# Parental occupational exposure to solvents and risk of developing testicular germ cell tumors among sons: a French nationwide case-control study (TESTIS study)

Margot Guth, Marie Lefevre, Corinne Pilorget, Astrid Coste, Shukrullah

Ahmadi, Aurélie Danjou, Brigitte Dananché, Delphine Praud, Isabelle

Koscinski, Aline Papaxanthos, et al.

► To cite this version:

Margot Guth, Marie Lefevre, Corinne Pilorget, Astrid Coste, Shukrullah Ahmadi, et al. Parental occupational exposure to solvents and risk of developing testicular germ cell tumors among sons: a French nationwide case-control study (TESTIS study). Scandinavian Journal of Work, Environment and Health, 2023, 49 (6), pp.405-418. 10.5271/sjweh.4102. hal-04314966

HAL Id: hal-04314966

https://hal.science/hal-04314966v1

Submitted on 24 Oct 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>
<figure><img src="image_2.png" /></figure>

Scand J Work Environ Health 2023;49(6):405-418

https://doi.org/10.5271/sjweh.4102

Published online: 05 Jul 2023, Issue date: 01 Sep 2023

**Parental occupational exposure to solvents and risk of developing testicular germ cell tumors among sons: a French nationwide case-control study (TESTIS study)**

by Guth M, Lefevre M, Pilorget C, Coste A, Ahmadi S, Danjou A, Dananché B, Praud D, Koscinski I, Papaxanthos A, Blagosklonov O, Fauque P, Pérol O, Schüz J, Bujan L, Olsson A, Fervers B, Charbotel B; The TESTIS study group

Overall, no substantial role of parental occupational exposure to solvents and testicular germ cell tumors (TGCT) risk was observed, however, sons of mothers exposed to fuels / petroleum-based solvents in the 1970s experienced an increased risk. Our results may also suggest a modest increased of non-seminoma for sons whose fathers were highly exposed to trichloroethylene (TCE). Future studies, including molecular mechanisms, should further investigate these potential associations.

**Affiliation:** Prevention Cancer Environnement Departement, Centre Léon Bérard, Lyon, France. beatrice.fervers@lyon.unicancer.fr

Refers to the following text of the Journal: 2018;44(6):658-669

**Key terms:** cancer; epidemiology; JEM; job-exposure matrix; occupational exposure; organic solvent; parental exposure; parental occupational exposure; prenatal exposure; solvent; testicular cancer; testicular germ cell tumor; TESTIS study

This article in PubMed: www.ncbi.nlm.nih.gov/pubmed/37649372

**Additional material**

Please note that there is additional material available belonging to this article on the *Scandinavian Journal of Work, Environment & Health* -website.

<figure><img src="image_3.png" /></figure>

This work is licensed under a Creative Commons Attribution 4.0 International License.
Scand J Work Environ Health. 2023;49(6):405-418. doi:10.5271/sjweh.4102

# Parental occupational exposure to solvents and risk of developing testicular germ cell tumors among sons: a French nationwide case-control study (TESTIS study)

by Margot Guth, MSc,<fnref n="1" /> Marie Lefevre, MSc,<fnref n="1" /> Corinne Piloget, PhD,<fnref n="2" /> Astrid Coste, PhD,<fnref n="3" />,<fnref n="4" /> Shukrullah Ahmadi, PhD,<fnref n="5" /> Aurélie Danjou, PhD,<fnref n="5" /> Brigitte Dananché, DipEng,<fnref n="4" /> Delphine Praud, PhD,<fnref n="3" />,<fnref n="4" />,<fnref n="5" /> Isabelle Koscinski, PhD,<fnref n="6" /> Aline Papaxanthos, PhD,⁷ Oxana Blagosklonov, PhD,<fnref n="8" /> Patricia Fauque, PhD,<fnref n="9" />,<fnref n="10" /> Olivia Pérol, MSc,<fnref n="4" /> Joachim Schüz, PhD,<fnref n="5" /> Louis Bujan, PhD,<fnref n="11" />,<fnref n="12" /> Ann Olsson, PhD,<fnref n="5" /> Béatrice Fervers, PhD,<fnref n="3" />,<fnref n="4" /> Barbara Charbotel, PhD,<fnref n="1" />,<fnref n="13" /> and the TESTIS study group

Guth M, Lefevre M, Piloget C, Coste A, Ahmadi S, Danjou A, Dananché B, Praud D, Koscinski I, Papaxanthos A, Blagosklonov O, Fauque P, Pérol O, Schüz J, Bujan L, Olsson A, Fervers B, Charbotel B, TESTIS study group. Parental occupational exposure to solvents and risk of developing testicular germ cell tumors among sons: a French nationwide case-control study (TESTIS study). *Scand J Work Environ Health*. 2023;49(6):405-418.

**Objectives** The etiology of testicular germ cell tumors (TGCT) is suspected to be related to prenatal environmental risk factors. Some solvents have potential endocrine disrupting or carcinogenic properties and may disrupt male genital development in utero. The aim of this study was to examine the association between parental occupational exposure to solvents and TGCT risk among their offspring.

**Methods** A French nationwide case-control study, TESTIS included 454 TGCT cases and 670 controls frequency-matched on region and 5-year age strata. Participants were interviewed via telephone and provided information on parental occupations at birth. Job-exposure matrices (JEM) developed in the French Matgéné program were used to assign exposure to five petroleum-based solvents, five solvents or groups of oxygenated solvents, and five chlorinated solvents. Odds ratios (OR) for TGCT and 95% confidence intervals (CI) were estimated using conditional logistic regression, adjusting for TGCT risk factors.

**Results** Occupational exposure to at least one solvent during the year of their son's birth was 41% among fathers and 21% among mothers. Paternal exposure to at least one solvent showed OR 0.89 (95% CI 0.68-1.15). Exposure to perchloroethylene (OR 1.41, 95% CI 0.55-3.61), methylene chloride (OR 1.13, 95% CI 0.54-2.34) and diesel/kerosene/fuel oil (OR 1.17, 95% CI 0.80-1.73) disclosed OR >1 but with low precision. Our results suggest a possible modest increase in non-seminoma risk for sons whose fathers were highly exposed to trichloroethylene (OR 1.44, 95% CI 0.79-2.63). Maternal exposure to at least one solvent showed OR 0.90 (95% CI 0.65-1.24). When stratifying by birth year, men born in the 1970s experienced an increased TGCT risk following maternal exposure to fuels and petroleum-based solvents (OR 2.74, 95% CI 1.11-6.76).

**Conclusion** Overall, no solid association was found between parental occupational exposure to solvents and TGCT risk. The association found with maternal occupational exposure to fuels and petroleum solvents among older men needs further investigation.

**Key terms** cancer; epidemiology; JEM; job-exposure matrix; organic solvent; prenatal exposure; testicular cancer.

<footnote n="1">1 UMRESTTE, UMR T 9405, IFSTTAR, Lyon 1 University, Lyon University, Eiffel University, Lyon, France.</footnote>

<footnote n="2">2 Santé publique France - French National Public Health Agency, Saint-Maurice, France.</footnote>

<footnote n="3">3 INSERM UMR1296 Radiation: Defense, Health, Environment, Lyon, France.</footnote>

<footnote n="4">4 Prevention Cancer Environnement Departement, Centre Léon Bérard, Lyon, France.</footnote>

<footnote n="5">5 Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer/World Health Organization (IARC/WHO), Lyon, France.</footnote>

<footnote n="6">6 Laboratory of Biology of Reproduction-CECOS Lorraine, University Hospital of Nancy, Nancy, France. 7 Reproductive Medicine and Biology Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France.</footnote>

<footnote n="8">8 CECOS Franche-Comté Bourgogne Besançon, CHU de Besançon, Besançon, France.</footnote>

<footnote n="9">9 University of Bourgogne Franche-Comté - INSERM UMR1231, Dijon, France.</footnote>

<footnote n="10">10 Laboratory of Biology of Reproduction-CECOS, University Hospital of Dijon, Dijon, France.</footnote>

<footnote n="11">11 DEFE (Développement Embryonnaire, Fertilité, Environnement) INSERM 1202 Universités Montpellier et Toulouse 3, CECOS Hôpital Paule de Viguier, CHU de Toulouse, Toulouse, France.</footnote>

<footnote n="12">12 Fédération Française des CECOS, Paris, France.</footnote>

<footnote n="13">13 CRPPE-Lyon, Hospices Civils de Lyon, Lyon, France.</footnote>
Testicular cancer is the most common cancer affecting
Caucasian men, aged 15–44 years (1–3). Most cases
(>95%) are germ cell tumors (TGCT), the majority of
which derive from germ cell neoplasia in situ (GCNIS-
TGCT) developed in utero and are subdivided into two
main histological subtypes: seminoma and non-semi-
noma (3, 4). GCNIS-TGCT incidence has increased in
recent decades and continues to rise (2, 5). In light of the
rapid incidence increase, a contribution of environmen-
tal and lifestyle factors to the increased risk of TGCT is
suspected (4), although the precise causal factors remain
largely unknown (6). The impact of the fetal environ-
ment is also supported by large geographical variation
in incidence (7) and the evolution of TGCT incidence
among migrant populations (8).

TGCT has been suggested to be part of testicu-
lar dysgenesis syndrome (TDS), which includes other
male reproductive system disorders, ie, cryptorchidism,
hypospadias and poor semen quality (9). TDS could be
a consequence of intrauterine exposure to environmental
compounds with endocrine disrupting properties, which
disrupt the physiological actions of endogenous hor-
mones during the fetal "masculinization programming
window (MPW)" (3, 6, 8), and stop the development of
immature germ cells that persist outside of fetal/perina-
tal life (CGNIS) (10).

Many workers are exposed to solvents that are
widely used in a range of industrial products (11).
Some are suspected of acting as endocrine disrupting
chemicals (EDC) (12) and may interfere in the mas-
culinization process in utero (13) or are classified as
carcinogenic by the International Agency for Research
on Cancer (IARC) monographs (14). In addition, in the
2000s, about one-third of the industrial solvents tested
were considered reproductive toxicants in laboratory
animals by inhalation and dermal routes, suggesting that
they may have a high potential for reproductive toxic-
ity in humans by the same exposure routes (15, 16).
Experimental studies have recently suggested that expo-
sure to trichloroethylene (TCE) may induce epigenetic
alterations (17, 18), which may result in developmental
disorders (19).

Epidemiological studies suggest that maternal expo-
sure to some EDC during pregnancy is associated with
birth urogenital anomalies, but observations of a link
to the adverse adult male reproductive health, such
as TGCT, are inconsistent (20). In addition, only few
previous studies have examined parental exposures to
solvents and TGCT in their offspring. A registry-based
case-control study in Finland, Norway, and Sweden
(NORD-TEST) suggested an increase in TGCT risk
associated with maternal occupational exposure to tolu-
ene, but none for paternal exposure, except for tetra-
chloroethylene [or perchloroethylene (PCE)] exposure
in Finland (21). The Denmark NORD-TEST study and

a US case–control study found no association between
parental solvent exposure and TGCT among sons (22,
23). These studies had limitations related to the registry-
based nature of the data (ie, missing information of
potential cofounders and delay between the child’s birth
and the nearest census to assess occupational exposure)
or the small numbers of cases.

This study aims to examine the associations between
parental occupational exposure to solvents and the risk
of developing TGCT in the sons in a French national
case–control study.

Methods

Study population

The TESTIS study (24) is a multicenter prospective
case–control study. Cases of histologically confirmed
TGCT (aged 18–45 years), referred to a CECOS (Cen-
tres d’étude et de conservation des oeufs et du sperme
/ Center for the Study and Conservation of Eggs and
Sperm) for sperm cryopreservation prior to treatment,
were identified between January 2015 and April 2018. A
TGCT expert reviewed the cases and confirmed GCNIS-
related TGCT cases based on pathology reports and
serum tumor markers and classified them into seminoma
and non-seminomatous tumors (3, 25).

