Br Med i 1:779-784. Townsend JC. Bodner KM, Van Peenen PFD. Olson RD. Cook RR (1982): Survey of reproductive events of wives of employees exposed to chlorinated dioxins. Am J Epidemiol 115:695-713. U.S. Department of Health and Human Services. Centers lor Disease Control (1989): "Health Statu* of Vietnam veterans, Vol. V, Reproductive Outcomes and Child Health." Atlanta, Georgia. Whorton D, Krauss RM, Marshall S 09771' Infertility in male pesticide workers. Lancet 2:1259-1261. Wilcox AJ, Horney LF (1984): Accuracy of spontaneous abortion recall. Am J Epidemiol 120:727-733. Wilcox AJ. Weinberg CR, O'Connor JF. Baird DD. Schlattcrer JP. Canfield RE, Armstrong EG. Nisul* BC (1988): Incidence of esriy loss of pregnancy. N Engl J Med 319:189-194. Williamson DF. Serdula MK, Kendrick J5. Sinkln NJ (1969): Comparing the prevalence of smoking in pregnant and nonpregnant women. 1985 to 1986. JAMA 261:70-74, Wyrobek AJ. Gordon LA. Burkhart JO, Francis MW. Kapp RW. Jr,, Letz G, Moiling HV. Topham JC. Whorton MD (1983a): An evaluation of the mouse sperm morphology test and other sperm tests in nonhuman animals. A report of the U.S. Environmental Protection Agency Gene-Tox Program, Mutat Res 115:1-72. Wyrobek AJ. Gordon LA. Burkhart JG. Francis MW, Kapp RW, Jr.. Letz G, Mailing HV, Topham JC. Whorton MQ (1983b): An evaluation of human sperm as indicators of chemically induced titer, moos of spermatogenic function. A report of the U.S. Environmental Protection Agency GeneTox Program. Mum Res 115:73-148. Yaztgt RA. Odcm RR. Polakoski KL (1991): Demonstration of specific binding of cocaine to human spermatozoa. JAMA 266:1956-1959. CMA 119012 CMA 119013 APPENDIX- hknol Occupational ifun and Sfodanauis Abortisn: Study Type, ConJounders, Case DeflnHiaas JUfaeooe CdkeactaJ [WM Boned J*. (19751 Coin el aL |1975J KiuIMak* d al [19751 Mined Ji IIV7M Sanobko [1976) Roseithag & V:iTtUiftc* 11*381 TomBa [ 19791 Cductal [I9S0J Khaw*o cl al. | IWHf Cumelfc ct ni | I9SI| Lanwoysci al. [I9fl] Bcdonan 4 NoidsiJern IIM2] Hwlti al. |iyiit KJneetaJ. | I9K| Snilh el *L |I9WJ Tuwjtsend ti al-119131 CadiL [l9BJf Hemnink] <* M. (I9U1 Nuximoin cl al. II9SJI Lifidbulunei aJ- |19V4J Study localtoa Uattol Stales France United StatesUnited Kingdom United States Sivpict Union Fmlaad United Kingian United Slates linel United Sutcr Birlgwjai Sweden United Stales Unite)} Sum .Study type Rcro&pcciite cohort CMss-ieciKiail Remspouivc eohem Rctnuprcuvc cohort Rcbcspecovc cohort RetmtpTLQve what Rclrospci.vc cohort. RrirasfechAC JteUuxfcvlTv c cohort JCciauN(*r\ tin: enhon NestrJ Cii^vCMinH RcLlOSpC* HI*" RrliosfcviiAa: cohort Rctrosperwvc cohort Case control New Zealand UnUsd States Victual Finland Sweden Finland Retufcipc^trve Retrospective oobcri Retrospective cobon Retrospective Cfllul felrospeckve colon Reiiospctuve cohort Gudaundcii addteswd Maternal age. stacking None Matronal Age, smoking, pregnancy history M aici ul age, smoking. bub order; paternal age Pivviutis SAh*. yoaer nat age NA* MatciMl age Nuiiir Maternal age. smoking. previous SAb Makrod age MArinal .uc, cigarette. aarijraaa smote. paternal age, cdoratkm. mxnfalkw aawital scans, pnnna SAb Snicking, drug ccasuAftkm Maternal age. smoking, occupation. ft*> dity. paternal age, alcohol Prternal afcofcoJ. smoking. race, marital status Maternal age, previous SAb, alcohol, smoking, patron*] uampkiysncnl, ethnicity, poblic^mvaie frlaiesNdl age, smoking, cihrocii? Maternal age. bank control rocihnd, mcdKatLon dining