Table 1.
Epidemiologic studies examining environmental risk factors for liver cancer (2013–2018)
| Study | Location | Study design |
Time period |
Study population |
Exposure | Exposure assessment |
Outcome | Main findings |
|---|---|---|---|---|---|---|---|---|
| Aflatoxin | ||||||||
| Higher AFB1-DNA adduct levels (≥2.01 μmol/mol DNA) compared to lower levels (<1.00 μmol/mol DNA) was associated with increased risk for HCC (OR 6.43, 95% CI 5.28–7.83) adjusting for age, sex, ethnicity, HBV, HCV, dietary aflatoxin | ||||||||
| Main effect for XRCC4 gene is associated with HCC risk | ||||||||
| Long et al. (2013) [47] | China | Retrospective case-control, GxE | 2004–2010 | Hospital-based; n=2,045 healthy controls matched on age, sex, ethnicity, HBV, HCV | Aflatoxin | Serum AFB1-DNA adducts | HCC (n=1,499) confirmed via histology | Evidence of GxE interaction was observed for XRCC4 gene (multiplicative scale) (p int. not reported) |
| Higher AFB1-albumin levels (>2.98 ln fmol/mg) compared to lower levels (2.18 ln fmol/mg) were associated with increased risk for HCC (OR 6.52, 95% CI 5.46–7.79) adjusting for age, sex, ethnicity, HBV, HCV | ||||||||
| Main effects for XRCC1, XRCC3, XRCC7, XRCC4, XPC, and XPD genes are associated with HCC risk | ||||||||
| Yao et al. (2014) [63] | China | Retrospective case-control, GxE | 2004–2012 | Hospital-based; n=1,996 healthy controls matched on age, sex, ethnicity, HBV, HCV | Aflatoxin | Serum AFB1albumin adducts | HCC (n=1,486) confirmed via histology | GxE interactions were observed for each gene (multiplicative scale) (p int. <0.01) |
| Chu et al. (2017) [41] | Taiwan | Prospective nested casecontrol | 1991–2004 | Chronic HBV carriers; n=577 controls matched on age, sex, residence, date of blood collection | Aflatoxin | Serum AFB1-albumin adducts | HCC (n=262) confirmed via cancer registry and medical records (histology, imaging, or serum AFP ≥400 ng/mL) | Higher AFB1-albumin levels (≥21.5 fmol/mg) compared to undetectable levels were associated with increased risk for cirrhotic HCC (OR 5.47, 95% CI 2.20–13.63) and non-cirrhotic HCC (OR 5.39, 95% CI 1.11–26.18) adjusting for age, sex, alcohol consumption, serum ALT |
| Lai et al. (2014) [46] | China | Retrospective case-control | 1994–2013 | Sugar and papermaking factory workers; n=150 healthy controls who worked for same company | Aflatoxin | Self-reported airway exposure | HCC (n=68) confirmed via medical records | Occupational airborne aflatoxin dust exposure compared to no exposure was associated with increased risk for HCC (OR 5.24, 95% CI 2.77–9.88) adjusting for sex, alcohol consumption, smoking, HBV, family history of HCC |
| Air pollution | ||||||||
| Pan et al. (2016) [49] | Taiwan | Prospective cohort | 1991–2009 | Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer- Hepatitis B Virus (REVEAL-HBV) study (n=22,062) | PM2.5 | Geocoded address linked to GIS-based exposure model developed using kriging methods | HCC (n=464) confirmed via histology, imaging, AFP, and cancer registry | PM2.5 exposure was associated with increased risk for HCC on the Taiwan Penghu Islands (HR 1.22, 95% CI 1.02–1.47 per IQR 0.73 μg/m3 increase) adjusting for age, sex, alcohol consumption, smoking, ALT, HBV, HCV |
