Chang, V. C., Andreotti, G., Ospina, M., Parks, C. G., Liu, D., Shearer, J. J., Rothman, N., Silverman, D. T., Sandler, D. P., Calafat, A. M., Beane Freeman, L. E., & Hofmann, J. N. (2023). “Glyphosate exposure and urinary oxidative stress biomarkers in the Agricultural Health Study.” JNCI: Journal of the National Cancer Institute, 115(4), 394–404. https://doi.org/10.1093/jnci/djac242
Glyphosate is the most widely applied herbicide worldwide, and its use has been associated with increased risks of certain hematopoietic cancers in epidemiologic studies. Animal and in vitro experiments suggest that glyphosate may induce oxidative stress, a key characteristic of carcinogens; however, evidence in human populations remains scarce. We investigated associations between glyphosate exposure and urinary oxidative stress biomarkers in the Biomarkers of Exposure and Effect in Agriculture study, a molecular epidemiologic subcohort in the Agricultural Health Study.
This analysis included 268 male farmers selected based on self-reported recent and lifetime occupational glyphosate use and 100 age- and geography-matched male nonfarmers. Concentrations of glyphosate and oxidative stress biomarkers (8-hydroxy-2′-deoxyguanosine [8-OHdG], 8-iso-prostaglandin-F2α, and malondialdehyde [MDA]) were quantified in first-morning-void urine. We performed multivariable linear regression to evaluate associations of urinary glyphosate and self-reported glyphosate use with each oxidative stress biomarker.
Urinary glyphosate concentrations were positively associated with levels of 8-OHdG (highest vs lowest glyphosate quartile; geometric mean ratio = 1.15, 95% confidence interval = 1.03 to 1.28; Ptrend = .02) and MDA (geometric mean ratio = 1.20, 95% confidence interval = 1.03 to 1.40; Ptrend = .06) overall. Among farmers reporting recent glyphosate use (last 7 days), use in the previous day was also associated with statistically significantly increased 8-OHdG and MDA levels. Compared with nonfarmers, we observed elevated 8-iso-prostaglandin-F2α levels among farmers with recent, high past 12-month, or high lifetime glyphosate use.
Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans and may inform evaluations of the carcinogenic potential of this herbicide. FULL TEXT
Benbrook C, Mesnage R, Sawyer W. “Genotoxicity Assays Published since 2016 Shed New Light on the Oncogenic Potential of Glyphosate-Based Herbicides.” Agrochemicals. 2023; 2(1):47-68. https://doi.org/10.3390/agrochemicals2010005
Controversy over the oncogenicity of glyphosate-based herbicides (GBHs) persists seven years after a 2015 IARC Monograph classified glyphosate/GBHs as “probably carcinogenic” to humans. Most regulatory authorities have concluded that technical glyphosate poses little or no oncogenic risk via dietary exposure. The US EPA classified glyphosate as “not likely” to pose cancer risk in 1991, a decision reaffirmed in reports issued in 2017 and 2020. A Federal Circuit Court of Appeals in the US vacated EPA’s assessment of glyphosate human-health risks in 2022 and required EPA to revisit old and take into account new data in its forthcoming, possibly final glyphosate/GBH reregistration decision. Divergent assessments of GBH genotoxicity are the primary reason for differing conclusions regarding GBH oncogenic potential. We assessed whether assays published since completion of the EPA and IARC reviews shed new light on glyphosate/GBH genotoxicity. We found 94 such assays, 33 testing technical glyphosate (73% positive) and 61 on GBHs (95% positive). Seven of 7 in vivo human studies report positive results. In light of genotoxicity results published since 2015, the conclusion that GBHs pose no risk of cancer via a genotoxic mechanism is untenable. FULL TEXT
EPA, “Choosing a Percentile of Acute Dietary Exposure as a Threshold of Regulatory Concern,” Office of Pesticide Programs, 2000, Available at: https://www.epa.gov/sites/default/files/2015-07/documents/trac2b054_0.pdf.
Kutz, F. W., Cook, B. T., Carter-Pokras, O. D., Brody, D., & Murphy, R. S.; “Selected pesticide residues and metabolites in urine from a survey of the U.S. general population;” Journal of Toxicology and Environmental Health, 1992, 37(2), 277-291; DOI: 10.1080/15287399209531670.