Two control groups with no personal history of
testicular cancer or cryptorchidism were frequency-
matched to cases on year of birth (+/-5 years) and hos-
pital center’s region: Group A controls – sperm donors
with normal sperm production and partners of women
consulting for fertility disorders in CECOS; Group B
controls – partners of women treated for a pathological
pregnancy in specialized maternity clinics adjacent to
the CECOS.

Detailed information on study population and rea-
sons for non-participation has been reported previously
(24). Briefly, a total of 1463 eligible subjects were
invited to participate in the study. Of these, 1367 par-
ticipants (93.4%) agreed to participate, and 96 cases and
147 controls were excluded for various reasons, includ-
ing non-GCNIS TGCT, incomplete telephone interview,
or not born in "metropolitan France". Thus, 1124 par-
ticipants were included in the analyses (supplementary
material, www.sjweh.fi/article/4102, figure S1).

Data collection

A trained investigator (IPSOS company) conducted a
telephone interview where participants provided infor-
mation on residential history since birth, characteristics
at birth, medical history, lifestyle factors (smoking and
drug use), and parental employment at year of birth. The telephone interview was conducted using a structured, pretested, computer-assisted questionnaire, and the interviewers were blinded to case-control status. Moreover, participants received on inclusion written support to prepare for the interview.

## Exposure assessment

An industrial hygienist coded parental occupations according to the International Standard Classification of Occupation, 1968 version (ISCO-68) (26) and industries according to the *Nomenclature d'activités française* 1999 version (French classification of economic activities NAF-99, updated version of NAF-93) (27). Job-exposures matrices (JEM) developed for the French population in the context of the Matgéné program (28) were used to assess occupational exposures to: (i) five solvents or groups of oxygenated solvents (alcohols; ketones and esters; ethylene glycol; diethyl ether; tetrahydrofuran); (ii) five chlorinated solvents [TCE; PCE; methylene chloride (MC); carbon tetrachloride; chloroform]; and (iii) five fuels & petroleum-based solvents (benzene; automobile gasoline; white spirits and other aromatics; diesel, kerosene and fuel oil (KDF); special petroleum products and other aliphatics).

For each parental job at birth, defined as a combination of ISCO and NAF codes, the JEM provided three indices of exposure for each individual solvent: probability of exposure (P), expressed as the percentage of exposed workers; intensity of exposure (I), expressed in parts per million (ppm) or according to a semi-quantitative scale; and frequency of exposure (F), expressed as a percentage of working time with solvent exposure. For exposure to at least one solvent within the same family, the JEM provided an average level (L) of exposure during a usual working day, combining intensity, and frequency indices. To account for changes in exposure over this period, indices have been provided for different calendar periods (eg, periods defined for TCE exposure are: 1950–1969; 1970–1984; 1985–1994, 1995–2012 and 2013–2016). Each of the four indices (P, I, F, L) was divided into different classes of values, which may vary depending on the solvent considered (supplementary table S1). Some jobs could not be coded due to insufficient information or lack of details and were therefore considered as missing data (N=36 mothers’ jobs, N=47 fathers’ jobs). Unemployed, students, and military jobs were treated as unexposed, unless additional information was available on student or military employment.

Finally, parental occupational exposure estimates (PEE) were calculated as the product of exposure P, F, I, using the central value of the classes (weight table S1). For exposure to at least one solvent within the same family, L was used in PEE calculation (P×L). Each PEE

was classified in three categories: "unexposed" (referent group), "low exposed" and "high exposed". The cutoffs of exposure were specific to each solvent based on the distribution of PEE among fathers and mothers of controls and were set at the 50th percentile (supplementary table S2). Models were built using the unexposed group of each solvent individually as the reference category.

Because exposure to one solvent does not preclude exposure to others, exposure to a given solvent was also categorized as a three-category exposure using a method previously applied (21): "unexposed to any solvents" (referent group), "exposed to the specific solvent" (with or without exposure to other solvents) and "exposed only to solvent(s) other than the specific solvent".

## Statistical methods

Odds ratios (OR) and corresponding 95% confidence intervals (CI) for TGCT in adulthood were estimated for parental occupational exposure to solvents, using conditional logistic regression models. All models were conditioned for matching factors (region and birth year grouped in 5-year categories). Univariate analysis was used to assess associations of TGCT with literature-based considered factors (29–31). These included: birth weight, gestational age, birth order, sibship size and born from multiple pregnancy, family history of testicular cancer, family history of cryptorchidism, personal tobacco smoking (32), personal consumption of alcoholic beverages (33) and personal history of testicular trauma (30). As suggested by Hodes-Simeon et al (34), we also used 'age at voice change' as a proxy of the timing of pubertal development to consider delayed puberty, which is a protective factor for TGCT. We selected those with P<0.20. All selected covariates were then included in one single regression model, and a manual backward stepwise selection procedure was performed. The final model included the following variables significantly associated with TGCT (P<0.05): sibship size, being born from multiple pregnancy, personal history of testicular trauma, family history of TGCT, and family history of cryptorchidism.

Spearman correlation coefficients were computed to assess pair-wise correlations between solvent exposures. To consider of multicollinearity between solvents, a principal component analysis (PCA) was also used to confirm possible association between solvents' exposure and TGCT risk. Only the PC whose eigenvalue was superior to 1 were retained. The association between the PC scores and TGCT risk was then estimated using conditional logistic regression analysis. Main analyses were repeated for histological subtype of tumors and the heterogeneity of associations was tested using polytomous logistic regression for matched case-control studies (SAS macro %subtype) (35). P-values for heterogeneity were derived from the likelihood ratio test (35).
Given the identified toxicity of some solvents, such as benzene and TCE, regulations concerning their uses have largely evolved over time, suggesting that exposures levels may have decreased in recent decades (28). Thus, the analysis was stratified by birth cohort (1969–1980; 1981–1990; 1991–1999). The Wald test was used to assess homogeneity across birth years (36).

Additionally, we conducted several sensitivity analyses: we excluded cases with a personal history of cryptorchidism (N=40) and cases not confirmed by pathology reports (N=43). Given the broad age strata (5-year categories), we further adjusted for age to avoid residual confounding by age in birth age strata.

Data analysis was performed using SAS statistical software version 9.4 (SAS Institute Inc, Cary, NC, USA). In all statistical analyses, P-values were two-sided and considered statistically significant if <0.05.

## Results

The main characteristics of TGCT cases and controls are shown in table 1. Cases [mean 31.9 (SD 6.1) years] were younger than controls [33.6 (SD 5.4) years] (P<0.001). Cases were more often born from multiple pregnancies (P=0.02), first born (P=0.04). Also, more cases than controls reported personal history of: inguinal hernia (P=0.01), testicular trauma (P=0.004), family history of TGCT (P=0.001), and cryptorchidism (P=0.01). Cases reported also greater alcohol consumption (P=0.03) than controls. Finally, there was no difference between cases and both control groups in 'age at voice change', smoking status, cannabis use, birth weight or gestational age.

About 67% of mothers and 97% of fathers were professionally active in the year of their son's birth. Supplementary table S3 shows the most held occupation titles among fathers and mothers according to PEE of exposure to oxygenated, chlorinated and petroleum-based solvents.

## Correlations between exposures to solvents

Spearman correlations coefficients between solvent exposures ranged from r=-0.03 (between diethylether and TCE) to 1.00 (between ethylene glycol and automobile gasoline) for maternal exposures and from -0.05 (between kerosene/diesel oil/fuel oils and tetrahydrofuran) to 0.74 (between carbon tetrachloride and chloroform) for paternal exposures (supplementary table S4).

## Parental occupational exposures to solvents

The reported parental jobs were in the period 1969–1999. Approximately, 21% of the mothers and 41% of

