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Journal of Andrology, Vol. 30, No. 5, September/October 2009 Copyright E American Society of Andrology

Occupational Exposures Obtained by Questionnaire in Clinical Practice and Their Association With Semen Quality GWENDOLINE DE FLEURIAN,*{{ JEANNE PERRIN,*{ RENE´ ECOCHARD,§ EMMANUELLE DANTONY,§ ANDRE´ LANTEAUME,* VINCENT ACHARD,{ JEAN-MARIE GRILLO,*{ MARIE-ROBERTE GUICHAOUA,*{ ALAIN BOTTA,*{ AND IREŃE SARI-MINODIER*{ From the *Laboratoire de Biogeńotoxicologie et Mutagene`se Environnementale, Fe´de´ration de Recherche ECCOREV, Faculte´ de Me´decine, Marseille, France; the Service Hospitalo-Universitaire de Me´decine et Sante´ au Travail, AP-HM et Faculte´ de Me´decine, Marseille, France; the `Laboratoire de Biologie de la Reproduction, AP-HM–La Conception, Marseille, France; and the §Hospices Civils de Lyon, Service de Biostatistique, Lyon, France; the §Universite´ de Lyon, Villeurbanne, France; and the §Laboratoire Biostatistique Sante´, Pierre-Beńite, France.

ABSTRACT: In industrial countries, evidence suggests that semen quality has been steadily decreasing over the past 5 decades. We employed a short questionnaire to examine the association between self-reported physical or chemical occupational exposures and semen quality. The study included 402 men consulting for couple infertility (314 with oligospermia, asthenospermia, or teratospermia and 88 with normal semen; World Health Organization criteria). Exposure effects on global sperm quality and total sperm count, sperm motility, and sperm morphology were investigated. We found significant associations between semen impairment and occupational risk factors such as exposure to heavy metals (adjusted odds ratio [OR] 5 5.4; 95% confidence interval [CI], 1.6–18.1), solvents (OR 5 2.5; 95% CI, 1.4–4.4), fumes (OR 5 1.9; 95% CI, 1.1–3.4), and polycyclic aromatic hydrocarbons (OR 5 1.9; 95% CI, 1.1–3.5). Exposure to pesticides or cement was nearly significant (OR 5 3.6; 95% CI, 0.8–15.8, and OR 5 2.5; 95% CI, 0.95–6.5, respectively). Physical risk factors were associated with some sperm anomalies,

such as mechanical vibrations with oligospermia and teratospermia as well as excess heat and extended sitting periods with impaired motility. Exposure to ionizing radiation and electromagnetic fields was not associated with semen impairment; these results, however, may be skewed, because very few subjects reported such exposure. Despite the small dataset, self-reported exposures were correlated with semen impairment. This approach may be recommended in routine clinical practice to seek relationships between occupational exposures to reprotoxic agents and impaired semen parameters. This knowledge would allow preventive measures in the workplace to be established and could be complemented by the use of biomarkers to better characterize exposure to chemical substances and their spermiotoxic effects. Key words: Semen, male infertility, occupational exposure, questionnaire, self-reported exposures. J Androl 2009;30:566–579

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is to identify these factors and to reduce the occurrence of infertility through preventive means. Because men are frequently exposed to different chemical and physical agents simultaneously, many studies that explore the relationships between occupational backgrounds and semen impairment have been conducted with different epidemiological methodologies. Many studies focused on specific exposures (Chia et al, 1996; Thonneau et al, 1996; Stoy et al, 2004) or occupations (Figa Talamanca et al, 1992; Kurinczuk and Clarke, 2001). In these studies, the collection of data is very accurate regarding one risk factor with subcategories (Welch et al, 1988) or dose measurements (Bujan et al, 2000). Because data collection is time-consuming and expensive, however, such studies have to be conducted when a given factor is already suspected. Conversely, general occupational exposure questionnaires may be used to identify risk factors. Some are self-administered (Gracia et al, 2005) or physicianadministered in infertility centers (Tielemans et al,

n industrial countries, 15% of couples of reproductive age have difficulty conceiving naturally. A male factor is involved in half of these couples, and the etiology remains unknown in 25% of male infertility cases (Skakkebaek et al, 1994). Because medical history cannot explain all male infertility cases, these observations may be linked to a growing impact of potential occupational and environmental factors. For this reason, one priority of research in industrial countries

Supported by a grant from the public Direction Re´gionale du Travail, de l’Emploi et de la Formation Professionnelle (DRTEFP) of Provence-Alpes-Coˆte d’Azur Region, France. Correspondence to: Dr Jeanne Perrin, Laboratoire de Biologie de la Reproduction, Assistance Publique Hoˆpitaux de Marseille–CHU La Conception, 147, Bd. Baille, 13385 Marseille Cedex 05, France (e-mail: [email protected]). Received for publication June 10, 2008; accepted for publication February 4, 2009. DOI: 10.2164/jandrol.108.005918

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An Occupational Questionnaire in a Fertility Clinic

1999; Wong et al, 2003). Most of them are ad hoc questionnaires designed to assess specific new risk factors for semen impairment. Within this context, we took advantage of relevant literature to design a questionnaire in order to obtain information about occupational exposures via a selfreport. This allowed for the evaluation of associations between occupational exposures and semen quality in men who had consulted our reproductive biology laboratory for couple infertility. This questionnaire had to be short enough to be used in routine consultation and complete enough to include and accurately capture the occupational factors that could alter semen quality. The questionnaire was applied in a clinical setting and was designed to ascertain the effect of known occupational hazards and foster collaboration between occupational and reproductive health.

