Do glyphosate-based herbicides cause cancer, liver disease and metabolic dysfunction? Part 1.

Despite accumulated data, the evidence of causality remains inconclusive.

Much discussion in the health dissident/freedom/alternative circles has been dedicated to food and environmental causes of chronic illness. These causes are at the forefront of MAHA strategy, too. This article is not about MAHA, however. I wanted to look into the issue of pesticides and herbicides, specifically much discussed glyphosate as a possible major cause of chronic and terminal illness. I would like to state upfront, that I am in no way advocating for glyphosate nor defending Monsanto. In general, these chemicals are dangerous and their use should be minimized. Use of less environmentally harmful methods of weed and insect control should be promoted.

The objective of this article is to look at the balance of evidence for CAUSALITY of chronic illness by glyphosate.

Glyphosate exposure vs chronic liver disease and metabolic dysfunction.

A very extensive review paper "Are glyphosate or glyphosate-based herbicides linked to metabolic dysfunction-associated steatotic liver disease (MASLD)? The weight of current evidence” was published recently. This narrative review paper examines the epidemiological and (pre)clinical data linking glyphosate (GLY) and glyphosate-based herbicides (GBH) to metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). Glyphosate [GLY, N-(phosphonomethyl) glycine (CAS 1071–83–6)] is the most extensively applied herbicide worldwide. The development and adoption of glyphosate-tolerant crops have significantly increased GLY application, by up to 15 times. The use of GBHs as pre-harvest desiccants contributes to higher GLY residue levels in food. Continuous human exposure occurs through environmental contamination (soil and water) and food. In the USA, "80–60 % of vegetables contain pesticide residues, and up to 6.5 % exceeded established levels." In Brazil, "41–33 % of analyzed products contained pesticide residues, with 25 % showing irregularities."

The authors are from Latin America, and reviewed dozens of studies - human, animal models, and cellular-based models of mechanisms of toxicity. For my purposes, I reviewed the section summarizing studies in humans only.

Epidemiological Evidence: Association Between Urinary GLY and MASLD Outcomes:

• Human studies, primarily reanalyzes of USA data (NHANES), show a link between urinary GLY levels and various MASLD outcomes and related comorbidities (steatosis risk, advanced fibrosis, increased transaminases) and comorbidities (higher risk for metabolic syndrome, diabetes, obesity and cardiovascular diseases).

• Increased urinary GLY is positively associated with the fatty liver index (FLI) score.

• Increased urinary GLY in NASH patients (vs. not NASH) (0.84 vs. 0.53 μg/L) and in patients with advanced fibrosis (stages 2–4) (vs. stages 0–1) (0.93 vs. 0.38 μg/L)."

• Higher urinary GLY levels were linked to increased levels of liver enzymes (ALP, ALT, AST) and fibrosis scores and were associated with a higher proportion of individuals with "steatosis, but also with Type 2 diabetes (T2DM), hypertension, cardiovascular diseases (CVD), chronic kidney diseases, and obesity, which are hallmarks of NAFLD/MASLD.

• Increased urinary GLY were associated with a "29 % higher risk for all-cause mortality" and a "32 % higher risk for cardiovascular mortality."

• A 2-fold increase in urinary AMPA (a GLY metabolite) was associated with an increased risk of elevated liver transaminases and metabolic syndrome in adolescents.

• Living near agricultural GLY applications during early childhood was associated with an increased risk for metabolic syndrome in adulthood.

In summary, this review established a convincing association between urinary levels of glyphosate and various chronic liver and kidney diseases as well as corresponding increases in all-cause mortality.

Limitation of this review - all studies were retrospective database reviews, and thus only a statistical association between parameters of interest could be demonstrated. Causality is difficult to establish with this method. Most of the studies assess urinary levels of GLY and tie them to the liver disease, however, higher levels of urinary GLY could be the result of liver dysfunction/microbiome destruction by other vectors which impair GLY clearance as well as other toxin clearance from the body. Metabolic dysfunction can occur as a result of destroyed gut biome, and liver injury is also a downstream effect from this damage. The authors of the paper state the same as their conclusions - association, yes, causality - not really:

The reviewed literature suggests a potential link between glyphosate and glyphosate-based herbicide exposure and the development and progression of MASLD and its associated comorbidities. While epidemiological studies show associations, and in vitro and rodent studies provide insights into potential mechanisms across the liver, adipose tissue, and gut microbiome axes, further research using more realistic exposure levels, complex in vitro models, and diverse human populations is needed to definitively establish causality and better understand the long-term health implications of chronic GLY/GBH exposure. The distinct effects observed between pure glyphosate and commercial formulations also emphasize the importance of considering the role of adjuvants.

