Environmental Pollutants, Occupational Exposures, and Liver Disease

Abstract

Environmental pollutants significantly impact liver disease development, progression, and outcomes. This review examines the complex relationship between environmental exposures and liver pathology, from malignant conditions like hepatocellular carcinoma to steatotic and cholestatic liver diseases. Key environmental factors include air pollutants, volatile organic compounds, persistent organic pollutants, heavy metals, and per- and polyfluoroalkyl substances. These compounds can act through multiple mechanisms, including endocrine disruption, metabolic perturbation, oxidative stress, and direct hepatotoxicity. The impact of these exposures is often modified by factors such as sex, diet, and genetic predisposition. Recent research has revealed that even low-level exposures to certain chemicals can significantly affect liver health, particularly when combined with other risk factors. The emergence of exposomics as a research tool promises to enhance our understanding of how environmental factors influence liver disease. Importantly, exposure effects can vary by demographic and socioeconomic factors, highlighting environmental justice concerns. Implementation of this knowledge in clinical practice requires new diagnostic approaches, healthcare system adaptations, and increased awareness among medical professionals. In conclusion, this review provides a comprehensive examination of current evidence linking environmental exposures to liver disease and discusses implications for clinical practice and public health policy.

Graphical Abstract

Lay Summary

Environmental chemicals found in air pollution, contaminated food and drinking water, and consumer products can harm the liver. These exposures may cause or worsen liver diseases depending on individual susceptibility. Understanding the effects of pollution on liver health has important implications for medical care and public health policy.

Occupational and environmental hepatology is the medical subdiscipline that includes research, clinical evaluation, and treatment of patients with liver diseases associated with chemical exposures. The hepatotoxicity of occupational and environmental chemicals has long been documented. Classically described examples include acute liver failure related to solvent or mushroom poisoning, hepatic cholestasis related to consumption of contaminated food or cooking oil,^1,2 and liver cancer due to occupational vinyl chloride or environmental aflatoxin exposures.³

In 1962, Rachel Carson observed in Silent Spring that “As the tide of chemicals born of the industrial age has arisen to engulf our environment, a drastic change has come about in the nature of the most serious health problems.”⁴ Indeed, hepatology practice has seen a change in the incidence of specific liver diseases, most notably the observed dramatic increase in metabolic dysfunction-associated steatotic liver disease (MASLD), advanced fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Environmental pollutant exposures impact liver disease development, severity, and complications, and serve as disease modifiers.⁵ For example, an astonishingly high 95.3% of National Health and Nutrition Examination Survey (NHANES) participants with advanced liver fibrosis had polychlorinated biphenyl (PCB) exposures in the highest exposure quartile.⁶ Likewise, per- and polyfluoroalkyl substances (PFAS) exposures were positivelyassociated with adult MASLD and its severity using histologic or elastographic biomarkers.^7–12

The Agency for Toxic Substances and Disease Registry (ATSDR) maintains a list of substances commonly found at sites of National Priority (Superfund Sites). In 2022, this list identified 275 environmental chemicals posing the most significant potential threats to human health, with all top 10 highest priority chemicals associated with liver toxicity. The exposome is a paradigm-shifting concept in the environmental health sciences. It is the integrated compilation of environmental influences across the lifespan. These influences include chemical pollutants, diet, exercise, structural determinants of health, etc.¹³ Exposomics, the study of the exposome, serves as the environmental counterpart to genomics.^13,14

This review focuses specifically on occupational and environmental hepatology, considering exposomics as a research tool. We have actively investigated this area since 2010, reporting on the development of steatohepatitis in highly exposed vinyl chloride workers, termed toxicant-associated steatohepatitis (TASH). Research in chemical hepatocarcinogenesis spans nearly 50 years, following the 1974 identification of hepatic hemangiosarcoma in highly exposed polyvinyl chloride workers at a local chemical plant, and continues to the present day.^15,16

Previous reviews have covered chemicals associated with liver disease and their proposed modes of action,^5,17–22 various conceptual frameworks,^13,14,23,24 and limited practice guidance.^25,26 However, many clinicians remain unaware of key concepts, and barriers persist in implementing new scientific knowledge in clinical practice. This review examines key environmental health science concepts impacting hepatology practice and evidence that common chronic liver diseases may be impacted by specific exposures (Tables 1 and 2), while identifying current scientific and clinical barriers.

Table 1.

Environmental and occupational chemicals and associated liver disease and mechanisms

Category of the Exposure		Associated liver disease	Mechanisms /Animal study	Clinical index/Epidemiological study
Air pollutants	PM2.5	MASLD, ↑increased hospitalization, TAFLD	TAFLD263	Associated with MASLD,100,264 ↑GGT265
	Vinyl chloride	Angiosarcoma49,54–56 HCC,56 MASLD41,110	↑ROS53,103	Increased mortality from HCC266 ↑ALT, ↑AST92
Aflatoxin B		HCC60,61
Dioxin	TCDD/PCDFS/dioxin-like PCBs	HCC, cirrhosis, SLD		↑Incidence of HCC and mortality124 Cirrhosis124
Brominated flame retardants (BFR)	PBDE/BTPDE/DEHP	MASLD	(+) PPARa Gut microbiome change Inflammation ROS	↑ALT, ↑AST, ↑GGT,147 ↑ALT, ↑Bilirubin148
Pesticide	DTT Organochlorine Organophosphorus Carbamates Pyrethroids Neonicotinoids	SLD, MASLD PSC, PBC43	↑ROS76 EDC, MDC267 MDC268 Dyslipidemia221	↑Tumor biomarkers78 ↑Liver enzymes137 Association with obesity DM2219 PSC, PBC43
Fungicide	Triazole (Flutriafol) Oxazolidinedione (Famoxadone)	↑ MASLD risk SLD, MASLD	↑Lipid accumulation226 EDC, ↓ lipid oxidation228
Herbicide	Glyphosate (Roundup)	Liver injury and metabolic syndrome	↑Liver congestion and mortality222 EDC224	↑Liver enzymes, ↑metabolic syndrome225
Personal care products/Cosmetic products	Parabens Alkylphenol ethoxylates Synthetic musk	SLD	EDC ↓ AST ↑liver weight ↑cholesterol, ↑creatinine238
Microplastic/Plasticizers	Phthalates/ Bisphenol A (BPA) /Polystyrene	MASLD	Induce inflammatory,184 EDC204↑ROS183	Obesity187
PFAS	PFOA/PFOS		Altered androgen269	↓ Liver function12
Heavy metals	Arsenic	HCC,270 MASLD161	↑ Cancer growth and metastasis87 ↑ Steatosis, inflammation271	HCC29 Stronger association of HCC with female88
	Cadmium	↑Risk of HCC MASLD163	↑ HCC risk270↑	Linked to tumor formation,272 liver disease mortality273
PCBs	TASLD115	HCC73	EDC, MDC, (+) AHR (+) CAR,132 (−) EGFR274	HCC,74↑ALT, ↑AST, ↑CK18116–120
Miscellaneous	Microcystins	SLD, acute liver failure or chronic liver injury241		↑MASLD241