Materials and Methods Study Population In this study, all subjects were recruited between November 2004 and May 2006 from the population of men seen during routine consultations of the Reproductive Medicine Laboratory, La Conception University Hospital, Marseille, France. Patients were interviewed and asked to provide a semen sample the same day. Inclusion criteria of participants were as follows: male volunteers aged 18 to 55 with good command of the French language and residing in southeast France, coming to our laboratory for evaluation of couple infertility in absence of an identifiable cause of male infertility (ie, bilateral cryptorchidism, bilateral testicular hypotrophy, bilateral varicocele, congenital absence of vas deferens, endocrine hypogonadism, history of radiotherapy or chemotherapy, genetic or chromosomal abnormalities, or exposure to diethylstilbestrol in utero) (Whitehead and Leiter, 1981), and absence of current medication known to impair semen parameters such as psychotropics (Levin et al, 1981; Tanrikut and Schlegel, 2007), antiepileptics (Isojarvi et al, 2004), or cardiotropics (Pichini et al, 1994); see the full list in the questionnaire, Appendix. A total of 107 men were excluded from this study because these criteria were not fulfilled. Of these men, 23 were excluded because of identifiable causes of male infertility. The participation rate among eligible men was excellent; only 3 men (0.7%) refused to participate. A total of 402 participants were included: 314 men whose semen quality was later found impaired and 88 men whose semen was later found normal (ie, with normal semen parameters according to World Health Organization [WHO] criteria; see details below). In the present study, the fertile status of the subjects (ie, potentiality of conception) was not considered. Thus, the men with impaired semen quality were not necessarily infertile.

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Questionnaire Design The questionnaire (full text in Appendix) was designed after an extensive PubMed search for articles about occupational and nonoccupational risk factors well known to be responsible for semen impairment or male infertility. The search was restricted to articles published in English between January 1980 and July 2006. We first used a combination of general keywords (semen impairment, occupational exposure, and questionnaire), followed by refining the search using a combination of keywords specific to semen parameters (eg, oligospermia, asthenospermia, teratospermia) to occupations (eg, painter, driver) and to toxic occupational and nonoccupational exposures (eg, tobacco, marijuana, or alcohol use; hot baths; extended sitting; exposure to electromagnetic fields, solvents, metals, fumes, etc). Articles about questionable factors, such as exposure to mobile phones, were not included. Reference lists from identified articles were also examined for additional articles to include. The selected publications included meta-analyses, evidence-based reviews, randomized controlled trials, review articles, and case reports. Subsequently, the vast majority of the items of the questionnaire corresponded to the most frequently cited medical causes and occupational risks of semen impairment set by consensus among the members of the research team according to their experience and expertise. Table 1 shows the occupational factors considered by the questionnaire, the associated impaired semen parameters, and the corresponding references in the medical literature.

Questionnaire Contents The items of the questionnaire were divided into 4 parts. Part 1 collected general information on the participant: age, place of birth, age at arrival in France (for those born outside France). Part 2 addressed the known risk factors for semen impairment, including history of genital pathology (mumps with orchitis, unilateral cryptorchidism, unilateral testicular torsion, scrotal trauma, unilateral varicocele, surgery for inguinal hernia in childhood, and urogenital tract infections), high fever ($38.5uC) during the previous 3 months, and current hot baths ($1/week). Part 3 asked about lifestyle: current (for a duration of at least 3 months) consumption of tobacco, alcohol, or marijuana. Because of the small sample size and for study feasibility, categories were set for cigarette smoking (none, #10 cigarettes/ d, 11–20 cigarettes/d, .20 cigarettes/d), marijuana use (none, occasional, regular), and alcohol use (,1 glass/d, $1 glass/d). We were unable to separate data for alcohol consumption into high, moderate, and low consumption because the data for these categories were unequally distributed: 2 subjects declared high alcohol consumption, and all others declared a very moderate consumption (occasional to 2 glasses/d). Part 4 assessed the subjects’ professional exposure using 3 parameters: 1) the social and economic class as defined by the Institut National de la Statistique et des Etudes Economiques (INSEE) was collected as an indirect occupational indicator (INSEE, 2003a); 2) current and past occupations based on the

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Table 1. Occupational factors considered by the questionnaire, associated impaired semen parameters, and examples of references in the medical literature Risk Factors and Semen Parameters

References

Chemical factors Heavy metals Total sperm count (lead, cadmium, chromium VI, copper) Sperm motility (lead, cadmium, copper, zinc) Sperm morphology (lead, cadmium, copper, zinc) Pesticides Total sperm count (greenhouse workers) Solvents Total sperm count (glycol ethers, hydrocarbons) Sperm motility (global exposure, hydrocarbons) Sperm morphology (trichloroethylene, hydrocarbons) Welding fumes Total sperm count Polycyclic aromatic hydrocarbons Total sperm count Sperm morphology

Sheiner et al, 2003 Telisman et al, 2000

Abell et al, 2000 Veulemans et al, 1993 Cherry et al, 2001 Chia et al, 1996 De Celis et al, 2000 Bonde, 1993 Gaspari et al, 2002 Hsu et al, 2006

Physical factors Ionizing radiation Total sperm count Electromagnetic fields Total sperm count Sperm motility Sperm morphology No effect on semen parameters Mechanical vibrations Total sperm count Sperm motility Sperm morphology Excess heat Sperm motility Sperm morphology Extended periods of sitting Sperm motility Sperm morphology

INSEE list of 226 jobs (INSEE, 2003b); because of the small sample size, these were grouped into occupational sectors (see Table 2); and 3) occupational exposure considering the exact professional activity. The occupational chemicals we searched for were heavy metals, pesticides, solvents, fumes, and polycyclic aromatic hydrocarbons (PAHs). We considered a subject exposed to fumes if he was exposed to at least 1 of the following: plastic fumes, vegetable fumes, welding fumes, engine fumes, or metallurgy fumes (separate questions). Subjects exposed to welding fumes were considered as exposed to heavy metals as well. Among the chemicals mentioned by the subjects, cement was noted and analyzed, in particular because of the large number of exposed subjects. An exposure to a chemical product was considered positive in the case of either current exposure ($1 h/wk and since 3 months or more) or past exposure (not current; lasting for 1 or more years in the past and $1 h/wk). The occupational physical agents considered were ionizing radiation, electromagnetic fields, mechanical vibrations, excess heat, and extended periods of sitting. An exposure to a

Sheiner et al, 2003 Weyandt et al, 1996 Kumar, 2004 Lancranjan et al, 1975 Lundsberg et al, 1995 Penkov et al, 1996

Figa Talamanca et al, 1992 Hjollund et al, 2002 Bujan et al, 2000

physical agent was considered positive only in the case of current exposure ($1 h/wk and since 3 months or more). To introduce a dose effect assessment, an exposure index was calculated: 1) for chemicals, the index was the product of the number of years of exposure by a weight proportional to the frequency of exposure (weight 1 for ,2 h/wk, 2 for 2–10 h/ wk, 3 for 11–20 h/wk, 4 for .20 h/wk); 2) for physical exposure, we considered only current exposures, and the index was simply the exposure frequency (expressed as a ranked variable, 1 to 4).

