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Influence of methyl donor nutrients as epigenetic regulators in colorectal cancer: A systematic review of observational studies.
Chávez-Hidalgo, LP, Martín-Fernández-de-Labastida, S, M de Pancorbo, M, Arroyo-Izaga, M
World journal of gastroenterology. 2023;29(7):1219-1234
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Colorectal cancer (CRC) is the third most frequent type of cancer and yet has the second highest mortality rate in cancer patients worldwide. Hence there is an urgency to understand more about dietary and lifestyle factors that can help to prevent this type of cancer. It is known that folate has a preventive function in CRC, possibly due to its role in DNA methylation. Methylation is the addition of methyl groups to DNA, which influences gene expression and regulation. This systematic review investigated how folate and other dietary methyl groups and methyl influencers such as B vitamins and alcohol influence the development of CRC, whilst also considering various genetic variants in methyl-metabolising enzymes (polymorphisms). The analysis included a total of 19 case-control and cohort studies and highlighted that potential interactions between methyl donor nutrients, genetic variants, and alcohol influence CRC risk. For most, high levels of folate intake were considered a protective factor, while high alcohol consumption proved to be a risk factor. Yet these interactions appear to be complex, with gender, genetic variations and folate status appearing to contribute to variable and, in some cases, contradictory outcomes. The authors suggested in their findings that Vitamin B6, Vitamin B3 (Niacin), and alcohol may affect CRC by influencing its risk by acting on both the genetic code itself and the epigenetic factors that control gene activity. Further research is needed to better understand the complexity of these mechanisms, and to help clarify the influence of methyl group donors as epigenetic regulators of gene activity in CRC development.
Abstract
BACKGROUND Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). However, whether the influence of methyl donor intake is modified by polymorphisms in such epigenetic regulators is still unclear. AIM: To improve the current understanding of the molecular basis of CRC. METHODS A literature search in the Medline database, Reference Citation Analysis (https:// www.referencecitationanalysis.com/), and manual reference screening were performed to identify observational studies published from inception to May 2022. RESULTS A total of fourteen case-control studies and five cohort studies were identified. These studies included information on dietary methyl donors, dietary components that potentially modulate the bioavailability of methyl groups, genetic variants of methyl metabolizing enzymes, and/or markers of CpG island methylator phenotype and/or microsatellite instability, and their possible interactions on CRC risk. CONCLUSION Several studies have suggested interactions between methylenetetrahydrofolate reductase polymorphisms, methyl donor nutrients (such as folate) and alcohol on CRC risk. Moreover, vitamin B6, niacin, and alcohol may affect CRC risk through not only genetic but also epigenetic regulation. Identification of specific mechanisms in these interactions associated with CRC may assist in developing targeted prevention strategies for individuals at the highest risk of developing CRC.
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Mycotoxin-Linked Mutations and Cancer Risk: A Global Health Issue.
Ekwomadu, T, Mwanza, M, Musekiwa, A
International journal of environmental research and public health. 2022;19(13)
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Mycotoxins are toxic substances produced by fungi, which can be found in common foods like maize, wheat, nuts, and foods containing them. Mycotoxins such as aflatoxins, ochratoxin, fumonisins, zearalenone, and some Penicillium toxins can alter genetic material. According to previous studies, they can damage genetic material and affect cell growth. Usage of chemicals such as fertilizers and fungicides is a common practice in the agricultural industry to protect plants from fungus and to feed them. However, fungicides can accelerate mycotoxin production. 16 studies were included in this Systematic Review and 11 in Meta-Analysis. This research looked at the harmful effects of mycotoxins such as aflatoxins, fumonisins, ochratoxin, T2, zearalenone, and some Penicillium toxins in causing cancers. The researchers evaluated the link between aflatoxin exposure and liver cancer, fumonisin B1 exposure and liver cancer, zearalenone exposure and breast cancer, zearalenone exposure and cervical cancer, citrinine and patulin exposure and colorectal cancer, and NEO, HT-2, and T-2 exposure and Oesophageal cancer. This research did not show significant associations between various mycotoxins and cancer risk. As currently, most studies are primarily focused on aflatoxin; more robust studies are needed to assess the cancer risk associated with different mycotoxin exposure. Using the results of this study, healthcare professionals can gain a better understanding of how mycotoxins affect our bodies.