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BTPDE, dichlorodiphenyltrichloroethane; DDT, dichlorodiphenyltrichloroethane; DEHP, di(2-ethylhexyl) phthalate; EDC, endocrine disrupting chemical; GGT, gamma-glutamyl transferase; HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; MDC, metabolism disrupting chemical; PBDE, polybrominated diphenyl ethers; PCB, polychlorinated biphenyl; PCDFS, polychlorinated dibenzofurans; PFAS, per- and polyfluoroalkyl substances; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate; PSC, primary sclerosing cholangitis; ROS, reactive oxygen species; SLD, steatotic liver disease; TAFLD, toxicant-associated fatty liver disease; TASLD, toxicant-associated steatotic liver disease; TCDD, tetrachlorodibenzo-p-dioxin.

Table 2.

Impact of environmental exposures on alcohol-associated liver disease in animalmodels: Summary of recent studies examining the interaction between environmental toxicants and alcohol consumption in rodent models

Environmental exposure	Animal model	Study duration	Key findings	Mechanisms	Reference
1,2-Dichloroethane (1,2-DCE)	Female Kunming mice	6 days EtOH (1.5–3.0 g/kg) + 3 days 1,2-DCE (1.0 mg/L, 3.5 h/day inhalation)	↑ Liver damage ↑ CYP2E1 expression ↑ Inflammatory response ↑ Antioxidant defense	↑ CYP2E1-mediated oxidative stress ↑ NLRP3 inflammasome activation Insufficient antioxidant compensation Confirmed via CYP2E1 inhibition	70
Ambient particulate matter (PM)	Male C57BL/6 mice	12 weeks	↑ Liver fibrosis ↑ Hepatic oxidative stress ↑ Mitochondrial ROS ↑ Hepatic ferroptosis	↑ ROS-ferroptosis pathway ↑ TGF-β1/collagen-I Altered GSH/GSSG ratio Stellate cell activation	249
Gulf War Illness-related chemicals (Permethrin + Pyridostigmine-bromide)	Male C57BL/6 mice	10 days exposure + 4 months recovery + 10 days EtOH challenge	↑ Microvesicular steatosis ↑ Chronic inflammation ↑ Liver fibrosis ↑ Liver enzymes	Macrophage-mediated damage Prolonged liver sensitization Enhanced inflammatory response	250
Polychlorinated biphenyl 126 (PCB126)	Male C57BL/6J mice	Single exposure (0.2 mg/kg) + chronic-binge alcohol model	↑ Hepatic steatosis ↑ Hepatomegaly ↓ Albumin levels ↓ Glycogen stores	↑ Lipid retention ↓ Lipid oxidation AHR/CAR activation Enhanced malnutrition	247
Polychlorinated biphenyl 126 (PCB126)	Male C57BL/6J mice	Single exposure (0.2 mg/kg) + chronic-binge alcohol model	Altered transcriptome ↓ Metal homeostasis ↓ Essential metals Modified metabolism	>4,000 altered genes ↓ Mg, Co, Zn levels Modified tyrosine pathways	246

Abbreviations: AHR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor.

Key Concepts in Environmental Health Science and Hepatotoxicity

The liver serves as the primary target organ for chemical exposures, largely due to its central role in xenobiotic metabolism. Primary routes of hepatotoxic chemical exposures include inhalation of air pollution and ingestion of contaminated food and drinking water.^27,28 Emerging data suggest that these exposures are not evenly distributed across the general population, with disproportionate impacts alongdemographic (e.g., race/ethnicity and sex), geographic, and socioeconomic lines, increasing risk for advanced liver fibrosis and HCC.^21,29 Environmental justice initiatives aim to address such inequitable risks. A positive recent example of environmental justice is the Promise to Address Comprehensive Toxics (PACT) Act of 2022 which addresses the toxic chemical exposures among United States military service personnel. Under this legislation, HCC is established as a presumptive health condition. More research is required on military exposures and MASLD, which has rapidly increased in active-duty service personnel and shows higher prevalence in Veterans than in the general population.^30,31

Following absorption, pollutants undergo hepatic phase 1 and 2 metabolism. While some chemicals form hepatotoxic intermediates, others like PFAS undergo enterohepatic circulation, prolonging exposure. PFAS and other environmental chemicals such as PCBs and some toxic metals bioaccumulate in liver tissue, supporting their hepatotoxic potential. Chemical toxicity is often dose-dependent and can have a prolonged latency period, as demonstrated with vinyl chloride–related hepatic hemangiosarcomas.¹⁶ Post-exposure risk for liver disease development appears dependent on race/ethnicity, sex, diet/nutritional status, and timing of the exposure in relation to windows of enhanced susceptibility during the lifespan.¹⁶ For example, animal models demonstrate diet-dependent hepatotoxic effects for some chemicals which required a second hit such as hypercaloric diet to manifest toxicity.^17,32,33 This concept gains importance as environmental levels of some pollutants decrease while their clinical toxicity could increase due to dietary changes and rising obesity rates.

