The authors have declared that no competing interests exist.
Performed the experiments: RB CLC. Analyzed the data: RB CLC JS BF. Contributed reagents/materials/analysis tools: RB CLC. Wrote the manuscript: RB CLC. Arbitration during the appraisal of the studies methodology: JS BF. Article revision and supervision: JS BF.
Testicular germ cell tumours (TGCT) are the most common cancers in men aged between 15 and 44 years and the incidence has increased steeply over the past 30 years. The rapid increase in the incidence, the spatial variation and the evolution of incidence in migrants suggest that environmental risk factors play a role in TGCT aetiology. The purpose of our review is to summarise the current state of knowledge on occupational and environmental factors thought to be associated with TGCT.
A systematic literature search of PubMed. All selected articles were quality appraised by two independent researchers using the ‘Newcastle-Ottawa Quality Assessment Scale’.
After exclusion of duplicate reports, 72 relevant articles were selected; 65 assessed exposure in adulthood, 7 assessed parental exposures and 2 assessed both. Associations with occupation was reported for agricultural workers, construction workers, firemen, policemen, military personnel, as well as workers in paper, plastic or metal industries. Electromagnetic fields, PCBs and pesticides were also suggested. However, results were inconsistent and studies showing positive associations tended to had lower quality ranking using the assessment scale (p=0.02).
Current evidence does not allow concluding on existence of any clear association between TGCT and adulthood occupational or environmental exposure. The limitations of the studies may partly explain the inconsistencies observed. The lack of association with adulthood exposure is in line with current hypotheses supporting the prenatal origin of TGCT. Future research should focus on prenatal or early life exposure, as well as combined effect of prenatal and later life exposure. National and international collaborative studies should allow for more adequately powered epidemiological studies. More sophisticated methods for assessing exposure as well as evaluating gene–environment interactions will be necessary to establish clear conclusion.
Testicular cancer is the most common cancer in men aged 15 - 44 years. Incidence rates have increased steeply in developed countries, with the highest incidence rates in Europe and in the USA [
The possibility of an early life induction of TGCT is supported by the young age of cases, by the association with congenital abnormalities of the testis (cryptorchidism and hypospadias) and results from numerous experimental studies suggesting that seminomas and non-seminomas could have a common precursor – the carcinoma in situ cell [
So far, no animal models expressing TGCT type of the young adult have been found, although cases of spermatocytic seminomas have been reported. Our knowledge about TGCT risk factors is therefore based on epidemiological research [
We followed the PRISMA statement for systematic reviews and meta-analysis for literature search, study selection, data extraction and synthesis (
The following search algorithm was used: (
Possibly relevant articles were selected through assessment of titles and abstract. Only original articles focusing on humans and written in English or French were kept in the review. Given the high survival rate of TGCT (more than 95% for localised tumours, 80% if metastatic), mortality studies lead to a selection of the population and were considered inappropriate for the purpose of our review [
For each publication, we abstracted the following information: first author’s name; year of publication; journal; country of the studied population; study design; population size and characteristics (source, age structure, follow up, composition); approaches for exposure and outcome assessment; variable for stratification, groups matching or adjustment; and main results. When two or more publications reported data from the same study populations, we kept only the most detailed and/or the most recent publication. Publications with partially overlapping populations were retained when they provided complementary information.
Two researchers (RB and CLC) independently assessed the methodological quality of each study using the “Newcastle-Ottawa Quality Assessment Scale” (NOS). (
Statistical analyses were performed using SAS software package (version 9.3; SAS Institute Inc., Cary, NC, USA). The Newcastle-Ottawa Quality Assessment Scale (NOS) quality scores were compared using the Wilcoxon test.