<table><caption>**Table 1.** Characteristics of testicular germ cell tumors (TGCT) cases and controls in the TESTIS study, 2015–2018 (N=1124).</caption><thead><tr><th rowspan="2">Characteristics</th><th>TGCT cases<br>(N=454)</th><th>Controls<br>(N=670)</th><th rowspan="2">P-value<br>cases / all<br>controls*</th></tr><tr><th>N (%)</th><th>N (%)</th></tr></thead><tbody><tr><td>Age at diagnosis (years)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>≤25</td><td>64 (14.1)</td><td>32 (4.8)</td><td></td></tr><tr><td>26–30</td><td>106 (23.4)</td><td>144 (21.5)</td><td></td></tr><tr><td>31–35</td><td>113 (24.9)</td><td>239 (35.7)</td><td></td></tr><tr><td>36–40</td><td>85 (18.7)</td><td>162 (24.2)</td><td></td></tr><tr><td>≥41</td><td>43 (9.5)</td><td>93 (13.9)</td><td></td></tr><tr><td>Missing</td><td>43 (9.5)</td><td>0 (0.0)</td><td></td></tr><tr><td>Year of birth</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Before 1975</td><td>37 (8.2)</td><td>50 (7.5)</td><td></td></tr><tr><td>1975–1979</td><td>80 (17.6)</td><td>128 (19.1)</td><td></td></tr><tr><td>1980–1984</td><td>117 (25.8)</td><td>218 (32.5)</td><td></td></tr><tr><td>1985–1989</td><td>130 (28.6)</td><td>203 (30.3)</td><td></td></tr><tr><td>1990–1994</td><td>70 (15.4)</td><td>63 (9.4)</td><td></td></tr><tr><td>1995–1999</td><td>20 (4.4)</td><td>8 (1.2)</td><td></td></tr><tr><td>Education</td><td></td><td></td><td>0.10</td></tr><tr><td>Secondary</td><td>180 (39.7)</td><td>203 (30.3)</td><td></td></tr><tr><td>1–2 years university degree</td><td>97 (21.4)</td><td>148 (22.1)</td><td></td></tr><tr><td>>3 years university degree</td><td>128 (28.2)</td><td>234 (34.9)</td><td></td></tr><tr><td>Other</td><td>48 (10.6)</td><td>85 (12.7)</td><td></td></tr><tr><td>Missing</td><td>1 (0.2)</td><td>0 (0.0)</td><td></td></tr><tr><td>Smoking status</td><td></td><td></td><td>0.12</td></tr><tr><td>Former smoker</td><td>102 (22.5)</td><td>171 (25.5)</td><td></td></tr><tr><td>Current smoker</td><td>147 (32.4)</td><td>185 (27.6)</td><td></td></tr><tr><td>Never smoker</td><td>205 (45.2)</td><td>314 (46.9)</td><td></td></tr><tr><td>Birth weight (g)</td><td></td><td></td><td>0.49</td></tr><tr><td>&lt;2500</td><td>25 (5.5)</td><td>33 (4.9)</td><td></td></tr><tr><td>2500–4000</td><td>356 (78.4)</td><td>561 (83.7)</td><td></td></tr><tr><td>≥4000</td><td>46 (10.1)</td><td>58 (8.7)</td><td></td></tr><tr><td>Missing</td><td>27 (6.0)</td><td>18 (2.7)</td><td></td></tr><tr><td>Gestational age (weeks)</td><td></td><td></td><td>0.16</td></tr><tr><td>≤36</td><td>32 (7.1)</td><td>34 (5.1)</td><td></td></tr><tr><td>>36</td><td>415 (91.4)</td><td>629 (93.9)</td><td></td></tr><tr><td>Missing</td><td>7 (1.5)</td><td>7 (1.0)</td><td></td></tr><tr><td>Born from multiple pregnancy</td><td></td><td></td><td>0.02</td></tr><tr><td>No</td><td>433 (95.4)</td><td>652 (97.3)</td><td></td></tr><tr><td>Yes</td><td>21 (4.6)</td><td>17 (2.5)</td><td></td></tr><tr><td>Missing</td><td>0 (0.0)</td><td>1 (0.2)</td><td></td></tr><tr><td>Birth order</td><td></td><td></td><td>0.04</td></tr><tr><td>First</td><td>213 (46.9)</td><td>305 (45.5)</td><td></td></tr><tr><td>Second</td><td>163 (35.9)</td><td>224 (33.4)</td><td></td></tr><tr><td>Third</td><td>63 (13.9)</td><td>93 (13.9)</td><td></td></tr><tr><td>Fourth or more</td><td>15 (3.3)</td><td>48 (7.2)</td><td></td></tr><tr><td>Sibship size</td><td></td><td></td><td>0.03</td></tr><tr><td>1</td><td>25 (5.5)</td><td>59 (8.8)</td><td></td></tr><tr><td>2</td><td>192 (42.3)</td><td>254 (37.9)</td><td></td></tr><tr><td>3</td><td>153 (33.7)</td><td>206 (30.8)</td><td></td></tr><tr><td>≥4</td><td>84 (18.5)</td><td>150 (22.4)</td><td></td></tr><tr><td>Missing</td><td>0 (0.0)</td><td>1 (0.2)</td><td></td></tr><tr><td>Personal history of inguinal hernia</td><td></td><td></td><td>0.01</td></tr><tr><td>No</td><td>414 (91.2)</td><td>637 (95.1)</td><td></td></tr><tr><td>Yes</td><td>39 (8.6)</td><td>32 (4.8)</td><td></td></tr><tr><td>Missing</td><td>1 (0.2)</td><td>1 (0.2)</td><td></td></tr><tr><td>Personal history of testicular trauma</td><td></td><td></td><td>0.004</td></tr><tr><td>No</td><td>387 (85.2)</td><td>611 (91.2)</td><td></td></tr><tr><td>Yes</td><td>67 (14.8)</td><td>59 (8.8)</td><td></td></tr><tr><td>Family history of TGCT</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>No</td><td>419 (92.3)</td><td>651 (97.2)</td><td></td></tr><tr><td>Yes</td><td>33 (7.3)</td><td>16 (2.4)</td><td></td></tr><tr><td>Missing</td><td>2 (0.4)</td><td>3 (0.4)</td><td></td></tr><tr><td>Family history of cryptorchidism</td><td></td><td></td><td>0.01</td></tr><tr><td>No</td><td>422 (93)</td><td>645 (96.3)</td><td></td></tr><tr><td>Yes</td><td>28 (6.2)</td><td>18 (2.7)</td><td></td></tr><tr><td>Missing</td><td>4 (0.9)</td><td>7 (1.0)</td><td></td></tr><tr><td>Age at voice change (years)</td><td></td><td></td><td>0.61</td></tr><tr><td>&lt;12</td><td>16 (3.5)</td><td>26 (3.9)</td><td></td></tr><tr><td>12–16</td><td>375 (82.6)</td><td>532 (79.4)</td><td></td></tr><tr><td>>16</td><td>53 (11.7)</td><td>94 (14.0)</td><td></td></tr><tr><td>Missing</td><td>10 (2.2)</td><td>18 (2.7)</td><td></td></tr><tr><td>Cannabis use (12–17 years)</td><td></td><td></td><td>0.30</td></tr><tr><td>No</td><td>312 (68.7)</td><td>443 (66.1)</td><td></td></tr><tr><td>Yes</td><td>142 (31.3)</td><td>227 (33.9)</td><td></td></tr><tr><td>Frequency of cannabis use (12–17 years)</td><td></td><td></td><td>0.24</td></tr><tr><td>Never</td><td>312 (68.72)</td><td>443 (66.1)</td><td></td></tr><tr><td>&lt;Once / month</td><td>51 (11.23)</td><td>84 (12.5)</td><td></td></tr><tr><td>≥Once / month</td><td>22 (4.85)</td><td>47 (7.0)</td><td></td></tr><tr><td>Once / week</td><td>37 (8.15)</td><td>39 (5.8)</td><td></td></tr><tr><td>Once / day</td><td>32 (7.05)</td><td>57 (8.5)</td><td></td></tr><tr><td>Cannabis use (18–25 years)</td><td></td><td></td><td>0.68</td></tr><tr><td>No</td><td>262 (57.71)</td><td>393 (58.7)</td><td></td></tr><tr><td>Yes</td><td>192 (42.29)</td><td>276 (41.2)</td><td></td></tr><tr><td>Missing</td><td>0 (0.0)</td><td>1 (0.2)</td><td></td></tr></tbody></table>

Continues
<table><caption>**Table 1.** continues</caption><thead><tr><th rowspan="2">Characteristics</th><th>TGCT cases<br>(N=454)</th><th>Controls<br>(N=670)</th><th rowspan="2">P-value<br>cases / all<br>controls*</th></tr><tr><th>N (%)</th><th>N (%)</th></tr></thead><tbody><tr><td>Frequency of cannabis use (18–25 years)</td><td></td><td></td><td>0.09</td></tr><tr><td>Never</td><td>262 (57.7)</td><td>393 (58.7)</td><td></td></tr><tr><td>&lt;Once / month</td><td>62 (13.7)</td><td>107 (16.0)</td><td></td></tr><tr><td>≥1 time / month</td><td>23 (5.1)</td><td>46 (6.9)</td><td></td></tr><tr><td>Once / week</td><td>41 (9.0)</td><td>54 (8.1)</td><td></td></tr><tr><td>Once / day</td><td>66 (14.5)</td><td>69 (10.3)</td><td></td></tr><tr><td>Missing</td><td>0 (0.0)</td><td>1 (0.2)</td><td></td></tr><tr><td>Paternal occupation at childbirth (ISCO-68)</td><td></td><td></td><td>0.09</td></tr><tr><td>Professional, technical &amp; related workers</td><td>91 (20.0)</td><td>175 (26.1)</td><td></td></tr><tr><td>Administration and managerial workers</td><td>21 (4.6)</td><td>41 (6.1)</td><td></td></tr><tr><td>Clerical and related workers</td><td>37 (8.2)</td><td>53 (7.9)</td><td></td></tr><tr><td>Sales workers</td><td>35 (7.7)</td><td>42 (6.3)</td><td></td></tr><tr><td>Service workers</td><td>38 (8.4)</td><td>33 (4.9)</td><td></td></tr><tr><td>Agricultural, animal husbandry and for-stry workers, fishermen and hunters</td><td>32 (7.1)</td><td>37 (5.5)</td><td></td></tr><tr><td>Production and related workers, transport equipment operators and laborers</td><td>164 (36.1)</td><td>234 (34.9)</td><td></td></tr><tr><td>Unemployed</td><td>11 (2.4)</td><td>24 (3.6)</td><td></td></tr><tr><td>Military</td><td>1 (0.2)</td><td>8 (1.2)</td><td></td></tr><tr><td>Missing</td><td>24 (5.3)</td><td>11 (2.4)</td><td></td></tr><tr><td>Maternal occupation at childbirth (ISCO-68)</td><td></td><td></td><td>0.66</td></tr><tr><td>Professional, technical &amp; related workers</td><td>88 (19.4)</td><td>137 (20.5)</td><td></td></tr><tr><td>Administration and managerial workers</td><td>6 (1.3)</td><td>11 (1.6)</td><td></td></tr><tr><td>Clerical and related workers</td><td>97 (21.4)</td><td>125 (18.7)</td><td></td></tr><tr><td>Sales workers</td><td>24 (5.3)</td><td>35 (5.2)</td><td></td></tr><tr><td>Service workers</td><td>47 (10.4)</td><td>75 (11.2)</td><td></td></tr><tr><td>Agricultural, animal husbandry and for-stry workers, fishermen and hunters</td><td>10 (2.2)</td><td>14 (2.1)</td><td></td></tr><tr><td>Production and related workers, transport equipment operators and laborers</td><td>19 (4.2)</td><td>46 (6.9)</td><td></td></tr><tr><td>Unemployed</td><td>145 (31.9)</td><td>209 (31.2)</td><td></td></tr><tr><td>Missing</td><td>18 (4.0)</td><td>18 (4.0)</td><td></td></tr><tr><td>Paternal industry at childbirth (NAF-99)</td><td></td><td></td><td>0.87</td></tr><tr><td>Agriculture, hunting and forestry</td><td>32 (7.1)</td><td>38 (5.7)</td><td></td></tr><tr><td>Fishing</td><td>1 (0.2)</td><td>0 (0.0)</td><td></td></tr><tr><td>Mining and quarrying</td><td>1 (0.2)</td><td>3 (0.5)</td><td></td></tr><tr><td>Manufacturing</td><td>61 (13.4)</td><td>105 (15.7)</td><td></td></tr><tr><td>Electricity, gas and water supply</td><td>5 (1.1)</td><td>5 (0.8)</td><td></td></tr><tr><td>Construction</td><td>48 (10.6)</td><td>69 (10.3)</td><td></td></tr><tr><td>Wholesale and retail trade; *repair of motor vehicles, motorcycles and personal and household goods</td><td>50 (11.0)</td><td>62 (9.3)</td><td></td></tr><tr><td>Hotels and restaurants</td><td>11 (2.4)</td><td>13 (1.9)</td><td></td></tr><tr><td>Transport, storage and communication</td><td>44 (10.0)</td><td>60 (9.0)</td><td></td></tr><tr><td>Financial intermediation</td><td>11 (2.4)</td><td>19 (2.8)</td><td></td></tr><tr><td>Real estate, renting and business activities</td><td>21 (4.6)</td><td>43 (6.4)</td><td></td></tr><tr><td>Public administration and defence; *com-pulsory social security</td><td>41 (9.0)</td><td>45 (6.7)</td><td></td></tr><tr><td>Education</td><td>17 (3.7)</td><td>33 (4.9)</td><td></td></tr><tr><td>Health and social work</td><td>21 (4.6)</td><td>41 (6.1)</td><td></td></tr><tr><td>Other community, social and personal ser-vices activities</td><td>7 (1.5)</td><td>13 (1.9)</td><td></td></tr><tr><td>Private households with employed persons</td><td>0 (0.0)</td><td>0 (0.0)</td><td></td></tr><tr><td>Extra-territorial organizations and bodies</td><td>0 (0.0)</td><td>1 (0.2)</td><td></td></tr><tr><td>Unemployed</td><td>11 (2.4)</td><td>22 (3.3)</td><td></td></tr><tr><td>Missing or unknown</td><td>72 (15.9)</td><td>98 (14.6)</td><td></td></tr><tr><td>Maternal industry at childbirth (NAF-99)</td><td></td><td></td><td>0.97</td></tr><tr><td>Agriculture, hunting and forestry</td><td>10 (2.2)</td><td>14 (2.2)</td><td></td></tr><tr><td>Fishing</td><td>0 (0.0)</td><td>0 (0.0)</td><td></td></tr><tr><td>Mining and quarrying</td><td>0 (0.0)</td><td>0 (0.0)</td><td></td></tr><tr><td>Manufacturing</td><td>21 (4.6)</td><td>43 (6.4)</td><td></td></tr><tr><td>Electricity, gas and water supply</td><td>0 (0.0)</td><td>2 (0.3)</td><td></td></tr><tr><td>Construction</td><td>0 (0.0)</td><td>1 (0.2)</td><td></td></tr><tr><td>Wholesale and retail trade; *repair of motor vehicles, motorcycles and personal and household goods</td><td>27 (6.0)</td><td>44 (6.6)</td><td></td></tr><tr><td>Hotels and restaurants</td><td>10 (2.2)</td><td>19 (2.8)</td><td></td></tr><tr><td>Transport, storage and communication</td><td>9 (2.0)</td><td>14 (2.1)</td><td></td></tr><tr><td>Financial intermediation</td><td>6 (1.3)</td><td>15 (2.2)</td><td></td></tr><tr><td>Real estate, renting and business activities</td><td>15 (3.3)</td><td>19 (2.8)</td><td></td></tr><tr><td>Public administration and defence; *com-pulsory social security</td><td>18 (4.0)</td><td>34 (5.1)</td><td></td></tr><tr><td>Education</td><td>37 (8.2)</td><td>49 (7.3)</td><td></td></tr><tr><td>Health and social work</td><td>56 (12.3)</td><td>93 (13.9)</td><td></td></tr><tr><td>Other community, social and personal ser-vices activities</td><td>9 (2.0)</td><td>14 (2.1)</td><td></td></tr><tr><td>Private households with employed persons</td><td>5 (1.1)</td><td>10 (1.5)</td><td></td></tr><tr><td>Extra-territorial organizations and bodies</td><td>0 (0.0)</td><td>0 (0.0)</td><td></td></tr><tr><td>Unemployed</td><td>145 (91.9)</td><td>206 (30.9)</td><td></td></tr><tr><td>Missing or unknown</td><td>86 (18.9)</td><td>92 (13.7)</td><td></td></tr></tbody></table>

the fathers were occupationally exposed to at least one solvent during the year of their son’s birth (supplementary table S5). For the fathers’ and mothers’ jobs exposed to TCE, PCE, MC and benzene, most were assessed as exposed in the low/medium exposure level classes for an 8-hour workday (supplementary table S6).