The developmental origins of health and disease (DOHaD) concept extends from maternal nutrition to environmental exposures affecting liver disease risk of the offspring.³⁴ Recent research shows that gestational PFAS exposures were associated with the changes in the metabolome and increased liver disease risk (primarily MASLD) in adolescent children.³⁵

Beyond xenobiotic metabolism, the liver orchestrates intermediary metabolism in the body. Dysregulated hepatic intermediary metabolism has been associated with steatotic (e.g., altered lipid metabolism) and cholestatic (e.g., altered bile acid metabolism) liver diseases. Several key hypotheses refined over the last two decades have been proposed to explain the observed associations between pollutants and related endocrine, metabolic, and liver diseases. These include the endocrine disrupting chemical (EDC), obesogen, and metabolism disrupting chemical (MDC) hypotheses. EDCs, first described during 1991 Wingspread Conference, are currently defined by the Endocrine Society as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action.”³⁶ Over 1,000 potential EDCs have been identified and human exposure sources include industrial activity, food production (e.g., pesticides, food additives, and packaging materials), personal and home care products, as well as medical products and equipment (Fig. 1).^32,37

Fig. 1. Sources and pathways of environmental liver toxicants.

Major exposure sources that can impact liver health include food production (green), industrial activity (gray), personal and home care products (pink), and medical care (blue). Many compounds, such as per- and polyfluoroalkyl substances (PFAS), phthalates, and bisphenols derive from multiple sources, highlighting their pervasive presence in commonly used products and environmental media. (Created with BioRender.com.)

A decade after the EDC hypothesis emerged, researchers first proposed chemical exposures’ potential role in weight gain and adiposity.³⁸ In 2006, the term environmental “obesogen” was introduced, supported by increasing experimental evidence.^39,40 While some laboratories investigated pollutants associated with obesity and dyslipidemia, our group began examining industrial chemicals (e.g., vinyl chloride) associated with altered liver lipid metabolism, hepatic steatosis, and TASH.⁴¹ Recognizing the central theme of altered liver and systemic metabolism, the MDC hypothesis was proposed in 2016.³² This unifying hypothesis states that environmental chemicals promote metabolic changes resulting in obesity, type 2 diabetes, or fatty liver,³² along with associated conditions like metabolic syndrome, dyslipidemia, and hypertension. More recently, environmental chemical exposures including PCBs and pesticides were associated with human cholestatic liver diseases and disruption of bile acid and other metabolic pathways.^42,43 These reports suggest that MDCs can affect other liver diseases in addition to MASLD. The U.S. Environmental Protection Agency has recently implemented actions to limit exposure of population to MDCs, including certain PFAS and solvents. Further research is required to document the potential reversibility of established exposure-related chronic liver diseases following exposure reduction or elimination.

Although mechanisms of hepatotoxic chemicals are well-established (Fig. 2), traditional methods cannot assess all 219 million registered chemical substances. Modern approaches combine mechanistic studies with epidemiological data to identify key characteristics of hepatotoxicants. To address this and other challenges, the key characteristic (KC) approach has been applied to provide the basis for a knowledge-based approach to evaluate mechanistic data rather than hypothesis-based approaches in toxicology (Fig. 2). Recently published KCs for EDCs,⁴⁴ MDCs,⁴⁵ carcinogens,⁴⁶ and human hepatotoxicants provide broad insight into hepatotoxic chemical actions.²⁴ These KCs include: reactivity of parent compound or metabolite, causes liver cell death, induces oxidative stress, triggers immune-mediated responses in liver, causes mitochondrial dysfunction, causes cholestasis, causes liver fibrosis, disrupts liver metabolism, etc. (Fig. 2).²⁴ Receptor-based mechanisms in chemical hepatotoxicity include ligand activation of transcription factors such as the aryl hydrocarbon receptor (by dioxins or dioxin-like molecules) or nuclear receptors such as the pregnane x receptor (by PFAS or PCBs).¹⁷ These, and other indirect mechanisms (Fig. 2), including epigenomic modifications, lead to hepatic transcriptional reprogramming and liver disease risk.¹⁷

Fig. 2. Overview of hepatotoxic mechanisms.

Schematic representation of the major pathways through which hepatotoxicants can cause liver injury. These mechanisms include structural alterations (disruption of cellular cytoskeleton), metabolic perturbations (energy and bile acid metabolism, mitochondrial function), inflammatory responses (immune system activation), cell death, transport dysfunction, oxidative damage, transcriptional reprogramming, altered microbiome, and tissue remodeling (fibrosis). Hepatotoxicants can act through one or multiple pathways simultaneously, leading to various manifestations of liver injury. The central illustration depicts the liver, with arrows indicating the convergence of these diverse pathogenic mechanisms. (Created with BioRender.com.)

Malignant Liver Diseases

HCC stands as the sixth most common malignancy and the second most common cause of cancer-related fatalities worldwide. As the predominant form of liver cancer and one of the primary causes of cancer-related deaths globally,⁴⁷ its impact on global health is substantial, particularly given that non-resectable cases may have limited 5-year survival rates.⁴⁸ The complex relationship between environmental factors and liver cancers such as HCC and hepatic hemangiosarcoma has been revealed by occupational and environmental epidemiology studies. Environmental exposures can directly cause liver cancer through their genotoxicity, or indirectly cause liver cancer by promoting progressive liver fibrosis and cirrhosis.