Questionnaire Administration An observational, epidemiological design was conducted in a clinical setting that was based on voluntary participation and did not involve any interventions or changes in patient care. Thus, according to French legislation, it did not require an agreement from the Local Ethical Committee. Nevertheless, the aim of the study was described to eligible subjects, and the project was registered at the French Commission Nationale de l’Informatique et des Liberte´s.

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Table 2. Distribution of occupational characteristics (yes/no) between men with altered and men with normal semen P Value Total (n 5 402)

Men With Altered Semen (n 5 314)

Men With Normal Semen (n 5 88)

Univariate Analysisa

Logistic Regressionb

c

Current social/economic class, n (%)

Farmer Craftsman, merchant, and businessman Upper middle class Middle class Employee Workman Student and unemployed

4 33 44 51 125 118 27

(1.0) (8.2) (10.9) (12.7) (31.1) (29.4) (6.7)

4 23 31 33 101 101 21

(1.3) (7.3) (9.9) (10.5) (32.2) (32.2) (6.7)

0 10 13 18 24 17 6

(11.4) (14.8) (20.5) (27.3) (19.3) (6.8)

.287 .223 .193 .013 .381 .019 .966

.295 .212 .203 .033 .377 .025 .978

Occupational sector, n (%) Current administrative work Current driving trades Current/past construction trades Current/past security trades Current/past mechanics and servicing Current/past commerce trades Current/past agricultural/gardening trades

56 53 83 53 63 56 30

(13.9) (13.2) (20.6) (13.2) (15.7) (13.9) (7.5)

43 44 69 44 51 47 27

(13.8) (14.1) (22.1) (14.1) (16.3) (15.1) (8.7)

13 9 14 9 12 9 3

(14.4) (10.0) (15.6) (10.0) (13.3) (10.0) (3.3)

.873 .378 .716 .378 .517 .234 .091

.894 .412 .728 .384 .523 .221 .098

a

Unadjusted P value stemming from the x2 test. P value obtained after logistic regression adjusted for age and known risk factor variables. c For examples, see questionnaire, Appendix. b

Approximately 30 minutes before the interview, each subject was given written information about the aim of the study and the contents of the questionnaire. The questionnaire was administered prior to semen analysis and the report of its results. The same occupational physician administered the entire questionnaire to all subjects. Each interview lasted approximately 20 minutes. The physician first questioned the subject about his current and past occupations and the subject then described his exact professional activities. The physician then asked questions about the occupational exposure to chemical and physical factors, the number of hours of exposure per week, and the start and end dates of exposure. Although the questioning was directed by the physician, each subject was also able to mention other occupational chemical exposures. These exposures were examined in the same way as the other chemicals. Appointed tasks and examples of jobs involved in the exposure are shown in Table 3.

Semen Sample Analysis Ejaculate was obtained by masturbation into a sterile collection tube after a period of sexual abstinence for 2 to 6 days. Semen analysis was performed after 30 minutes of liquefaction at 37uC. The analysis included determination of ejaculate volume, sperm count, sperm motility, and viability according to the current WHO guidelines (WHO, 1999). Sperm morphology was assessed on semen smears prepared according to a standardized method from a 10-mL drop of airdried sample fixed with a cytology fixative spray (CytoRAL; RAL, Martillac, France). Smears were stained with Schorr staining according to the WHO manuals (WHO, 1999). Sperm morphology defects were assessed according to the method described by David et al (1975) and modified by Jouannet et al (1988). This classification distinguishes normal morphology, 7

head abnormalities, 3 midpiece abnormalities, and 5 tail abnormalities. The percentages of morphologically normal spermatozoa and of spermatozoa showing various morphological abnormalities were evaluated on 100 spermatozoa at 10006 magnification. According to the WHO criteria, semen quality was considered normal when the 3 following criteria or parameters were met: 1) total sperm count was at least 40 million spermatozoa per ejaculate (if not: oligospermia), 2) sperm motility was at least 50% progressive motility or 25% rapid progressive motility (if not: asthenospermia), and 3) sperm morphology was at least 30% normal morphology (if not: teratospermia) according to the David modified classification (David et al, 1975; Jouannet et al, 1988).

Statistical Analysis In the first round of analysis, the outcome was the overall semen quality, considered either normal or altered (if altered, sperm was determined to be oligospermia, asthenospermia, and/or teratospermia). Univariate tests were performed to determine differences between subjects with normal semen or altered semen and to search for potential confounders: the x2 test was used for qualitative/categorical variables (such as lifestyle characteristics and occupational sector), and Student’s t test was used to compare the means of quantitative/ continuous variables (eg, age, total sperm count). The exposure index was a continuous variable for chemical factors, but the number of exposed and unexposed subjects was lower than 30 per group in most cases and the distributions were not normal. The exposure index for chemical factors was therefore tested using the Mann-Whitney nonparametric test instead of the t test. Because exposure index was a ranked variable for the physical factors, a logistic

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Table 3. Appointed tasks and examples of jobs involving potential exposurea Examples of Exposing Jobsb