The best way to address the causal relationship, of course, would be to conduct a prospective randomized trial, selecting people who are frequently exposed to glyphosate and those who are not exposed as much and comparing the outcomes in these cohorts. That would be a long and expensive study, however, with all the grant money collectively spent on publishing review papers such as the one I have quoted, why not invest in something like this instead? It seems that, as usual, there is more academic interest in endlessly studying this issue vs. finding the answer.

We can try to look for more indirect evidence. Specifically, if glyphosate is indeed causative agent of chronic disease, then we should see an increased incidence of the disease in people who are routinely exposed to herbicides - farm workers vs general population. I could not find data for liver and metabolic disease, but I found a large cohort analysis of the incidence of various cancers in people exposed to herbicides vs general public, in France.

Cancers in farmworkers vs general public in France.

While liver disease, metabolic dysfunction and cancers are reported in agricultural workers overall, very few studies compare these reports between agricultural workers and general population. If glyphosate is a leading cause of chronic disease, then, people who are exposed to it more than general population should have a higher incidence of the disease.

AGRICAN is a large prospective cohort study including farmowners and farmworkers and a significant proportion of women. Among the 567,157 subjects who met the inclusion criteria, 181,842 returned the self-administered questionnaire and were included in the cohort.

More than 180,000 participants in the AGRICAN cohort were matched to cancer registries to identify cancer cases diagnosed from enrolment (2005-2007) to 31^st December 2011 and calculate standardized incidence ratios (SIRs) and 95% confidence interval (CI). Over the period, 11,067 incident cancer cases were identified (7,304 men and 3,763 women). The results showed an unexpected picture: the cancer risk was overall not different between the pesticide users and the general population, while in several types of cancer the risk was reduced for people heavily exposed to pesticides.

Conclusion from AGRICAN cohort study (emphasis mine):

There was no difference in the incidence of cancer between cohort members and the general population. However, the risk in farmowners was decreased for both genders.

These findings are consistent with previous meta-analyses [3,4], a large Nordic cohort study [14] and the AHS study investigating private pesticide applicators (mainly farmowners) [19,20]. In a complementary analysis, after excluding all prevalent cancers and when cancer cases were censored at the first date of diagnosis, a significant lower incidence of overall cancer was observed.

Even if the increase in risk did not persist among the understudied population of farmworkers, the lower cancer incidence remained more pronounced among farmowners, a finding that deserves further attention. (Supplementary materials 4).

Overall cancer: incidence is LOWER in pesticide users.

During the 5.1 years of follow-up (Supplementary materials 3), there were 7,304 incident cancer cases among men and 3,763 among women. No difference was observed for overall cancer incidence for both males (SIR= 0.99, 95%CI 0.97-1.01) and females (SIR= 0.98, 95%CI 0.95-1.02) even if the risk was decreased in farmowners in both genders and was increased in male farmworkers (SIR= 1.07, 95%CI 1.03-1.12) (Table 3). Cancer incidence was lower among male pesticide users on crops (SIR= 0.94, 95%CI 0.91-0.97) and among other pesticide users for both males (SIR= 0.89, 95%CI 0.81-0.99) and females (SIR= 0.88, 95%CI 0.79-0.99)

Upper aero-digestive tract and respiratory cancers: incidence is LOWER in pesticide users.

