Exposures to pesticides and risk of cancer: Evaluation of recent epidemiological evidence in humans and paths forward.

Knowledge of the role in cancer etiology of environmental exposures as pesticides is a prerequisite for primary prevention. We review 63 epidemiological studies on exposure to pesticides and cancer risk in humans published from 2017 to 2021, with emphasis on new findings, methodological approaches, and gaps in the existing literature. While much of the recent evidence suggests causal relationships between pesticide exposure and cancer, the strongest evidence exists for acute myeloid leukemia (AML) and colorectal cancer (CRC), diseases in which the observed associations were consistent across several studies, including high-quality prospective studies and those using biomarkers for exposure assessment, with some observing dose-response relationships. Though high-quality studies have been published since the IARC monograph on organophosphate insecticides in 2017, there are still gaps in the literature on carcinogenic evidence in humans for a large number of pesticides. To further knowledge, we suggest leveraging new techniques and methods to increase sensitivity and precision of exposure assessment, incorporate multi-omics data, and investigate more thoroughly exposure to chemical mixtures. There is also a strong need for better and larger population-based cohort studies that include younger and nonoccupationally exposed individuals, particularly during developmental periods of susceptibility. Though the existing evidence has limitations, as always in science, there is sufficient evidence to implement policies and regulatory action that limit pesticide exposure in humans and, hence, further prevent a significant burden of cancers.

From old pollutants to the regulation of bisphenol A: Lessons learned for health promotion and disease prevention.

Citizens deserve regulatory changes and policies more sensitive to the current needs of humans, the climate, and nature. In this work we draw on prior experiences of preventable human suffering and economic losses caused by delayed regulation of legacy and emerging pollutants. Heightened awareness of environmental health problems is necessary among health professionals, the media, and citizens' organizations. Improved translation from research to the clinical world and to policy is critical to reduce the population burden of diseases caused by exposure to endocrine disruptors and other environmental chemicals. Numerous lessons can be learned from science-to-policy processes built for "old pollutants" (as persistent organic pollutants, heavy metals, tributyltin), as well as from current trends regarding the regulation of non-persistent chemicals, such as the prototypical endocrine disruptor bisphenol A. We end discussing relevant pieces of the puzzle to tackle the environmental and regulatory challenges faced by our societies.

Supporting legislative action: Urinary levels of phthalates and phenols among influencers in the 'Plastics in the spotlight' advocacy initiative.

BACKGROUND: Society-wide initiatives to prevent human exposure to plastic residues include laws and policies. Such measures require citizens' support, which can be increased by honest advocacy and pedagogic projects. These efforts must have a scientific basis. OBJECTIVE: To assist the 'Plastics in the spotlight' advocacy initiative raise awareness among the general public of the presence of plastic residues in the human body, and to increase citizens' support for legislation on plastic control in the European Union. METHODS: Spot urine samples of 69 volunteers with cultural and political influence from Spain, Portugal, Latvia, Slovenia, Belgium, and Bulgaria were collected. Concentrations of 30 phthalate metabolites and phenols were determined through a high-performance liquid chromatography with tandem mass spectrometry and ultra-high-performance liquid chromatography with tandem mass spectrometry, respectively. RESULTS: At least 18 compounds were detected in all urine samples. The maximum number of compounds detected per participant was 23, and the mean, 20.5. Phthalates were detected more frequently than phenols. Median concentrations were highest for monoethyl phthalate (41.6 ng/mL, adjusted for specific gravity), and maximum concentrations were highest for mono-iso-butyl phthalate (1345.1 ng/mL), oxybenzone (1915.1 ng/mL), and triclosan (949.6 ng/mL). Most reference values were not exceeded. Women had higher concentrations of the 14 phthalate metabolites and oxybenzone than men. Urinary concentrations were not correlated with age. DISCUSSION: The study had three main limitations: method of subject selection (volunteers), small sample size, and limited data on determinants of exposure. Studies on volunteers do not pretend to be representative of the general population and are no substitute for biomonitoring studies in representative samples of the populations of interest. Studies as ours can only illustrate the existence and some aspects of the problem, and can raise awareness among citizens concerned by the evidence that the studies provide in a group of subjects who are humanly appealing. CONCLUSIONS: The results illustrate that human exposure to phthalates and phenols is widespread. All countries appeared to be similarly exposed to these contaminants, with higher levels in females. Most concentrations did not exceed reference values. The effects of this study on the objectives of the 'Plastics in the spotlight' advocacy initiative deserve a specific analysis from policy science.