Appointed Tasks Chemical factors Heavy metals Grinding, polishing, welding, flame cutting, soldering Contact with old paint (containing lead) Pesticides Spraying Solvents Using or inhaling paints, coloring, lacquers, glues, degreasers, printing inks Fumes Inhaling plastic, vegetable, welding, vehicle, metallurgy fumes Polycyclic aromatic hydrocarbons Inhaling or touching bitumen, organic oil Inhaling diesel fumes Coke oven work

Plumber, electrician, welder, microprocessor manufacture technician, tanner, restorer of old-paint furniture, building trades worker Farmer, gardener Painter, bricklayer, furniture assembler, welder, window cleaner, launderer, hairdresser, photographer who develops photos, artist Gardener, garbage collector, plumber, heating engineer, driver, fireman Vehicle driver/mechanic, motorway worker, driver, firefighter, underground car park valet

Physical factors Ionizing radiation Medical radiology, industrial radiology, research laboratory work using ionizing radiation, nuclear medicine and industry Electromagnetic fields Train, helicopter, plane driving or air crew Aerial relay repair or maintenance Medical RMN Mechanical vibrations Driving building trade engine, driving truck, driving farm vehicle, using vibrating tool Excess heat Working in hot environment Extended periods of sitting Driving car, forklift truck, bus, truck, farm vehicle, building trade engine Desk work a b

Medical and industrial radiologist, technician in medical radiology

Air pilot, medical doctor, technician in medical radiology

Forklift driver, farmer, joiner, use of pneumatic drill

Baker, cook, pizzeria employee, fireman, welder Clerical worker, driver, canvasser, student, motor handicapped, pianist (we did not consider the unemployed)

This table is based on our study sample. These examples do not preclude multiple-exposure jobs (eg, driver or farmer).

regression analysis was performed, adjusted for age and the presence of at least 1 known risk factor (dichotomous variable). Multivariate tests (logistic regression) were performed for occupational characteristics (eg, social and economic class or occupational sectors) as well as each chemical and physical occupational exposure factor. Each variable was put into a different multivariate model, including the tested variable, the age, and the presence of known risk factors (dichotomous variable). The cohort for this dichotomous variable was split into 2 categories: ‘‘presence’’ in the case of history of at least 1 of the 9 known risk factors (eg, mumps; see Table 4) and ‘‘absence’’ in the case of absence of all these known risk factors. In a second analysis round, the outcomes were the semen parameters: sperm count (normal or oligospermia), motility (normal or asthenospermia), and morphology (normal or teratospermia). First, univariate analyses (Student’s t test) were performed to test statistical differences between the means of each semen parameter in exposed vs unexposed subjects. Second, a logistic regression adjusted by age and the presence of at least 1 known risk factor (dichotomous variable)

was performed to test higher risks of oligospermia, asthenospermia, or teratospermia in exposed vs unexposed subjects. Notice that semen parameters may have been impaired in exposed or unexposed subjects, but not abnormal if they stayed equal or above the WHO thresholds. We tested only the occupational exposures for which impairment or abnormality in semen parameters was already reported in the specialized literature (see Table 1). For example, there are no literature data regarding the effect of whole fumes on semen impairment. We therefore did not explore exposure to whole fumes but to welding fumes, which are reported to impair semen parameters. Each semen parameter was also tested for exposure to cement. This was an exception because, to our knowledge, there is no literature about this factor. All tests were performed only when 15 or more subjects were exposed to a given agent. This threshold was arbitrarily defined because of feasibility criteria (ie, small sizes of samples). The statistical significance was set at P , .05. Whenever possible, according to the statistical analysis, adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) were added.

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Table 4. Participants’ characteristics and search for potential confounders Total (n 5 402)


Men With Normal Semen (n 5 88)

P Valuea

Demographic characteristics Mean age 6 SD, y Minimum–maximum, y Place of birth, n (%) France European Union (except France) Out of the European Union Age at arrival in France (for foreigners) Mean age 6 SD (number) Minimum–maximum (yr)

35.5 6 6.6 22–55

35.6 6 6.8 22–55

35.1 6 5.5 26–49

.528 .078

309 (76.9) 4 (1.0) 89 (22.1) 26.0 6 9.2 (n 5 93) 2–49

246 (78.8) 4 (1.3) 62 (19.9) 25.9 6 9.8 (n 5 66) 2–48

63 (70.0) 0 (0.0) 27 (30.0) 26.2 6 7.4 (n 5 27) 12–49

.915

Lifestyle characteristics (current exposure), n (%) Cigarette smoking None #10 cigarettes/d 11–20 cigarettes/d .20 cigarettes/d Marijuana use None or occasional Regular Alcohol use None or ,1 glass/d $1 glass/d

.496 196 83 104 19

(48.8) (20.6) (25.9) (4.7)

150 63 84 17

(47.8) (20.1) (26.8) (5.4)

46 20 20 2

(52.3) (22.7) (22.7) (2.3) .181

370 (92) 32 (8.0)

286 (91.1) 28 (8.9)

84 (95.5) 4 (4.5)

313 (77.9) 89 (22.1)

246 (78.8) 67 (21.3)

67 (74.4) 22 (25.0)

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Known risk factors for semen impairment, n (%) Mumps with orchitis Unilateral cryptorchidism Unilateral testicular torsion Scrotal trauma Unilateral varicocele Inguinal hernia (with surgery in childhood) Urogenital tract infections Fever $38.5uC Hot bath $1/wk a b

3 28 4 31 23 16 62 26 56

(0.7) (7.0) (1.0) (7.7) (5.7) (4.0) (15.4) (6.5) (13.9)

1 25 2 29 22 9 43 22 48

(0.3) (8.0) (0.6) (9.2) (7.0) (2.9) (13.7) (7.0) (15.3)

2 3 2 2 1 7 19 4 8

(2.3) (3.4) (2.3) (2.3) (1.1) (7.9) (21.6) (4.5) (9.1)

. . .b .160 ... .039 .037 .059 .584 .472 .117

Unadjusted P value stemming from the x2 test. Tests were not performed when there were less than 15 exposed subjects in total.