We identified 265 articles published between 1st January 1990 and 31st December 2012. We excluded 189 reviews, editorials and animal studies, 2 articles published in a language other than English or French, 23 publications that were out of scope, and 6 mortality studies. By analysing the reference lists of the 45 remaining articles and existing reviews on TGCT [
14 of the 80 selected publications reported data from the same study populations [
The characteristics of the 72 selected articles and their NOS quality scores are summarized in
Alavanja 2005 [ |
Cohortb | 57311 exposed / 27 cases | No detailsc | Questionnaire | 1993 - 2002 | USA | 3 | 2 | 2 | |
Andersson 2003 [ |
Cohortb,e | 65637 exposed / 49 cases | 31 - 84 | Registry | 1971 - 1990 | Sweden | 3 | 2 | 3 | |
Andersson 2012 [ |
Cohortb | 18113 workers / 26 cases | No details | Registry | 1958 - 2001 | Sweden | 2 | 1 | 3 | |
Band 2001 [ |
Cohortb | 28278 exposed / 23 cases | No details | Registry | 1950 - 1992 | Canada | 3 | 1 | 3 | |
Bates 2001 [ |
Cohortb | 3668 exposed / 11 cases | No details | Registry | 1977 - 1995 | New Zealand | 3 | 1 | 2 | |
Dement 2003 [ |
Cohortb | 13354 exposed / 19 cases | No details | Registry | 1979 - 2000 | New Jersey | 3 | 1 | 3 | |
Dich 1996 [ |
Cohortb | 20025 exposed / 18 cases | No details | Registry | 1965 - 1991 | Sweden | 3 | 1 | 3 | |
Finkelstein 1998 [ |
Cohortb | 20601 exposed / 23 cases | No details | Registry | 1964 - 1995 | Ontario | 1 | 1 | 2 | |
Fleming 1999 [ |
Cohortb | 30155 exposed / 23 cases | 18 - 89 | Registry | 1981 - 1993 | Florida | 3 | 1 | 3 | |
Floderus 1999 [ |
Cohortb | 1596959 men / 607 cases | 20 - 70 | Registry | 1971 - 1984 | Sweden | 2 | 0 | 3 | |
Frost 2011 [ |
Cohortb | 62960 exposed / 102 cases | No details | Registry | 1987 - 2004 | UK | 2 | 1 | 2 | |
Giles 1993 [ |
Cohortb | 2865 exposed / 2 cases | 15 / +d | Registry | 1980 - 1989 | Melbourne | 3 | 1 | 3 | |
Grayson 1996 [ |
Cohortb | 227203 exposed / 59 cases | No details | Registry | 1975 - 1989 | USA | 2 | 1 | 2 | |
Guo 2004 [ |
Cohortb,e | 667121 workers / 387 cases | 25 / +d | Registry | 1971 - 1995 | Finland | 3 | 2 | 3 | |
Guo 2005 [ |
Cohortb,e | 667121 workers / 387 cases | 25 / +d | Registry | 1971 - 1995 | Finland | 3 | 2 | 3 | |
Gustavsson 2004 [ |
Cohortb | 8750 exposed / 8 cases | No details | Registry | 1989 - 1999 | Sweden | 3 | 1 | 2 | |
Hansen 1996 [ |
Cohortb | 10059 exposed / 4 cases | No details | Questionnaire | 1968 - 1986 | Denmark | 1 | 1 | 3 | |
Helmfrid 2012 [ |
Cohortb | 641 cancers / 7 testis cancer | No details | Registry | 1960 - 2003 | Sweden | 3 | 1 | 3 | |
Hobbesland 1999 [ |
Cohortb | 5918 exposed / 13 cases | No details | Registry | 1953 - 1991 | Norway | 1 | 1 | 3 | |
Kelleher 1998 [ |
Cohortb | About 150000 men / 47 cases | 16 - 65 | Registry | 1980 - 1990 | Ireland | 3 | 1 | 1 | |
Kristensen 1996 [ |
Cohortb | 166291 exposed / 158 cases | 0 - 39 | Registry | 1965 - 1991 | Norway | 3 | 2 | 2 | |
Kristensen 2000 [ |
Cohortb | 47285 men and 36787 son exposed / 70 and 63 cases | 0 - 70 | Registry | 1967 - 1995 | Norway | 2 | 2 | 2 | |
