Why do so many people think glyphosate (Roundup) causes cancer whereas most studies show no link between glyphosate and cancer?

For context, this is a question I answered on Quora

Is Glyphosate and its various formulas linked to Cancer through Endocrine Disruption?

This is a question none of the detractors against the thousands of lawsuits filed against Bayer have bothered to ask, likely because it doesn’t fit their narrative. However, the evidence that it is on top of being a Neurotoxin (through its main metabolite), Hepatotoxin and Nephrotoxin, can kill symbiotic gut microbiota that have a shikimate pathway and can also disturb the endocrine system at current background concentrations has not been considered. While its main effect on the human body is via oxidative stress in multiple organs, below legally admissible levels, it also changes production of key steroid hormones in the body at concentrations below what the EPA considers cytotoxic.

Endocrine Disruption is evident below cytotoxicity thresholds

A cell culture study that measured the endocrine-disrupting effects of glyphosate, five co-formulants, and six commercially available formulations (including RoundUp) on aromatase enzyme activity (conversion of androgens to estrogen) in human placental cells found that all inert co-formulants inhibited this particular enzyme and disrupted mitochondrial respiration well below both agricultural dilution levels and no observed effect concentrations for cytotoxicity. All co-forumulants inhibited this enzyme at 20-67% below the no observed effect concentration while all glyphosate based formulas inhibited this enzyme at 20-200% below the no observed effect concentration while glyphosate itself was negligible at concentrations below the toxicity threshold. This is not surprising since glyphosate itself has been found to be far less cytotoxic than its inert co-formulants. One inert co-formulant in particular, polyethoxylated tallow amine, has been found to be 2,000x more cytotoxic than glyphosate itself.

Two prior cell culture studies published in Environmental Health Perspectives and Toxicology also found that both glyphosate formulas and glyphosate alone inhibited aromatase activity, changed aromatase gene expression, disrupted estrogen and androgen dependent transcriptional activities, and reduced cell viability of placental cells and human liver cells with hepatocellular carcinoma below both the agricultural dilution level and observed cytotoxicity level.

A fourth cell culture study found that RoundUp formula and glyphosate alone inhibited estrogen synthesis at non-toxic concentrations in human embryonic kidney cells and that glyphosate inhibited estrogen synthesis even when its acidity was neutralized. These results were replicated in placental microsomes as well.

A fifth cell culture study that used follicular cells from pig ovaries found that glyphosate exposure decreased cell proliferation, inhibited intracellular ATP production and steroidogenesis at every concentration tested included below the cyctotoxicity threshold.

These cell culture experiments likely underestimate the endocrine disrupting potential of glyphosate and glyphosate formulas because they last no more than 3 days and thus do not account for chronic exposure and bioaccumulation that occurs over decades.

A rodent study of newborns exposed to glyphosate based formula, through water, at the no observed adverse effect level, found that the exposed group experienced a significant delay in the pubertal age over the course of the 30 day experiment.

In rodent experiments using adult male rats, exposure to glyphosate based herbicides has been found to diminish blood testosterone levels. This result has been replicated in cell culture where glyphosate exposure is found to inhibit testosterone synthesis and lower the rate of steroidogenesis.

The harm from glyphosate exposure via endocrine disruption is evident even in the general population.

A retrospective urinalysis study of a subset of elderly adults who participated in the Rancho Bernardo Study and had routine morning spot urinary biospecimens (n = 100) found that their mean urinary glyphosate concentrations increased 13x over 2 decades from 0.024 micrograms/L between 1993-96 to 0.314 micrograms/L between 2014-16. Among 70 participants with urinary glyphosate concentrations above the limit of detection, mean concentration was 0.45 micrograms/L ( between 2014-16 and among 71 participants with urinary AMPA (main metabolite of glyphosate) concentrations above the limit of detection the mean concentration was 0.4 micrograms/L.

A birth cohort study among women receiving prenatal care in central Indiana who provided two urine samples and a drinking water sample, medical charts after giving birth and filled out questionnaires related to dietary/life style and demographics (n = 71) found that 93% of participants (66/71) had urinary glyphosate concentrations above the limit of detection 0.1 ng/mL. Mothers in rural areas had significantly higher concentrations of urinary glyphosate than mothers in urban areas and urinary glyphosate concentrations were inversely correlated with gestational duration.

A prospective urinalysis study of high risk pregnant women in the first trimester and their newborns selected from the Indiana Pregnancy Environmental Exposures Study who provided samples between 2013 and 2016 (n = 187) found that urinary glyphosate concentration is inversely related to newborn birth weight adjusted for gestation (percentile) even after controlling for social demographic, geographic, health, and behavioral variability in their linear regression model. They also found that this relationship was more likely to be found for pregnant women who lived outside the Indianapolis metro area. In a logistic regression model they found a significant positive relationship between maternal urinary glyphosate concentrations and NICU admission of newborn among a subset of participants ‘with no use of alcohol or opioid/THC or polysubstance use, no hypertension, and those living in Indiana’s large central metropolitan area.’ Mean maternal urinary glyphosate concentration was 3.3 ng/L in 186/187 samples above the limit of detection.