Abstract
Humans continue to be constantly exposed to mycotoxins, mainly through oral exposure (dietary), inhalation, or dermal contact. Recently, it has been of increasing interest to investigate mycotoxin-linked carcinogenicity. This systematic review was conducted to synthesize evidence of the association between mycotoxin-linked mutations and the risk of cancer, to provide an overview of the data linking exposure to different mycotoxins with human cancer risk, and to provide an update on current research on the risk of cancer associated with human exposure to mycotoxins. PRISMA guidelines were used when conducting the systematic review. PubMed, MEDLINE, and CINAHL electronic databases were comprehensively searched to extract the relevant studies published from inception to May 2022. A total of sixteen relevant studies (4907 participants) were identified and included in this review. Of these, twelve studies were from Asia, while four of the studies were conducted in Africa. The overall meta-analysis result found no significant association, although some of the studies confirmed an association between mycotoxin-linked mutations and primary liver cancer risk. Mainly, the experimental studies have shown associations between mycotoxin-linked mutations and cancer risk, and there is a need for researchers to confirm these links in epidemiological studies in order to guide public health policies and interventions.
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Evidence on Human Exposure to Pesticides and the Occurrence of Health Hazards in the Brazilian Population: A Systematic Review.
Panis, C, Kawassaki, ACB, Crestani, APJ, Pascotto, CR, Bortoloti, DS, Vicentini, GE, Lucio, LC, Ferreira, MO, Prates, RTC, Vieira, VK, et al
Frontiers in public health. 2021;9:787438
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The use of pesticides to eradicate pests is a common agricultural practice. Between 2009 and 2019, Brazilians used more chemicals to eradicate weeds, fungi, and insects. Brazil is a heavy user of pesticides, but their toxic effects, including their health and environmental effects, have not been well studied. A total of 44 studies are included in this systematic review. There is a link between pesticide exposure and neurological damage, cancer, gastrointestinal issues, poisoning, hormonal irregularities, and malformations in children, according to the studies included in this review. The systematic review shows that pesticides are toxic to both rural and urban workers regardless of their age and gender. For a comprehensive assessment of pesticides' toxic effects on the environment and human health, more robust research is needed. Despite this, healthcare professionals can use the research findings to identify pesticide health impacts and make informed clinical decisions.
Abstract
Brazil is among the biggest pesticide consumers in the world, with its population severely exposed to tons of such substances, both because of environmental contamination and occupational use. The health consequences of pesticide exposure are well-documented, but still sparse regarding Brazilian population. This study systematically reviewed the Brazilian studies published that address the relationship between exposure to pesticides and health problems in the Brazilian population. Also, information about pesticide use in Brazil is provided. The included studies showed that exposure to pesticides has a relevant impact on the health of the Brazilian population, regardless of age and gender, and on workers in rural areas or not. Most poisoning events seem to result from the continuous use of pesticides, whether occupationally or environmentally, characterizing a public health problem. The major consequences reported in literature were damage to the central nervous system, cancer, deleterious effects on rural workers' health, intoxications, malformations, and endocrine changes. These findings point out the need to understand the impact of chronic exposure to pesticides on severely exposed people and highlight the importance of creating public policies to protect them and avoid disease occurrence.
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Exposure to glyphosate and risk of non-Hodgkin lymphoma: an updated meta-analysis.