Langard 2000 [ |
Cohortb | 428 exposed / 1 cases | No details | Registry | 1953 - 1993 | Norway | 3 | 1 | 3 | |
Ma 2006 [ |
Cohortb | 34796 exposed / 54 cases | 18 / +d | Registry | 1981 - 1999 | Florida | 2 | 1 | 3 | |
Milanov 1999 [ |
Cohort | 52963 person-year / 6 cases | No details | Registry | 1964 - 1994 | Bulgaria | 1 | 1 | 3 | |
Rix 1998 [ |
Cohortb | 11130 men / 29 cases | No details | Registry | 1943 - 1996 | Denmark | 3 | 1 | 3 | |
Rodval 2003 [ |
Cohortb | About 14000 exposed / 2 cases | 0 - 36 | Registry | 1958 - 1994 | Sweden | 3 | 1 | 2 | |
Pollan 2001 [ |
Cohortb | 1779646 men / 1189 cases | 24 - 79 | Registry | 1970 - 1989 | Sweden | 3 | 2 | 3 | |
Sigurdson 2003 [ |
Cohortb,f | 20781 exposed / 16 cases | No details | Questionnaire | 1983 - 1998 | USA | 2 | 2 | 3 | |
Sonneveld 1999 [ |
Cohortb | 7473676 men / 2591 cases | No limits | Registry | 1989 - 1995 | Netherland | 3 | 1 | 2 | |
Sulem 2003 [ |
Cohortb | 3874 exposed / 0 cases | 18 / +d | Registry | 1968 - 1998 | Iceland | 2 | 1 | 3 | |
Tynes 1992 [ |
Cohortb | 37945 exposed / 41 cases | 20 / +d | Registry | 1961 - 1985 | Norway | 3 | 1 | 3 | |
Yamane 2006 [ |
Cohortb,f | From 281604 to 489590 exposed / 354 cases | 18 - 51 | Registry | 1989 - 2002 | USA | 2 | 2 | 3 | |
Zandjani 1994 [ |
Cohortb | 1756 exposed / 7 cases | No details | Registry | 1953 - 1992 | Norway | 3 | 1 | 3 | |
Bates 2007 [ |
Case-controlb,e,f | 70 cases / 804107 controls | 21 - 80 | Registry | 1988 - 2003 | California | 2 | 2 | 2 | |
Baumgardt-Elms 2002 [ |
Case-control | 269 cases / 797 controls | 15 - 69 | Interview | 1995 - 1997 | Germany | 3 | 2 | 2 | |
Baumgardt-Elms 2005 [ |
Case-control | 145 cases / 196 controls | 15 - 69 | GIS | 1995 - 1997 | Germany | 3 | 1 | 3 | |
Biggs 2008 [ |
Case-control | 272 cases / 726 controls | 18 - 44 | Biol. sample | 1999 - 2008 | Washington | 4 | 1 | 2 | |
Bullman 1994 [ |
Case-controlb | 97 cases / 311 controls | 28 / + d | Registry | 1982 - 1991 | USA | 1 | 0 | 2 | |
Chia 2010 [ |
Case-controlf | 577 cases / 707 controls | 18 - 45 | Biol. sample | 1988 - 2003 | USA | 4 | 2 | 3 | |
Foley 1995 [ |
Case-controlb | 148 cases | 17 - 49 | Registry | 1984 - 1989 | UK | 3 | 1 | 2 | |
Giannandrea 2011 [ |
Case-controle | 50 cases / 48 controls | 18 - 45 | Interview + biol. sample | 2006 - 2008 | Italia | 2 | 2 | 2 | |
Hansen 1999 [ |
Case-controlb | 3745 cases / 7490 controls | 16 - 75 | Registry | 1970 - 1989 | Denmark | 3 | 2 | 2 | |
Hardell 2006 [ |
Case-control | 61 cases / 58 controls | 18 - 45 | Biol. Sample | 1997 - 2000 | Sweden | 3 | 1 | 2 | |
Hardell 2004 [ |
Case-control | 791 paired cases and controls | 20 - 75 | Questionnaire | 1993 - 1997 | Sweden | 3 | 1 | 2 | |
Hayes 1990 [ |
Case-control | 266 cases / 271 controls | 18 - 42 | Interview | 1976 - 1981 | Washington | 2 | 2 | 2 | |
Kardaun 1991 [ |
Case-control | 308 cases / 288 controls, 225 and 212 mothers, respectively | 18 - 42 | Interview | 1976 - 1981 | Washington | 2 | 1 | 2 | |
Knoke 1998 [ |
Case-controlb,f | 134 cases / 371 controls | 17 - 65 | Registry | 1990 - 1996 | USA | 2 | 2 | 1 | |
Knight 1996 [ |