| Pedersen et al. (2017) [51] | Austria, Denmark, Italy | Prospective cohort | 1985–2012 | Four cohorts in European Study of Cohorts for Air Pollution Effects (ESCAPE) study (n=174,770) | Available for all cohorts: NO2 and NOx; available for Denmark and Austria only: PM10, PM2.5, PM2.5–10, PM absorbance (soot), traffic density | Baseline geocoded residential address linked to GIS-based exposure models developed using land use regression | Liver cancer (n=279) confirmed via cancer registry | Higher exposures to NO2 (HR 1.10, 95% CI 0.93–1.30 per 10 μg/m3), NOx (HR 1.12, 95% CI 0.96–1.30 per 20 μg/m3), PM2.5 (HR 1.34, 95% CI 0.76–2.35 per 5 μg/m3), PM2.5 absorbance (HR 1.21, 95% CI 0.68–2.15 per 10−5 μg/m3), PM10 (HR 1.44, 95% CI 0.83–2.52 per 10 μg/m3), PM2.510 (HR 1.34, 95% CI 0.65–2.78 per 5 μg/m3), traffic density (HR 1.04, 95% CI 0.89–1.20 per 5,000 vehicles/day) were associated with non-statistically significant positive associations with liver cancer risk adjusting for age, sex, year, smoking, alcohol consumption, occupational exposures, employment status, education, area-specific SES |
| Niu et al. (2016) [48] | China | Retrospective case-control | 2011–2014 | Residents of Xiamen; n=346 healthy controls frequency-matched on age, sex | Indoor air pollution, pesticides, environmental tobacco smoke (ETS) | Self-reported exposure | HCC (n=314) confirmed via histology | Pesticide exposure (OR 1.99, 95% CI 1.10–3.60), indoor air pollution (OR 2.46, 95% CI 1.47–4.14), ETS at home (OR 2.16, 95% CI 1.25–3.72), and ETS at work (OR 1.90, 95% CI 1.08–3.35) were associated with increased risk for HCC adjusting for education, HBV, liver disease history, alcohol consumption, fruit consumption, tea consumption |
| Polycyclic aromatic hydrocarbons | ||||||||
| Su et al. (2014) [54] | China | Retrospective case-control | 2007–2009 | Hospital-based; n=961 healthy controls matched on age, sex, ethnicity | B[a]P | BPDE-DNA adducts in blood | HCC (n=345) confirmed via histology | Higher BPDE-DNA adduct levels (>0.71 fmol/μg) compared to lower levels (<0.31 fmol/μg) were associated with increased risk for HCC (OR 7.44, 95% CI 5.29–10.45) adjusting for age, sex, education, HBV, alcohol consumption, smoking, contaminated water drinking |
| Higher BPDE-albumin adduct levels were observed among cases (median 1.79 fmol/mg, no IQR reported) compared to controls (median 1.51 fmol/mg) (p<0.01) | ||||||||
| Higher GSTP hypermethylation was observed among cases (53.3%) compared to controls (17.2%) (p<0.01) | ||||||||
| Tian et al. (2016) [55] | China | Retrospective case-control | Not reported | Hospital-based; n=99 healthy volunteers | B[a]P | Serum BPDE-albumin adducts | HCC (n=90) confirmed via clinical diagnosis or imaging | Evidence of interaction was observed between BPDE-albumin adducts and GSTP gene methylation (multiplicative scale) adjusting for age, sex, BMI, alcohol consumption, smoking, liver cirrhosis, HBV, HCV |
| Hogstedt et al. (2013) [43] | Sweden | Retrospective cohort | 1958–2006 | Male chimney sweep trade union members (n=6,320) | Chimney sweeping occupation | Occupational title from Swedish Municipal Workers’ Union | Liver cancer (n=18) confirmed via cancer registry | Chimney sweepers compared to the general Swedish male population had an increased risk for liver cancer (SIR 2.48, 95% CI 1.47–3.91) |
| Asbestos | ||||||||
| Boulanger et al. (2015) [38] | France | Retrospective cohort | 1978–2009 | Asbestos-exposed workers (n=2,024) | Asbestos | JEM | Liver cancer (n=18 males; n=1 female) confirmed via cancer registry | Asbestos-exposed workers compared to the general population in Calvados, France had an increased risk for liver cancer among males (SIR 1.85, 95% CI 1.09–2.92) but not females (SIR 2.55, 95% CI 0.03–14.2) |