All data analyses were performed with SPSS software version 11.5 (SPSS, Chicago, Illinois).

Results Overall Semen Quality Participants’ characteristics and the potential confounders are listed in Table 4. Men with altered semen were similar in terms of demographic and lifestyle characteristics compared to men with normal semen. Among the 9 known risk factors for semen impairment, history of scrotal trauma or varicocele was more frequent in men with altered semen than in men with normal semen (9.2% vs 2.3%, P 5 .039, and 7.0% vs 1.1%, P 5 .037, respectively). Overall, the presence of at least 1 risk factor was observed in 148 men with altered semen and in 33 men with normal semen (47.1% vs 37.5%, P 5 .116).

The occupational characteristics of the participants are shown in Table 2. Participants were primarily construction trade workers, administrative workers, and drivers. Subjects from the middle class had a lower risk for semen alteration compared to subjects from the other classes (P 5 .013). This association persisted after adjusting for age and known risk factor variables (OR 5 0.5; 95% CI, 0.3–0.9; P 5 .033). Conversely, workmen had a higher risk for semen impairment compared to other social/economic classes (P 5 .019). This association persisted after adjusting for age and known risk factor variables (OR 5 1.96; 95% CI, 1.1–3.5; P 5 .025). Occupational sector was not associated with semen quality. The influence of occupational exposures on overall semen quality is shown in Table 5 through a comparison of exposure (yes/no) to chemical and physical factors between men with altered semen or with normal semen.

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Table 5. Influence of occupational exposures on overall semen quality: comparison of the distributions of chemical and physical factors (yes/no) between men with altered and men with normal semen Logistic Regressionb Total (n 5 402)


Men With Normal Univariate Adjusted OR Semen (n 5 88) Analysis P Valuea (95% CI)

Adjusted P Value

Chemical occupational factors (current or past exposure), n (%) Heavy metals Pesticides Solvents Fumes Plastic fumes Vegetable fumes Welding fumesd Engine fumes Metallurgy fumes PAHs Cement

49 25 150 136 9 10 44 92 8 115 48

(12.2) (6.2) (37.3) (33.8) (2.2) (2.5) (10.9) (22.9) (2.0) (28.6) (11.9)

46 23 131 115 9 10 41 75 7 98 43

(14.6) (7.3) (41.7) (36.6) (2.9) (3.2) (13.1) (24.0) (2.2) (31.2) (13.7)

3 2 19 21 0 0 3 17 1 17 5

(3.4) (2.4) (21.6) (23.9) (0.0) (0.0) (3.4) (19.3) (1.1) (19.3) (5.7)

.006 .085 ,.001 .022 . . .c ... .011 .323 ... .012 .040

5.4 (1.6–18.1) 3.6 (0.8–15.8) 2.5 (1.4–4.4) 1.9 (1.1–3.4) ... ... 4.7 (1.4–15.7) 1.4 (0.7–2.5) ... 1.9 (1.1–3.5) 2.5 (0.95–6.5)

.007 .087 .001 .016 ... ... .012 .304 ... .026 .065

Physical occupational factors (current exposure), n (%) Electromagnetic fields Mechanical vibrations Excess heat Extended periods of sitting .20 h/wk

25 (6.2) 94 (23.4) 33 (8.2)

20 (6.4) 79 (25.2) 29 (9.3)

5 (5.7) 15 (17.0) 4 (4.4)

.334 .195 .190

1.1 (0.6–1.7) 1.6 (0.9–2.9) 2.2 (0.7–6.4)

.866 .133 .164

168 (41.8)

127 (40.4)

41 (46.6)

.411

0.9 (0.5–1.4)

.476

Abbreviations: OR, odds ratio; CI, confidence interval. a Unadjusted P value stemming from the x2 test. b Adjusted OR and P value obtained after logistic regression adjusted for age and known risk factor variable. c Tests were not performed when there were less than 15 exposed subjects in total. d Subjects exposed to welding fumes were included in the ‘‘heavy metals’’ category too.

In univariate analyses after adjusting for age and known risk factor variables, men with altered semen were significantly more frequently exposed to each tested chemical agent than men with normal semen: heavy metals (OR 5 5.4; 95% CI, 1.6–18.1; P 5 .007), solvents (OR 5 2.5; 95% CI, 1.4–4.4; P 5 .001), fumes (OR 5 1.9; 95% CI, 1.1–3.4; P 5 .016), and PAHs (OR 5 1.9; 95% CI, 1.1–3.5; P 5 .026). This association was nearly significant for pesticides (OR 5 3.6; 95% CI, 0.8–15.8; P 5 .087) and cement (OR 5 2.5; 95% CI, 0.95–6.5; P 5 .065). Note that, among all sorts of fumes, exposure to welding fumes was more frequent in men with altered semen than in men with normal semen (OR 5 4.7; 95% CI, 1.4–15.7; P 5 .012). We found no statistical association between any of the mentioned physical risk factors and overall semen quality. The mean exposure index to some chemicals was significantly higher in men with altered semen than in men with normal semen: solvents (P , .001), fumes (P 5 .021), PAHs (P 5 .016), and cement (P 5 .050) (Table 6).