Table 2 shows the adjusted OR (OR<sub>adj</sub>) for TGCT associated with PEE of organic solvents. For fathers the OR<sub>adj</sub> for exposure to "any solvent" was 0.89 (95% CI 0.68–1.15). For KDF, the risk seems mainly driven by the low-exposure category (OR<sub>adj</sub> 1.52, 95% CI 0.98–2.37). An inverse association with TGCT risk (OR<sub>adj</sub> 0.71, 95% CI 0.52–0.97), and seminomas (OR<sub>adj</sub> 0.75, 95% CI 0.57–0.97) was observed related to fathers’ exposure to oxygenated solvents. Among the chlorinated solvents, the low-exposure category to TCE was inversely associated with seminomas (OR<sub>adj</sub> 0.45, 95% CI 0.23–0.90). Conversely, these analyses were also suggestive a positive association with non-seminomas among sons whose fathers were highly exposed to TCE (OR<sub>adj</sub> 1.44, 95% CI 0.79–2.63). However, CI were wide and included the null hypothesis.

The OR<sub>adj</sub> for maternal exposures to "any solvent" was 0.90 (95% CI 0.65–1.24) (table 3). Most OR<sub>adj</sub> associated with maternal exposures were ≤1.0. When exposure was subdivided into low and high exposure categories, none of the maternal exposures were found to be associated with TGCT risk. The associations of TGCT with maternal exposures to solvents showed no heterogeneity between seminomas and non-seminomas.

Table 4 presents the results based on the second analytical approach where the reference category is mothers/fathers who have not been exposed to the solvents in the category of interest. Except for an inverse association observed for sons of fathers exposed to oxygenated solvents in the year of their birth (OR<sub>adj</sub> 0.72, 95% CI 0.52–0.99), no associations between paternal and maternal exposures to solvents and TGCT risk was observed.

Depending on the exposure to the solvent of interest, variability in the OR<sub>adj</sub> across different birth decades was observed (table 5). For paternal exposure, the OR<sub>adj</sub> for oxygenated solvents exposure shows an inverse association in the 1970s (0.45, 95% CI 0.26–0.78), but an elevated OR<sub>adj</sub> in the 90s (1.87; 95% CI 0.61–5.72), although the CI was wide. The associations between maternal occupational exposure to petroleum-based solvents and TGCT risk in sons varied by decade (P=0.01). A positive association was observed between mothers exposed to petroleum-based solvents in the 1969–1980 decades and TGCT risk in the offspring (OR<sub>adj</sub> 2.74, 95% CI 1.11–6.76), but with a wide CI, and was not found among mothers exposed in the 1980s/90s. The other solvents did not appear to vary among son’s decade of birth.

The PCA approach identified 2–3 PC depending on the solvent and the parent. None of them showed an

<footnote>*P-values from bivariate conditional logistic regression models conditioned on region and birth year– except for the year of birth which was a matching factor.</footnote>
<table><caption>**Table 2.** Odds ratios (OR) and 95% confidence intervals (CI) for testicular germ cell tumors (TGCT) associated with paternal occupational exposure to solvents in the year of the child's birth, overall and according to histological subtypes, TESTIS study, 2015–2018. [Ca/Co=Cases/controls; P-Het=P for heterogeneity].</caption><thead><tr><th rowspan="2">Solvents exposure</th><th colspan="2">All TGCT cases</th><th colspan="2">Non-seminomas <sup>d</sup></th><th colspan="2">Seminomas <sup>c</sup></th><th rowspan="2">P-Het<sup>b</sup></th></tr><tr><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Any solvents</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>251/377</td><td>1.00</td><td>103/377</td><td>1.00</td><td>126/377</td><td>1.00</td><td rowspan="2">0.59</td></tr><tr><td>Exposed to at least one solvent</td><td>162/264</td><td>0.89 (0.68-1.15)</td><td>67/264</td><td>0.85 (0.58-1.25)</td><td>75/264</td><td>0.74 (0.52-1.05)</td></tr><tr><td><strong>Oxygenated solvents</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">0.05</td></tr><tr><td>None</td><td>326/473</td><td>1.00</td><td>128/473</td><td>1.00</td><td>167/473</td><td>1.00</td></tr><tr><td>Exposure</td><td>87/168</td><td>0.71 (0.52-0.97)</td><td>42/168</td><td>0.87 (0.67-1.15)</td><td>34/168</td><td>0.75 (0.57-0.97)</td><td rowspan="3">0.18</td></tr><tr><td>Low</td><td>47/84</td><td>0.74 (0.50-1.11)</td><td>27/84</td><td>1.17 (0.70-1.97)</td><td>14/84</td><td>0.44 (0.24-0.83)</td></tr><tr><td>High</td><td>40/84</td><td>0.68 (0.45-1.03)</td><td>15/84</td><td>0.66 (0.36-1.21)</td><td>20/84</td><td>0.67 (0.39-1.14)</td></tr><tr><td><strong>Alcohols</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.20</td></tr><tr><td>None</td><td>361/539</td><td>1.00</td><td>147/539</td><td>1.00</td><td>176/539</td><td>1.00</td></tr><tr><td>Exposure</td><td>52/102</td><td>0.76 (0.52-1.11)</td><td>23/102</td><td>0.91 (0.54-1.53)</td><td>25/102</td><td>0.69 (0.42-1.13)</td></tr><tr><td>Low</td><td>25/51</td><td>0.68 (0.40-1.14)</td><td>13/51</td><td>1.09 (0.54-2.20)</td><td>9/51</td><td>0.44 (0.20-0.95)</td></tr><tr><td>High</td><td>27/51</td><td>0.85 (0.51-1.40)</td><td>10/51</td><td>0.75 (0.36-1.58)</td><td>16/51</td><td>0.97 (0.53-1.76)</td></tr><tr><td><strong>Ketones and esters</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.14</td></tr><tr><td>None</td><td>381/577</td><td>1.00</td><td>154/577</td><td>1.00</td><td>190/577</td><td>1.00</td></tr><tr><td>Exposure</td><td>32/64</td><td>0.79 (0.50-1.25)</td><td>16/64</td><td>1.00 (0.55-1.83)</td><td>11/64</td><td>0.56 (0.28-1.11)</td></tr><tr><td>Low</td><td>20/44</td><td>0.72 (0.41-1.27)</td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>12/20</td><td>0.94 (0.44-2.00)</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Ethylene glycol</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="3">0.82</td></tr><tr><td>None</td><td>404/624</td><td>1.00</td><td></td><td></td><td></td><td></td></tr><tr><td>Exposure</td><td>9/17</td><td>0.69 (0.29-1.61)</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Chlorinated solvents</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.24</td></tr><tr><td>None</td><td>344/519</td><td>1.00</td><td>138/519</td><td>1.00</td><td>175/519</td><td>1.00</td></tr><tr><td>Exposure</td><td>69/122</td><td>0.78 (0.55-1.10)</td><td>32/122</td><td>1.03 (0.77-1.38)</td><td>26/122</td><td>0.73 (0.54-0.99)</td></tr><tr><td>Low</td><td>31/66</td><td>0.63 (0.40-1.01)</td><td>15/66</td><td>0.77 (0.41-1.43)</td><td>11/66</td><td>0.43 (0.22-0.86)</td></tr><tr><td>High</td><td>38/56</td><td>0.96 (0.61-1.52)</td><td>17/56</td><td>1.21 (0.65-2.24)</td><td>15/56</td><td>0.68 (0.36-1.28)</td></tr><tr><td><strong>Trichloroethylene</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.26</td></tr><tr><td>None</td><td>346/525</td><td>1.00</td><td>138/525</td><td>1.00</td><td>176/525</td><td>1.00</td></tr><tr><td>Exposure</td><td>67/116</td><td>0.80 (0.56-1.13)</td><td>32/116</td><td>1.03 (0.64-1.64)</td><td>25/116</td><td>0.54 (0.33-0.88)</td></tr><tr><td>Low</td><td>29/63</td><td>0.61 (0.38-1.00)</td><td>14/63</td><td>0.74 (0.39-1.41)</td><td>11/63</td><td>0.45 (0.23-0.90)</td></tr><tr><td>High</td><td>38/53</td><td>1.02 (0.65-1.63)</td><td>18/53</td><td>1.44 (0.79-2.63)</td><td>14/53</td><td>0.64 (0.33-1.23)</td></tr><tr><td><strong>Perchloroethylene</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="3">0.60</td></tr><tr><td>None</td><td>403/631</td><td>1.00</td><td></td><td></td><td></td><td></td></tr><tr><td>Exposure</td><td>10/10</td><td>1.41 (0.55-3.61)</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Methylene chloride</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.31</td></tr><tr><td>None</td><td>399/622</td><td>1.00</td><td>165/622</td><td>1.00</td><td>195/622</td><td>1.00</td></tr><tr><td>Exposure</td><td>14/19</td><td>1.13 (0.54-2.34)</td><td>5/19</td><td>1.07 (0.36-3.18)</td><td>6/19</td><td>0.91 (0.35-2.36)</td></tr><tr><td>Low</td><td>6/10</td><td>0.85 (0.29-2.47)</td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>8/9</td><td>1.45 (0.54-3.89)</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Fuels &amp; petroleum-based solvents</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.04</td></tr><tr><td>None</td><td>295/458</td><td>1.00</td><td>117/458</td><td>1.00</td><td>151/458</td><td>1.00</td></tr><tr><td>Exposure</td><td>118/183</td><td>0.95 (0.71-1.27)</td><td>53/183</td><td>0.95 (0.72-1.25)</td><td>50/183</td><td>0.89 (0.69-1.13)</td></tr><tr><td>Low</td><td>72/105</td><td>1.07 (0.75-1.51)</td><td>40/105</td><td>1.42 (0.90-2.23)</td><td>23/105</td><td>0.64 (0.38-1.07)</td></tr><tr><td>High</td><td>46/78</td><td>0.81 (0.54-1.23)</td><td>13/78</td><td>0.66 (0.34-1.28)</td><td>27/78</td><td>0.89 (0.54-1.47)</td></tr><tr><td><strong>Benzene</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.10</td></tr><tr><td>None</td><td>396/610</td><td>1.00</td><td>162/610</td><td>1.00</td><td>195/610</td><td>1.00</td></tr><tr><td>Exposure</td><td>17/31</td><td>0.85 (0.45-1.60)</td><td>8/31</td><td>1.08 (0.47-2.52)</td><td>6/31</td><td>0.53 (0.21-1.35)</td></tr><tr><td>Low</td><td>7/16</td><td>0.71 (0.28-1.84)</td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>10/15</td><td>0.98 (0.42-2.28)</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Automobile gasoline</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.10</td></tr><tr><td>None</td><td>389/598</td><td>1.00</td><td>163/598</td><td>1.00</td><td>188/598</td><td>1.00</td></tr><tr><td>Exposure</td><td>24/43</td><td>0.74 (0.43-1.28)</td><td>7/43</td><td>0.55 (0.23-1.32)</td><td>13/43</td><td>0.74 (0.37-1.47)</td></tr><tr><td>Low</td><td>14/22</td><td>0.83 (0.40-1.70)</td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>10/21</td><td>0.65 (0.29-1.45)</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Special petroleum products</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="3">0.67</td></tr><tr><td>None</td><td>400/623</td><td>1.00</td><td>162/623</td><td>1.00</td><td>196/623</td><td>1.00</td></tr><tr><td>Exposure</td><td>13/18</td><td>1.03 (0.48-2.20)</td><td>8/18</td><td>1.64 (0.65-4.12)</td><td>5/18</td><td>0.80 (0.28-2.26)</td></tr><tr><td><strong>White spirits</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.10</td></tr><tr><td>None</td><td>336/500</td><td>1.00</td><td>133/500</td><td>1.00</td><td>174/500</td><td>1.00</td></tr><tr><td>Exposure</td><td>77/141</td><td>0.82 (0.60-1.14)</td><td>37/141</td><td>1.06 (0.69-1.64)</td><td>27/141</td><td>0.53 (0.33-0.84)</td></tr><tr><td>Low</td><td>47/80</td><td>0.87 (0.58-1.30)</td><td>23/80</td><td>1.09 (0.64-1.85)</td><td>16/80</td><td>0.55 (0.30-1.01)</td></tr><tr><td>High</td><td>30/61</td><td>0.77 (0.48-1.24)</td><td>14/61</td><td>1.02 (0.53-1.95)</td><td>11/61</td><td>0.49 (0.25-0.97)</td></tr><tr><td><strong>Diesel, kerosene, fuel oil</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="4">0.67</td></tr><tr><td>None</td><td>355/565</td><td>1.00</td><td>147/565</td><td>1.00</td><td>173/565</td><td>1.00</td></tr><tr><td>Exposure</td><td>58/76</td><td>1.17 (0.80-1.73)</td><td>23/76</td><td>1.24 (0.72-2.13)</td><td>28/76</td><td>1.06 (0.64-1.74)</td></tr><tr><td>Low</td><td>46/50</td><td>1.52 (0.98-2.37)</td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>12/26</td><td>0.58 (0.28-1.23)</td><td></td><td></td><td></td><td></td></tr></tbody></table>

