Variation in Methylmercury Metabolism and Elimination in Humans: Physiological Pharmacokinetic Modeling Highlights the Role of Gut Biotransformation, Skeletal Muscle, and Hair

Abstract

The biological half-life (t1/2) of methylmercury (MeHg) shows considerable individual variability (t1/2 < 30 to > 120 days), highlighting the importance of mechanisms controlling MeHg metabolism and elimination. Building on a prior physiologically based pharmacokinetic (PBPK) model, we elucidate parameters that have the greatest influence on variability of MeHg t1/2 in the human body. Employing a dataset of parameters for mean organ volumes and blood flow rates appropriate for man and woman (25–35 years) and child (4 − 6 years), we demonstrate model fitness by simulating data from our prior controlled study of MeHg elimination in people. Model predictions give MeHg t1/2 of 46.9, 38.9, and 31.5 days and steady-state blood MeHg of 2.6, 2.6, and 2.3 µg/l in man, woman, and child, respectively, subsequent to a weekly dose of 0.7 µg/kg body weight. The major routes of elimination are biotransformation to inorganic Hg in the gut lumen (73% in adults, 61% in child) and loss of MeHg via excretion within growing hair (13% in adults, 24% in child). Local and global sensitivity analyses of model parameters reveal that variation in biotransformation rate in the gut lumen, and rates of transport between gut lumen and gut tissue, have the greatest influence on MeHg t1/2. Volume and partition coefficients for skeletal muscle (SM) and gut tissue also show significant sensitivity affecting model output of MeHg t1/2. Our results emphasize the role of gut microbiota in MeHg biotransformation, transport kinetics at the level of the gut, and SM mass as moderators of MeHg kinetics in the human body.

Navigating a Two-Way Street: Metal Toxicity and the Human Gut Microbiome

“… 50 For MeHg, Rand’s group developed computational pharmacokinetic models that predicted a shorter MeHg half-life in women than men and a shorter half-life in children than adults. 49 The models also identified skeletal muscle mass as a potential storage compartment that can delay the fecal excretion of MeHg. 49 Because both iAs and MeHg are transported across the gut epithelium into the bloodstream and from the liver into the blood or bile, any host or microbial effects on transport efficiency, gut barrier function, and tissue absorption rates also modulate metabolism and body burden.…”

“… 49 The models also identified skeletal muscle mass as a potential storage compartment that can delay the fecal excretion of MeHg. 49 Because both iAs and MeHg are transported across the gut epithelium into the bloodstream and from the liver into the blood or bile, any host or microbial effects on transport efficiency, gut barrier function, and tissue absorption rates also modulate metabolism and body burden. 54 , 68 , 69 , 70 , 71 …”

Fecal microbiota transplantation in treating methylmercury-poisoned rats: Reconstruction of gut microbiome and modulation of gut-brain axis related metabolites

“…On the other hand, it has been reported that MeHg can affect the gut microbiota of various organisms [18] , such as pregnant women, walruses and zebra sh [19][20][21] . The destruction of gut microbiota accelerated the accumulation of mercury in organs [22][23][24] . For example, it was found that antibiotics treatment led to increased accumulation of MeHg in sh [25] .…”