Case-controle | 495 cases / 974 controls | 16 - 59 | Questionnaire | 1987 - 1989 | Ontario | 3 | 2 | 1 | |
Knight 1997 [ |
Case-controle | 495 cases / 974 controls, 343 and 524 mothers, respectively | 16 - 59 | Questionnaire | 1987 - 1989 | Ontario | 3 | 1 | 1 | |
Marshall 1990 [ |
Case-control | 18 cases / 259 controls | 20 - 54 | Registry | 1974 - 1986 | New York | 2 | 1 | 1 | |
McGlynn 2009 [ |
Case-controlf | 736 cases / 913 controls | 18 - 45 | Biol. Sample | 1988 - 2003 | USA | 4 | 2 | 3 | |
McGlynn 2008 [ |
Case-controlf | 739 cases / 915 controls | 18 - 45 | Biol. Sample | 1988 - 2003 | USA | 4 | 2 | 3 | |
Moller 1997 [ |
Case-controlf,g | 296 cases / 287 controls | 16 - 42 | Questionnaire | 1986 - 1988 | Denmark | 3 | 2 | 1 | |
Nori 2006 [ |
Case-controle,f,g | 103 cases / 215 controls ; 63 and 123 mothers, respectively | 18 / +d | Interview | 1996 - 2003 | Italia | 2 | 2 | 1 | |
Ohlson 2000 [ |
Case-control | 148 cases / 314 controls | 30 - 75 | Questionnaire | 1989 - 1992 | Sweden | 3 | 1 | 2 | |
Rhomberg 1995 [ |
Case-control | 165 cases / 187 controls | 18 / +d | Interview | 1971 - 1978 | Germany | 3 | 0 | 0 | |
Ryder 1997 [ |
Case-controlb | 110 cases / 440 controls | 15 - 59 | Registry | 1976 - 1994 | UK | 4 | 1 | 3 | |
Stang 2003 [ |
Case-controlg | 269 cases / 797 controls | 15 - 69 | Interview | 1995 - 1997 | Germany | 3 | 2 | 1 | |
Stenlund 1997 [ |
Case-controlb | 134 cases / 1121 controls | 25 -70 | Registry | 1985 - 1987 | Sweden | 3 | 2 | 2 | |
Swerdlow 1991 [ |
Case-control | 259 cases / 489 controls | 10 / +d | Interview | 1977 - 1981 | UK | 1 | 1 | 1 | |
Tarone 1991 [ |
Case-controlg | 156 cases / 130 controls | 18 - 42 | Interview | 1976 - 1981 | Washington | 2 | 2 | 2 | |
Van der Eeden 1991 [ |
Case-controlf,g | 390 cases / 729 controls | 20 - 69 | Interview | 1977 - 1984 | Washington | 4 | 2 | 2 | |
Walchaert 2007 [ |
Case-controlg | 229 cases / 800 controls | 20 - 45 | Questionnaire | 2002 - 2005 | France | 2 | 1 | 1 | |
Yamane 2003 [ |
Case-controlb,f | 74 cases / 296 controls | 23 - 55 | Registry | 1989 - 1999 | USA | 2 | 2 | 3 | |
Zhang 1995 [ |
Case-controle,g | 250 cases and control | 15 / +d | Interview | 1977 - 1980 | New York | 3 | 2 | 1 | |
Behrens 2012 [ |
Nested case-control | 169 cases / 988 controls | No details | Interview | 1989 - 2006 | Germany | 4 | 2 | 2 | |
Cohn 2010 [ |
Nested case-controlf | 15 cases / 45 controls | 17 - 37 | Biol. sample | 1957 - 2000 | California | 3 | 2 | 3 | |
Purdue 2009 [ |
Nested case-control | 49 cases / 51 controls | No details | Biol. Sample | 1972 - 1999 | Norway | 3 | 1 | 3 | |
Koifman 2002 [ |
Ecological study | No details | 0 - 49 | N/A | 1999 - 2000 | Brazil | N/A | N/A | N/A | |
Mills 1998 [ |
Ecological studyf | No details | No details | N/A | 1988 - 1992 | California | N/A | N/A | N/A | |
Davis 1993 [100] | Cluster | 6 case / 340 controls | 27 - 47 | Interview | 1979 - 1991 | Washington | 1 | 0 | 3 |
Abbreviations: sel. = Selection; Com. = comparability; out. = outcome. Biol. Sample = biological sample. N/A = not applicable; GIS = Geographic Information System.