Vinyl Chloride Exposure, Hepatic Hemangiosarcoma, and HCC

Hepatic hemangiosarcoma, a high-grade vascular tumor with a 3:1 male to female ratio, primarily affects those over 60 years of age. Despite constituting only 1 to 2% of liver tumors as the third most frequent primary hepatic tumor,⁴⁹ it carries particular significance due to its strong association with exposures and poor prognosis, with median survival of only 10 months even with surgical resection.⁵⁰ Several factors have been definitively linked to human hemangiosarcoma including rare genetic conditions, and exposures to radiation, thorotrast, or vinyl chloride (VC).^51,52 VC represents a widespread environmental contaminant, particularly as a solvent breakdown product in groundwater near military installations, garbage sites, and natural gas drilling locations. Its primary industrial use is in the rubber manufacturing sector as an intermediate monomer for polyvinyl chloride synthesis.⁵³ The connection between VC and liver angiosarcoma was first established in 1974 when multiple cases were identified among chemical workers at a VC polymerization company in Louisville, Kentucky.¹⁵ Subsequently, additional cases were documented in Louisville and other locations, consistently associated with long-term VC exposure.^49,54–56 Other studies demonstrate associations between occupational VC exposures and HCC.⁵⁷ VC is classified by the International Agency for Research on Cancer (IARC) as carcinogenic to humans (Group 1). More recent data suggest a potential role for environmental VC exposures and HCC. Liver cancer mortality rates show significant geographic variation in the United States. Texas, with an HCC incidence rate nearly double the national average, ranks third in the country. The state’s extensive petrochemical industry, the second largest in the nation, suggests industrial air pollution may contribute to this elevated incidence.⁵⁸ Although one study suggested an association between residential toxic air exposures, including vinyl chloride, and Texas HCC, a follow-up study did not confirm this association.²⁹ More data are required.

Synergistic Effects of Environmental and Viral Factors: Aflatoxins, HBV, and HCC

The geographic distribution of HCC risk reflects the complex interplay of environmental factors, including endemic oncogenic viruses and dietary carcinogens, and HCC. Varying mechanisms of action (Fig. 2) and population-specific effects underscore the critical importance of considering both chemical exposure and demographic factors in comprehensive HCC risk assessment. Understanding these intricate interactions provides crucial insights into the environmental determinants of liver cancer development. The interaction between chronic hepatitis B infection (HBV) and chronic aflatoxin exposure provides a compelling example of this relationship.⁵⁹ Aflatoxins, carcinogenic mycotoxins produced by Aspergillus fungi, are widespread environmental contaminants in foods like nut crops or grains. Aflatoxins are IARC Group 1 carcinogens. The most toxic variant is aflatoxin B1 (AFB1), and its metabolites exhibit a range of biological activities, such as acute toxicity, teratogenicity, mutagenicity, and carcinogenicity. It has been well established that these compounds have been associated HCC in both humans and animals.^60,61 Particularly, AFM1, a measurable metabolite that serves as an index of chronic aflatoxin exposure, has been correlated with increased HCC incidence. Although Hispanic population showed lower AFM1 levels, their socioeconomic status may have influenced their exposure through consumption of lower-grade foods potentially contaminated with aflatoxins.⁶² The synergistic relationship between HBV infection and aflatoxin exposure in liver cancer development was first documented in a Chinese cohort study.⁶³ Subsequent investigations in various contexts, particularly in African regions where HBV is endemic, have consistently confirmed this interaction. Evidence suggests that aflatoxins may enhance viral oncogenicity and potentially increase infection rates.⁵⁹ Even moderate aflatoxin exposures tripled the incidence of HCC development in a cohort of HBV-infected men.⁶⁴ Large-scale public health interventions aimed at reducing aflatoxin exposures and viral hepatitis infections promise to decrease the incidence of HCC related to these synergistic factors.⁶⁵ Proof-of-concept studies demonstrated the potential efficacy of pharmacologic and nutritional strategies that promoted the phase 2 metabolism of toxic aflatoxin metabolites in the chemoprevention of HCC.⁶⁶

Additional Examples of Environmental Exposures and HCC

Select examples include benzo(a)pyrene (B[a]P), persistent organic pollutants, and metals. Data for these chemicals provide further proof of concept and support the need for future exposomics research in this area. B[a]P is an environmental toxicant commonly found in tobacco smoke, charcoal-grilled foods, engine exhaust, and contaminated air and water. B[a]P is an IARC Group 1 carcinogen. As a polycyclic aromatic hydrocarbon (PAH) formed during incomplete combustion of organic materials, B[a]P is a procarcinogen—meaning it requires metabolic activation to become carcinogenic.⁶⁷ It is activated by several cytochrome P450 enzymes and epoxide hydrolase to form the reactive metabolite, B[a]P diol epoxide (BPDE).⁶⁸ BPDE forms DNA adducts through covalent binding.⁶⁹ B[a]P promotes the development of reactive oxygen species (ROS) while simultaneously decreasing the activity of protective antioxidant enzymes like glutathione reductase.⁶⁸ The formation of ROS due to intrahepatic B[a]P triggers multiple pathological changes in the liver: it damages cellular components, disrupts normal metabolic processes, and creates an environment conducive to hepatocarcinogenesis.⁷⁰ In epidemiological studies done in Xiamen, China, significantly higher levels BPDE-DNA adducts were observed in patients with HCC. Elevated BPDE-DNA adducts also indicated increased HCC risk, showing it to be an independent risk factor for HCC.⁶⁹ Experimental studies demonstrate that B[a]P stimulated cell migration and enhanced angiogenesis, which are important HCC mechanisms.⁶⁷ In a murine HCC model, B[a]P exposure increased metastases and decreased survival.⁷¹

Several persistent organic pollutants (POPs) have been associated with HCC in epidemiologic studies. As thermodynamically stable molecules, POPs are resistant to degradation in the environment. These so-called “forever chemicals” bioaccumulate and oftentimes concentrate within the liver. PCBs are POPs and IARC Group 1 carcinogens. PCBs were manufactured for a variety of industrial educations before their use was banned approximately 40 years ago.⁷² The carcinogenic potency of PCBs varies based on their chemical structure: higher chlorinated PCBs primarily promote cell proliferation, while lower chlorinated PCBs can form DNA-binding adducts.⁷³ PCBs have been associated with HCC in experimental models, with administration showing increased liver tumors in rats. These experimental findings align with human epidemiological data. For example, a population-based study in Northern California found that certain PCB congeners, such as those that are highly chlorinated, were associated with an increased risk of HCC.⁷⁴

