Glyphosate continues to attract controversial debate following the International Agency for Research on Cancer carcinogenicity classification in 2015. Despite its ubiquitous presence in our environment, there remains a dearth of data on human exposure to both glyphosate and its main biodegradation product aminomethylphosphonic (AMPA). Herein, we reviewed and compared results from 21 studies that use human biomonitoring (HBM) to measure urinary glyphosate and AMPA. Elucidation of the level and range of exposure was complicated by differences in sampling strategy, analytical methods, and data presentation. Exposure data is required to enable a more robust regulatory risk assessment, and these studies included higher occupational exposures, environmental exposures, and vulnerable groups such as children. There was also considerable uncertainty regarding the absorption and excretion pattern of glyphosate and AMPA in humans. This information is required to back-calculate exposure doses from urinary levels and thus, then compare these levels with health-based guidance values. Back-calculations based on animal-derived excretion rates suggested that there were no health concerns in relation to glyphosate exposure (when compared with EFSA acceptable daily intake (ADI)). However, recent human metabolism data has reported as low as a 1% urinary excretion rate of glyphosate. Human exposures extrapolated from urinary glyphosate concentrations found that upper-bound levels may be much closer to the ADI than previously reported.

Human health risk assessment is historically built upon animal testing, often following Organisation for Economic Co-operation and Development (OECD) test guidelines and exposure assessments. Using combinations of human relevant in vitro models, chemical analysis and computational (in silico) approaches bring advantages compared to animal studies. These include a greater focus on the human species and on molecular mechanisms and kinetics, identification of Adverse Outcome Pathways and downstream Key Events as well as the possibility of addressing susceptible populations and additional endpoints. Much of the advancement and progress made in the Next Generation Risk Assessment (NGRA) have been primarily focused on new approach methodologies (NAMs) and physiologically based kinetic (PBK) modelling without incorporating human biomonitoring (HBM). The integration of toxicokinetics (TK) and PBK modelling is an essential component of NGRA. PBK models are essential for describing in quantitative terms the TK processes with a focus on the effective dose at the expected target site. Furthermore, the need for PBK models is amplified by the increasing scientific and regulatory interest in aggregate and cumulative exposure as well as interactions of chemicals in mixtures. Since incorporating HBM data strengthens approaches and reduces uncertainties in risk assessment, here we elaborate on the integrated use of TK, PBK modelling and HBM in chemical risk assessment highlighting opportunities as well as challenges and limitations. Examples are provided where HBM and TK/PBK modelling can be used in both exposure assessment and hazard characterization shifting from external exposure and animal dose/response assays to animal-free, internal exposure-based NGRA.

Glyphosate has recently received much public attention following its 'Group 2A - probably carcinogenic to humans' classification from the International Agency for Research on Cancer. Despite the widespread use of glyphosate, there is limited data on potential exposures during common occupational uses. The study aimed to characterise occupational exposures to glyphosate among amenity horticulturists through the collection and analysis of urine samples following pesticide application. The impact of work practices on personal exposure, as well as suitability of collecting multiple spot urine samples as a sampling strategy for the assessment of occupational exposure for glyphosate were also examined. A minimum of three spot urine samples were collected per work task; before the work task began, after the work task completion and the following first morning void. All samples were analysed separately for glyphosate using liquid chromatography tandem mass spectrometry and for creatinine. Differences in urinary glyphosate concentrations between the pre-task samples versus the post-task and the peak urinary samples were both analysed using paired Student t-tests. Determinants of exposure on glyphosate urine concentrations were evaluated using Pearson's correlation coefficients and linear regression. A multivariate mixed effect model were elaborated to compare the glyphosate concentrations between post-task and following first morning void samples. In these models, worker identity was entered as a random effect to account for the presence of correlations between repeated measurements from the same individuals. Peak urine glyphosate concentrations measured for work tasks were 2.5, 1.9, 1.9 and 7.4 μg L-1 (arithmetic mean, geometric mean, median and maximum value, respectively). Concentrations were highest in samples taken up to 3 h after completing the work task. Regression analysis showed that workers who sprayed the day before the sampling task had higher glyphosate concentrations in pre-task samples than those who did not spray the day before (p < 0.01). Similarly, workers who took breaks during the work task had higher peak urinary glyphosate concentrations (p < 0.01). The multivariate mixed effect model showed that the following first morning void samples were approximately a factor 0.7 lower than post-task values. Occupational exposures to glyphosate among amenity horticulturalists are greater than those reported in environmental studies and comparable with previously reported agricultural studies. A suitable sampling strategy for occupational exposures to glyphosate is the collection of a spot urine sample up to 3 h after completing the application of a glyphosate based pesticide product, which provides a reliable marker of peak exposure.