<footnote><sup>a</sup>Estimates obtained comparing TGCT cases to group A and group B controls combined and adjusted for sibship size, being born from multiple pregnancy, personal history of testicular trauma, family history of TGCT and family history of cryptorchidism. Analysis was restricted to subjects with no missing data for the adjustment variables (N=12). If the "Low"/"High" categories have less than 5 cases or controls, the categories are grouped into "None" or "All" if the number of subjects was sufficient, otherwise the line is shaded.</footnote>

<footnote><sup>b</sup>P-value for heterogeneity derived from the Likelihood Ratio Test, comparing seminoma versus non-seminoma tumours.</footnote>

<footnote><sup>c</sup>219 cases of seminoma TGCT were present in the TESTIS study.</footnote>

<footnote><sup>d</sup>191 cases of non-seminoma TGCT were present in the TESTIS study.</footnote>
<table><caption>**Table 3.** Odds ratios (OR) and 95% confidence intervals (CI) for testicular germ cell tumors (TGCT) associated with maternal occupational exposure to solvents in the year of the child's birth, overall and according to histological subtypes, TESTIS study, 2015–2018. [Ca/Co=Cases/controls; P-Het=P for heterogeneity].</caption><thead><tr><th rowspan="2">Solvents exposure</th><th colspan="2">All TGCT cases</th><th colspan="2">Non-Seminomas<sup>d</sup></th><th colspan="2">Seminomas<sup>c</sup></th><th rowspan="2">P-Het<sup>b</sup></th></tr><tr><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th></tr></thead><tbody><tr><td>Any solvents</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>341/509</td><td>1.00</td><td>139/509</td><td>1.00</td><td>170/509</td><td>1.00</td><td>0.89</td></tr><tr><td>Exposed to at least one solvent</td><td>84/136</td><td>0.90 (0.65-1.24)</td><td>34/136</td><td>0.89 (0.57-1.40)</td><td>42/136</td><td>0.93 (0.62-1.40)</td><td></td></tr><tr><td>Oxygenated solvents</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>348/518</td><td>1.00</td><td>140/518</td><td>1.00</td><td>176/518</td><td>1.00</td><td>0.69</td></tr><tr><td>Exposure</td><td>77/127</td><td>0.87 (0.63-1.22)</td><td>33/127</td><td>0.94 (0.60-1.48)</td><td>36/127</td><td>0.83 (0.54-1.27)</td><td></td></tr><tr><td>Low</td><td>72/113</td><td>0.89 (0.63-1.26)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>5/14</td><td>0.69 (0.24-1.98)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Alcohols</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>352/524</td><td>1.00</td><td>141/524</td><td>1.00</td><td>179/524</td><td>1.00</td><td>0.52</td></tr><tr><td>Exposure</td><td>73/121</td><td>0.86 (0.61-1.20)</td><td>32/121</td><td>0.96 (0.61-1.52)</td><td>33/121</td><td>0.78 (0.50-1.21)</td><td></td></tr><tr><td>Low</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ketones and esters</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>410/619</td><td>1.00</td><td>167/619</td><td>1.00</td><td>205/619</td><td>1.00</td><td>0.81</td></tr><tr><td>Exposure</td><td>15/26</td><td>0.99 (0.51-1.96)</td><td>6/26</td><td>0.94 (0.36-2.45)</td><td>7/26</td><td>0.80 (0.33-1.97)</td><td></td></tr><tr><td>Low</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Diethylether</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>392/588</td><td>1.00</td><td>159/588</td><td>1.00</td><td>197/588</td><td>1.00</td><td>0.77</td></tr><tr><td>Exposure</td><td>33/57</td><td>0.93 (0.58-1.48)</td><td>14/57</td><td>1.02 (0.53-1.95)</td><td>15/57</td><td>0.89 (0.48-1.65)</td><td></td></tr><tr><td>Low</td><td>24/35</td><td>1.13 (0.64-1.97)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>9/22</td><td>0.62 (0.27-1.44)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Chlorinated solvents</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>413/622</td><td>1.00</td><td>168/622</td><td>1.00</td><td>206/622</td><td>1.00</td><td>0.77</td></tr><tr><td>Exposure</td><td>12/23</td><td>0.88 (0.43-1.82)</td><td>5/23</td><td>1.03 (0.37-2.86)</td><td>6/23</td><td>0.83 (0.33-2.12)</td><td></td></tr><tr><td>Low</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Trichloroethylene</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>417/628</td><td>1.00</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Exposure</td><td>8/17</td><td>0.77 (0.32-1.83)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Low</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fuel & petroleum-based solvents</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>392/598</td><td>1.00</td><td>159/598</td><td>1.00</td><td>196/598</td><td>1.00</td><td>0.94</td></tr><tr><td>Exposure</td><td>33/47</td><td>0.97 (0.60-1.57)</td><td>14/47</td><td>0.94 (0.49-1.82)</td><td>16/47</td><td>0.97 (0.52-1.81)</td><td></td></tr><tr><td>Low</td><td>25/35</td><td>0.97 (0.56-1.68)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>8/12</td><td>0.99 (0.39-2.51)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>White spirits</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>399/604</td><td>1.00</td><td>160/604</td><td>1.00</td><td>202/604</td><td>1.00</td><td>0.39</td></tr><tr><td>Exposure</td><td>26/41</td><td>0.85 (0.50-1.45)</td><td>13/41</td><td>1.02 (0.52-2.03)</td><td>10/41</td><td>0.66 (0.31-1.38)</td><td></td></tr><tr><td>Low</td><td>20/29</td><td>0.85 (0.46-1.56)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td>6/12</td><td>0.87 (0.32-2.42)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Diesel, kerosene, fuel oil</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>418/637</td><td>1.00</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Exposure</td><td>7/8</td><td>1.39 (0.48-4.07)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Low</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

<footnote><sup>a</sup> Estimates obtained comparing TGCT cases to group A and group B controls combined and adjusted for sibship size, being born from multiple pregnancy, personal history of testicular trauma, family history of TGCT and family history of cryptorchidism. Analysis was restricted to subjects with no missing data for the adjustment variables (N=12). If the "Low"/"High" categories have less than 5 cases or controls, the categories are grouped into "None" or "All" if the number of subjects was sufficient, otherwise the line is shaded.</footnote>

<footnote><sup>b</sup> P-value for heterogeneity derived from the Likelihood Ratio Test, comparing seminoma versus non-seminoma tumours.</footnote>

<footnote><sup>c</sup> 219 cases of seminoma TGCT were present in the TESTIS study.</footnote>

<footnote><sup>d</sup> 191 cases of non-seminoma TGCT were present in the TESTIS study.</footnote>
<table><caption>**Table 4.** Odds ratios (OR) and 95% confidence intervals (CI) for testicular germ cell tumors (TGCT) associated with parental occupational exposure to different solvents in the year of the child's birth, with unexposed to any of the solvents as reference category, TESTIS study, 2015–2018. [Ca/Co=cases/controls]. Note: Exposed=exposed to the solvents of interest but can also be exposed to other solvents; Exposed only to others=exposed to any other solvents but the solvent of interest; Unexposed=unexposed to any of the individual or groups of solvents.</caption><thead><tr><th rowspan="2"></th><th colspan="2">Paternal exposure<br>All TGCT cases</th><th colspan="2">Maternal exposure<br>All TGCT cases</th></tr><tr><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Oxygenated<br>solvents exposure</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>251/377</td><td>1.00</td><td>341/509</td><td>1.00</td></tr><tr><td>Exposed</td><td>87/168</td><td>0.72 (0.52-0.99)</td><td>77/127</td><td>0.88 (0.63-1.22)</td></tr><tr><td>Exposed only to<br>other solvents</td><td>75/96</td><td>1.04 (0.72-1.49)</td><td>7/9</td><td>1.20 (0.43-3.35)</td></tr><tr><td><strong>Chlorinated solvents<br>exposure</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>251/377</td><td>1.00</td><td>341/509</td><td>1.00</td></tr><tr><td>Exposed</td><td>69/122</td><td>0.76 (0.53-1.08)</td><td>12/23</td><td>0.86 (0.42-1.79)</td></tr><tr><td>Exposed only to<br>other solvents</td><td>93/142</td><td>0.90 (0.65-1.25)</td><td>72/113</td><td>0.90 (0.64-1.28)</td></tr><tr><td><strong>Fuels &amp; petroleum-<br>based solvents<br>exposure</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>251/377</td><td>1.00</td><td>341/509</td><td>1.00</td></tr><tr><td>Exposed</td><td>118/183</td><td>0.90 (0.67-1.21)</td><td>33/47</td><td>0.95 (0.59-1.54)</td></tr><tr><td>Exposed only to<br>other solvents</td><td>44/81</td><td>0.70 (0.45-1.07)</td><td>51/89</td><td>0.87 (0.59-1.28)</td></tr></tbody></table>

association with TGCT risk, confirming the absence of association between parental solvent exposure and TGCT risk in their son (supplementary tables S6 – S7).

In supplementary analyses, the results remained globally unchanged when we excluded cases with a personal history of cryptorchidism in the model (supplementary table S8) or when we excluded TGCT cases not confirmed by pathology reports (supplementary table S9). Further adjustment for age did not modify the results (supplementary table S10). The ORadj showed no substantial change from the crude OR (data not shown).

Discussion

This study documents the relationship between parental occupational exposure to solvents and TGCT risk among their offspring in France. Parental occupation at birth was considered as a proxy of solvent exposure before

and at conception (37). No solid evidence of an association between parental occupational exposure to solvents at birth and TGCT among sons was found. However, an increased risk with maternal exposure to petroleum-based solvents in the 1970s was observed. Our results may also suggest a modest increased risk of non-seminoma for sons whose fathers were highly exposed to TCE.

