LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants.

Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

Efficacy of Unregulated Minimum Risk Products to Kill and Repel Ticks.

Human-biting ticks threaten public health in the United States. Registration by the Environmental Protection Agency of products to kill host-seeking ticks or repel ticks contacting humans is indicative of their safety and effectiveness. Unregulated minimum risk products, exempt from Environmental Protection Agency registration and often based on botanical oils, are proliferating in the marketplace, but there is concern about their effectiveness to kill and repel ticks. Evaluations of such products are limited in the published literature. A review showed considerable variability among minimum risk products to kill host-seeking blacklegged ticks, with effectiveness similar to chemical pesticide products for some minimum risk products but minimal impact on the ticks for other products. Evaluations of minimum risk tick repellents have typically focused on individual active ingredients rather than formulated products, which often combine multiple active ingredients. Consumers should be aware that effectiveness to kill and repel ticks can differ among unregulated minimum risk products.

How Do Environmental Toxicants Affect Oocyte Maturation Via Oxidative Stress?

In mammals, oogenesis initiates before birth and pauses at the dictyate stage of meiotic prophase I until luteinizing hormone (LH) surges to resume meiosis. Oocyte maturation refers to the resumption of meiosis that directs oocytes to advance from prophase I to metaphase II of meiosis. This process is carefully modulated to ensure a normal ovulation and successful fertilization. By generating excessive amounts of oxidative stress, environmental toxicants can disrupt the oocyte maturation. In this review, we categorized these environmental toxicants that induce mitochondrial dysfunction and abnormal spindle formation. Further, we discussed the underlying mechanisms that hinder oocyte maturation, including mitochondrial function, spindle formation, and DNA damage response.

High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage.

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

Epidemiology of Parkinson's Disease: An Update.

PURPOSE OF REVIEW: In recent decades, epidemiological understanding of Parkinson disease (PD) has evolved significantly. Major discoveries in genetics and large epidemiological investigations have provided a better understanding of the genetic, behavioral, and environmental factors that play a role in the pathogenesis and progression of PD. In this review, we provide an epidemiological update of PD with a particular focus on advances in the last five years of published literature. RECENT FINDINGS: We include an overview of PD pathophysiology, followed by a detailed discussion of the known distribution of disease and varied determinants of disease. We describe investigations of risk factors for PD, and provide a critical summary of current knowledge, knowledge gaps, and both clinical and research implications. We emphasize the need to characterize the epidemiology of the disease in diverse populations. Despite increasing understanding of PD epidemiology, recent paradigm shifts in the conceptualization of PD as a biological entity will also impact epidemiological research moving forward and guide further work in this field.

Autistic Regression and Exposure to Industrial Chemicals: Preliminary Observations.

Exposure to industrial pollutants is a potential risk factor not fully explored in ASD with regression (ASD+R). We studied geographical collocation patterns of industrial air chemical emissions and the location of homes of children with ASD+R at different exposure times, compared with ASD cases without regression (ASD-R). Fifteen of 111 emitted chemicals collocated with ASD+R, and 65 with ASD-R. ASD+R collocated more strongly with different neurotoxicants/immunotoxicants a year before diagnosis, whereas ASD-R were moderately collocated with chemicals across all exposure periods. This preliminary exploratory analysis of differences in exposure patterns raises a question regarding potential pathophysiological differences between the conditions.

CircRNA: a rising therapeutic strategy for lung injury induced by pulmonary toxicants.

Lung injury has been a serious medical problem that requires new therapeutic approaches and biomarkers. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) that exist widely in eukaryotes. CircRNAs are single-stranded RNAs that form covalently closed loops. CircRNAs are significant gene regulators that have a role in the development, progression, and therapy of lung injury by controlling transcription, translating into protein, and sponging microRNAs (miRNAs) and proteins. Although the study of circRNAs in lung injury caused by pulmonary toxicants is just beginning, several studies have revealed their expression patterns. The function that circRNAs perform in relation to pulmonary toxicants (severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2), drug abuse, PM2.5, and cigarette smoke) is the main topic of this review. A variety of circRNAs can serve as potential biomarkers of lung injury. In this review, the biogenesis, properties, and biological functions of circRNAs were concluded, and the relationship between circRNAs and pulmonary toxicants was discussed. It is expected that the new ideas and potential treatment targets that circRNAs provide would be beneficial to research into the molecular mechanisms behind lung injury.

Tumor growth and population modeling in a toxicant-stressed random environment.