| Wu et al. (2015) [61] | Taiwan | Retrospective cohort | 1985–2008 | Shipbreaking Workers Union; n=4,427 shipbreaking workers and population-based cohort (n=22,135) matched on age, sex, place of residence | Asbestos | Occupational title and Total Exposure Potential (TEP) Score estimated by panel of occupational experts | Liver cancer (n=349) confirmed via cancer registry | Shipbreaking workers compared to the population-based matched cohort had an increased risk for liver cancer (HR 1.50, 95% CI 1.16–1.94) adjusting for premium ratable wage per month |
| Wu et al. (2014) [62] | Taiwan | Retrospective cohort | 1985–2008 | Shipbreaking Workers Union (n= 4,155 males) | Asbestos | Occupational title and TEP Score estimated by panel of occupational experts | Liver cancer (n=72) confirmed via cancer registry | Liver cancer incidence was not elevated among shipbreaking workers compared to the general population in Taiwan (5-year latency period: SIR 1.05, 95% CI 0.82–1.33) |
| Organic solvents | ||||||||
| Workers exposed to TCE compared to the general population in Denmark, Finland, and Sweden had an increased risk for liver cancer (SIR 1.93, 95% CI 1.19–2.95) | ||||||||
| Hansen et al. (2013) [42] | Denmark, Finland, Sweden | Prospective cohort | 1958–2008 | Workers exposed to TCE (n=5,553) | TCE | Occupational title and urinary TCE metabolite (UTCA) | Liver cancer (n=15 males; n=5 females) confirmed via cancer registry | Higher U-TCA levels (>50 mg/L) compared to lower levels (<5 mg/L) were not associated with liver cancer risk (HR 0.63, 95% CI 0.22–1.68) adjusting for age, sex, country, calendar time |
| Higher TCE exposure (highest tertile median 0.77 unit-years) compared to the occupationally unexposed was not associated with liver cancer risk (HR 1.00, 95% CI 0.90–1.11) | ||||||||
| Vlaanderen et al. (2013) [57] | Denmark, Finland, Iceland, Norway, Sweden | Prospective nested casecontrol | 1960–2005 | Nordic Occupational Cancer Cohort (n>45 million); n=119,480 controls matched on age, sex, country | TCE and PER | JEM | Liver cancer (n=23,896) confirmed via cancer registry | PER exposure (highest tertile median 0.77 unit-years) compared to the occupationally unexposed was suggestively associated with liver cancer risk (HR 1.13, 95% CI 0.92–1.38) |
| Press et al. (2016) [52] | US | Cancer cluster | 1988–2011 | Greater Bay Area Cancer Registry catchment area in California | TCE | Residence in Middlefield-Ellis-Whisman (MEW) Superfund study area defined using Census tracts at diagnosis | Liver cancer (n≤17) confirmed via cancer registry | Liver cancer incidence was not elevated among residents in the MEW study area compared to the general population in Monterey, San Benito, Santa Clara, and Santa Cruz counties (1988–1995: SIR 0.8, 95% CI 0.1–2.8; 1996–2005: SIR 0.9, 95% CI 0.3–2.1; 2006–2011: SIR 0.6, 95% CI 0.1–1.6) |
| Pesticides | ||||||||
| Yi et al. (2014) [64] | Korea | Prospective cohort | 1992–2003 | Korean Veterans Health Study (n=180,251 males) | Agent Orange | Exposure Opportunity Index model (E4) using GIS-based proximity of military unit to area sprayed with Agent Orange | Liver cancer (n=1,956) confirmed via cancer registry | High Agent Orange exposure (log10 E4 ≥5) compared to no exposure (log10 E4 <0.1) was associated with increased risk for liver cancer (HR 1.16, 95% CI 1.01–1.34) adjusting for age at cohort entry, military rank |