Individual blood concentrations of persistent organic pollutants and chemical elements, and COVID-19: A prospective cohort study in Barcelona.

BACKGROUND: There is wide, largely unexplained heterogeneity in immunological and clinical responses to SARS-CoV-2 infection. Numerous environmental chemicals, such as persistent organic pollutants (POPs) and chemical elements (including some metals, essential trace elements, rare earth elements, and minority elements), are immunomodulatory and cause a range of adverse clinical events. There are no prospective studies on the effects of such substances on the incidence of SARS-CoV-2 infection and COVID-19. OBJECTIVE: To investigate the influence of blood concentrations of POPs and elements measured several years before the pandemic on the development of SARS-CoV-2 infection and COVID-19 in individuals from the general population. METHODS: We conducted a prospective cohort study in 154 individuals from the general population of Barcelona. POPs and elements were measured in blood samples collected in 2016-2017. SARS-CoV-2 infection was detected by rRT-PCR in nasopharyngeal swabs and/or by antibody serology using eighteen isotype-antigen combinations measured in blood samples collected in 2020-2021. We analyzed the associations between concentrations of the contaminants and SARS-CoV-2 infection and development of COVID-19, taking into account personal habits and living conditions during the pandemic. RESULTS: Several historically prevalent POPs, as well as arsenic, cadmium, mercury, and zinc, were not associated with COVID-19, nor with SARS-CoV-2 infection. However, DDE (adjusted OR = 5.0 [95% CI: 1.2-21]), lead (3.9 [1.0-15]), thallium (3.4 [1.0-11]), and ruthenium (5.0 [1.8-14]) were associated with COVID-19, as were tantalum, benzo(b)fluoranthene, DDD, and manganese. Thallium (3.8 [1.6-8.9]), and ruthenium (2.9 [1.3-6.7]) were associated with SARS-CoV-2 infection, and so were lead, gold, and (protectively) iron and selenium. We identified mixtures of up to five substances from several chemical groups, with all substances independently associated to the outcomes. CONCLUSIONS: Our results provide the first prospective and population-based evidence of an association between individual concentrations of some contaminants and COVID-19 and SARS-CoV-2 infection. POPs and elements may contribute to explain the heterogeneity in the development of SARS-CoV-2 infection and COVID-19 in the general population. If the associations are confirmed as causal, means are available to mitigate the corresponding risks.

Prepandemic personal concentrations of per- and polyfluoroalkyl substances (PFAS) and other pollutants: Specific and combined effects on the incidence of COVID-19 disease and SARS-CoV-2 infection.

OBJECTIVE: To investigate the specific and combined effects of personal concentrations of some per- and polyfluoroalkyl substances (PFAS), other persistent organic pollutants (POPs), and chemical elements -measured in individuals' blood several years before the pandemic- on the development of SARS-CoV-2 infection and COVID-19 disease in the general population. METHODS: We conducted a prospective cohort study in 240 individuals from the general population of Barcelona. PFAS, other POPs, and chemical elements were measured in plasma, serum, and whole blood samples, respectively, collected in 2016-2017. PFAS were analyzed by liquid chromatography-triple quadrupole mass spectrometry. SARS-CoV-2 infection was detected by rRT-PCR in nasopharyngeal swabs and/or antibody serology in blood samples collected in 2020-2021. RESULTS: No individual PFAS nor their mixtures were significantly associated with SARS-CoV-2 seropositivity or COVID-19 disease. Previously identified mixtures of POPs and elements (Porta et al., 2023) remained significantly associated with seropositivity and COVID-19 when adjusted for PFAS (all OR > 4 or p < 0.05). Nine chemicals comprised mixtures associated with COVID-19: thallium, ruthenium, lead, benzo[b]fluoranthene, DDD, other DDT-related compounds, manganese, tantalum, and aluminium. And nine chemicals comprised the mixtures more consistently associated with SARS-CoV-2 seropositivity: thallium, ruthenium, lead, benzo[b]fluoranthene, DDD, gold, and (protectively) selenium, indium, and iron. CONCLUSIONS: The PFAS studied were not associated with SARS-CoV-2 seropositivity or COVID-19. The results confirm the associations between personal blood concentrations of some POPs and chemical elements and the risk of COVID-19 and SARS-CoV-2 infection in what remains the only prospective and population-based cohort study on the topic. Mixtures of POPs and chemical elements may contribute to explain the heterogeneity in the risks of SARS-CoV-2 infection and COVID-19 in the general population.