When examining some factors that contribute to the growth or decline of a population or tumor, it is essential to consider a random hypothesis. By analyzing the effects of stress on a population (or volume of tumor growth) in a random environment, we develop stochastic models describing the dynamics of the population (or tumor growth) based on random adjustments to the population's intrinsic growth rate, carrying capacity, and harvesting efforts (or tumor treatments). Apart from the models' ability to capture fluctuations, the availability of a shape parameter in the models gives it the flexibility to describe a variety of population/tumor data with different shapes. The distribution of the stressed population size with or without harvesting (or treatments) is derived and used to calculate the maximum expected amount of harvests that can be taken from the population without depleting resources in the long run (or the minimum amount of chemotherapy needed to cause shrinkage or eradication of a tumor). The work done is applied to analyze tumor growth using published data comprising of the volume of breast tumor obtained by orthotopically implanting LM2-[Formula: see text] cells into the right inguinal mammary fat pads of 6- to 8-week-old female Severe Combined Immuno-Deficient mice.

Toxicants improve glycerol production in the fermentation of undetoxified hydrolysate by Candida glycerinogenes.

OBJECTIVES: Toxicants inhibit microbial fermentation and reduce product titres. This work investigated the glycerol production characteristics of Candida glycerinogenes in highly toxic unwashed undetoxified hydrolysate and provided new ideas for high glycerol production from hydrolysates. RESULTS: The unwashed hydrolysate contains higher concentrations of toxicants, such as furfural, acetic acid, phenols and NaCl than the washed alkali-treated bagasse hydrolysate. C. glycerinogenes fermented unwashed undetoxified hydrolysate yielded 36.1 g/L glycerol, 15.8% higher than the washed hydrolysate, suggesting that the toxicants stimulated glycerol synthesis. qRT-PCR analysis showed that toxicants of unwashed undetoxified hydrolysates greatly up-regulated the transcript levels of the genes GPD1, HXT4 and MSN4 et al. Overexpressing the above genes increased glycerol production by 27.9% to 46.1 g/L. And it was further increased by 8.8% to 50.1 g/L in a 5 L bioreactor. CONCLUSIONS: This result proves that toxicants in lignocellulosic hydrolysates can increase the titre of microbial glycerol production.

Toxic effects of combined exposure to homoyessotoxin and nitrite on the survival, antioxidative responses, and apoptosis of the abalone Haliotis discus hannai.

Homoyessotoxin (homo-YTX) and nitrite (NO2-N), released during harmful dinoflagellate cell lysis adversely affect abalones. However, their toxicity mechanisms in shellfish remain unclear. This study investigated the economic abalone species Haliotis discus hannai exposed to varying concentrations of homo-YTX (0, 2, 5, and 10 µg L-1) and NO2-N (0, 3, and 6 mg L-1) on the basis of their 12 h LC50 values (5.05 µg L-1 and 4.25 mg L-1, respectively) and the environmentally relevant dissolved concentrations during severe dinoflagellate blooms, including mixtures. The test abalones were exposed to homo-YTX and NO2-N for 12 h. The mortality rate (D), reactive oxygen species (ROS) levels, antioxidant defense capabilities, and expression levels of antioxidant-related, Hsp-related, and apoptosis-related genes in abalone gills were assessed. Results showed that the combined exposure to homo-YTX and NO2-N increased the D and ROS levels and upregulated B-cell lymphoma-2 (BCL2)-associated X (BAX) and caspase3 (CASP3) expression levels while reducing glutathione peroxidase (GPx) activity and GPx, CuZnSOD, and BCL2 expression levels. High concentrations of homo-YTX (10 µg L-1) and NO2-N (6 mg L-1) solutions and the combinations of these toxicants inhibited the activities of superoxide dismutase (SOD) and catalase (CAT) and downregulated the expression levels of MnSOD, CAT, Hsp70, and Hsp90. The ROS levels were negatively correlated with the activities of SOD, CAT, and GPx and the expression levels of MnSOD, CuZnSOD, CAT, GPx, Hsp70, Hsp90, and BCL2. These results suggest that homo-YTX, in conjunction with NO2-N, induces oxidative stress, disrupts antioxidant defense systems, and triggers caspase-dependent apoptosis in the gills of abalone. ROS-mediated antioxidative and heat-shock responses and apoptosis emerge as potential toxicity mechanisms affecting the survival of H. discus hannai due to homo-YTX and NO2-N exposure.