Oxidative stress and endocrine disruption can both indirectly lead to cancer on their own, but are much more likely to do so in combination. Phosphate toxicity is another condition that can stimulate cancer cell growth especially after chronic exposure to nephrotoxins, which glyphosate and its formulas are, that cause nephropathy by damaging the nephrons and proximal tubules that are needed to regulate inorganic phosphate levels in the blood. Inevitable phosphate accumulation in the kidneys and surrounding tissue can cause oxidative stress, inflammation, and mitochondrial dysfunction itself and disrupt the endocrine network involving the kidneys, intestines, parathyroid glands, and bones, which normally regulates phosphate homeostasis. Phosphate toxicity also creates a tumor friendly environment by inducing new blood vessel formation, chromosome instability, and drive RNA biogenesis and protein synthesis critical for cancer cell growth.

Carcinogenesis associated with Toxic Nephropathy

Pesticide use is already extensively associated with higher cancer rates. In the real world glyphosate isn’t used by itself but mixed with co-formulates that are hundreds of times more cytotoxic than glyphosate and glyphosate based formulas are mixed and spread with other pesticide formulas as well.

A follow-up comprehensive systematic review and meta-analysis utilizing a random effects model to synthesize 40 years of epidemiological data from studies examining the relationship between farming and brain cancer (n = 52) found that farming is associated with a 13% increased relative risk of brain cancer morbidity or mortality compared to non-farmers. 40 of the 52 studies reported positive associations between farming and brain cancer, with effect estimates ranging from 1.03 to 6.53 which were particularly elevated among white farmers while farmers with documented pesticide exposure had greater than a 20% increased relative risk of brain cancer.

A hospital-based, case-control study of glioma and meningioma patients diagnosed between 1994-98 (n = 657) and healthy controls (n = 765) found, through personal interviews detailing occupational histories and questionnaires assessing pesticide exposure combined with measurement data from published sources to improve exposure classification, that women who had ever used herbicides occupationally had a significantly increased risk of meningioma compared to women who never used herbicides (Odds Ratio (OR): 2.4, 95% Confidence Interval (CI): 1.4, 4.3). The risk of meningioma diagnosis increased on a dose dependent curve as a function of cumulative exposure and years of exposure.

An ecological, county-level study assessing joint exposure to agrichemical mixtures and pediatric cancer incidence utilizing a Generalized Weighted Quantile Sum Regression model to analyze data on agrichemical use and pediatric cancer collected from 1992 to 2014 found a statistically significant positive association between exposure to agrichemical mixtures and overall pediatric cancer incidence, including major subtypes such as brain and CNS tumors and leukemia. A 10% increase in exposure to these pesticide mixtures was associated with a 36% increase in brain and CNS cancer rates, a 23% increase in leukemia rates, and a 30% increase in overall pediatric cancer rates. Herbicides and insecticides—including dicamba, glyphosate, paraquat, quizalofop, triasulfuron, and tefluthrin—were among the largest contributors to these associations.These results remain statistically significant even after adjusting for social vulnerability and after repeated holdout validation.

Another ecological, county-level study found statistically significant correlations between higher pesticide use and increased incidence rates of selected cancers at the county level.

A population level study of the carcinogenicity of pesticide use across the U.S. that employed latent class analysis to measure patterns of pesticide use at the county level (n = 3,143), which were extracted from the U.S. The Geological Survey found that the counties most affected by pesticide use are concentrated in the midwest where pesticide use is associated with 21,000 additional cases of colon cancer and 3,800 additional cases of pancreatic cancer. Pesticide use patterns in the midwest and west coast were associated with 4,600 additional cases of leukemia and 7,600 additional cases of non-Hodgkin's lymphoma. The corn producing states of Iowa, Illinois, Nebraska, Missouri, Indiana, and Ohio consistently had the highest added risk for these cancers. The increased pancreatic cancer risk associated with pesticide use patterns is similar to the pancreatic cancer risk associated with smoking habits.

A meta-analysis and systematic literature review of epidemiological studies investigating the association between parental pesticide exposure and childhood brain tumor risk (n =15) found that maternal agriculture exposures during pregnancy were associated with a significantly increased risk of childhood brain tumors: RR = 1.48 (95% CI: 1.18–1.84) and that maternal exposure to non-agricultural pesticides during pregnancy had a lower but still elevated risk (RR = 1.36, 95% CI: 1.10–1.68) of childhood brain tumors with a dose dependent pattern. Paternal exposure to pesticides during preconception also showed a significantly higher risk: combined analysis from three studies produced an odds ratio of 2.29 (95% CI: 1.39–3.78) while paternal exposure during pregnancy yielded a higher odds ratio of 1.63 (95% CI: 1.16–2.31) from five separate studies.

By most studies do you mean studies conducted by Monsanto employees including those they ghost wrote for “independent academics” who they paid to put their names on Monsanto controlled studies? Do you mean the studies where they disingenuously analyzed technical glyphosate isolated from its much more cytotoxic co-formulates and other herbicides that glyphosate based formulas are mixed with in real world settings eliminating not only the synergistic toxicity of co-formulates but also the synergistic toxicity of other herbicide formulas. Science isn’t a purely quantitative discipline. Just because you have a higher number of highly biased studies with low external validity doesn’t mean you have more evidence.