Prevalence of exposure to at least one oxygenated solvent reported in our study was higher among fathers but similar in mothers (ie, 24% fathers and 19% mothers) (supplementary table S5) than those observed in the population of French workers in 1999. (ie, 9% of men and 16% of women) (38). The prevalence of maternal exposures to specific solvents were lower than those reported for women during similar periods in another French case-control study (ICARE study) that also used the Matgéné JEM (39). The prevalence of paternal exposures were slightly higher than those assessed for men during similar periods for chlorinated solvents in the ICARE study (40), particularly for TCE (8% for controls in ICARE study), based on the whole career.

Some solvents, and other EDC, can cross the placental barrier, enter the fetal circulation (8), and interfere with hormone levels during fetal development (41). It has also been reported in two previous animal studies that fetal exposure to toluene and styrene was associated with reduced testosterone synthesis and secretion in the fetal testes and decreased male reproductive organ weights (42, 43). Nevertheless, in our study, no overall association between maternal occupational exposure to solvents at birth and TGCT in their offspring was observed. The exception was a positive association with maternal exposure to petroleum-based solvents in the 1970s. This finding must be interpreted with caution, as the number of mothers exposed was limited, and the CI was wide indicating substantial uncertainty around available estimates. However, this result was consistent with those observed in the two NORD-TEST studies (21, 22), particularly with the higher risk of TGCT (OR 1.44, 95% CI 1.00–2.08) for maternal exposure to aromatic hydrocarbon solvents (ie, petroleum solvents) among sons born in 1970–1979 shown in Denmark NORD-TEST study. Nevertheless, because of insufficient numbers, it was not possible to identify in our study whether this positive association observed for petroleum-based solvents in the 1970s was mainly driven by the aromatic hydrocarbon solvent category, as in NORD-TEST studies.

The association between maternal occupational solvents exposure and congenital malformations has been investigated in previous studies (11, 44–51). Contrasting results between maternal solvent exposures and hypospadias were observed (11, 45, 52). Overall, petroleum-based solvents have frequently been found to be associated with birth defects. Moreover, an experi-

<footnote><sup>a</sup> Estimates obtained comparing TGCT cases to group A and group B controls combined and adjusted for sibship size, being born from multiple pregnancy, personal history of testicular trauma, family history of TGCT and family history of cryptorchidism. Analysis was restricted to subjects with no missing data for the adjustment variables (N=12). If the "Low"/"High" categories have less than 5 cases or controls, the categories are grouped into "None" or "All" if the number of subjects was sufficient, otherwise the line is shaded.</footnote>

<footnote><sup>b</sup> At least one of the following solvents: benzene; automobile gasoline; white spirits and other aromatics; diesel, kerosene and fuel oil; special petroleum products and other aliphatics; alcohols; ketones and esters; ethylene glycol; diethyl ether; tetrahydrofuran; trichloroethylene; perchloroethylene; methylene chloride; carbon tetrachloride; chloroform.</footnote>
<table><caption>**Table 5a.** Odds ratios (OR) and 95% confidence intervals (CI) for TGCT associated with **paternal** occupational exposure to different solvents in the year of the child's birth, by period of birth year, TESTIS study, 2015–2018. [Ca/Co=cases/controls].</caption><thead><tr><th rowspan="2">Solvents exposure</th><th colspan="2">1969-80 (N=339)</th><th colspan="2">1981-90 (N=612)</th><th colspan="2">1991-99 (N=110)</th><th rowspan="2">P-value<sup>b</sup></th></tr><tr><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Oxygenated solvents exposure</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Unexposed</td><td>98/142</td><td>1.00</td><td>186/292</td><td>1.00</td><td>46/39</td><td>1.00</td><td>0.09</td></tr><tr><td>Exposed</td><td>27/72</td><td>0.45 (0.26-0.78)</td><td>46/87</td><td>0.85 (0.56-1.29)</td><td>14/9</td><td>1.87 (0.61-5.72)</td><td></td></tr><tr><td><strong>Chlorinated solvents exposure</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Unexposed</td><td>104/164</td><td>1.00</td><td>195/316</td><td>1.00</td><td>45/39</td><td>1.00</td><td>0.67</td></tr><tr><td>Exposed</td><td>21/50</td><td>0.62 (0.34-1.13)</td><td>37/63</td><td>0.97 (0.61-1.55)</td><td>11/9</td><td>0.88 (0.26-2.98)</td><td></td></tr><tr><td><strong>Fuels & petroleum-based solvents exposure</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Unexposed</td><td>90/147</td><td>1.00</td><td>167/277</td><td>1.00</td><td>38/34</td><td>1.00</td><td>0.75</td></tr><tr><td>Exposed</td><td>35/67</td><td>0.83 (0.49-1.39)</td><td>65/102</td><td>1.01 (0.68-1.48)</td><td>18/14</td><td>1.07 (0.40-2.89)</td><td></td></tr></tbody></table>

<sup>a</sup> Estimates obtained comparing TGCT cases to group A and group B controls combined and adjusted for sibship size, being born from multiple pregnancy, personal history of testicular trauma, family history of TGCT and family history of cryptorchidism. Analysis was restricted to subjects with no missing data for the adjustment variables (N=12).

<sup>b</sup> If the categories of birth decades have less than 5 cases or controls, the categories "1981-90" and "1991-99" were combined into a single category (1981-99), otherwise the line is shaded.

<table><caption>**Table 5b.** Odds ratios (OR) and 95% confidence intervals (CI) for TGCT associated with **maternal** occupational exposure to different solvents in the year of the child's birth, by period of birth year, TESTIS study, 2015–2018. [Ca/Co=cases/controls].</caption><thead><tr><th rowspan="2">Solvents exposure</th><th colspan="2">1969-80 (N=345)</th><th colspan="2">1981-90 (N=614)</th><th colspan="2">1991-99 (N=111)</th><th rowspan="2">P-value<sup>b</sup></th></tr><tr><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th><th>Ca/Co</th><th>OR (95% CI)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Oxygenated solvents exposure</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Unexposed</td><td>99/176</td><td>1.00</td><td>196/302</td><td>1.00</td><td>53/40</td><td>1.00</td><td>0.42</td></tr><tr><td>Exposed</td><td>30/40</td><td>1.17 (0.66-2.07)</td><td>38/78</td><td>0.75 (0.48-1.18)</td><td>9/9</td><td>0.67 (0.21-2.11)</td><td></td></tr><tr><td><strong>Chlorinated solvents exposure</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Unexposed</td><td>125/207</td><td>1.00</td><td>288/415</td><td></td><td></td><td>1.00</td><td>0.91</td></tr><tr><td>Exposed</td><td>4/9</td><td>0.85 (0.25-2.88)</td><td>8/14</td><td></td><td></td><td>0.99 (0.40-2.46)</td><td></td></tr><tr><td><strong>Fuels & petroleum-based solvents exposure</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Unexposed</td><td>115/206</td><td>1.00</td><td>277/392</td><td></td><td></td><td>1.00</td><td>0.01</td></tr><tr><td>Exposed</td><td>14/10</td><td>2.74 (1.11-6.76)</td><td>19/37</td><td></td><td></td><td>0.65 (0.35-1.18)</td><td></td></tr></tbody></table>

<sup>a</sup> Estimates obtained comparing TGCT cases to group A and group B controls combined and adjusted for sibship size, being born from multiple pregnancy, personal history of testicular trauma, family history of TGCT and family history of cryptorchidism. Analysis was restricted to subjects with no missing data for the adjustment variables (N=12).

<sup>b</sup> If the categories of birth decades have less than 5 cases or controls, the categories "1981-90" and "1991-99" were combined into a single category (1981-99), otherwise the line is shaded.

mental study in laboratory animals suggested that rats exposed prenatally to toluene have an increased risk of cryptorchidism (53). Thus, it seems possible that maternal exposure to solvents increases the risk of two other TDS conditions.

The role of paternal exposure to organic solvents has received less attention. Mechanisms by which male occupational exposure may cause reproductive and developmental defects are still largely unknown, however, it was suggested that transmission may also occur via epigenetic changes from father to child (19). The evidence for epigenetic alterations caused by carcinogens, and the potential association with genotoxic endpoints, is rapidly growing (19). Recently, exposure to TCE has been shown to cause changes in sperm histones in rats (18). These results raise the question of the role of epigenetic inheritance through histone modifications in the offspring after TCE exposure. Our findings also showed a modest positive association with non-seminoma and paternal TCE exposure, although CI were wide and included negative and null association values. The NORD-TEST study also observed a modest increase

in the risk of TGCT in sons whose fathers were exposed to TCE, although the OR was higher in the low-TCE exposure category in this study (OR 1.12, 95%CI 0.96–1.32). As is our study, no association between fathers not exposed/exposed or not exposed/low/highly exposed to other solvents was observed in the two previous Nordic registry-based studies (21, 22).

In France, the occupational exposure limit (OEL) of 8 hours (ie, average exposure limit value) in effect at the time of the relevant exposures, was set at 75 ppm for TCE (1983–2020), 50 ppm for PCE (until 2012). None of the exposure levels observed for fathers and mothers to these three solvents in our study were above the established OEL (supplementary table S6). Nevertheless, the OEL have decreased or regulated over time, and were set to date at 10 ppm for TCE (updated in 2021) at 20 ppm for PCE (2012) and at 50 ppm for MC (regulated since 2012) in France. About 5% of fathers in this study were exposed to TCE above the OEL. This could potentially explain the increase in TGCT risk suggested by our findings, albeit modest and with wide CI, for offspring whose fathers were highly exposed to TCE. Some moth-
ers were also exposed to TCE (N=13), PCE (N=1) above
the currently set OEL. Nevertheless, very few mothers
were exposed to chlorinated solvents in our study, then
it is possible that the power of the study did not allow
us to show an increased risk of TGCT for sons whose
mothers were exposed to these solvents.

Our study has several strengths. JEM applied in
this study were developed by experienced industrial
hygienists, specifically for the French population (28).
Matgéné's JEM integrate the probability of exposure,
semi-quantitative indices of exposure level and the
period of exposure, which allows the assignment of
exposure to evolve over time, in connection with the
evolution of techniques, occupation conditions and
regulations. We were also able to adjust for a significant
number of known or suspected risk factors, which had
not been the case in previous studies of the association
between parental exposures to solvents and TGCT risk
in their offspring. However, information about other
suspected risk factors, such as maternal bleeding dur-
ing pregnancy or maternal smoking, was not available
in our study (31). Therefore, it cannot be excluded that
the associations reported in this study may be related to
these other factors.