A lower incidence was observed among both men and women for oral cavity and pharynx cancers (SIR= 0.61, 95%CI 0.53-0.70 and SIR= 0.48, 95%CI 0.33-0.69 respectively), for lung cancers (SIR= 0.58, 95%CI 0.54-0.63 and SIR= 0.66, 95%CI 0.56-0.77 respectively), and, for men only, for laryngeal cancers (SIR= 0.56, 95%CI 0.43-0.72) and mesothelioma (SIR= 0.36, 95%CI 0.21-0.56). For most of these cancers, the decrease in risk was more pronounced among people who ever worked on farm, especially farmowners. No difference was observed according to pesticide use.

Digestive cancers: incidence is LOWER in pesticide users.

There was reduction on oesophageal, colon and pancreatic cancers in males, in rectal and anal cancer in females and in liver cancer in both. Men who ever worked on farm had a lower colon cancer incidence (SIR= 0.82, 95%CI 0.75-0.90) unlike males who did not work on a farm. Among women, pancreatic cancer was decreased among farmowners (SIR= 0.67, 95%CI 0.48-0.92) but was greater than one among farmworkers. No overall difference was observed for stomach cancer even though the risk was decreased in male farmowners (SIR=0.79, 95%CI 0.65-0.96) and was increased in female farmworkers and women who never used pesticides.

Reproductive and endocrine system cancers: Some types of cancers are HIGHER, some LOWER in the pesticide users.

Men, especially those who ever worked on farm, had a significantly increased incidence of prostate cancer (SIR= 1.07, 95%CI 1.03-1.12), which was more pronounced among farmworkers and in subjects who ever (SIR= 1.09, 95%CI 1.03-1.15) or never used pesticides (SIR= 1.27, 95%CI 1.06-1.50) (Table 4). The number of male breast cancer cases was higher than expected. Decreased risks were observed for breast and cervix uteri cancers among all women and those who ever worked on farm (SIR= 0.84, 95%CI 0.79-0.91 and SIR= 0.64, 95%CI 0.42-0.95 respectively). Breast cancer risk was lower in women who used pesticides on crops (SIR= 0.70, 95%CI 0.57-0.84). No overall difference was observed for corpus uteri and ovarian cancers, but there were a higher number of ovarian cancers in pesticide users on crops.

Thyroid cancer was significantly reduced in men who ever worked on farm (SIR= 0.62, 95%CI 0.40-0.93) especially farmowners. No overall difference was observed in women whereas an increase was observed in female farmowners and those who never used pesticides.

Lip and cutaneous cancers: HIGHER risk in pesticide users

Unlike men, women experienced an increased risk of skin melanoma (SIR= 1.23 95%CI 1.05-1.43), mainly those using pesticides on crops (Table 5). An excess of lip cancer was observed in men, almost all cases occurring in men using pesticides on crops (SIR= 2.05, 95%CI 1.27-3.13). These excesses were more pronounced among farmworkers.

Hematological malignancies: Some HIGHER and some LOWER risk in pesticide users.

Men had an increased incidence of non-Hodgkin lymphoma (NHL) (SIR= 1.09, 95%CI 1.01-1.18) (Table 6). Higher risks were observed in men and women for multiple myeloma (SIR= 1.38, 95%CI 1.18-1.62 and SIR= 1.26, 95%CI 1.02-1.54 respectively), more pronounced in male farmowners (SIR=1.59 95%CI 1.29-1.95) and pesticide users on crops (SIR= 1.49, 95%CI 1.19-1.84). The incidence of follicular lymphoma was lower in men (SIR= 0.67, 95%CI 0.45-0.97). In contrast, myelodysplastic syndromes (MDS) were more numerous among women (SIR= 1.34, 95%CI 1.08-1.63), particularly among farmowners (SIR=1.57 95%CI 1.12-2.13).

I would like to also point out that the statistically significant increases in cancer risk, calculated from the data, should be calculated on the absolute basis, not just relative basis as presented in the paper. There can be a large increase in calculated risk, but if it is for a very rare type of cancer, that increase doesn’t translate to anything particularly dangerous for an individual. As an example, taking the value for multiple myeloma, where male pesticide users were found to have a 38% increased risk. American Cancer Society estimates the background risk of developing this cancer in men at 1%. Therefore in people heavily exposed to pesticides, the risk becomes about 1.38%.