Boffetta, P, Ciocan, C, Zunarelli, C, Pira, E
La Medicina del lavoro. 2021;112(3):194-199
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Glyphosate is an herbicide and crop desiccant widely used by professional applicators and consumers. The aim of this study was to update a recent systematic review and meta-analysis of epidemiologic studies to help clarify the association between exposure to glyphosate and risk of non-Hodgkin lymphoma (NHL). Results confirmed the conclusions drawn on the previous systematic review and meta-analysis i.e. that there was no association between exposure to glyphosate and the risk of NHL even though larger better-designed studies were analysed. Authors conclude that an association with risk of diffuse large B-cell lymphoma [happens when healthy B-cells change into fast-growing cancer cells that do not die] cannot be ruled out.
Abstract
OBJECTIVE We updated a recent systematic review and meta-analysis of epidemiologic studies to help clarifying the association between exposure to glyphosate and risk of non-Hodgkin lymphoma (NHL). METHODS We conducted an updated search of the literature, and identified a total of 15 relevant publications, from which we extracted results from six non-overlapping studies. We performed random-effects meta-analyses for ever-exposure to glyphosate, dose-response, and risk of specific NHL subtypes Results: The meta-RR for ever-exposure to glyphosate was 1.05 (95% confidence interval [CI] 0.90-1.24; I2 = 0%). The meta-RR for the highest category of exposure was 1.15 (95% CI 0.72-1.83; 3 studies). The meta-RR for diffuse large B-cell lymphoma (DLBCL) was 1.29 (95% CI 1.02-1.63; 4 studies), that for follicular lymphoma was 0.84 (95% CI 0.61-1.17), and that for chronic lymphocytic leukemia/small lymphocytic lymphoma was 1.33 (95% CI 0.65-2.70). There was indication of publication bias. CONCLUSIONS This updated meta-analysis reinforces our previous conclusion of a lack of an association between exposure to glyphosate and risk of NHL overall, although an association with DLBCL cannot be ruled out.
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Association between pesticide exposure and colorectal cancer risk and incidence: A systematic review.
Matich, EK, Laryea, JA, Seely, KA, Stahr, S, Su, LJ, Hsu, PC
Ecotoxicology and environmental safety. 2021;219:112327
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Pesticides that are applied to farms or yards can remain in the environment for longer than intended. The aim of this study was to investigate the association between human pesticide exposure and colorectal cancer (CRC) risk and incidence. This study is a systematic review of 139 studies (qualitative analysis). This review showed that there are similar numbers of significant positive and inverse associations between pesticide exposure and colon cancer, rectal cancer, or CRC risk. However, certain pesticides are of high concern in relation to these types of cancers. Authors conclude that further biological sample measurement studies are needed to determine the amount of time the pesticides or their metabolites remain in the environment or bio specimen from the population.
Abstract
BACKGROUND Studies investigating the association between pesticide exposure and colorectal cancer (CRC) risk have been inconclusive. OBJECTIVES Investigate the association between pesticide exposure and CRC risk through a systematic literature review. METHODS CRC has the fourth-highest rate of cancer-caused death in the US after lung cancer, breast cancer in women, and prostate cancer in men. Here we have conducted a systematic literature search on studies examining the association between any pesticide exposure and CRC risk using PubMed, MEDLINE via EBSCO host, and Embase according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. RESULTS Following the review, 139 articles were included for qualitative evaluation. Study participants were farmers, pesticide applicators, pesticide manufacturers, spouses of pesticide applicators, farm residents, Korean veterans of the Vietnam War, rural communities, and those who consumed food with pesticide residues. The studies' results were split between those with significant positive (39 significant results) and inverse (41 significant results) associations when comparing pesticide exposure and CRC risk. DISCUSSION From our literature review, we have identified a similar number of significant positive and inverse associations of pesticide exposure with CRC risk and therefore cannot conclude whether pesticide exposure has a positive or inverse association with CRC risk overall. However, certain pesticides such as terbufos, dicamba, trifluralin, S-ethyl dipropylthiocarbamate (EPTC), imazethapyr, chlorpyrifos, carbaryl, pendimethalin, and acetochlor are of great concern not only for their associated elevated risk of CRC, but also for the current legal usage in the United States (US). Aldicarb and dieldrin are of moderate concern for the positive associations with CRC risk, and also for the illegal usage or the detection on imported food products even though they have been banned in the US. Pesticides can linger in the soil, water, and air for weeks to years and, therefore, can lead to exposure to farmers, manufacturing workers, and those living in rural communities near these farms and factories. Approximately 60 million people in the US live in rural areas and all of the CRC mortality hotspots are within the rural communities. The CRC mortality rate is still increasing in the rural regions despite the overall decreasing of incidence and mortality of CRC elsewhere. Therefore, the results from this study on the relationship between pesticide exposure and CRC risk will help us to understand CRC health disparities.