Pesticide exposures have been associated with human HCC.⁷⁵ Dichlorodiphenyltrichloroethane (DDT) is used as an insecticide and anti-malarial agent. It is an IARC Group 2A carcinogen (probably carcinogenic to humans), and it has been associated with incidence of liver cancer. The mode of carcinogenesis is primarily due to oxidative stress.⁷⁶ Animal studies have demonstrated that DDT promotes oxidative stress at both high and low doses, as evidenced by increased levels of 8-OHdG, an established marker of oxidative DNA damage.⁷⁷ These mechanistic findings are supported by population-based studies in China, where analyses of serum DDT levels revealed a 4-fold increase in HCC risk. The risk appears particularly pronounced in men, possibly due to DDT’s endocrine-disrupting properties.⁷⁸

PFAS, another class of synthetic POPs, contain fluorinated carbon chains of variable lengths. PFAS have been widely used in nonstick coating applications (e.g., cookware, thermal insulation, electrical equipment).^79,80 PFAS are primarily ingested through contaminated drinking water or food and distribute either freely or bound to serum proteins.^81,82 Like other POPs, PFAS have long biological half-lives⁸³ and tend to bioaccumulate in liver.⁸⁴ Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are PFAS that were recently designated as human carcinogens by IARC (Groups 1 and 2a, respectively). A recently published nested case-control study demonstrated that elevated PFOS levels were associated with 4.5-fold increased risk of HCC.⁸⁵ Metabolomics analysis demonstrated that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also associated with HCC risk.⁸⁵

Ranking first on ATSDR’s Substance Priority List, arsenic is a metalloid and IARC Group 1 carcinogen that has been associated with human HCC.⁸⁶ Arsenic exposure in mouse models increased cancer growth and metastasis.⁸⁷ Interestingly, in humans the association between arsenic and liver cancer is stronger in females compared with males.⁸⁸ A recent geospatial study found variability in arsenic exposures along racial–ethnic and sex groups.²⁹ Arsenic exposures were positively associated with elevated HCC rates, and these rates varied by demographic variables.⁸⁸ Like aflatoxin, there appear to be environmental justice concerns for arsenic in liver cancer.

Non-malignant Liver Diseases

Metabolic Associated Steatotic Liver Disease (MASLD)

MASLD, formerly known as non-alcoholic fatty liver disease (NAFLD), affects approximately 30% of adults worldwide.⁸⁹ Characterized by excessive hepatic fat accumulation, MASLD is linked to metabolic abnormalities such as obesity and insulin resistance. The disease can progress from potentially reversible stages (steatosis and steatohepatitis) to more severe irreversible stages including fibrosis and cirrhosis if left untreated.⁹⁰ Disease progression is influenced by multiple factors including genetic predisposition, metabolic dys-regulation, and the exposome—the totality of environmental exposures throughout an individual’s life (Fig. 2).⁵ Environmental influences such as air pollutants have increasingly become the focus of environmental studies.^91,92 Emerging research continues to highlight the potential of environmental factors as key contributors to MASLD and its severity (Table 1).

Particulate Matter 2.5 (PM_2.5) and Air Pollution

PM_2.5 includes small (less than 2.5 microns) airborne particles released by anthropogenic sources (e.g., automobile emissions, wildfires, industrial combustion) and natural sources (e.g., dust storms, volcanic eruptions). Recent large environmental epidemiology studies reproducibly demonstrate the adverse human hepatic effects of PM_2.5 and related air pollutants. With sample sizes of up to 45M subjects, these include some of the largest environmental hepatology studies ever conducted.^93–100 Air pollution was associated with increased risk for incident MASLD and/or cirrhosis in longitudinal studies.^93,96–100 These exposures were associated with alterations in the circulating metabolome⁹⁸ and proteome.⁹⁹ These alterations mediated, in part, the observed associations between air pollution and MASLD. Other studies in young adults or Latino youth demonstrated PNPLA3-dependent associations between air pollution and liver stiffness, as well as air pollution-related excess MASLD risk associated with serum microRNA networks.^101,102 Longitudinal studies demonstrate that exposures to residential green and blue spaces decreased risk for incident MASLD or severe liver disease, and that this protective effect was mediated by reduction in PM_2.5 and other air pollutants.^96,97 The scientific understanding of the hepatic effects of air pollution is rapidly evolving and warrants continued attention.

Volatile Organic Compounds (VOCs)

Originating from natural and artificial sources, VOCs are characterized by their limited water solubility and high volatility.¹⁰³ These compounds include known hepatotoxic substances such as perchloroethylene (PCE), trichloroethylene (TCE), and vinyl chloride (VC), which are present in various industrial and consumer products, including metal degreasing and dry-cleaning agents.^104,105 The health effects of VOCs extend beyond their carcinogenic properties, ranging from acute manifestations such as headaches and dizziness to chronic conditions including respiratory disease and cancer.¹⁰⁶

VC exposure, which gained renewed attention following a 2023 train derailment and chemical spill,¹⁰⁷ exemplifies the complexities of VOC-induced liver injury. Recent experimental studies using various diet models demonstrate that VC induces hepatotoxicity at both high concentrations and at levels previously considered safe. When combined with a high fat diet, VC inhalation significantly exacerbated liver damage through altered mitochondrial function and increased ROS production.^53,103

Clinical evidence supports these experimental findings. A study examining liver biopsies from VC-exposed workers found that 80% exhibited MASLD despite normal liver enzyme levels.⁴¹ Sex-specific differences in VOC-related liver injury have been documented in both Canadian¹⁰⁸ and U.S. populations,¹⁰⁹ with recent clinical studies demonstrating significant associations between VOC exposure and MASLD development.¹¹⁰ Additionally, studies on VOC-exposed e-waste dismantling workers have shown positive correlations between exposure and liver damage markers such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST).⁹²