pregnancy, smoking, afcofcuf None Season. ruieiaal occupation Mmettwl age. smoking, akotaf. medicacigns. gravidity, chemical exposure* Maternal age. place of rcsidentc. pahly, amriial status Miscarriage case ddmuion GA* <20 weeks GA < l? woclu and abnormal karyroyp* GA <20 weeks MeanGA - U weeks (eaeludcs sidtoirths) SAbs and stBHhrltn NA Cbatcaiky recugnircd NA GA <20 weeks- NA EscCwks udlbicdsi heavy ia)c fuwcls Excludes alaliHrlhs Eaclntks stilfoirihv Guides with Ustury of SAb GA <-23 weeks wift known karyotype fexdndcs NiBNrtJu GA < 20 weeks Excludes snJIbiirtH tlospitalrcrd SAbs lift <28 weeks Exclude* zuMhints Hospitalized SAbs GA <. 23 weeks Baseline risk ul spontaneous abortion 4?) IZ 5 NA' 90 111.9 3.8 NA U2 b7 rt.6 11-M* fr.l 7J H-S NA IU0 11.9 59 9-S 9V P .37/28 :0 4 48PM ADMIN 1803 BLDG 51? 638 1875 18 Uuffiil *4 -A fc I9K-L| KiijM cl at |J#-I| SjhI/ i*f j| L19IM| SulLuuI &: Ik'nibcry f J9I-IJ JJ4Jsky ti j|. ||*8S| Darnell & Vugkun L19S8J Ciiiktl State* ClliWiI -SldlCv Uftttcd Aiders Uotfed Strike Unicd Stittvi. Untied Slides itrtduuncrl ^,1 | I9SBJ CL)C J l*M) timed Slate* liftuof Slate* Alt-nl cl J) P'X'J| Anhcaj'iuu 2t AWmin 119891 *.VDu.u*Jcl jl |j9*9t TavlurR cl jl ll'*M| Ciuicyuis rt ij. LI99U| ko4rL|iUal [JSfJ0| Coxher Cl dt. 11991) Lindbaihai u al J 199 la| Imlkuhni cl d JtV9Jfct Jtupoci al. ||99L| thuteJ Si ale-* Lhuted Sidles ( aiadu FinLinJ llnUri*. C.maia Ccrionibu France FmLmiI FmIojiJ 'CicMulkuut age. hSpum!ineous abortion*Nol available. '`Includes exposed population. *Ciled in .Sterling and Arundel |I986|. tiled u McDonald cl al. JI987|. FtciriM-iicx rt^ e cukuti KciTt>spC\|l%c ciiUvin; Aelti^xiuiie eaten RclKApccihi: tutital hdiirfvcdVL: Cnlhun Rdjosfxcijvc cohort Rcirusprciivc cobun Rdru^evtive eutktt ttCVi's|hXhvC ildKiTi KcikasplJLUVC Odt'tllf) Nisced tiuc cutiIkJ RclMipcCTve coboct Redospcckvc cefmrt ftciroigcrtivc cohort Kctnnfcchve cohort Nested cue control Bdraspccthe Culon M-UlClIijJ fJLL- ,!>.,, L'.JlM Ul-<ll. SJrlitLu^, dlO'llOj MdUird JpC palermu I Jv'L id It.Jib * MjtcroJ nipc, pdLcriijJ uci\ urc murad Jjivs Nunc Miuriul aye. xnuiist Marcr&d jyr. ituiiul h.ums. ripl<i>atil icaritx ccrtMA ic*.i. ptcdian income. ^uvuluy. previous SAfe. otrue since Ul prcynuic?. puicaiul aye Mukful ajft. sanAint- paternal ape. combat eiposioe Fufcxul age. line. a-nli-ftiucm status. nAujum. nulkary rpciults, im-Atne .akithid. Jrug aw. nanul MJtBs .MdJCIIVjJ JfT. MIHlk MIL1. .Ao-ldMil *m 0tU|4u\tllk-at. pJfVaUUbS-S.Viv ei^ki iml |'i|r1ld jpe MjicijuI rh cHi|4r% niv a a -a~ 4xmt.. fumy, pntw (treebjeurs Ui%vs i.naioil .iwriii. |Uk'm<il Jpc. lAi: tslialLi-ll V'rtfc|ll.k.> MdltTitri cusiilei j'loiuni S \i. cil*at j|'^. CliUCjUUfl MluLlAp, IM'UJMdUIII. Maicroid iyc. date .* itiwcfOor MKstojJ dp: Miwkiiljl kmib *tdi i. |il b-UHia SAb Milrroai age, fjotklity. surmLinf. Jeobti. plejrul age, Length ol recall Muterreal vk'tuccwinjink -lUlus. iHoupaiiuiul Maternal agp,, vtiuLing. febiilc diseases. pdkiiul itgC> smoking. previous SAb Internal alcohol. ameftiag. drug imt. auin*aal Mifrs. louc tapunorcs uul sullhmlts SAhs ori salltenlu SAJii and jiiJlhinh* Eschnic-a ^ullhuihs GA <2t> weeki Pnur ios*c> noicii on biria ccndkaic lULhidea bllllbkrltls E-tcludei siillbkibs S.ibi iihJ sidlbnkfr. GA ?S ilEs (A -`i weeks Quiu-aI!^ ittn|jiii-il f(iA - 6 2M acCls.1 CiA <20 wei'ts UA <20 iVLtla GA <-21 weeks Clinically rccogmeed Cliotcalfy rerogpiud GA <30 weeks 1 .i 12 92 il 9 13 114 51 87 93 NA to r da 51 l9 94 8.9 MA II 4