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The Human Vulvar Microbiome: A Systematic Review.
Pagan, L, Ederveen, RAM, Huisman, BW, Schoones, JW, Zwittink, RD, Schuren, FHJ, Rissmann, R, Piek, JMJ, van Poelgeest, MIE
Microorganisms. 2021;9(12)
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Vaginal microbiome composition and its link with cancer is an emerging area in research. Imbalances in the vaginal microbiome could initiate carcinogenesis by altering immunity and metabolism and accelerating inflammation. This systematic review included ten studies and assessed the vulvar microbiome in premalignant vulvar disease and healthy vulvar skin. The healthy vulvar skin showed several bacterial taxa of Lactobacillus, Corynebacterium, Staphylococcus and Prevotella of intestinal, cutaneous and vaginal origin. L. crispatus and L. iners were dominant on the vulva of most healthy women. L. gasseri dominance was non-significantly associated with vestibulodynia. Menstruation did not alter the bacterial composition. Premenarchial Lichen sclerosus may have an association with microbial dysbiosis. Further robust studies are required to identify the vaginal microbial composition due to the high heterogeneity of the studies included, small sample size and methodological limitations. Healthcare professionals can utilise the data from this study to better understand how the vulvar microbiome influences disease aetiology and its importance as a target for therapy.
Abstract
The link between cancer and the microbiome is a fast-moving field in research. There is little knowledge on the microbiome in ((pre)malignant) conditions of the vulvar skin. This systematic review aims to provide an overview of the literature regarding the microbiome composition of the healthy vulvar skin and in (pre)malignant vulvar disease. This study was performed according to the PRISMA guidelines. A comprehensive, electronic search strategy was used to identify original research articles (updated September 2021). The inclusion criteria were articles using culture-independent methods for microbiome profiling of the vulvar region. Ten articles were included. The bacterial composition of the vulva consists of several genera including Lactobacillus, Corynebacterium, Staphylococcus and Prevotella, suggesting that the vulvar microbiome composition shows similarities with the corresponding vaginal milieu. However, the vulvar microbiome generally displayed higher diversity with commensals of cutaneous and fecal origin. This is the first systematic review that investigates the relationship between microbiome and vulvar (pre)malignant disease. There are limited data and the level of evidence is low with limitations in study size, population diversity and methodology. Nevertheless, the vulvar microbiome represents a promising field for exploring potential links for disease etiology and targets for therapy.
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An updated systematic review and meta-analysis on adherence to mediterranean diet and risk of cancer.