Influence of KRAS mutations, persistent organic pollutants, and trace elements on survival from pancreatic ductal adenocarcinoma.

INTRODUCTION: Reasons why pancreatic ductal adenocarcinoma (PDAC) continues to have poor survival are only partly known. No previous studies have analyzed the combined influence of KRAS mutations, persistent organic pollutants (POPs), and trace elements upon survival in PDAC or in any other human cancer. OBJECTIVE: To analyze the individual and combined influence of KRAS mutations, POPs, and trace elements upon survival from PDAC. METHODS: Incident cases of PDAC (n = 185) were prospectively identified in five hospitals in Eastern Spain in 1992-1995 and interviewed face-to-face during hospital admission. KRAS mutational status was determined from tumour tissue through polymerase chain reaction and artificial restriction fragment length polymorphism. Blood and toenail samples were obtained before treatment. Serum concentrations of POPs were analyzed by high-resolution gas chromatography with electron-capture detection. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Multivariable Cox proportional hazards regression was used to assess prognostic associations. RESULTS: Patients with a KRAS mutated tumor had a 70% higher risk of early death than patients with a KRAS wild-type PDAC (hazard ratio [HR] = 1.7, p = 0.026), adjusting for age, sex, and tumor stage. KRAS mutational status was only modestly and not statistically significantly associated with survival when further adjusting by treatment or by treatment intention. The beneficial effects of treatment remained unaltered when KRAS mutational status was taken into account, and treatment did not appear to be less effective in the subgroup of patients with a KRAS mutated tumor. POPs did not materially influence survival: the adjusted HR of the highest POP tertiles was near unity for all POPs. When considering the joint effect on survival of POPs and KRAS, patients with KRAS mutated tumors had modest and nonsignificant HRs (most HRs around 1.3 to 1.4). Higher concentrations of lead, cadmium, arsenic, vanadium, and aluminium were associated with better survival. When KRAS status, POPs, and trace elements were simultaneously considered along with treatment, only the latter was statistically significantly related to survival. CONCLUSIONS: In this study based on molecular, clinical, and environmental epidemiology, KRAS mutational status, POPs, and trace elements were not adversely related to PDAC survival when treatment was simultaneously considered; only treatment was independently related to survival. The lack of adverse prognostic effects of POPs and metals measured at the time of diagnosis provide scientific and clinical reassurance on the effects of such exposures upon survival of patients with PDAC. The weak association with KRAS mutations contributes to the scant knowledge on the clinical implications of a genetic alteration highly frequent in PDAC.

Blood Concentrations of Persistent Organic Pollutants and Unhealthy Metabolic Phenotypes in Normal-Weight, Overweight, and Obese Individuals.