Isolated Semen Parameters Table 7 shows a comparison of semen parameters between exposed subjects and those who were not

exposed to occupational factors known in the literature to impair semen parameters. Most of the alterations known in the medical literature regarding chemical risk factors were found in our analysis: 1) a higher risk of asthenospermia (OR 5 3.2; 95% CI, 1.4–7.3; P 5 .007) in subjects exposed to heavy metals; 2) a higher risk of oligospermia (OR 5 1.8; 95% CI, 1.1–2.8; P 5 .013), of asthenospermia (OR 5 2.3; 95% CI, 1.4–3.7; P 5 .001), of impaired motility (P 5 .014), and of impaired sperm morphology (P 5 .027) in subjects exposed to solvents; 3) a higher risk of oligospermia (OR 5 2.6; 95% CI, 1.4– 5.1; P 5 .040) and of total sperm count impairment (P 5 .050) in subjects exposed to welding fumes; and 4) a higher risk of oligospermia (OR 5 1.6; 95% CI, 1.03– 2.6; P 5 .038) and total sperm count impairment (P 5 .010) in subjects exposed to PAHs. The other chemical exposures were collected by the physician even if they were unknown to be toxic for reproduction. Among them, exposure to cement was found to be correlated to a higher risk of teratospermia (OR 5 2.3; 95% CI, 1.2– 4.4; P 5 .009) and of impaired sperm motility (P 5 .006) and morphology (P 5 .037). Regarding the physical risk factors, we found a higher risk of oligospermia (OR 5 1.9; 95% CI, 1.2–3.1; P 5 .011), teratospermia (OR 5 2.0; 95% CI, 1.3–3.2; P 5

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Table 6. Exposure dose effect on semen quality: comparison of the distribution of chemical and physical factors (yes/no) between men with altered and men with normal semen Exposed Men With Altered Semen

Exposed Men With Normal Semen

P Value

Chemical occupational factors (current or past exposure), mean exposure index 6 SD (n)a Heavy metals Pesticides Solvents Fumes PAHs Cement

22.1 19.3 31.6 26.1 26.9 2.7

6 6 6 6 6 6

17.3 16.2 30.9 21.9 23.7 11.1

Physical occupational factors (current exposure), n (%)b Electromagnetic fields ,2 h/wk 5 (25.0) 2–10 h/wk 7 (35.0) 11–20 h/wk 3 (15.0) .20 h/wk 5 (25.0) Mechanical vibrations ,2 h/wk 14 (17.7) 2–10 h/wk 22 (27.8) 11–20 h/wk 15 (19.0) .20 h/wk 28 (35.4) Excess heat ,2 h/wk 1 (3.4) 2–10 h/wk 14 (48.3) 11–20 h/wk 3 (10.3) .20 h/wk 11 (37.9) Extended periods of sitting ,2 h/wk 6 (3.0) 2–10 h/wk 33 (16.4) 11–20 h/wk 35 (17.4) .20 h/wk 127 (63.2)

(46) (23) (131) (115) (98) (314)

50.0 6 17.3 (3) 24.5 6 28.9 (2) 17.4 6 12.8 (19) 22.2 6 18.2 (21) 16.8 6 13.9 (17) 2.2 6 12.2 (88)

.060 .084 ,.001 .021 .016 .050 .767

2 (40.0) 2 (40.0) 0 1 (20.0) .953 3 4 2 6

(20.0) (26.7) (13.3) (40.0) .103

1 (25.0) 0 0 3 (75.0) .431 0 12 (19.7) 8 (13.1) 41 (67.2)

a

Unadjusted P value stemming from the Mann-Whitney nonparametric test. Exposure index for chemicals (arbitrary unit) is the product of the number of years of exposure times a weight proportional to frequency of exposure (weight 1 for ,2 h/wk, 2 for 2–10 h/wk, 3 for 11–20 h/wk, 4 for .20 h/wk). b P value obtained after logistic regression adjusted for age and known risk factor variable.

.040), impaired forward motility (P 5 .027), and impaired sperm morphology (P 5 .028) in subjects exposed to mechanical vibrations. In subjects exposed to excess heat, we found more men with asthenospermia (OR 5 3.3; 95% CI, 1.1–9.5; P 5 .032). Finally, we found a higher risk of impaired forward motility in subjects exposed to extended periods of sitting (.20 h/wk; P 5 .047).

Discussion This study investigated the association between semen quality and self-reported occupational exposures using a questionnaire that we designed for use during routine consultation. A great number of reprotoxic factors are already well known but, to date, have not been systematically investigated during reproductive medicine consultation. The present questionnaire was designed to last no more than 20 minutes when conducted in routine practice. The questionnaire was not too restrictive,

however, because we had the opportunity to explore some additional associations. One strong point of our study is that, based on a PubMed search, the questionnaire was designed according to the experience of specialists in occupational and reproductive medicine. Furthermore, all interviews were conducted by the same occupational physician. Another methodological strong point is that we used an approach based on semen characteristics (ie, on information regarding the quantitative and qualitative aspects of testicular function) whereas other measures of male fecundity (such as fertility rate and time to pregnancy) are female partner–dependent. Nonetheless, the analysis of a single semen sample per subject does not allow for the physiological variability of semen parameters. Moreover, semen quality may not predict fertility. To minimize bias, the interviews were conducted without prior knowledge of semen analysis results. In addition, all subjects were recruited in the same center,

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Table 7. Comparison of semen parameters between subjects exposed and unexposed to occupational factors likely to impair semen parameters Abnormal Semen Parametersb

Impaired Semen Parameters: P Valuea Total Sperm Forward Count Motility

Oligospermia

Sperm Normal Morphology

OR (95% CI)

Asthenospermia

Teratospermia

P Value

OR (95% CI)

P Value

OR (95% CI)

P Value

.335 .084 .013 .040 .038 .361

3.2 (1.4–7.3) ... 2.3 (1.4–3.7) ... ... 2.3 (1.04–5.0)

.007 ... .001 ... ... .065

0.96 (0.5–1.7) ... 1.4 (0.96–2.2) ... 1.4 (0.9–2.1) 2.3 (1.2–4.4)

.903 ... .092 ... .155 .009

Chemical occupational factors Heavy metals Pesticides Solvents Welding fumes PAHs Cement

.207 .069 .235 .050 .010 .249

Physical occupational factors Electromagnetic fields .511 Mechanical vibrations .148 Excess heat ... Extended periods of sitting .20 h/wk ...

.348 . . .c .014 ... ... .006

.823 ... .027 ... .069 .037

1.4 0.3 1.8 2.6 1.6 1.5

(0.7–2.7) (0.1–1.1) (1.1–2.8) (1.4–5.1) (1.03–2.6) (0.8–2.7)

.104 .027 .117

.266 .028 .507

1.1 (0.4–3.1) 1.9 (1.2–3.1) ...

