Biomarker of glyphosate exposure
In the metabolism analysis, the maximum concentrations of glyphosate and AMPA were observed at 2.42–5.16 h after the intravenous injection of glyphosate (Anadon et al. 2009). A study was designed in which 12 participants consumed a test meal with a known concentration of glyphosate residue and a lower concentration of AMPA, and the results showed that the estimated elimination half-life for glyphosate was 9 h (Zoller et al. 2020). Therefore, the measurements of glyphosate and AMPA in urine samples can be a short-term marker for external exposure.
Mills et al. (2017) have reported that the average glyphosate and AMPA concentrations in the general population of USA were 0.024 µg/L and 0.314 µg/L, increasing from 0.008 µg/L to 0.401 µg/L in 1993–1996 and 2014–2016 in the aging healthy population in the United States, whereas a decreasing trend in glyphosate residues in urine in Germany youngers was found (Conrad et al. 2017). This study and the other one all found that chronically ill patients had significantly higher urinary concentrations of glyphosate residues than healthy individuals (Krüger et al. 2014). Moreover, the glyphosate and AMPA concentrations in urine samples from adults and elders in this study were higher than those found in other countries (Krüger et al. 2014; Mills et al. 2017).
Although a review paper that collected data from seven studies revealed no health concerns because the glyphosate exposure estimation for general population was far below than “acceptable daily intake“ or “acceptable operator exposure level”, exposure was predominantly resulted from the occupational and dietary exposure routes in Europe and North America (Niemann et al. 2015).
Many researchers have reported that glyphosate and AMPA residues were present in soy-based infant formula, maize-derived food, beer, wine, fruit juice (González-Ortega et al. 2017; Jansons et al. 2018; Rodrigues et al. 2018), and that glyphosate was detectable in nearly all honey samples in Switzerland (Zoller et al. 2018) and in American mothers’ breastmilk (Honeycutt et al. 2014). Therefore, the evaluation of glyphosate exposure via food consumption in patients with CKD is important.
With regard to As, higher exposures were found in this study compared with biological monitoring data from urine samples of other countries (Aguilera et al. 2008; Feng et al. 2015; Morton et al. 2014). For Cd exposure, the urine Cd concentrations in this study were clearly higher than those of other studies in Western countries (Aguilera et al. 2008; Baeyens et al. 2014; Heitland et al. 2006; Morton et al. 2014; Tellez-Plaza et al. 2008) and in Thailand (Nishijo et al. 2014), but were equal to those reported by Liao et al. in Taiwan (Liao et al. 2019). Overall, the concentrations of bio-exposure markers, such as glyphosate, AMPA, Cd, and As, were higher than those of other countries.
Metals, glyphosate exposure and renal function
In discussing the relationship between exposure biomarkers and eGFR, the variation in climate, temperature, air quality, water quality, and drought, and exposure to fertilizers, soil conditioners, herbicides, fungicides, and pesticides have been considered as contributing factors for the development of CKD in South Asia (Wilke et al. 2019). For example, in Thailand, the serum creatinine concentrations were associated with glyphosate use and pesticide exposure index in the occupational group (Mueangkhiao et al. 2020), which indicated that glyphosate exposure might be related to renal dysfunction. Meanwhile, an acute kidney injury developed after the ingestion of glyphosate-based herbicide, indicating epithelial injury in proximal tubules, and glyphosate mitochondrial toxicity was also found (Kimura et al. 2020). Other environmental contaminants, such as heavy metals (e.g., Cd, As, and Pb) and organic pesticides (e.g., glyphosate) in the drinking water, even at safe levels, can impair kidney development at an early age; and may play a role in the childhood onset and progression of kidney dysfunction (Babich et al. 2020). However, in three cohorts across different phases of child development, the authors confirmed detectable glyphosate in children’s urine at various ages and stages of development, but found no evidence for renal injury in children exposed to low concentrations of glyphosate (Trasande et al. 2020). Meanwhile, Gunatilake (2019) suggested that glyphosate’s synergistic health effects when combined with paraquat, and the continuous high temperatures of lowland tropical regions could result in renal damage. Glyphosate exposure, such as enhancing the growth of Clostridia species and ruminal metabolism in vitro (Riede et al. 2016), promotes As toxicity in renal dysfunction (Jayasumana et al. 2015a), and the low-dose exposure of glyphosate-based herbicides disrupted the urine metabolome and its interaction with gut microbiota has been dysregulated in related diseases through the commensal microbiome (Hu et al. 2021). Overall, several pathologies associated with MeN, a type of CKDu, may be linked to glyphosate exposure, such as altered gut microbiota (Rueda-Ruzafa et al. 2019), increased As toxicity, suppressed synthesis of adrenocorticotropic hormone, disruption of fructose metabolism, and promotion of dehydration and high serum urate (Seneff et al. 2018).
For metal exposure, the higher concentrations of Zn and nickel (Ni) in farms close to the residence of patients with CKD were associated with a higher risk of progression to end-stage kidney disease in Taiwan (Tsai et al. 2018). An epidemiology study has suggested that high plasma selenium (Se) and low red blood cell Pb levels or Cd levels can interact to increase the eGFR (20.70, 15.56–26.01 mL/min/1.73 m2) in CKD (Wu et al. 2019). However, a report showed that the non-association between glyphosate, aluminum (Al), and As exposure and decreased kidney function in 350 young adults living in area of Central America with an epidemic of MeNs (Smpokou et al. 2019). Meanwhile, the exposure and risk assessment showed that there was no treatment risk with glyphosate (Honeycutt et al. 2014; Krüger et al. 2014; Niemann et al. 2015). All of the above studies were retrospective, and used biological biomarker data for external exposure, and APMA was not included in the above studies. However, in our study, the co-exposure of As and glyphosate was found in patients after CKD stage 3b. The alternative importance of glyphosate and Cd or As exposure in the progression of CKD have been seen in patients with CKD stage 3 or above. These results can respond to the conclusion from Seneff et al. (2018), who reported that the most likely way to prevent end-stage renal failure in sugarcane workers was to stop the use of glyphosate in Brazil, and that the progression of patients with CKD into end-stage renal failure may be prolonged by a reduction in glyphosate exposure.