Morze, J, Danielewicz, A, Przybyłowicz, K, Zeng, H, Hoffmann, G, Schwingshackl, L
European journal of nutrition. 2021;60(3):1561-1586
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The development of cancer is associated with a number of risk factors, including smoking, obesity, sedentary lifestyles, alcohol consumption, infections, pollution, and dietary imbalances. Based on previous research, optimal consumption of fruits, vegetables, and whole grains, along with reduced consumption of red and processed meat, reduces cancer risk. According to this systematic review and meta-analysis, adherence to the Mediterranean diet is associated with lower cancer mortality and site-specific cancer development. A Mediterranean diet includes fruits, vegetables, nuts, legumes, fish, whole grains, extra virgin olive oil, and low amounts of red meat, processed meat, egg, and dairy, along with moderate amounts of red wine. According to this systematic review and meta-analysis, adherence to the Mediterranean diet reduces the risk of cancer mortality and the risk of developing cancers specific to the site, such as colorectal cancer, bladder cancer, gastric cancer, and lung cancer. Among the components of the Mediterranean diet, fruits, vegetables, and whole grains have been shown to reduce cancer risk. Bioactive substances found in Mediterranean diet components require additional robust studies to evaluate their benefits. A healthcare professional can use the results of this study to make clinical decisions and recommend therapeutic interventions to cancer patients.
Abstract
PURPOSE The aim of current systematic review was to update the body of evidence on associations between adherence to the Mediterranean diet (MedDiet) and risk of cancer mortality, site-specific cancer in the general population; all-cause, and cancer mortality as well as cancer reoccurrence among cancer survivors. METHODS A literature search for randomized controlled trials (RCTs), case-control and cohort studies published up to April 2020 was performed using PubMed and Scopus. Study-specific risk estimates for the highest versus lowest adherence to the MedDiet category were pooled using random-effects meta-analyses. Certainty of evidence from cohort studies and RCTs was evaluated using the NutriGrade scoring system. RESULTS The updated search revealed 44 studies not identified in the previous review. Altogether, 117 studies including 3,202,496 participants were enclosed for meta-analysis. The highest adherence to MedDiet was inversely associated with cancer mortality (RRcohort: 0.87, 95% CI 0.82, 0.92; N = 18 studies), all-cause mortality among cancer survivors (RRcohort: 0.75, 95% CI 0.66, 0.86; N = 8), breast (RRobservational: 0.94, 95% CI 0.90, 0.97; N = 23), colorectal (RRobservational: 0.83, 95% CI 0.76, 0.90; N = 17), head and neck (RRobservational: 0.56, 95% CI 0.44, 0.72; N = 9), respiratory (RRcohort: 0.84, 95% CI 0.76, 0.94; N = 5), gastric (RRobservational: 0.70, 95% CI 0.61, 0.80; N = 7), bladder (RRobservational: 0.87, 95% CI 0.76, 0.98; N = 4), and liver cancer (RRobservational: 0.64, 95% CI 0.54, 0.75; N = 4). Adhering to MedDiet did not modify risk of blood, esophageal, pancreatic and prostate cancer risk. CONCLUSION In conclusion, our results suggest that highest adherence to the MedDiet was related to lower risk of cancer mortality in the general population, and all-cause mortality among cancer survivors as well as colorectal, head and neck, respiratory, gastric, liver and bladder cancer risks. Moderate certainty of evidence from cohort studies suggest an inverse association for cancer mortality and colorectal cancer, but most of the comparisons were rated as low or very low certainty of evidence.
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Dietary Intake of Acrylamide and Risk of Breast, Endometrial, and Ovarian Cancers: A Systematic Review and Dose-Response Meta-analysis.
Adani, G, Filippini, T, Wise, LA, Halldorsson, TI, Blaha, L, Vinceti, M
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020;29(6):1095-1106
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Acrylamide is an organic industrial chemical that is white, odourless, and crystalline in structure. It is used primarily in paper and plastic production as a flocculating agent to purify drinking water and wastewater, and as a sealing agent in buildings. The study is a dose–response meta-analysis based on epidemiologic studies of acrylamide dietary intake and risks of female breast, endometrial, and ovarian cancer. Results show that acrylamide intake was associated with small increased risks of endometrial and ovarian cancer, with stronger and almost linear associations among never smokers. However, no positive relation emerged for breast cancer, except among premenopausal women for exposure above 20 mg/day. Authors conclude that their findings support the currently ongoing efforts to monitor and minimize acrylamide intake.