The Role of Endocrine Disruption Chemical-Regulated Aryl Hydrocarbon Receptor Activity in the Pathogenesis of Pancreatic Diseases and Cancer.

The aryl hydrocarbon receptor (AHR) serves as a ligand-activated transcription factor crucial for regulating fundamental cellular and molecular processes, such as xenobiotic metabolism, immune responses, and cancer development. Notably, a spectrum of endocrine-disrupting chemicals (EDCs) act as agonists or antagonists of AHR, leading to the dysregulation of pivotal cellular and molecular processes and endocrine system disruption. Accumulating evidence suggests a correlation between EDC exposure and the onset of diverse pancreatic diseases, including diabetes, pancreatitis, and pancreatic cancer. Despite this association, the mechanistic role of AHR as a linchpin molecule in EDC exposure-related pathogenesis of pancreatic diseases and cancer remains unexplored. This review comprehensively examines the involvement of AHR in EDC exposure-mediated regulation of pancreatic pathogenesis, emphasizing AHR as a potential therapeutic target for the pathogenesis of pancreatic diseases and cancer.

[Discussion on the application status and method improvement of gas chromatography in occupational health inspection standards in China].

As a rapid, accurate and efficient analytical technique, gas chromatography is widely used in the detection of volatile organic compounds and inorganic small molecule toxins, and it is the main analytical method in the national testing standards for occupational health. The existing effective national standards of gas chromatography for the detection of some substances have low column efficiency, high toxicity of reagents, poor correlation of the standard curve and low desorption efficiency and other problems, some of which can be solved through method improvement. At the same time, with the use of new materials and new processes, new types of toxic substances are emerging, and there are still many occupational disease hazards of limited value without supporting detection methods, gas chromatography can be applied to the detection of some toxic substances to better complement the vacancy of China's occupational health detection methods. This paper analyzes the current situation of the application of gas chromatography in occupational health testing standards, discusses the improvement of some of these methods, and helps to promote the application and development of gas chromatography in occupational health testing.

Three perspectives on the prediction of chemical effects in ecosystems.

The increasing production, use and emission of synthetic chemicals into the environment represents a major driver of global change. The large number of synthetic chemicals, limited knowledge on exposure patterns and effects in organisms and their interaction with other global change drivers hamper the prediction of effects in ecosystems. However, recent advances in biomolecular and computational methods are promising to improve our capacity for prediction. We delineate three idealised perspectives for the prediction of chemical effects: the suborganismal, organismal and ecological perspective, which are currently largely separated. Each of the outlined perspectives includes essential and complementary theories and tools for prediction but captures only part of the phenomenon of chemical effects. Links between the perspectives may foster predictive modelling of chemical effects in ecosystems and extrapolation between species. A major challenge for the linkage is the lack of data sets simultaneously covering different levels of biological organisation (here referred to as biological levels) as well as varying temporal and spatial scales. Synthesising the three perspectives, some central aspects and associated types of data seem particularly necessary to improve prediction. First, suborganism- and organism-level responses to chemicals need to be recorded and tested for relationships with chemical groups and organism traits. Second, metrics that are measurable at many biological levels, such as energy, need to be scrutinised for their potential to integrate across levels. Third, experimental data on the simultaneous response over multiple biological levels and spatiotemporal scales are required. These could be collected in nested and interconnected micro- and mesocosm experiments. Lastly, prioritisation of processes involved in the prediction framework needs to find a balance between simplification and capturing the essential complexity of a system. For example, in some cases, eco-evolutionary dynamics and interactions may need stronger consideration. Prediction needs to move from a static to a real-world eco-evolutionary view.

Identifying Toxic Consumer Products: A Novel Data Set Reveals Air Emissions of Potent Carcinogens, Reproductive Toxicants, and Developmental Toxicants.

Consumer products are important sources of exposure to harmful chemicals. Product composition is often a mystery to users, however, due to gaps in the laws governing ingredient disclosure. A unique data set that the California Air Resources Board (CARB) uses to determine how volatile organic chemicals (VOCs) from consumer products affect smog formation holds a partial solution. By analyzing CARB data on VOCs in consumer products, we identified and quantified emissions of volatile chemicals regulated under the California Safe Drinking Water and Toxic Enforcement Act ("Prop 65"). We here highlight individual chemicals as well as consumer product categories that people are likely to be exposed to as individual consumers, in the workplace, and at the population level. Of the 33 Prop 65-listed chemicals that appear in the CARB emissions inventory, we classified 18 as "top tier priorities for elimination". Among these, methylene chloride and N-methyl-2-pyrrolidone were most prevalent in products across all three population groups. Of 172 consumer product categories, 105 contained Prop 65-listed chemicals. Although these chemicals are known carcinogens and reproductive/developmental toxicants, they remain in widespread use. Manufacturers and regulators should prioritize product categories containing Prop 65-listed chemicals for reformulation or redesign to reduce human exposures and associated health risks.