| Yi et al. (2013) [65] | Korea | Cross-sectional | 2004 | Korean Veterans Health Study (n=114,562) | Agent Orange | Self-report and E4 using GIS-based proximity of military unit to area sprayed with Agent Orange | Liver cancer (n=2,242) from self-report | Self-reported high Agent Orange exposure (levels not reported) compared to low exposure was associated with increased risk for liver cancer (OR 1.74, 95% CI 1.54–1.96) adjusting for age, BMI, military rank, smoking, alcohol consumption, physical activity, education, household income, herbicide use |
| Silver et al. (2015) [53] | US | Prospective cohort | 1993–2011 | Agricultural Health Study (n=49,616) | Metolachlor | Lifetime days and intensity-weighted lifetime days (from self-report) | Liver cancer (n=40) confirmed via cancer registry | Higher lifetime days (>108.5 days; RR 3.99, 95% CI 1.43–11.1) and higher intensity-weighted lifetime days (>4,103 units; RR 3.18, 95% CI 1.10–9.22) of metolachlor use compared to unexposed individuals was associated with increased risk for liver cancer adjusting for age, smoking, alcohol consumption, applicator status, family history of cancer, state of residence, pesticides correlated with metolachlor (e.g., atrazine) |
| VoPham et al. (2015) [59] | US | Retrospective case-control | 2000–2009 | SEER-Medicare; n=14,991 controls frequency-matched on age, sex, race, duration of California residence, year | Pesticides (organochlorines, organophosphates, carbamates) | Residential ZIP Code linked with GIS-based exposure model | HCC (n=3,034) confirmed via cancer registry | Higher pesticide exposure (≥1.85 kg/km2) compared to lower exposure (≤0.07 kg/km2) was not associated with HCC risk (OR 0.95, 95% CI 0.82–1.09) adjusting for age, sex, race, duration of California residence, year, liver disease, diabetes, rare genetic disorders, SES |
| Kachuri et al. (2017) [40] | Canada | Retrospective cohort | 1991–2010 | Canadian Census Health and Environment Cohort (CanCHEC) (n=2,051,315) | Agricultural occupation | Self-reported occupation | Liver cancer (n=45 males; n=15 females) confirmed via cancer registry | There was an inverse association with liver cancer risk among male agricultural workers (HR 0.51, 95% CI 0.38–0.68) and no association among female agricultural workers (HR 0.90, 95% CI 0.51–1.57) compared to other employed individuals adjusting for age at cohort entry, province of residence, education |
| Perfluorooctanoic acid | ||||||||
| Vieira et al. (2013) [56] | US | Retrospective case-control | 1996–2005 | C8 Health Project (n=25,107 cancer cases) residents living near DuPont Teflonmanufacturing plant; other-cancer controls excluding kidney, pancreatic, testicular, and liver | PFOA | Residential water district and for Ohio residents only: predicted serum PFOA levels estimated using pharmacokinetic model and geocoded residential addresses at diagnosis linked with GIS-based exposure model | Liver cancer (n=179) confirmed via cancer registry | Residence in a contaminated water district (OR 1.1, 95% CI 0.7–1.6) and predicted serum PFOA levels (high 30.8–109.0 μg/L compared to unexposed: OR 1.0, 95% CI 0.3–3.1) was not associated with liver cancer risk adjusting for age, sex, race, diagnosis year, insurance provider, smoking |
| Barry et al. (2013) [39] | US | Retrospective cohort | 1952–2011 | Residents of MidOhio Valley as part of C8 Health Project and DuPont Worker Cohort (n=32,254) | PFOA | Predicted serum PFOA levels described above [56]; JEM was used for DuPont workers | Liver cancer (n=9) confirmed via cancer registry and medical records | PFOA exposure was not associated with liver cancer risk (HR 0.73, 95% CI 0.43–1.23) adjusting for age, sex, smoking, alcohol consumption, education, birth year |