Abstract
Acrylamide is a probable human carcinogen. Aside from occupational exposures and smoking, diet is the main source of exposure in humans. We performed a systematic review of the association between estimated dietary intake of acrylamide and risk of female breast, endometrial, and ovarian cancers in nonexperimental studies published through February 25, 2020, and conducted a dose-response meta-analysis. We identified 18 papers covering 10 different study populations: 16 cohort and two case-control studies. Acrylamide intake was associated with a slightly increased risk of ovarian cancer, particularly among never smokers. For endometrial cancer, risk was highest at intermediate levels of exposure, whereas the association was more linear and positive among never smokers. For breast cancer, we found evidence of a null or inverse relation between exposure and risk, particularly among never smokers and postmenopausal women. In a subgroup analysis limited to premenopausal women, breast cancer risk increased linearly with acrylamide intake starting at 20 μg/day of intake. High acrylamide intake was associated with increased risks of ovarian and endometrial cancers in a relatively linear manner, especially among never smokers. Conversely, little association was observed between acrylamide intake and breast cancer risk, with the exception of premenopausal women.
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Anti-aging Effects of Calorie Restriction (CR) and CR Mimetics based on the Senoinflammation Concept.
Kim, DH, Bang, E, Jung, HJ, Noh, SG, Yu, BP, Choi, YJ, Chung, HY
Nutrients. 2020;12(2)
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Low grade, systemic, chronic inflammation is a feature of ageing and underlies many age-related chronic diseases states. As cells age their capacity to proliferate declines, which is referred to as cell senescence. Such senescent cells release multiple inflammatory markers contributing to a pro-inflammatory state. This is further aggravated by elevated oxidative stress and a reduced capacity to manage it, eventually leading to improper gene regulation and DNA damage. To define this age-related, complex inflammatory phenomena the authors introduced the term senoinflammation. A well-established intervention to reverse or slow down the ageing process and many ageing-associated diseases is calorie restriction (CR), by means of reducing overall caloric intake without malnutrition. CR exhibits potent anti-inflammatory effects, reduces age-associated oxidative stress, improves age-related metabolic dysregulation and enhances favourable gene expression. This review summarises how CR and CR-mimicking substances exert their anti-inflammatory effect and some of the cellular mechanism involved and may be of interest to those who are looking to get a more detailed understanding on ageing, inflammation and the benefits of CR.
Abstract
Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view, as proposed in our previous work. In this review, we discuss the effects of CR on multiple phases of proinflammatory networks and inflammatory signaling pathways to elucidate the basic mechanism underlying aging. Based on studies on senoinflammation and CR, we recognized that senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. These results further support and enhance our understanding of the novel concept of senoinflammation, which is related to the metabolic changes that occur in the aging process. Furthermore, a thorough elucidation of the effect of CR on senoinflammation will reveal key insights and allow possible interventions in aging mechanisms, thus contributing to the development of new therapies focused on improving health and longevity.
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Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence.
Zhang, L, Rana, I, Shaffer, RM, Taioli, E, Sheppard, L
Mutation research. Reviews in mutation research. 2019;781:186-206
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Glyphosate is a highly effective broad-spectrum herbicide that is typically applied in mixtures known as glyphosate-based herbicides (GBHs). Glyphosate and its metabolites persist in food, water, and dust, potentially indicating that everyone may be exposed ubiquitously. The objective of this study was to focus on an a priori hypothesis - the highest biologically relevant exposure to GBHs, i.e., higher levels, longer durations and/or with sufficient lag and latency, will lead to increased risk of non-Hodgkin lymphoma (NHL) in humans. This study is a meta-analysis of six studies (one cohort and five case-control control studies) with almost 65,000 participants. Results demonstrated a significantly increased NHL risk in highly GBH-exposed individuals. Authors conclude that the overall evidence from human, animal, and mechanistic studies presented in this study, supports a compelling link between exposures to GBHs and increased risk for NHL.
Abstract
Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.