Therefore, should we conclude from this study that exposure to glyphosate is protective against cancers in general? If this were an mRNA vaccine study, the authors would claim that and rags like NEJM and Lancet would publish without blushing. Of course, GLY is not a cancer cure, the AGRICAN study simply demonstrates that it is not the causative agent of cancer, and therefore something else is going on. As in all academic research, adjustments for vaccination status are strictly forbidden when looking for causes of chronic disease. However, let’s note that France is one of the world’s most vaccine skeptical countries, with ~1/3 of adults believing that vaccines are not safe. While I could not find any studies specifically looking at vaccine skepticism in French farmworkers, I found data showing lower % of vaccination uptake in the Southern regions of France vs. the North, which would roughly indicate that resistance to vaccinations is more prevalent in agricultural areas. This trend - the tendency for (very healthy!) distrust of the government in the rural areas - is consistent among practically all nations, including the United States.

Finally, in the United States, the agricultural Amish community is consistently much healthier than the general population. The Amish do use pesticides and herbicides, as much as any other small to medium size farmers do, and their children are exposed to them. What is the main difference vs general America? The Amish do not vaccinate.

Additional considerations - economic and environmental impact of banning/limiting glyphosate use.

A study in Austria looked into toxic exposure and toxic load on pollinator insects, earthworms and birds (all natural helpers and pest controllers in agriculture) from limiting use of glyphosate: Reduced use of pesticides and herbicides may increase toxic loads on pollinator insects, earthworms and birds.

The substantial 24% decrease in herbicide amounts between 2010 and 2019 can be attributed to several circumstances. First, in 2013, crop desiccation was banned in Austria for glyphosate, the most commonly used AI, mainly due to public pressure following herbicide-contaminated food and human urine samples [109]. Glyphosate was reduced by 38% from 408 tonnes in 2010 to 252 t in 2019. Second, Austrian Federal Railways, the second largest user of herbicides after agriculture, committed to reduce herbicide use [15]. Third, organically managed farmland with herbicide bans increased by 18% from 568,193 ha in 2010 to 669,921 ha in 2019 [69]. While organic farms typically use cover crops, tillage, and other mechanical methods to control weeds, some organically approved “burn-down” herbicides containing simple organic acids such as acetic acid, capric acid, caprylic acid, and pelargonic acid are available and are used in some crops.

The table shows an overall decline of pesticide use in Austria (representative trend for EU):

This indicates a shift towards active ingredients (chemicals in pesticides and herbicides) that are less hazardous to humans. However, over the same period, the decrease in herbicide amounts resulted in a 487% increase in persistence-weighted toxic loads for honeybees, 498% for earthworms, and 580% for birds. This result is relevant in that the reduction of herbicide amounts and risks to humans is partially close to the pesticide reduction targets set by the European Union under the “farm-to-fork”-strategy, but drastically missed the target of also reducing ecotoxicological risks for non-target organisms and biodiversity [108]. It is important to note that ecotoxicological risks are based on effects of toxicity versus exposure, while this study only considered toxic loads but not the exposure routes and factors that modify the actual exposure.

However, in contrast to Austria, glyphosate, which has low acute toxicity to honeybees and low persistence, increased in the USA over the years [116]. The increase of glyphosate in the USA is also associated with increasing toxicity to native plant species in soybean production [61], which negatively affects plant-pollinator-relationships. Although the acute toxicity of glyphosate to honeybees, earthworms and birds is rather low, several sublethal effects considering activity, embryonic development, reproduction, gut microbiota, foraging and navigation, have been reported [32, 33, 117, 118].

Finally, herbicides can have high toxic loads because they are either toxic (e.g., diquat), very persistent (e.g., diquat, iron sulphate), or used in large amounts (e.g., glyphosate), or have a combination of these properties.

Conclusions:

My article was intended to provide a balanced analysis of glyphosate as a causative agent of chronic illness. The data shows a conflicting picture, with no clear causality established, especially with regard to cancers. While reducing use of harmful chemicals in the environment and food supply is a worthy goal by itself, it is highly unlikely that it would solve the chronic disease crisis, especially in younger people and children that we are experiencing in the US and in the Western world in general.

Art for today: Fallen Leaf Lake and Mt Tallac, watercolor, 11x14 in.