Residues of toxic chemicals in human tissues and fluids can be important indicators of exposure. Urine collected from a subsample of the second National Health and Nutrition Examination Survey was analyzed for organochlorine, organophosphorus, and chlorophenoxy pesticides or their metabolites. Urine concentration was also measured. The most frequently occurring residue in urine was pentachlorophenol (PCP), found in quantifiable concentrations in 71.6% of the general population with an estimated geometric mean level of 6.3 ng/ml. Percent quantifiable levels of PCP were found to be highest among males. Quantifiable concentrations of 3,5,6-trichloro-2-pyridinol (5.8%), 2,4,5-trichlorophenol (3.4%), para-nitrophenol (2.4%), dicamba (1.4%), malathion dicarboxylic acid (0.5%), malathion alpha-monocarboxylic acid (1.1%), and 2,4-D (0.3%) were found, but at much lower frequencies. No quantifiable levels of 2,4,5-T or silvex were found. Preliminary analyses showed an apparent relationship between residue concentration and two measures of urine concentration (osmolality and creatinine). A large segment of the general population of the United States experienced exposure to certain pesticides, including some considered biodegradable, during the years 1976-1980. FULL TEXT
Environmental Protection Agency, “Evaluation of the Carcinogenic Potential of Glyphosate Case No. 1071-83-6 .” Office of Chemical Safety and Pollution Prevention, October 1, 2015.
On September 16, 2015, the Cancer Assessment Review Committee (CARC) of the Health
Effects Division, of the Office of Pesticide Programs evaluated the carcinogenic potential of
Glyphosate in accordance with the EPA ‘s Final Guidelines for Carcinogen Risk Assessment
(March, 2005). Attached please find the final Cancer Assessment Document.
Benbrook, Charles; “Tracking pesticide residues and risk levels in individual samples—insights and applications;” Environmental Sciences Europe, 2022, 34(1); DOI: 10.1186/s12302-022-00636-w.
BACKGROUND: A method is now available to quantify the number of pesticide residues and relative pesticide dietary risks in individual servings of food. The Dietary Risk Index (DRI) system combines the results of United States and United Kingdom pesticide residue testing programs with data on food serving sizes and each pesticide’s chronic Reference Dose or Acceptable Daily Intake. Chronic DRI values are a ratio: the amount of residue in a serving of food relative to the maximum amount allowed by regulators.
RESULTS: The DRI system generates individual sample tables reporting the number of residues detected and individual pesticide and aggregate-pesticide DRI values in specific, individual samples of food. It is the first such system to do so worldwide. Output tables produce accurate estimates of real-world dietary risks based on current toxicology data and exposure benchmarks set by regulators. System outputs allow assessment of the distribution of pesticide dietary risks across foods and pesticides and demonstrate that dietary risk levels are highly skewed. A large number of samples pose moderate, low, or very-low risks, and relatively few samples pose high or very-high risks.
CONCLUSIONS: The DRI system provides the food industry, regulators and analysts with a simple, accessible online tool to assess pesticide dietary-risk levels by food, by pesticide, as a function of country of origin, and on food grown on conventional versus organic farms. DRI system output tables show that the number of residues in a sample of food is a consistently poor indicator of dietary risk levels. By identifying the relatively small number of high-risk samples, efforts to mitigate pesticide dietary risks can be targeted where the most worrisome risks are.
Bienvenu, J. F., Belanger, P., Gaudreau, E., Provencher, G., & Fleury, N.; “Determination of glyphosate, glufosinate and their major metabolites in urine by the UPLC-MS/MS method applicable to biomonitoring and epidemiological studies;” Analytical and Bioanalytical Chemistry, 2021; DOI: 10.1007/s00216-021-03194-x.
The preoccupation concerning glyphosate (GLYP) has rapidly grown over recent years, and the availability of genetically modified crops that are resistant to GLYP or glufosinate (GLUF) has increased the use of these herbicides. The debate surrounding the carcinogenicity of GLYP has raised interest and the desire to gain information on the level of exposure of the population. GLYP and aminomethylphosphonic acid (AMPA) are commonly simultaneously analysed. GLUF is sometimes also monitored, but its major metabolite, 3-[hydroxy(methyl)phosphinoyl]propionic acid (3MPPA), is rarely present in the method. Using a pentafluorobenzyl derivative to extract the analytes from human urine, we present a method that contains four important analytes to monitor human exposure to GLYP and GLUF. The use of the flash freeze technique speeds up the extraction process and requires less organic solvent than conventional liquid-liquid extraction. The limits of detection in the low mug/L range enable the use of this method for epidemiological studies. The results obtained for 35 volunteers from the Quebec City area are presented with the results from multiple interlaboratory comparisons (G-EQUAS, HBM4EU and OSEQAS). This methodology is currently being used in the Maternal-Infant Research on Environmental Chemicals (MIREC-ENDO) study and in the Canadian Health Measures Survey (CHMS).
Freisthler, Marlaina S., Robbins, C. Rebecca, Benbrook, Charles M., Young, Heather A., Haas, David M., Winchester, Paul D., & Perry, Melissa J.; “Association between increasing agricultural use of 2,4-D and population biomarkers of exposure: findings from the National Health and Nutrition Examination Survey, 2001–2014;” Environmental Health, 2022, 21(1); DOI: 10.1186/s12940-021-00815-x.