“Questionnaire” means self-administered questionnaire, in contrast to “Interview”. All studies were stratified or adjusted on age but four [
a
b Registry-based studies.
c
d
e Adjustment on socioeconomic status
f
g Adjustment on (or exclusion of) cryptorchidism
Of the 72 publications included in this review, 65 investigated exposure of the index subject (
Agriculture, forestry | [ |
Paternal | Childhood | OR = 0.4 [0.1-0.9] | - | - |
Agriculture, forestry | [ |
Paternal | Prenatal | OR = 0.9 [0.4-1.8] | OR = 0.7 [0.1-2.7] | - |
Employed in agriculture | [ |
Maternal | Prenatal | OR = 1.23 [0.56-2.69] | OR = 1.34 [0.50-3.57] | OR = 1.32 [0.51-3.40] |
Employed in agriculture with animals | [ |
Paternal | Prenatal | OR = 0.64 [0.42-0.99] | OR = 0.61 [0.34-1.08] | OR = 0.68 [0.40-1.16] |
Engaged in agriculture activity | [ |
Parental | - | SIR = 124 [1.1-152] | - | - |
Engaged in agriculture activity | [ |
Parental | - | OR = 2.44 [1.66-3.56] | OR = 1.70 [0.81-3.57] | OR = 4.21 [2.13-8.32] |
Application of ≥100kg nitrogen /hectare | [ |
Parental | - | RR = 1.84 [1.22-2.76] | - | - |
Farm worker | [ |
Parental | Prenatal | p = 0.35 | ||
[ |
Parental | - | OR = 1.19 [0.13-4.28] | - | - | |
[ |
Parental | Prenatal | p = 0.63 | |||
Metalworkers | [ |
Paternal | Year before conception | OR = 3.28 [1.03 - 10.52] | - | - |
Metal products | [ |
Paternal | Year before conception | OR = 5.77 [1.53 - 21.77] | - | - |
Wood processors | [ |
Paternal | Year before conception | OR = 10.46 [1.20 - 91.14] | - | - |
[ |
Paternal | Childhood | OR = 3.9 [0.4-190.7] | OR = 5.1 [0.1-405.8] | - | |
- | [ |
Paternal | Prenatal | OR = 1.4 [0.2-17.3] | OR = 5.2 [0.4-73.6] | - |
- | [ |
Maternal | Prenatal | OR = 1.4 [0.4-5.0] | OR = 4.6 [1.1-19.1] | - |
- | [ |
Maternal | Before conception | OR = 0.54 [0.26 - 1.13] | - | - |
Food and beverage services industry | [ |
Paternal | Year before conception | OR = 4.36 [1.50 - 12.63] | - | - |
Food products | [ |
Paternal | Year before conception | OR = 2.79 [1.34 - 5.79] | - | - |
HCB | [ |
Maternala | At son’s diagnostic | OR = 4.4 [1.7–12] | - | - |
p,p’- DDT | [ |
Maternala | 1-3 days after delivery | OR = 0.70 [0.26-1.64] | - | |
o,p-DDT | [ |
Maternala | 1-3 days after delivery | OR = 0.77 [0.37-1.33] | - | - |
p,p’- DDE | [ |
Maternala | 1-3days after delivery | OR = 0.19 [0.04-0.62] | - | |
[ |
Maternala | At son’s diagnostic | OR = 1.3 [0.5–3.0] | - | - | |
Total chlordanes | [ |
Maternala | At son’s diagnostic | OR = 1.9 [0.7–5.0] | - | - |
Ratio p,p′-DDT/ p,p′-DDE | [ |
Maternala | 1-3days after delivery | OR = 3.56 [1.34-11.88] | - | |
Sum of PCBs | [ |
Maternala | At son’s diagnostic | OR = 3.8 [1.4–10] | OR = 3.1 [0.7–14] | OR = 4.3 [1.3–14] |
Estrogenic PCBs | [ |
Maternala | At son’s diagnostic | OR = 2.4 [0.95–6.0] | OR = 2.3 [0.6–8.9] | OR = 2.4 [0.8–6.8] |
Enzyme-inducing PCBs | [ |
Maternala | At son’s diagnostic | OR = 2.6 [1.03–6.5] | OR = 1.4 [0.4–5.3] | OR = 3.3 [1.1–9.7] |
Toxic equivalents (TEQ) | [ |
Maternala | At son’s diagnostic | OR = 3.3 [1.3–8.4] | OR = 3.5 [0.8–15] | OR = 3.3 [1.1–9.8] |
Sum of PBDE | [ |
Maternala | At son’s diagnostic | OR = 2.5 [1.02–6.0] | OR = 1.8 [0.5–6.5] | OR = 2.9 [1.04–8.2] |
[ |
Maternal | Prenatal | OR = 0.97 [0.23-4.07] | OR = 0.99 [0.16-6.07] | OR = 1.13 [0.19-6.86] | |