Persistent Organic Pollutants (POPs)

POPs are synthetic polyhalogenated aromatic hydrocarbons resistant to biological, chemical, and photolytic degradation, resulting in environmental persistence.¹¹¹ These compounds accumulate in adipose tissue and disrupt endocrine, immune, and metabolic systems through xenobiotic receptor interactions.^32,112 Human exposure occurs primarily through ingestion of contaminated food, particularly high-fat animal products.¹¹³

PCBs, originally used as dielectric fluids, were first linked to liver damage during the “Yucheng” and “Yusho” poisoning incidents in the 1970s.^114,115 Studies of PCB-exposed populations have shown positive correlations between PCB body burdens and elevated liver enzymes (ALT, AST), cell death markers (CK18), and ultrasonography-diagnosed hepatic steatosis.^116–120 Recent studies have linked PCB levels in umbilical cord blood to elevated liver enzymes and circulating lipids in newborns.¹²¹ Notably, prenatal exposure to PCBs including PCB118, PCB153, and PCB180 was associated with increased CK-18 levels in children.¹²² Sex differences have been reported in PCB-exposed populations (“Yucheng” and “Yusho” cohorts), with females showing higher liver cancer mortality than males.^123,124

Dioxins, including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs, are characterized by their aryl hydrocarbon receptor (AHR)-binding activity. High-level dioxin exposures involving Agent Orange exposure, PCB/PCDF-contaminated cooking oil in the Yucheng population, and the Seveso industrial explosion have been associated with increased liver cancer incidence and mortality.^124–128 Additionally, Tetrachlorodibenzo-p-Dioxin (TCDD) exposure resulted in increased prevalence of liver cirrhosis in Korean Vietnam Veterans.^27,126

PCBs and dioxins contribute to liver disease as both endocrine and metabolic disruptors (EDCs and MDCs) through activation of hepatic receptors including AHR, constitutive androstane receptor (CAR), and pregnane-xenobiotic receptor (PXR).¹²⁹ These transcription factors regulate energy homeostasis through receptor–receptor crosstalk.¹³⁰ Moreover, PCBs interact with endobiotic receptors to modulate steatosis and bile acid homeostasis.¹²⁹

As EDCs, these compounds disrupt thyroid and sex hormone receptors,¹³¹ inhibit insulin production,¹³² and alter endocrine hormone levels.^17,32,133 Recent studies have demonstrated additional mechanisms including gut microbiome alterations,¹³⁴ modification of liver epitranscriptomics,¹³⁵ and changes in RNA splicing¹³⁶ (Fig. 2). These effects are often exacerbated by lifestyle factors such as high caloric intake and alcohol consumption.¹¹⁹

Organochlorine pesticides, including DDT and its metabolites (e.g., dichlorodiphenyldichloroethylene, DDE), have been increasingly associated with liver disease. Organochlorine pesticides have been linked with elevated liver enzymes,^137,138 steatosis,¹³⁹ and altered lipid metabolism.^140,141 Sex-specific effects include β-hexachlorocyclohexane (β-HCH) and transnonachlor associations with elevated ALT in post-bariatric surgery females, while β-HCH, DDE, and hexachlorobenzene (HCB) showed stronger associations with transaminases in Brazilian males.^142,143 Prenatal exposures to DDT and DDE were associated with increased odds of liver injury.¹²²

Emerging evidence links brominated flame retardants (BFRs) to hepatic abnormalities.^144–146 Analysis of NHANES data (2005–2016) showed positive associations between nine BFRs and elevated liver enzymes and MASLD risk scores, but not advanced fibrosis.¹⁴⁷ Novel BFRs like BTBPE have been associated with altered bilirubin levels.¹⁴⁸ BFRs act through PPAR α activation,¹⁴⁹ gut microbiome changes,¹⁵⁰ and inflammation and oxidative stress.¹⁵¹

Phthalates, though not traditional POPs, exhibit similar persistence and EDC activity.¹⁵² Cross-sectional studies have shown associations between urinary Di(2-ethylhexyl) phthalate (DEHP) metabolites and metabolic syndrome in postmenopausal females, and linked diisononyl phthalate to MASLD diagnosed by elastography.¹⁵³

Per- and Polyfluoroalkyl Substances (PFAS)

The National Academies report on PFAS (2022) described evidence of association of PFAS and dyslipidemia (sufficient evidence) or liver enzyme alterations (limited or suggestive evidence).¹⁵⁴ This committee recommended that clinicians should offer serum PFAS testing to patients likely to have elevated exposures. Robust epidemiological studies have associated PFAS exposure to various deleterious impacts including hepatocellular apoptosis, increased liver injury biomarkers, and altered blood lipids.^155–158 Since the publication of the National Academies guidance, six cross-sectional studies investigated associations between PFAS and MASLD characterized by either liver histology^7,8 (n = 100–105 subjects all with MASLD), or FibroScan, investigating adult NHANES 2017–2018 participants (n = 696–1,400).^10–12,159 The liver histology studies found significant positive associations between serum PFAS and hepatic steatosis,^7,8 MASH,⁸ and fibrosis.^7,8 Mechanistically, basic science research studies demonstrate that PFAS induce lipid accumulation and synthesis pathways while decreasing lipid export in hepatocytes. Further, serum PFAS were associated with alterations in the hepatic metabolome, including enrichment in pathways associated with MASLD (e.g., bile acids, sphingolipids, and glycerophospholipids).⁸

Recent manuscripts reported positive associations of PFAS with adult HCC or pediatric MASLD and altered metabolomes in these subjects with liver disease.^85,160 The four NHANES Fibro-Scan studies reported positive associations of PFASwith hepatic steatosis,¹⁵⁹ fibrosis (Liver Stiffness Measurement),^10,159 and MASLD.^11,12 More basic science, epidemiological work, and clinical research are required to further understand PFAS mechanisms and at-risk populations to propose guidelines of restricted use at the federal level and on clinical care.