Factors underlying metabolic phenotypes, such as the metabolically healthy but obese phenotype, remain unclear. Differences in metabolic phenotypes-particularly, among individuals with a similar body mass index-could be related to concentrations of persistent organic pollutants (POPs). To our knowledge, no studies have analyzed POPs and metabolic phenotypes in normal-weight persons. We investigated the relationships between serum concentrations of POPs and metabolic phenotypes in 860 normal-weight, overweight, and obese participants in the 2002 Catalan Health Interview Survey (Spain). POP concentrations were significantly higher in metabolically unhealthy than in metabolically healthy individuals. In models adjusting for body mass index and other confounders, hexachlorobenzene, ß-hexachlorocyclohexane, and polychlorinated biphenyls were associated with the unhealthy metabolic phenotype and metabolic syndrome. Among normal-weight individuals, the adjusted prevalence ratio of having an unhealthy phenotype for the upper category of the sum of orders of the 6 mentioned POPs (all individually associated with metabolic phenotypes) was 4.1 (95% confidence interval: 1.7, 10.0). Among overweight and obese individuals, the corresponding prevalence ratio for the sum of polychlorinated biphenyls was 1.4 (95% confidence interval: 1.0, 1.8). Our results supported the hypothesis that POP concentrations are associated with unhealthy metabolic phenotypes, not only in obese and overweight individuals but also (and probably more strongly) in normal-weight individuals.

Persistent organic pollutants and promoter hypermethylation of the O(6)-methylguanine-DNA methyltransferase gene.

Promoter hypermethylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) DNA repair gene is important during carcinogenesis. We explored whether organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), were associated with hypermethylation of the MGMT gene promoter in peripheral leukocytes among 368 Koreans without cancer. Hypermethylation decreased as OCPs increased (Ptrend = 0.02), while PCB concentrations showed an inverted U-shaped association (Pquadratic < 0.01). The prevalence of MGMT promoter hypermethylation was highest within the 2nd quintile of the PCB summary score (28.4%), while it was only 2.7% in the upper 10% score. Chronic exposure to these chemicals may affect methylation of the MGMT promoter, with possibly non-monotonic dose response relationships.

The current deconstruction of paradoxes: one sign of the ongoing methodological "revolution".

The current deconstruction of paradoxes is one among several signs that a profound renewal of methods for clinical and epidemiological research is taking place; perhaps for some basic life sciences as well. The new methodological approaches have already deconstructed and explained long puzzling apparent paradoxes, including the (non-existent) benefits of obesity in diabetics, or of smoking in low birth weight. Achievements of the new methods also comprise the elucidation of the causal structure of long-disputed and highly complex questions, as Berkson's bias and Simpson's paradox, and clarifying reasons for deep controversies, as those on estrogens and endometrial cancer, or on adverse effects of hormone replacement therapy. These are signs that the new methods can go deeper and beyond the methods in current use. A major example of a highly relevant idea is: when we condition on a common effect of a pair of variables, then a spurious association between such pair is likely. The implications of these ideas are potentially vast. A substantial number of apparent paradoxes may simply be the result of collider biases, a source of selection bias that is common not just in epidemiologic research, but in many types of research in the health, life, and social sciences. The new approaches develop a new framework of concepts and methods, as collider, instrumental variables, d-separation, backdoor path and, notably, Directed Acyclic Graphs (DAGs). The current theoretical and methodological renewal-or, perhaps, "revolution"-may be changing deeply how clinical and epidemiological research is conceived and performed, how we assess the validity and relevance of findings, and how causal inferences are made. Clinical and basic researchers, among others, should get acquainted with DAGs and related concepts.

Self-rated health and chronic conditions are associated with blood concentrations of persistent organic pollutants in the general population of Catalonia, Spain.