This study has also some limitations that may affect
the interpretation of the results. In general, young men
are known to be a difficult population to approach and
less likely to participate in research than other popula-
tion groups (54). Thus, low response rates make difficult
ascertaining a population-based control group represen-
tative of the general population. Since no perfect control
group was found, we choose two distinct control groups
to test our hypotheses on populations presenting differ-
ent aspects of the general population, as proposed by
Stang et al (55). Hospital-based control recruitment aims
to facilitate the recruitment of our young male popula-
tion, as well as the management of biological sampling.
Moreover, according to the TDS hypothesis, TGCT,
cryptorchidism, hypospadias and poor semen quality cor-
respond to the same prenatal alteration but with a different
clinical expression (9). By choosing controls supposed to
be fecund [Group B (partners of pregnant woman hospi-
talized for pathological pregnancy) recruited at the level
III maternity hospital] or having a normal sperm count
[Group A (sperm donors & fertile partners of infertile
woman) recruited at CECOS], we reduced the risk of
having controls with minor forms of this syndrome. Yet,
consequently, we cannot exclude that our controls may
be more fertile than the general population of the same
age (54). Data is limited in defining if this has biased the
results. However, to affect the associations examined in
the present study, it would require that factors responsible
for increased fertility in the controls are non-occupational
albeit correlated with parental occupations. Although pro-
spective recruitment of cases from one of the participating

CECOS for sperm cryopreservation appears to be the
most appropriate method to ensure good response rate in
the present study (54), this recruitment has some limita-
tions. Cases who presented for sperm cryopreservation
prior to cancer treatment may not be representative of all
men with TGCT, such as those who are already fathers,
or those with azoospermia may be underrepresented.
Moreover, occupational exposures were assessed by JEM,
which provide an average assessment for an ISCO-NAF
pair by considering the variability of exposures within
the same job. However, within the same ISCO-NAF pair,
there may be jobs with varying intensity and frequency of
exposure. A limitation of JEM is that they do not account
for individual variation on exposure within the same job,
which may generate non-differential misclassification
of exposure compared to an individual assessment, and
could result in bias toward the null (56). It is important
to note that our results may be limited in terms of sta-
tistical power because of the low prevalence of some
exposure variables and small numbers in the subgroup
analysis, leading to effect estimates with high statistical
uncertainty. Despite the consistency of the primary and
secondary analyses, we cannot rule out the possibility that
our results are due to chance because of multiple testing.
It should be noted that the few associations identified in
this study presented plausible hypotheses consistent with
the results of previous experimental and human studies
(18, 21, 22). Finally, because of the study design, we
had to assume that the parental job at birth reflected the
exposure at the time of conception and during intrauterine
development, following the example of other studies (21,
22, 37) even though a change in employment may have
occurred during these periods. In the TESTIS study, upon
written consent by the participants, the participants' moth-
ers were also contacted to offer them participation in the
study and a telephone interview. In this interview, like the
participants, the mothers described their work history as
well as that of the father. As a measure of quality, agree-
ment between parental employments at birth provided
by the participants and the ones provided by the mothers
was estimated, using Cohen's kappa coefficient (57). For
this analysis, data from 547 mothers (50% participation
rate in the two-stage recruitment process of case/control
mothers/relatives; 75% participation rate of mothers for
which the participating sons agreed to provide the con-
tact) (24) were used. Kappa values ranged from moderate
agreement for the more specific coding levels to perfect
agreement for the more general coding levels. The pri-
mary analysis was conducted with subjects' reported birth
parental occupations (son) to maximize the sample size
and therefore the power of the study.

Concluding remarks

Overall, this study suggests no substantial role of paren-
tal occupational exposure to solvents and TGCT risk, although maternal occupational exposure to petroleum-based solvents suggested a positive association among men born in the 1970s. Paternal occupation to high levels of TCE showed a slightly elevated non-seminoma risk that needs to be confirmed by further studies, which also requires research on the molecular mechanisms involved.

## Acknowledgments

The TESTIS study was supported by the French National Cancer Institute (INCa, N°2013-143) and the Institut National de la Santé et de la Recherche Médicale (Inserm, N°ENV201306/CLB). TESTISPro project was supported by the Fondation de France. Margot Guth was supported by a doctoral grant of University Lyon 1.

We gratefully acknowledge the participants and their mothers for providing data, and medical practitioners for providing pathology reports.

We acknowledge all the members of the TESTIS Study group. We are grateful to the medical teams of participating CECOS from the Fédération Française des CECOS, ART centers and maternity clinics that were involved in recruiting the study participants and their mothers. We acknowledge the Direction de la Recherche Clinique from the Toulouse University hospital for their contribution to the coordination of the investigation centers. We thank the IPSOS Company for conducting telephone interviews.

## Collaborators

Rémi Béranger, Helen Boyle, Aude Fléchon, and Elodie Belladame; Céline Chalas, Vanessa Gayet, Paul Pirtea, Pietro Santulli, Aurélie Vincent, Edouard Lecarpentier, François Goffinet, Dominique De Ziegler, Khaled Pocate, Virginie Barraud-Lange, Jean-Philippe Wolf, Emmanuel Dulioust, Nathalie Le Foll, Jacques Auger, Anne-Sophie Gille, Laurianne Kremer, Myriam Virlouvet, Lucile Ferreux, Guillemette Perier, Pauline Peretout, Diane Rivet, Véronique Drouineaud and Sandrine Rulle (Cochin Hospital, Paris); Rachel Levy, Nathalie Sermondade, Yassine Belaid, Marine Durand and Charlène Harbemont (Jean Verdier Hospital, Paris); Xavier Pollet-Villard, Vanina De Larouziere, Laurence Levy-Dutel, Florence Eustache and Isabelle Berthaut (Tenon Hospital, Paris); Jacqueline Saias-Magnan, Jeanne Perrin, Catherine Metzler-Guillemain, Carole Daoud-Deveze and Laurent Nasca (La Conception Hospital, Marseille); Myriam Daudin, Nathalie Moinard, François Isus, Célia Bettiol and Laure Connan (Paule de Viguier

Hospital, Toulouse); Laurent Janny, Valérie Bruhat, Florence Brugnon and Cyril Bouche (Estaing Hospital, Clermont-Ferrand); Laëtitia Ladureau-Fritsch, Cécile Greze, Françoise Schmitt, and Charles Pax (Obstetric medico-surgical center, Strasbourg); Clément Jimenez, Volcy Soula, Lucie Chansel and Olivier Delorme (Pellegrin maternity Hospital, Bordeaux); Sandrine Giscard d'Estaing, Pascale Dehee and Delphine Yalcinkaya (Femme-Mère-Enfant Hospital, Lyon); Céline Bouillon, Fabrice Guerif, Cynthia Frapsauce, Marie-Laure Couet, Véronique Ract, Olivia Gervereau, Elodie Poisson, Michel Lanoue, Anne Viallon and Catherine Guerin (Bretonneau Hospital, Tour); Bérengère Ducrocq, Julie Guitton, Marie Lefort and Valérie Mitchell (Calmette Hospital, Lille); Marie-Ange Clarotti, Ethel Serman, Amélie Ancelle, Catherine Muris, Corinne Fourmy-Chassel, Christine Denoual-Ziad, Claire De Vienne, Cécile Delesalle, Jean-Paul Bouiller and Antoine Clergeau (Caen Hospital, Caen); Alphée Bailly and Séverine Bey (Jean Minjoz Hospital, Besançon); Célia Ravel, Guilhem Jouve, Ségolène Veau, Laurent Vandenbroucke and Agnès Letremy (South Hospital, Rennes); Julie Barberet (Dijon Hospital, Dijon); Stéphanie Lattes, Emmanuelle Thibault, Fabienne Bernardin, Pierre Besnier and Clémence Martin (Archet Hospital, Nice); Catherine Diligent, Françoise Touati, Nicolas Monnin and Christel Hersant (Regional University maternity Hospital, Nancy); Vanessa Loup-Cabaniols, Alice Ferrieres, Anna Gala, Elodie Scalici, Lucile Sablayrolles, Tiffany Mullet, Audrey Chabert, Christelle Saintpeyre, Mélanie Caro, Michèle Nou and Marie Sicard (Arnaud de Villeneuve Hospital, Montpellier); Sylvianne Hennebicq, Pascale Hoffmann, Claire Thomas-Cadi, Nicole Quenard, Evylene Warembourg, Laure Villaret and Julien Bessonnat (Couple-Enfant Hospital, Grenoble); Marie-Claude Blocquaux, Frédérique Carre-Pigeon, Béatrice Delepine, Olivier Graesslin and Julie Burette (Maison Blanche Hospital, Reims).

## Contributors

AD, OP, LB, JS, BF and BC participated in the conception and design of the study. AD, OP, JS, LB, IK, AP, OB, PF, BF and BC participated in the acquisition of data. MG, ML, CP, AC, SA, AD, BD, AO, BF and BC participated in the analysis and interpretation of data. MG drafted the manuscript. ML, CP, AC, AD, AO, JS, BF and BC critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

## Conflicts of interests

The authors declare no conflicts of interests.
## Disclaimer

Where authors are identified as personnel of the Inter-national Agency for Research on Cancer/World Health Organization (IARC/WHO), they alone are responsible for the views expressed in this article, which do not necessarily represent the decisions, policy or views of the IARC/WHO.

## Ethics approval

The study received ethical approval from the French Ethics Committee (ref. no. A14-94), the French national agency for medicines and health products safety (ref. no. 140184B-12) and the IARC Ethics Committee (ref. no. 14-26) and was declared to the Commission nationale Informatique et Libertés (MR-001, ref. no. 2016-177).

## References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021 May;71(3):209-49. https://doi.org/10.3322/caac.21660.

2. Znaor A, Skakkebaek NE, Rajpert-De Meyts E, Laversanne M, Kuliš T, Gurney J et al. Testicular cancer incidence predictions in Europe 2010-2035: A rising burden despite population ageing. Int J Cancer 2020 Aug;147(3):820-8. https://doi.org/10.1002/ijc.32810.

3. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol 2016 Jul;70(1):93-105. https://doi.org/10.1016/j.eururo.2016.02.029.

4. Rajpert-De Meyts E. Testicular germ cell cancer: recent developments in biology and clinical management. Andrology 2019 Jul;7(4):391-3. https://doi.org/10.1111/andr.12675.

5. Znaor A, Skakkebaek NE, Rajpert-De Meyts E, Kuliš T, Laversanne M, Gurney J et al. Global patterns in testicular cancer incidence and mortality in 2020. Int J Cancer [Internet]. [cited 1 July 2022]. Available from: http://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.33999

6. van den Driesche S, Kilcoyne KR, Wagner I, Rebourcet D, Boyle A, Mitchell R et al. Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window. JCI Insight 2017 Mar;2(6):e91204. https://doi.org/10.1172/jci.insight.91204.

7. Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, Toppari J, Andersson AM, Eisenberg ML et al. Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility. Physiol Rev 2016 Jan;96(1):55-97. https://doi.org/10.1152/

physrev.00017.2015.

8. Bräuner EV, Lim YH, Koch T, Uldbjerg CS, Gregersen LS, Pedersen MK et al. Endocrine Disrupting Chemicals and Risk of Testicular Cancer: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab 2021 Nov;106(12):e4834-60. https://doi.org/10.1210/clinem/dgab523.

9. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001 May;16(5):972-8. https://doi.org/10.1093/humrep/16.5.972.

10. Rajpert-De Meyts E, McGlynn KA, Okamoto K, Jewett MA, Bokemeyer C. Testicular germ cell tumours. Lancet 2016 Apr;387(10029):1762-74. https://doi.org/10.1016/S0140-6736(15)00991-5.

11. Rouget F, Bihannic A, Cordier S, Multigner L, Meyer-Monath M, Mercier F et al. Petroleum and Chlorinated Solvents in Meconium and the Risk of Hypospadias: A Pilot Study. Front Pediatr 2021 Jun;9:640064. https://doi.org/10.3389/fped.2021.640064.

12. Baccarelli A, Pesatori AC, Bertazzi PA. Occupational and environmental agents as endocrine disruptors: experimental and human evidence. J Endocrinol Invest 2000 Dec;23(11):771-81. https://doi.org/10.1007/BF03345069.

13. Sharpe RM. Pathways of endocrine disruption during male sexual differentiation and masculinization. Best Pract Res Clin Endocrinol Metab 2006 Mar;20(1):91-110. https://doi.org/10.1016/j.beem.2005.09.005.

14. IARC monographs on the identification of carcinogenic hazards to humans. List of Classifications [Internet]. Lyon: International Agency for Research on Cancer; 2022 [cited 8 September 2022]. Report No.: Vol 1 to 130. Available from: https://monographs.iarc.who.int/list-of-classifications.

15. Schardein JL. Industrial solvents. In: Chemically induced birth defects. 3rd ed., rev.expanded. New York: Marcel Dekker; 2000.