.925 .011 ...

1.1 (0.4–2.7) 1.3 (0.8–2.0) 3.3 (1.1–9.5)

.892 .289 .032

0.4 (0.2–0.97) 2.0 (1.3–3.2) 0.5 (0.2–1.1)

.344 .040 .083

.047

.548

...

...

0.8 (0.5–1.3)

.574

0.9 (0.5–1.3)

.517

Abbreviation: OR, odds ratio. a

Unadjusted P value stemming from Student’s t test (total sperm count, forward motility and sperm morphology are continuous variables). Adjusted OR (95% CI) and P value obtained after logistic regression adjusted for age and known risk factor variable (oligospermia, asthenospermia, and teratospermia are dichotomous variables). c No test was performed when no effect was described in the medical literature, except for cement. Known references are shown in Table 1. b

and all semen samples were collected and analyzed using a standardized protocol. Several limitations, however, must be kept in mind when interpreting the results of this study. First, exclusion of subjects with limited command of the French language may have excluded subjects with unskilled jobs but with major exposure to reprotoxic agents. Second, the retrospective collection of exposure data could have introduced some memory bias, though we do not suspect there would be a difference in this bias between men with altered and men with normal semen. Finally, this questionnaire was designed according to scientific data available at a given moment. Recent data suggested that use of mobile phones, which are sources of electromagnetic frequency emissions, could impair semen parameters (Erogul et al, 2006; Deepinder et al, 2007; Wdowiak et al, 2007; Agarwal et al, 2008). Mobile phones, however, were not included in the questionnaire when it was designed (Dasdag et al, 2003; Fejes et al, 2005) because of conflicting reports regarding mobile phone usage, and only strongly supported data were usable in this study to draw our conclusions. Different exposure windows were considered for statistical analysis according to the exposure type. Most of the literature provides results about current exposures; however, it may be interesting to examine past exposures as well. Chemical exposures were analyzed for both current and past exposures

because their action could impair the current spermatogenesis (ie, in the last 3 months) as well as spermatogonial stem cells (Keck et al, 1993), leading to delayed spermatogenesis impairment. Recent data suggest that increasing exposures to endocrine disrupters are behind the trends in occurrence of male reproductive health problems, including poor semen quality (Skakkebæk et al, 2006). The alteration of semen parameters associated with physical factors such as heat should stop after the end of exposure (Carlsen et al, 2003), but little is known about the reversibility of semen impairment associated with electromagnetic fields (Al-Akhras et al, 2001), mechanical vibrations, or very low doses of ionizing radiation. Nevertheless, according to this hypothesis, only current exposures were considered as physical agents in our analysis. We found associations between impaired semen quality and self-reported occupational exposure to chemicals such as heavy metals, solvents, fumes (notably welding fumes), or PAHs, especially when exposure was considered dichotomous (yes/no). More refined analyses of each semen parameter confirmed the higher risk of asthenospermia in subjects exposed to heavy metals (Telisman et al, 2000), but the results of such analyses were not consistent with previously reported higher risks of oligospermia and teratospermia in those subjects (Telisman et al, 2000; Sheiner et al, 2003). The effects of

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solvents and welding fumes on sperm impairment were consistent with previous results (Bonde, 1993; Veulemans et al, 1993; De Celis et al, 2000; Cherry et al, 2001, 2008; Jensen et al, 2006). It is worth noting that men with normal semen were not exposed to plastic or vegetable fumes in our sample. Statistical analyses were not performed due to the small sizes of these groups. In subjects exposed to PAHs, the higher risk of oligospermia was also consistent with previous findings (Gaspari et al, 2002), but we did not find a relationship between exposure to PAHs and teratospermia (Hsu et al, 2006). Finally, we found that subjects exposed to cement had a higher risk of semen parameter alteration, in particular a higher risk of impaired or abnormal motility and impaired sperm morphology. No previous data were found in the literature regarding a possible relationship between exposure to cement and sperm parameter alteration. Cement composition is complex, and many different types exist, which have different heavy metal compositions. Moreover, most subjects exposed to cement are bricklayers, so they are also exposed to other chemicals known to cause semen parameter alteration (eg, solvents and fumes). In future studies, exposure characterization would be improved by an accurate questionnaire about the use and composition of cement. During the interview, exposure to cement was easily identifiable by the physician and the subjects. Many subjects were able to state that they were exposed to other chemicals, such as glue or resin, without providing further detail about what kinds of chemicals. The present study underlined the effects of only a few physical risk factors. Oligospermia and asthenospermia in subjects exposed to mechanical vibrations were consistent with previous results (Penkov et al, 1996). Moreover, compared to previous findings, we found more subjects with asthenospermia among men exposed to excess heat (Figa Talamanca et al, 1992) and a higher risk of asthenospermia among subjects exposed to extended periods of sitting (Bujan et al, 2000). In the present study, the fact that most physical agents were not associated with impaired semen parameters may be explained by 4 hypotheses: lack of power because of the low number of exposed subjects, inaccurate data regarding exposure, exposure that was lower than the effect detection threshold, or specific action of physical agents on some parameters and not on the overall semen quality. Many nonoccupational factors, such as smoking (Vine et al, 1994), marijuana use (Whan et al, 2006), and chronic alcohol use (Muthusami and Chinnaswamy, 2005) are also known to impair semen characteristics. One should note that lifestyle characteristics might be