| Iron foundry occupation | ||||||||
| Westberg et al. (2013) [60] | Sweden | Prospective cohort | 1958–2004 | Iron foundry workers (n=3,045 males) | Iron foundry occupation | Occupational title | Liver cancer (n=12) confirmed via cancer registry | Liver cancer incidence was not elevated among iron foundry workers compared to the general population in Sweden (SIR 1.59, 95% CI 0.82–2.78) |
| Radiation | ||||||||
| External gamma radiation dose was not associated with liver cancer risk (results not shown) | ||||||||
| Labutina et al. (2013) [45] | Russia | Prospective cohort | 1948–2004 | Mayak nuclear workers (n=22,373) | Radiation: nuclear | External gamma radiation from individual film badges and internal plutonium dose from urine samples and biokinetic models | Liver cancer (n=46) confirmed via cancer registry and medical records | Higher cumulative internal plutonium liver dose (≥4 Gy) compared to a lower lose (0 Gy) was associated with increased risk for liver cancer (RR 283.8, 95% CI 99.4–867.4) adjusting for age, sex, alcohol consumption |
| VoPham et al. (2017) [58] | US | Ecological | 2000–2014 | SEER | Radiation: ultraviolet (UV) | Residential county at diagnosis linked with GIS-based exposure model | HCC (n=56,245) confirmed via cancer registry | Higher ambient UV exposure was associated with decreased HCC risk (IRR 0.83, 95% CI 0.77–0.90 per IQR 32.4 mW/m2) adjusting for age at diagnosis, sex, race, year of diagnosis, SEER registry, and area-level alcohol consumption, smoking, obesity, diabetes, median household income, unemployment, urbanicity, PM2.5 |
| Brick kiln pollution | ||||||||
| Pasetto et al. (2013) [50] | Italy | Retrospective cohort | 1994–2007 | Residents in East quadrant, Ferrara, Italy (n=2,578) | Brick kiln pollution (e.g., vinyl chloride, chlorinated ethenes, ethanes) | Residence in polluted area | Liver cancer (n=8) confirmed via cancer registry | Liver cancer incidence was not elevated among residents of the East quadrant compared to the general population in Ferrara, Italy (SIR 1.35, 90% CI 0.672.43) |
| Parental occupational exposures to chemicals | ||||||||
| Janitz et al. (2017) [44] | US | Retrospective case-control | 2000–2008 | HOPE study; n=387 birth certificate controls frequency-matched on sex, region of birth, birth weight | Parental occupational exposures (e.g., plastics, paints, diesel) | Self-reported parental occupational exposures and JEM | Hepatoblastoma (n=383) prior to 15 years of age confirmed via histology | Likely paternal exposure to paints compared to unlikely exposure was associated with increased risk for hepatoblastoma (OR 1.71, 95% CI 1.04–2.81) adjusting for year of birth, sex, region of birth, birth weight, household income |
Abbreviations: AFB1, aflatoxin B1; AFP, alpha-febottomrotein; ALT, alanine aminotransferase; B[a]P, benzo[a]pyrene; BMI, body mass index; BPDE, benzo[a]pyrene diolepoxide; CI, confidence interval; GIS, geographic information system; GxE, gene-environment interaction; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; int, interaction; IRR, incidence rate ratio; JEM, job-exposure matrix; NO2, nitrogen dioxide; NOx, nitrogen oxides; OR, odds ratio; PER, perchloroethylene; PFOA, perfluorooctanoic acid; PM10, particulate matter <10 microns; PM2.5, particulate matter <2.5 microns; PM2.5–10, particulate matter 2.5–10 microns; RR, relative risk; SEER, Surveillance, Epidemiology, and End Results; SES, socioeconomic status; SIR, standardized incidence ratio; TCE, trichloroethylene; U-TCA, urinary trichloroacetate.