Establishment and application of a screening method for 354 organic toxicants in blood and urine with high-performance liquid chromatography-high-resolution orbitrap mass spectrometry.

A rapid and sensitive high-performance liquid chromatography-high-resolution orbitrap mass spectrometry method was developed for the simultaneous screening of 354 organic poisons and metabolites in blood and urine, including drugs, medications, pesticides, rodenticides, veterinary drugs, alkaloids, and mycotoxins with a multi-toxicant chromatography-mass spectrometry information library. The method and library showed good prospects in clinical poisoning screening and forensic toxicological identification. Blood and urine samples were extracted successively with ethyl acetate in acidic and alkaline conditions; then, the extract was blown to nearly dry by nitrogen gas and redissolved with methanol-aqueous solution (v:v, 50:50), and the dissolved solution was analyzed by LC-MS/MS after filtering. Precursor ions' m/z was set for identification, retention time, fragment ions, and isotopic pattern which were used for confirmation. No interference peaks were found in the blank samples, showing good specificity. The LODs of toxicants in urine and blood were 1.00×10-3-50.0 ng/mL and 2.07×10-3-50.0 ng/mL, respectively, while the LOQs were 3.30×10-3-1.67×102 ng/mL and 6.91×10-3-1.67×102 ng/mL. The intra-day precision and inter-day precision of urine samples were 2.31-9.13% and 4.75-12.3%, respectively, which were 1.92-10.8% and 2.01-12.1% in blood samples. The established method was applied to analyze 9 cases of clinical poisoning patients, and bromadiolone, carbofuran, and amanitins were detected, respectively. A total of 382 biospecimens from drug abusers were analyzed with the proposed method, which indicated that some drugs were detected in 62 cases, mainly including methamphetamine, heroin, and MDMA. The results were consistent with the information from traditional liquid chromatography-triple quadrupole mass spectrometry.

Arsenic may be a carcinogenic determinant of a subset of gallbladder cancer: A pilot study.

Gallbladder cancer (GBC) is one of the deadliest malignancy and treatment options are deplorably limited. Better strategies of prevention are urgently needed but knowledge on risk factors remains scarce. Recent data suggested that arsenic (As) may be involved in GBC carcinogenesis but the question remains debated. To date, there are no data on As measurement in GBC samples. This pilot study aimed to measure As concentrations in tissue samples from patients with GBC compared to non-cancerous gallbladder (NCGB). Included patients underwent cholecystectomy at Hospital Clinico Universidad de Chile, Santiago in Chile, a country with high As exposure, between 2001 and 2020. Tissue samples were preserved in formalin-fixed, paraffin-embedded blocks. Selected samples were retrieved, processed and submitted to inductively coupled plasma mass spectrometry (ICP-MS) to determine As concentrations. A total of 77 patients were included, including 35 GBC and 42 NCGB. The two groups were comparable, except for age (68 vs. 49 years, p < 0.001). Measured in 11 GBC and 38 NCGB, total As was detected in 5 GBC (14%) compared to 0 NCGB samples (p < 0.001). GBC group also showed higher median values of As compared to NCGB (p < 0.001). This pilot study provided a proof-of-concept to measure As concentrations in gallbladder samples and showed higher level of As in GBC samples compared to NCGB, paving the way for future studies aiming to investigate the impact of As on GBC, which may contribute to the prevention of this deadly disease.

Dietary per- and polyfluoroalkyl substance (PFAS) exposure in adolescents: The HOME study.