BACKGROUND: 2,4-Dichlorophenoxyacetic acid (2,4-D) is one of the most extensively used herbicides in the United States. In 2012, 2,4-D was the most widely used herbicide in non-agricultural settings and the fifth most heavily applied pesticide in the US agricultural sector. The objective of this study was to examine trends in 2,4-D urinary biomarker concentrations to determine whether increases in 2,4-D application in agriculture are associated with increases in biomonitoring levels of urine 2,4-D.
METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) with available urine 2,4-D biomarker measurements from survey cycles between 2001 and 2014 were utilized. Urine 2,4-D values were dichotomized using the highest limit of detection (LOD) across all cycles (0.40 mug/L or 0.4 ppb). Agricultural use of 2,4-D was estimated by compiling publicly available federal and private pesticide application data. Logistic regression models adjusted for confounders were fitted to evaluate the association between agricultural use of 2,4-D and urine 2,4-D level above the dichotomization threshold.
RESULTS: Of the 14,395 participants included in the study, 4681 (32.5%) had urine 2,4-D levels above the dichotomization threshold. The frequency of participants with high 2,4-D levels increased significantly (p < .0001), from a low of 17.1% in 2001-2002 to a high of 39.6% in 2011-2012. The adjusted odds of high urinary 2,4-D concentrations associated with 2,4-D agricultural use (per ten million pounds applied) was 2.268 (95% CI: 1.709, 3.009). Children ages 6-11 years (n = 2288) had 2.1 times higher odds of having high 2,4-D urinary concentrations compared to participants aged 20-59 years. Women of childbearing age (age 20-44 years) (n = 2172) had 1.85 times higher odds than men of the same age.
CONCLUSIONS: Agricultural use of 2,4-D has increased substantially from a low point in 2002 and it is predicted to increase further in the coming decade. Because increasing use is likely to increase population level exposures, the associations seen here between 2,4-D crop application and biomonitoring levels require focused biomonitoring and epidemiological evaluation to determine the extent to which rising use and exposures cause adverse health outcomes among vulnerable populations (particularly children and women of childbearing age) and highly exposed individuals (farmers, other herbicide applicators, and their families).
Hood, R. B., Liang, D., Chiu, Y. H., Sandoval-Insausti, H., Chavarro, J. E., Jones, D., Hauser, R., & Gaskins, A. J.; “Pesticide residue intake from fruits and vegetables and alterations in the serum metabolome of women undergoing infertility treatment;” Environment International, 2022, 160, 107061; DOI: 10.1016/j.envint.2021.107061.
BACKGROUND: Pesticide exposure is linked to a myriad of negative health effects; however, the mechanisms underlying these associations are less clear. We utilized metabolomics to describe the alterations in the serum metabolome associated with high and low pesticide residue intake from fruits and vegetables (FVs), the most common route of exposure in humans.
METHODS: This analysis included 171 women undergoing in vitro fertilization who completed a validated food frequency questionnaire and provided a serum sample during controlled ovarian stimulation (2007–2015). FVs were categorized as high or low-to-moderate pesticide residue using a validated method based on pesticide surveillance data from the USDA. We conducted untargeted metabolic profiling using liquid chromatography with high-resolution mass spectrometry and two chromatography columns. We used multivariable generalized linear models to identified metabolic features (p < 0.005) associated with high and low-to-moderate pesticide residue FV intake, followed by enriched pathway analysis.
RESULTS: We identified 50 and 109 significant features associated with high pesticide residue FV intake in the C18 negative and HILIC positive columns, respectively. Additionally, we identified 90 and 62 significant features associated with low-to-moderate pesticide residue FV intake in the two columns, respectively. Four metabolomic pathways were associated with intake of high pesticide residue FVs including those involved in energy, vitamin, and enzyme metabolism. 12 pathways were associated with intake of low-to-moderate pesticide residue FVs including cellular receptor, energy, intercellular signaling, lipid, vitamin, and xenobiotic metabolism. One energy pathway was associated with both high and low-to-moderate pesticide residue FVs.
CONCLUSIONS: We identified limited overlap in the pathways associated with intake of high and low-to-moderate pesticide residue FVs, which supports findings of disparate health effects associated with these two exposures. The identified pathways suggest there is a balance between the dietary antioxidant intake associated with FVs intake and heightened oxidative stress as a result of dietary pesticide exposure.
Porter, M. Jayson; Agrochemicals, Environmental Racism, and Environmental Justice in U.S. History. Northwestern University, The Organic Center (2022).
In theory, pesticides should have the toxicity to deter pests without harming plants or people. However, a closer look at pesticide history in the United States reveals an enduring legacy of environmental racism against communities of color and their collective action for environmental justice. Humans have harnessed the toxicity of chemicals to kill agricultural insects for millennia. However, the rapid proliferation of modern agrochemicals between 1870-1914 increased how much agriculture itself could hurt places and people. The burden of protecting people and places has always fallen on communities rather than governments and institutions.