Metals and Altered Metal Homeostasis

Heavy metals have deleterious effects on many organ systems, including the liver. Although some metals are required in trace amounts for the proper function of specific enzymes, others play no known role in normal biological function. Large epidemiological studies have revealed associations between MASLD and exposure to arsenic,¹⁶¹ cadmium,^162–164 lead,^165,166 and mercury.^163,164 Among the essential metals, zinc and copper may protect against MASLD progression, given that a deficiency in these metals is associated with increased disease.^167,168 Alternatively, the essential metal iron is associated with MASLD when it is present at high concentrations in the liver or in circulation.^169–212

Microplastics (MPs) and Plasticizers

MPs are fibers, spheres, and fragments of plastic particles less than 5 mm.¹⁷¹ MPs are deliberately produced for use in medical devices, personal care items, cosmetics, cleaning products, and food packaging. They are also produced through environmental breakdown of larger plastics. Improper plastic disposal has led to increased MP abundance in the environment, impacting both aquatic and terrestrial life.¹⁷² MPs have become ubiquitous globally, with detection in food and water.¹⁷³ Importantly, they have entered the food chain^174,175 and been detected in human, including stool, blood, breastmilk, saliva, liver and lungs.^176–181

In humans MP exposure occurs primarily through ingestion, inhalation, and dermal contact.¹⁷⁵ Although human toxicity data remain limited, preclinical studies have demonstrated that MPs can induce inflammatory responses,¹⁸⁴ generate ROS,¹⁸⁵ and cause metabolic disorders.^186–190 Phthalates and bisphenol A (BPA) are common plasticizers used to enhance material flexibility and durability of plastics produced for building materials, medical devices, food packaging, cleaning materials, and children’s toys.^191–193 Their widespread presence in dust and in the U.S. adult population has earned them the designation “everywhere chemicals.”^193–201 These compounds readily leach from plastics due to the absence of chemical bonds to the polymer matrix, leading to human exposure through ingestion, inhalation, and dermal contact.^{191,202–205} Both phthalates and BPA are EDCs^206,207 and have been classified as obesogens.^212–214 Clinical studies have associated these compounds with type 2 diabetes, obesity, cardiovascular disorders, hypertension, liver injury, and MASLD.^{199–201,210,211} Cross-sectional studies have shown associations between urinary metabolites and metabolic syndrome and MASLD.¹⁵⁵

Polycyclic Aromatic Hydrocarbons (PAHs)

PAHs are chemical compounds formed from incomplete combustion of coal, wood, and oil, as well as through cigarette smoking and charred meat. They exist ubiquitously in the environment and are frequently found in food, water, and air.²¹³ Analysis of PAH metabolites in urine from NHANES data (2003–2016) examined associations with liver function using ALT, AST, and Gamma-Glutamyl Transferase (GGT) as outcome variables. Results showed that for females, mixed PAH exposure was related to increased ALT levels. One specific PAH, 2-fluorene, showed associations with increased triglyceride and total cholesterol levels. These findings suggest PAHs may have toxic effects on the adolescent female liver, possibly mediated through inflammation and blood lipid alterations.²¹⁴

Other Environmental Exposures

Modern agricultural practices have exposed populations to widespread pesticide residues through air, soil, water, and food,^215,216 leading to various hepatic and metabolic effects. Organophosphorus compounds and carbamates demonstrate particular toxicity—the former showing associations with obesity and type 2 diabetes in both human and rodent studies,^217–220 while carbamates like bendiocarb induce liver steatosis, necrosis, and fibrosis, with links to primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC).⁴³ Other pesticide classes show similar concerns: pyrethroids (e.g., bifenthrin) induce oxidative stress genes, and neonicotinoids like thiamethoxam promote dyslipidemia and MASLD.²²¹

Glyphosate-based herbicides (GBH) represent a significant concern at human exposure levels. In rats, long-term GBH exposure causes liver congestion and necrosis in males and increased mortality in females,²²² while disrupting endocrine signaling and altering hepatic transcriptome profiles.^223,224 Clinical studies corroborate these findings—children aged 5 to 18 years with higher urinary concentrations of glyphosate and its degradation product AMPA show elevated liver transaminases and metabolic syndrome.²²⁵

Fungicides also demonstrate hepatotoxic effects through distinct mechanisms (Fig. 2). Triazoles like flutriafol impair mitochondrial function and induce lipid accumulation,²²⁶ mancozeb exacerbates fatty acid–induced steatosis,²²⁷ and famoxadone suppresses hepatic fatty acid β-oxidation while disrupting thyroid hormone signaling.²²⁸

Personal care products often contain heavy metals, endocrine-disrupting compounds, parabens (preservatives), bisphenols (plastic components), benzophenones (UV filters), and alkylphenol ethoxylates (emulsifiers).^229–233 These compounds demonstrate endocrine-disrupting properties and cause liver toxicity with extended daily use.²³⁴ Synthetic fragrances can affect liver function through various mechanisms.^235–237 Alpha-iso-methylionone, a common fragrance ingredient, reduces AST levels and increases cholesterol, creatinine, and total protein in blood, along with increased liver weight.²³⁸

Climate Change and Algal Toxins

Climate change has increased harmful algal blooms containing microcystins (MCs). Human exposure occurs through contaminated food, water, or recreational activities.²³⁹ MCs exhibit significant liver toxicity: acute exposure can lead to fatty liver disease and liver failure,²⁴⁰ while chronic exposure causes sustained liver injury and inflammation. Population studies show a 0.3% increase in non-alcoholic liver disease risk for each 1% increase in algal bloom-affected county area.²⁴¹

Alcohol-Associated Liver Disease (ALD)