BACKGROUND: Self-rated health (SRH) is a powerful predictor of mortality, morbidity, and need for health services. SRH generally increases with educational level, and decreases with age, number of chronic conditions, and body mass index (BMI). Because human concentrations of most persistent organic pollutants (POPs) also vary by age, education, and BMI, and because of the physiological and clinical effects of POPs, we hypothesized that body concentrations of POPs are inversely associated with SRH. OBJECTIVES: To analyze the relation between serum concentrations of POPs and SRH in the general population of Catalonia, Spain, taking into account sociodemographic factors and BMI, as well as chronic health conditions and mental disorders, measured by the General Health Questionnaire-12 (GHQ-12). METHODS: POP serum concentrations were measured by gas chromatography with electron-capture detection in 919 participants of the Catalan Health Interview Survey. RESULTS: Individuals with higher concentrations of POPs had significantly poorer SRH; e.g., the median concentration of HCB in subjects with poor SRH was twice as high as in subjects with excellent SRH (366 ng/g vs. 169 ng/g, respectively; p-value<0.001). In crude models and in models adjusted for sex and BMI, the POPs-SRH association was often dose-dependent, and the likelihood of poor or regular SRH was 2 to 4-times higher in subjects with POP concentrations in the top quartile. In models adjusted for age or for chronic conditions virtually all ORs were near unity. No associations were found between POP levels and GHQ-12. CONCLUSIONS: Individuals with higher concentrations of POPs had significantly poorer SRH, an association likely due to age and chronic conditions, but not to sex, education, social class, BMI, or mental disorders.

Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up.

OBJECTIVES: Substantial evidence associates persistent organic pollutants (POP) with metabolic disturbances related to diabetes, but longitudinal studies with repeated measures are scarce. We aimed to characterize the association between background exposures to POPs with repeated measures of glucose homeostasis over 23-years. METHODS: Within the Coronary Artery Risk Development in Young Adults study (year 0 ages: 18-30 years), we measured POPs in serum obtained in 1987-88 (follow-up year 2) in 90 non-diabetic controls and 90 cases diabetes-free at year 2 who became diabetic by year 20. We analyzed 32 POPs detectable in ≥75% of participants and created summary scores for 32 POPs, 23 polychlorinated biphenyls (PCB), and 8 organochlorine pesticides (OCP). Dependent variables were measures of glucose homeostasis at years 0-25 (up to 8 examinations). We explored associations using repeated measures regression adjusted for race, sex, concurrent body mass index (BMI), examination center and period, separately for cases and controls. RESULTS: The associations between the three summary scores and measures of glucose homeostasis were present for observations at ages 40-55 years, and particularly between 48-55 years: the 23 PCB summary was associated with HbA1c (never-diabetics: slope [value per unit of summary score], ß=0.008, p=0.02; diabetics: ß=0.03, p=0.07), fasting glucose (never-diabetics: ß=0.24, p=0.003; diabetics: ß=1.10, p=0.03), and insulin sensitivity% (never-diabetics: ß=-2.82, p<0.001, diabetics: ß=-0.31, p=0.30). No associations were observed at younger ages. CONCLUSIONS: Glucose homeostasis may worsen after decades of exposure to PCBs and OCPs at background environmental levels, independent of BMI and after participants reached the 5th decade of life.

The environmental roots of non-communicable diseases (NCDs) and the epigenetic impacts of globalization.

BACKGROUND: Non-communicable diseases (NCDs) are increasing worldwide. We hypothesize that environmental factors (including social adversity, diet, lack of physical activity and pollution) can become "embedded" in the biology of humans. We also hypothesize that the "embedding" partly occurs because of epigenetic changes, i.e., durable changes in gene expression patterns. Our concern is that once such factors have a foundation in human biology, they can affect human health (including NCDs) over a long period of time and across generations. OBJECTIVES: To analyze how worldwide changes in movements of goods, persons and lifestyles (globalization) may affect the "epigenetic landscape" of populations and through this have an impact on NCDs. We provide examples of such changes and effects by discussing the potential epigenetic impact of socio-economic status, migration, and diet, as well as the impact of environmental factors influencing trends in age at puberty. DISCUSSION: The study of durable changes in epigenetic patterns has the potential to influence policy and practice; for example, by enabling stratification of populations into those who could particularly benefit from early interventions to prevent NCDs, or by demonstrating mechanisms through which environmental factors influence disease risk, thus providing compelling evidence for policy makers, companies and the civil society at large. The current debate on the '25 × 25 strategy', a goal of 25% reduction in relative mortality from NCDs by 2025, makes the proposed approach even more timely. CONCLUSIONS: Epigenetic modifications related to globalization may crucially contribute to explain current and future patterns of NCDs, and thus deserve attention from environmental researchers, public health experts, policy makers, and concerned citizens.