- | [ |
Paternal | Prenatal | OR = 1.33 [0.65-2.70] | OR = 1.24 [0.51-3.01] | OR = 1.42 [0.55-3.67] |
Residency urban/rural | [ |
Parental | During fetal life | OR = 1.35 [0.49-3.71] | OR = 1.54 [0.44-5.35] | OR = 1.29 [0.34-4.94] |
Social class (professionals vs. manual workers) | [ |
Paternal | At birth | OR = 1.48 [0.69-3.16] | - | - |
Abbreviations: HCB = Hexachlorobenzene, DDT = dichlorodiphenyltrichloroethane; DDE = Dichlorodiphenyldichloroethylene; PCB = polychlorinated biphenyl; PBDE =
a Exposure assessment by biological samples, in contrast to questionnaire/registry-based exposure assessment.
Two of the six studies on workers in plastic-related industries [
Five of the eight identified studies found significant associations with occupations in metal industries [
Seven articles investigated the association between working in the paper industry and TGCT [
An excess risk for TGCT was reported for several white-collar or professional occupations [
Eight studies investigated TGCT risk in construction and related occupations [
Five studies investigated TGCT risk in firemen [
Four studies investigated the risk in policemen [
Ten studies investigated TGCT risk in military and related occupations [
Overall, 15 studies investigated TGCT risk among agricultural workers, pesticides applicators or in occupations associated with pesticides exposures [
Five studies investigated magnetic and electric field exposures [
Eight studies investigated environmental exposure to organochlorines using blood samples [
One study suggested an increased risk for self-reported domestic insecticides use, but blood analyses failed to confirm this association [
It has been suggested that living in rural areas could be a surrogate for environmental exposure to pesticides [
Leather workers exposed to dimethylformamide (DMF) have been suspected to be at risk for TGCT based on the report of a small cluster in a New York plant [
Among the 9 studies investigating occupational and environmental parental exposure, agriculture-related parental exposure has been the most studied (5 studies). No excess risk for TGCT was reported among the sons of farmers or pesticide applicators [
A positive association was found for hexachlorobenzene, PCBs, PBDE and chlordanes in maternal serum and the risk of TGCC among the women’s sons [
Other self-reported occupations in parents were reported to be associated with TGCT (e.g. healthcare professions, wood and metal-workers, working in food production) but these studies performed numerous statistical tests, had small subgroups and were exposed to possible selection bias [
To our knowledge, this is the most comprehensive review of studies published in the past two decades on environmental and occupational exposures possibly associated with TGCT, for prenatal childhood and adulthood periods. In contrast to previous reviews on TGCT [
For the first time, this review include systematic quality appraisal for all studies. Studies reporting a positive association with TGCT had significantly lower quality scores than studies showing no association. Also, some of the inconsistent results may be explained by methodological limitations or study design, as developed below.