BACKGROUND: Diet is the primary exposure pathway for per- and polyfluoroalkyl substances (PFAS) in non-occupationally exposed populations. Few studies have examined associations of dietary quality and macronutrient intake with PFAS exposure among US adolescents. OBJECTIVE: To assess relationships of self-reported dietary quality and macronutrient intake with serum PFAS concentrations in adolescents. METHODS: We used cross-sectional data from 193 Cincinnati, Ohio area adolescents (median age 12.3 years) collected from 2016 to 2019. Using 24-h food recalls completed by adolescents on three separate days, we derived Healthy Eating Index (HEI) scores, HEI components, and macronutrient intake. We measured perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) concentrations in fasting serum samples. Using linear regression, we estimated covariate-adjusted associations between dietary variables and serum PFAS concentrations. RESULTS: The median HEI score was 44 and median serum PFOA, PFOS, PFHxS, and PFNA concentrations were 1.3, 2.4, 0.7, and 0.3 ng/mL respectively. In adjusted models, higher total HEI scores, whole fruit and total fruit HEI component scores, and total dietary fiber intake were associated with lower concentrations of all four PFAS. For example, serum PFOA concentrations were 7% lower (95% CI: -15, 2) per standard deviation increase in total HEI score and 9% lower (95% CI: -18, 1) per standard deviation increase in dietary fiber. SIGNIFICANCE: Given adverse health effects associated with PFAS exposure, it is crucial to understand modifiable exposure pathways. Findings from this study may inform future policy decisions aiming to limit human exposure to PFAS.

A comprehensive review on environmental pollutants and osteoporosis: Insights into molecular pathways.

A significant problem that has an impact on community wellbeing is environmental pollution. Environmental pollution due to air, water, or soil pollutants might pose a severe risk to global health, necessitating intense scientific effort. Osteoporosis is a common chronic condition with substantial clinical implications on mortality, morbidity, and quality of life. It is closely linked to bone fractures. Worldwide, osteoporosis affects around 200 million people, and every year, there are almost 9 million fractures. There is evidence that certain environmental factors may increase the risk of osteoporosis in addition to traditional risk factors. It is crucial to understand the molecular mechanisms at play because there is a connection between osteoporosis and exposure to environmental pollutants such as heavy metals, air pollutants, endocrine disruptors, metal ions and trace elements. Hence, in this scoping review, we explore potential explanations for the link between pollutants and bone deterioration through deep insights into molecular pathways. Understanding and recognizing these pollutants as modifiable risk factors for osteoporosis would possibly help to enhance environmental policy thereby aiding in the improvement of bone health and improving patient quality of life.

Airborne levels of cadmium are correlated with urinary cadmium concentrations among young children living in the New York state city of Syracuse, USA.

Air pollution is a serious public health issue with early childhood exposure being of high concern because of the greater risk that children might experience negative health outcomes. Industrial sources in and near communities are one potential path of exposure that children might face with greater levels of air pollution correlating with higher levels of toxicants detected in children. We compare estimated ambient air concentrations of Cadmium (Cd) to a cohort (n = 281) of 9 to 11-year old children during their early childhood years (0-5 years of age) in a mid-size city in Upstate New York. Levels of Cd air pollution are compared to children's urine-Cd levels. Urine has been shown to be a superior biomarker to blood for Cd exposure particularly for longer-term exposures. We find that participants who reside in households that faced greater Cd air pollution during the child's early years have higher urine-Cd levels. This association is stable and stronger than previously presented associations for blood-Cd. Findings support expanded use of air modelling data for risk screening to reduce the potential health burden that industrial pollution can have.

Carcinogenic effect of arsenic in digestive cancers: a systematic review.

BACKGROUND: The carcinogenic effect of arsenic (As) has been documented in lung, bladder and skin cancers but remains unclear for digestive cancers, although metabolic pathways of As and recent data suggest that it may be an important determinant in these malignancies as well. OBJECTIVE: This study aimed to systematically review the available literature investigating the potential association between As and digestive cancers. METHODS: An extensive search was conducted in Medline Ovid SP, Cochrane, PubMed, Embase.com, Cochrane Library Wiley, Web of Science and Google Scholar. Studies providing original data in humans, with As measurement and analysis of association with digestive cancers including esogastric cancers (esophagus and stomach), hepato-pancreatico-biliary (HPB) cancers (including biliary tract, liver and pancreas) and colorectal cancers were eligible. RESULTS: A total of 35 studies were identified, 17 ecological, 13 case-control and 5 cohort studies. Associations between As and digestive cancers were reported for both risks of incidence and cancer-related mortality. Overall, 43% (3/7) and 48% (10/21) studies highlighted an association between As and the incidence or the mortality of digestive cancers, respectively. CONCLUSIONS: A substantial proportion of studies exploring the potential link between As and digestive cancers suggested an association, particularly in HPB malignancies. These findings emphasize the need to further investigate this topic with dedicated and high-quality studies, as it may have an important impact, including for prevention strategies.