Alcohol consumption remains one of the leading causes of liver disease worldwide, contributing substantially to liver-related morbidity and mortality.²⁴² Compared with MASLD, much less is known about the role of environmental exposures in ALD (Table 2). Toxic chemicals including PAHs have been shown to variably contaminate alcoholic beverages.²⁴³ Moreover, recent epidemiological data from two large cohort studies (n = 90,086 to 456,678 subjects) indicate that the increased risk for MASLD associated with air pollution and PM2.5 exposures was more pronounced in alcohol drinkers.^93,94 Likewise, PFAS exposures were associated with steatotic liver disease in alcohol drinkers but not in non-drinkers.¹² Similar to ethanol, certain pollutants including VOCs are metabolized by CYP2E1 to form toxic intermediates, suggesting that chronic ethanol consumption may enhance pollutant toxicity by increasing CYP2E1 levels and generating their toxic metabolites. Supporting this concept, VC workers who consumed alcohol showed increased risk for cirrhosis and liver cancer than those that did not drink alcohol.²⁴⁴ This CYP2E1-mediated interaction was confirmed in experimental models, where ethanol exposure increased the hepatotoxicity of 1,2 dichloroethane, which is a chemical intermediate used in VC production.²⁴⁵ Animal co-exposure models have revealed additional mechanisms by which environmental pollutants exacerbate experimental ALD, including altered zinc-dependent transcription factor function associated with PCBs,^246,247 mitochondrial dysfunction associated with the Northern contaminant mixture,²⁴⁸ oxidative stress associated with particulate matter,²⁴⁹ and activation of inflammatory mechanisms associated with Gulf War Illness related chemicals.²⁵⁰ Collectively, these and other data suggest an under-recognized role for environmental exposures in ALD. Further research is required to elucidate the interactions between environmental pollutants and alcohol-associated hepatitis and cirrhosis as well as MetALD.

Viral Hepatitis

Relatively little is known about the potential disease-modifying effects of environmental chemicals on viral hepatitis, and more research in this area is required. However, viral hepatitis does appear to increase the risk of liver cancer and/or cirrhosis related to aflatoxin or VC exposures.^59,244 The environmental aldehyde, acrolein, inhibited host interferon signaling and increased viral load in the HCV replicon system.²⁵¹ However, the potential clinical impact of this observation is unknown.

Cholestatic Liver Disease

Cholestatic liver disease is characterized by impaired bile flow through the biliary system. Published environmental health data exist for PBC and PSC. Although increased PBC risk in individuals with family history is well established, genetic factors alone do not explain all cases. More classically described environmental factors associated with PBC include frequent urinary tract infections, nail polish use, and cigarette smoking.^252,253 Some of these have been proposed to explain the higher prevalence of PBC in women. Chemical pollutant exposures have also been associated with PBC. In the United Kingdom, PBC incidence was higher in urban areas with histories of coal mining and high levels of cadmium. In New York, a higher incidence of PBC, but not PSC, was reported in zip codes that either contained or were adjacent to superfund toxic waste sites.^254,255 Recently, two important manuscripts, including a multinational comparison study, were published which applied integrative exposomics and metabolomics approaches to subjects with PBC or PSC compared with controls.^42,43 Multi-omics analyses were performed in plasma (PBC and PSC patients) or bile (PSC patients only).^42,43 A total of 12 environmental pollutants in plasma were associated with PSC, and 8 were associated with PBC. Some of these exposures were associated with metabolic pathways linked to the pathogenesis of cholestatic liver diseases including bile acid metabolism. Pollutants detected in the bile of PSC patients varied by country.⁴² PBCs in bile were associated with metabolic disruption, including bile acid metabolism, in these subjects.⁴² These results demonstrate the power of the exposomics approach in hepatology.

Clinical Implementation and Knowledge Gaps

It is time to implement this knowledge in patient care, health care systems, and at population health levels. At the patient level, approaches to reduce personal exposures can be already implemented.²⁵⁶ These approaches broadly include specific modifications to limit exposures encountered through some personal care and hygiene products, consumables, home and garden, etc.²⁵⁶ Clinical proof-of-concept studies have demonstrated potential effectiveness of pharmacologic and dietary interventions that increase fecal or urinary elimination of some pollutants to decrease burden.^257–260 Some patients may require specific risk-based laboratory exposure assessments. In its recent clinical guidance on PFAS, the National Academies recommended that clinicians should offer serum PFAS testing to patients with defined risk factors for PFAS exposures.²⁶¹ Reference laboratories as well as test and CPT codes were suggested. Specific clinical action items were recommended based on these test results, although none of the action items was related to liver disease.²⁶¹ For workers at risk for occupational liver disease, a diagnostic algorithm has been proposed and management guidance published.²⁶ However, health care providers require education and guidance on environmental hepatology. We urge the medical societies publishing clinical guidelines on liver diseases to include environmental health considerations. The Veteran’s Health Administration has already implemented changes demonstrating that health care systems can act on environmental health issues. New liver disease nomenclature, diagnosis, and billing codes may be required for full implementation within the electronic medical record systems used by healthcare systems. Nomenclature remains problematic as evidenced by the fact that environmental exposures were not considered in the recent Delphi consensus statement on steatotic liver disease (SLD) nomenclature,²⁶² even though TASH was described 15 years ago.⁴¹ The US Federal government has recently taken actions aimed at reducing specific toxic exposures that have been associated with liver disease (e.g., some PFAS and solvents). Leadership is required from the relevant medical societies in terms ofenvironmental health advocacy impacting government, commercial diagnostic laboratories, and payers. Despite considerable advances, key scientific knowledge gaps remain. Longitudinal data are required on pollution and fibrosis progression, HCC development, response to therapy, and clinical outcomes. More research is required on the interactions between gene and environment impacting liver diseases, the exposome, and on the diagnoses with currently limited data.

Conclusions

The evidence supports that patients and providers should care about the occupational and environmental factors influencing liver diseases. Pollution is a disease modifier associated with the development, severity, and complications of liver disease. It is now time to begin implementation of environmental health science in hepatology practice. Leadership from medical societies, health care systems, payers, and government are required to remove barriers impacting the translation of knowledge to clinical practice. The exposome is an important new concept in hepatology which could be incorporated in a future precision medicine approach to liver health.