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linked to occupation, which would explain the lack of their statistical identification. Here, each nonoccupational factor was tested by univariate analysis and not by stratification on social and economic classes or occupational sectors due to the small size of the dataset. Moreover, regardless of whether the factors were occupational or not, let us note that this questionnaire was administered to men who attended a Reproductive Medicine Laboratory without particular selection. The subjects, however, were primarily administrative workers, drivers, and construction trade workers. We therefore can assume that exposures in this population may be limited and that the questionnaire might perform differently with other occupational groups. Moreover, because of the high percentage of men with normal semen born outside the European Union, the questionnaire could also perform differently within other populations. With a close collaboration between occupational medicine and reproductive medicine, this study showed associations between self-reported occupational exposures and impaired semen parameters. This represents a promising approach for the assessment of men’s occupational reprotoxic exposure. Covering most of the occupational risk factors, it would allow a quantification of the impact of those factors on a broader population within the context of infertility clinics. Moreover, this questionnaire could be used to explore some additional associations between semen impairment and self-reported exposures, as was the case for the exposure to cement. In the future, an ongoing collaboration between occupational health and reproductive health is needed for individual and collective preventive means. Indeed, beyond global statistical results, this questionnaire may have individual interpretations for each subject and involve complementary investigations to define occupational exposures more precisely. Moreover, a follow-up of the subjects for many months after additional preventive means in the workplace could improve individual results. Finally, this approach allows patients who consult a reproductive biology laboratory to become aware of the relationships between some occupations and semen parameter alterations. In the future, we intend to proceed with patient inclusions to substantiate our findings with special attention to physical exposures. Trials of the questionnaire on larger datasets, with similar as well as different occupational groups, are a necessary step. We also intend to achieve a better exposure characterization using biomarkers to quantitatively assess potential relationships between chemical agents and spermiotoxic effects (ie, measures of chemicals in seminal fluid, PAHDNA adducts, and DNA breakage).

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Acknowledgments We thank Dr Valentina Baggio, MD, occupational physician, Assistance Publique des Hoˆpitaux de Marseille, for her preliminary questionnaire, and Dr Jean Iwaz, PhD, scientific advisor, Hospices Civils de Lyon, for revision and editing of the manuscript.

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Appendix. Questionnaire for identification of occupational exposure linked to reprotoxic agents Inclusion criteria

Response choices

A no response to any of the following questions stops the administration of the questionnaire 1. 2. 3. 4.

Age between 18 and 55 years old Good command of the French language Place of residence in southeast France Semen investigation because of couple infertility

yes yes yes yes

/ / / /

no no no no

A yes response to any of the following questions stops the administration of the questionnaire 5. Previous history of 1 of the following genital pathologies: bilateral cryptorchidism, bilateral testicular hypotrophy, bilateral varicocele, congenital absence of vas deferens 6. Endocrine hypogonadism 7. History of radiotherapy or chemotherapy 8. Genetic or chromosomal abnormalities 9. Exposure to diethylstilbestrol in utero 10. Current use or use within the past 6 mo of 1 of the following medications: psychotropic drugs, antiepileptic drugs, cardiotropic drugs, antimitotic drugs, colchicine, retinoic acid, infliximab, sulfasalazine

Name: Date of birth: Birthplace:

yes / no yes yes yes yes yes

/ / / / /

no no no no no

yes yes yes yes yes yes yes yes yes

/ / / / / / / / /

no no no no no no no no no

Age of arrival in France:

Previous history of disease: 1. 2. 3. 4. 5. 6. 7. 8. 9.

Mumps with orchitis Unilateral cryptorchidism Unilateral testicular torsion Scrotal trauma Unilateral varicocele Inguinal hernia, unilateral or bilateral, with surgery in childhood Urogenital tract infections: urethritis, orchitis, prostatitis, or orchiepididymitis Fever $38.5uC during the previous 3 mo Current hot baths (.20 min and $1/wk)

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Appendix. Continued. Addictive behavior (current or stopped less than 2 years ago) 1. Cigarette smoking If yes: Number of cigarettes per day: Date of beginning: 2. Marijuana use: If yes: Number of joints (specify: per day, week, year): Date of beginning: Occasional (.10/y) Regular (.1/wk) 3. Alcohol use: If yes: Number of glasses (specify: per d, wk, y): The standard dose in a glass is 10 g of alcohol Occasional (.1/mo) Regular moderate (.1/wk) Regular important (.4/d)

Current occupation (please detail):

Date of beginning:

yes / no Date of end: yes / no Date of end: yes / no yes / no yes / no

yes / no yes / no yes / no

Date of end:

Current social and economic class (from INSEE): 1. Farmer (all agriculture activities: animal husbandry, cultivation, market gardening, viticulture, etc) 2. Craftsman, merchant and businessman (boss of independent little firm with ,10 employees) 3. Upper middle-class (management, professor, engineer, scientist, etc) 4. Middle class (teacher, foreman, nurse, social worker, supervisor, technician, etc) 5. Employee (clerk, sales person, policeman, firefighter, cook, driver, hospital staff, domestic staff, etc) 6. Workman (skilled, semiskilled, and unskilled worker in industry or building trade) 7. Student and unemployed (retired persons included)

Past occupations (please detail): If occupation .6 mo 1. 2. 3.

Date of beginning:

Date of end:

... ... ...

... ... ...

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Appendix. Continued. Occupational exposures 1. Heavy metals If yes:

2. Pesticides If yes:

3. Solvents If yes:

4. Fumes If yes:

5. PAHs If yes:

6. Other chemicals If yes: 7. Ionizing radiation If yes: 8. Electromagnetic fields If yes: 9. Mechanical vibrations If yes: 10. Excess heat If yes: 11. Periods of sitting If yes:

yes / no Specify the occupation and types of metals a b c yes / no Fungicide Herbicide Insecticide yes / no Name of chemical substances containing solvent: a b c yes / no Plastic Vegetable Welding Engine Metallurgy yes / no Bitumen Organic oil Diesel fumes Coke-oven work yes / no

h/wk

Date of beginning:

Date of end:

... ... ...

... ... ...

... ... ...

... ... ...

... ... ...

... ... ...

... ... ...

... ... ...

... ... ...

... ... ... ...

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...

...

...

...

...

...

...

...

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... ...

... ...

...

...

...

... ... ... ...

... ... ... ...

... ... ... ...

yes / no yes / no yes / no Whole body (sited) Upper limbs (tool) yes / no yes / no Clerical occupation Driving car/forklift Driving bus/truck Driving commercial/farm vehicle