The low incidence of TGCT constitutes a barrier to conducting adequately powered epidemiological studies. None of the publications provided information on the minimum detectable risk based on the study population size. Lack of power could partly explain the inconsistent results reported. Furthermore, some positive associations may be due to chance, when multiple testing is performed without correction (e.g. more than 300 tests were performed by Pollan et al.) [
Large variations in TGCT risk have been reported for different ethnicities [
Heterogeneity of occupations and definitions of exposures may further explain inconsistencies across studies, and did not allow us to perform a pooled analysis. Moreover, while for some occupations the job title can be used as surrogate exposure variable (e.g., welders and welding fumes), the reliability of exposure assessment is limited for others (e.g., farmers and pesticides exposure). Misclassification of pesticide exposures could have resulted in weaker association since some farmers should not have been classified as exposed, whereas other occupations associated with pesticides exposure (e.g., carpenters, sawmill workers) in the general population were classified as not being exposed [
Self-reported exposures can provide detailed information, but potential recall bias may lead to over-estimation in comparison to JEM or independent assessment [
TGCT occurs mainly in young adults, a population with lower cumulative occupational exposure and shorter time-lag between occupational exposure and cancer diagnosis. Thus, occupational exposure of the index subject may not be relevant. While uncertainties remain concerning the exact window of exposure associated with occurrence of TGCT, events during the ‘testicle programming period’ has been proposed to originate in cryptochidism and hypospadias in rats [
In contrast, environmental or occupational exposure during adulthood might be associated with spermatocytic seminomas that occurring mainly after 50 years: the cumulative exposure is higher, particularly for occupational exposure, the latency periods are long enough, and the related precursor cells appeared only after puberty and during adulthood [
The NOS quality assessment scale has been criticized for potential inter-operator variability [
While the majority of publications in our review were identified through PubMed, additional studies were identified through the reference lists of relevant articles and recent reviews. The latter mainly focused on multiple cancer sites where TGCT was not the primary cancer of interest, and thus, not apparent in keywords of abstracts. However, we can be confident that the combination of these two methods has enabled us to identify all the pertinent studies on environmental or occupational risk factors for TGCT and the vast majority of studies exploring a wider range of cancers including TGCT.
The study limitations discussed above makes it difficult to detect or to interpret associations. Future studies on TGCT should consider intra-uterine and parental exposure, since it is plausible that exposure during early development leads to TGCT and this has been insufficiently explored. A combined effect of prenatal and postnatal, adolescent or adulthood exposure has also been suggested [
A national case-control is currently conducted in France (TESTIS project) to explore the impact of life-time pesticide exposure on TGCT risk using combined methods including job exposure assessment by experts, geographical information system technology and polymorphism analyses.
Despite of the numerous factors investigated in many studies, the reasons for the rapid increase of TGCT incidence remain unclear. Occupational exposures during adulthood are unlikely to be involved in TGCT aetiology because of the young age of patients. The lack of convincing association with adulthood exposure is in line with the current hypothesis of prenatal and/or early-life origin of TGCT. The limitations of the studies may partly explain the inconsistencies observed. Unfortunately, we were unable to perform a quantitative meta-analysis because of the heterogeneity in design, exposure assessment and population characteristics for the studies we identified. However, many risk factors investigated in current studies remain of interest, in particular pesticides, and recent studies highlight the potential role of gene-environment interactions. Further large studies are needed, and future research should focus on prenatal or early life exposure, as well as combined effect of prenatal and adolescent or adulthood exposure.
(DOCX)
(DOC)
Thanks to Niels Erik Skakkebaek of Rigshospitalet (Copenhagen, DENMARK), to Aude Flechon and Helen Boyle of the Centre Léon Bérard (Lyon, France), and to Helen Bailey of the International Agency for Research on Cancer (Lyon, France) for their helpful advice and assistance in the preparation of our manuscript. In addition, we would like to acknowledge editorial assistance from Margaret Haugh (MediCom Consult).