The impact of including different study designs in meta-analyses of diagnostic accuracy studies.

Diagnostic accuracy may be overestimated when using certain study designs; thus, the inclusion of studies using different designs in meta-analyses may have important effects on their results, and influence clinical decision making. The main aim of this study was to explore the influence of heterogeneity (based on the inclusion of different study designs) on diagnostic accuracy in a sample of published meta-analyses of diagnostic accuracy studies. We identified 30 systematic reviews which included 95 separate meta-analyses combining the results from a total of 976 individual studies. We classified each individual study according to the study design (case-control studies, clinically relevant patient series or other), and each meta-analysis according to the heterogeneity of the included studies. Furthermore, we registered how the methodological quality of the individual studies was assessed. Finally, for each meta-analysis, the summary measure of diagnostic accuracy was categorised as Good, Fair or Poor. We used logistic regression to assess the relationship between reporting good diagnostic accuracy and heterogeneity. Meta-analyses with heterogeneous populations were over three times more likely to report good diagnostic accuracy compared to meta-analyses that included only clinically relevant patient series (adjusted odds ratio 3.07 95% CI 1.16-8.11). The combination of studies that use different designs, within the same meta-analysis, may lead to higher estimates of diagnostic accuracy.

Adipose tissue concentrations of persistent organic pollutants and prevalence of type 2 diabetes in adults from Southern Spain.

There is increasing evidence that environmental factors play an important role in the development of type 2 diabetes. Several persistent organic pollutants are suspected to contribute to the increasing prevalence and risk of type 2 diabetes. The aim of this study was to investigate the association of the body burden of three organochlorine pesticides and three polychlorinated biphenyls and the overall estrogenic activity with the risk of type 2 diabetes in a sample of adults from Southern Spain. Samples of adipose tissue and serum were obtained from 386 subjects undergoing non-cancer-related surgery and were extracted using validated methodologies. Residues of persistent organic pollutants were analyzed by means of high-resolution gas chromatography with a mass spectrometry detector in tandem mode. The overall estrogenicity of the adipose tissue extracts was measured by using the total effective xenoestrogen burden (TEXB) biomarker. Data on lifestyle, dietary habits, and health status were gathered from face-to-face interviews and clinical records. Statistical analyses were performed with unconditional logistic regression and different adjustment levels. In the models adjusted for adipose tissue origin, sex, age, and body mass index, the 2nd and 3rd tertiles of adipose tissue concentrations of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were positively associated with the risk of diabetes [odds ratios (95% confidence interval)=3.6 (0.8-17.3) and 4.4 (1.0-21.0), respectively]. A positive association with ß-hexachlorocyclohexane was also found when body mass index and adipose tissue origin were removed from the models, with odds ratios (95% confidence interval) of 3.3 (1.0-10.4) and 5.5 (1.7-17.3), for the 2nd and 3rd tertiles of exposure, respectively. In addition, a statistically significant interaction was observed between p,p'-DDE and body mass index, such that the risk of diabetes increased with tertiles of exposure in a linear manner in non-obese subjects but not in the obese, in whom an inverted U-shape pattern was observed.

Pancreatic cancer risk and levels of trace elements.

BACKGROUND AND AIMS: Knowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. METHODS: The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. OR and 95% CI, adjusted for potential confounders, were calculated using logistic regression. RESULTS: Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88; p(trend)=5×10(-6)), arsenic (OR 2.02, 95% CI 1.08 to 3.78; p(trend)=0.009) and lead (OR 6.26, 95% CI 2.71 to 14.47; p(trend)=3×10(-5)) were in the highest quartile. High concentrations of selenium (OR 0.05, 95% CI 0.02 to 0.15; p(trend)=8×10(-11)) and nickel (OR 0.27, 95% CI 0.12 to 0.59; p(trend)=2×10(-4)) were inversely associated with the risk of EPC. CONCLUSION: Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis.

Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization.

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.