16. Vulimiri SV, Pratt MM, Kulkarni S, Beedanagari S, Mahadevan B. Chapter 21 - Reproductive and Developmental Toxicity of Solvents and Gases. In: Gupta RC, éditeur. Reproductive and Developmental Toxicology (Second Edition) [Internet]. Academic Press; 2017 [cited 17 August 2022]. p. 379-96. Available from: https://www.sciencedirect.com/science/article/pii/B9780128042397000214.

17. Gilbert KM, Blossom SJ, Reisfeld B, Erickson SW, Vyas K, Maher M, et al. Trichloroethylene-induced alterations in DNA methylation were enriched in polycomb protein binding sites in effector/memory CD4+ T cells. Environ Epigenet. 2017 Jul;3(3):dvx013. https://doi.org/10.1093/eep/dvx013.

18. Stermer AR, Wilson SK, Klein D, Hall SJ, Boekelheide K. Trichloroethylene exposure alters dimethylated histone three lysine four in protein kinase A signaling pathway chromatin of rat sperm†. Biol Reprod 2019 Nov;101(5):875-7. https://doi.org/10.1093/biolre/ioz155.
19. Goodman S, Chappell G, Guyton KZ, Pogribny IP, Rusyn I. Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: an update of a systematic literature review. Mutat Res Rev Mutat Res 2022;789:108408. https://doi.org/10.1016/j.mrrev.2021.108408.

20. Rodprasert W, Toppari J, Virtanen HE. Endocrine Disrupting Chemicals and Reproductive Health in Boys and Men. Front Endocrinol (Lausanne) 2021 Oct;12:706532. https://doi.org/10.3389/fendo.2021.706532.

21. Le Cornet C, Fervers B, Pukkala E, Tynes T, Feychting M, Hansen J et al. Parental Occupational Exposure to Organic Solvents and Testicular Germ Cell Tumors in their Offspring: NORD-TEST Study. Environ Health Perspect 2017 Jun;125(6):067023. https://doi.org/10.1289/EHP864.

22. Olsson A, Togawa K, Schüz J, Le Cornet C, Fervers B, Oksbjerg Dalton S, et al. Parental occupational exposure to solvents and heavy metals and risk of developing testicular germ cell tumors in sons (NORD-TEST Denmark). Scand J Work Environ Health. 2018 Nov 1;44(6):658–69. https://doi.org/10.5271/sjweh.3732.

23. Kardaun JW, Hayes RB, Pottern LM, Brown LM, Hoover RN. Testicular cancer in young men and parental occupational exposure. Am J Ind Med 1991;20(2):219–27. https://doi.org/10.1002/ajim.4700200208.

24. Danjou AM, Pérol O, Coste A, Faure E, Béranger R, Boyle H et al.; TESTIS study group. Domestic use of pesticides during early periods of development and risk of testicular germ cell tumors in adulthood: a French nationwide case-control study. Environ Health 2021 Oct;20(1):111. https://doi.org/10.1186/s12940-021-00795-y.

25. Fritz AG, editor. International classification of diseases for oncology: ICDO. In: 3rd edition, First revision. Geneva: World Health Organization; 2013. Available from: https://apps.who.int/iris/bitstream/handle/10665/96612/9789241548_496_eng.pdf; jsess ionid= 2FD0A 44B59 341F29EDEF 8AC81 817F8 9D? sequelce=1.

26. International Labour Office. International standard classification of occupations. Rev. ed. Geneva: International Labour Office; 1969.

27. INSEE. Nomenclature d'activités et de produits. Edition novembre 1999 [Internet]. Journaux officiels, 2000 [cited 9 Novemver 2021]. Available from: https://www.decitre.fr/livres/nomenclature-d-activites-et-de-produits-9782110747914.html.

28. Févotte J, Dananché B, Delabre L, Ducamp S, Garras L, Houot M et al. Matgéné: a program to develop job-exposure matrices in the general population in France. Ann Occup Hyg 2011 Oct;55(8):865–78.

29. Batool A, Karimi N, Wu XN, Chen SR, Liu YX. Testicular germ cell tumor: a comprehensive review. Cell Mol Life Sci 2019 May;76(9):1713–27. https://doi.org/10.1007/s00018-019-03022-7.

30. Dieckmann KP, Pichlmeier U. Clinical epidemiology of testicular germ cell tumors. World J Urol 2004 Apr;22(1):2–14. https://doi.org/10.1007/s00345-004-0398-8.

31. Elzinga-Tinke JE, Dohle GR, Looijenga LH. Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis. Asian J Androl 2015;17(3):381–93. https://doi.org/10.4103/1008-682X.148079.

32. Gurney J, Shaw C, Stanley J, Signal V, Sarfati D. Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. BMC Cancer 2015 Nov;15(1):897. https://doi.org/10.1186/s12885-015-1905-6.

33. Biggs ML, Doody DR, Trabert B, Starr JR, Chen C, Schwartz SM. Consumption of alcoholic beverages in adolescence and adulthood and risk of testicular germ cell tumor. Int J Cancer 2016 Dec;139(11):2405–14. https://doi.org/10.1002/ijc.30368.

34. Hodges-Simeon CR, Gurven M, Cárdenas RA, Gaulin SJ. Voice change as a new measure of male pubertal timing: a study among Bolivian adolescents. Ann Hum Biol 2013 May;40(3):209–19. https://doi.org/10.3109/03014460.2012.759622.

35. Wang M, Spiegelman D, Kuchiba A, Lochhead P, Kim S, Chan AT et al. Statistical methods for studying disease subtype heterogeneity. Stat Med 2016 Feb;35(5):782–800. https://doi.org/10.1002/sim.6793.

36. Kaufman JS, MacLehose RF. Which of these things is not like the others? Cancer 2013 Dec;119(24):4216–22. https://doi.org/10.1002/cncr.28359.

37. Ahmadi S, Guth M, Coste A, Bouaoun L, Danjou A, Lefevre M et al.; The Testis Study Group. Paternal Occupational Exposure to Heavy Metals and Welding Fumes and Testicular Germ Cell Tumours in Sons in France. Cancers (Basel) 2022 Oct;14(19):4962. https://doi.org/10.3390/cancers14194962.

38. Pilorget C, Lagarrigue R, Houot M, Groupe Matgéné. Trends of occupational exposure to oxygenated, petroleum and chlorinated solvents in France between 1999 and 2013. Results from the Matgéné Program. Bull Epidémiologique Hebd - BEH. 2018;(12-13):234–40.

39. Carton M, Barul C, Menvielle G, Cyr D, Sanchez M, Pilorget C et al.; ICARE Study Group. Occupational exposure to solvents and risk of head and neck cancer in women: a population-based case-control study in France. BMJ Open 2017 Jan;7(1):e012833. https://doi.org/10.1136/bmjopen-2016-012833.

40. Barul C, Fayossé A, Carton M, Pilorget C, Woronoff AS, Stücker I et al.; ICARE study group. Occupational exposure to chlorinated solvents and risk of head and neck cancer in men: a population-based case-control study in France. Environ Health 2017 Jul;16(1):77. https://doi.org/10.1186/s12940-017-0286-5.

41. Spinder N, Bergman JE, van Tongeren M, Boezen HM, Kromhout H, de Walle HE. Maternal occupational exposure to endocrine-disrupting chemicals and urogenital anomalies in the offspring. Hum Reprod 2021 Dec;37(1):142–51. https://doi.org/10.1093/humrep/deab205.
42. Ohyama K, Satoh K, Sakamoto Y, Ogata A, Nagai F. Effects of prenatal exposure to styrene trimers on genital organs and hormones in male rats. Exp Biol Med (Maywood) 2007 Feb;232(2):301-8.

43. Tsukahara S, Nakajima D, Kuroda Y, Hojo R, Kageyama S, Fujimaki H. Effects of maternal toluene exposure on testosterone levels in fetal rats. Toxicol Lett 2009 Mar;185(2):79-84. https://doi.org/10.1016/j.toxlet.2008.12.001.

44. Toppari J, Virtanen HE, Main KM, Skakkebaek NE. Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): environmental connection. Birt Defects Res A Clin Mol Teratol. 2010;88(10):910-9.

45. Kalfa N, Paris F, Philibert P, Orsini M, Broussous S, Fauconnet-Servant N et al. Is Hypospadias Associated with Prenatal Exposure to Endocrine Disruptors? A French Collaborative Controlled Study of a Cohort of 300 Consecutive Children Without Genetic Defect. Eur Urol 2015 Dec;68(6):1023-30. https://doi.org/10.1016/j.eururo.2015.05.008.

46. Cordier S, Garlantézec R, Labat L, Rouget F, Monfort C, Bonvallot N et al. Exposure during pregnancy to glycol ethers and chlorinated solvents and the risk of congenital malformations. Epidemiology 2012 Nov;23(6):806-12. https://doi.org/10.1097/EDE.0b013e31826c2bd8.

47. Spinder N, Prins JR, Bergman JEH, Smidt N, Kromhout H, Boezen HM, et al. Congenital anomalies in the offspring of occupationally exposed mothers: a systematic review and meta-analysis of studies using expert assessment for occupational exposures. Hum Reprod Oxf Engl. 2019;34(5):903-19.

48. Garlantézec R, Monfort C, Rouget F, Cordier S. Maternal occupational exposure to solvents and congenital malformations: a prospective study in the general population. Occup Environ Med 2009 Jul;66(7):456-63. https://doi.org/10.1136/oem.2008.041772.

49. Haraux E, Braun K, Buisson P, Stéphan-Blanchard E, Devauchelle C, Ricard J et al. Maternal Exposure to Domestic Hair Cosmetics and Occupational Endocrine Disruptors Is Associated with a Higher Risk of Hypospadias in the Offspring. Int J Environ Res Public Health 2016 Dec;14(1):27. https://doi.org/10.3390/ijerph14010027.

50. McDonald JC, Lavoie J, Côté R, McDonald AD. Chemical exposures at work in early pregnancy and congenital defect: a case-referent study. Br J Ind Med 1987 Aug;44(8):527-33. https://doi.org/10.1136/oem.44.8.527.

51. Warembourg C, Botton J, Lelong N, Rouget F, Khoshnood B, Le Gléau F et al. Prenatal exposure to glycol ethers and cryptorchidism and hypospadias: a nested case-control study. Occup Environ Med 2018 Jan;75(1):59-65. https://doi.org/10.1136/oemed-2017-104391.

52. García AM, Fletcher T. Maternal occupation in the leather industry and selected congenital malformations. Occup Environ Med 1998 Apr;55(4):284-6. https://doi.org/10.1136/oem.55.4.284.

53. Bowen SE, Batis JC, Mohammadi MH, Hannigan JH. Abuse pattern of gestational toluene exposure and early postnatal development in rats. Neurotoxicol Teratol 2005;27(1):105-16. https://doi.org/10.1016/j.ntt.2004.09.007.

54. Béranger R, Blain J, Baudinet C, Faure E, Fléchon A, Boyle H et al. [Testicular germ cell tumours and early exposures to pesticides: the TESTEPERA pilot study]. Bull Cancer 2014 Mar;101(3):225-35. https://doi.org/10.1684/bdc.2014.1901.

55. Stang A, Schmidt-Pokrzywniak A, Lash TL, Lommatzsch PK, Taubert G, Bornfeld N et al. Mobile phone use and risk of uveal melanoma: results of the risk factors for uveal melanoma case-control study. J Natl Cancer Inst 2009 Jan;101(2):120-3. https://doi.org/10.1093/jnci/djn441.

56. Blair A, Stewart P, Lubin JH, Forastiere F. Methodological issues regarding confounding and exposure misclassification in epidemiological studies of occupational exposures. Am J Ind Med 2007 Mar;50(3):199-207. https://doi.org/10.1002/ajim.20281.

57. Cohen J. A Coefficient of Agreement for Nominal Scales. Educ Psychol Meas 1960 Apr;20(1):37-46. https://doi.org/10.1177/001316446002000104.

Received for publication: 30 March 2023