title: Mathematical model insights into arsenic detoxification.
abstract: BACKGROUND
  Arsenic in drinking water, a major health hazard to millions of people in South and East Asia and in other parts of the world, is ingested primarily as trivalent inorganic arsenic (iAs), which then undergoes hepatic methylation to methylarsonic acid (MMAs) and a second methylation to dimethylarsinic acid (DMAs). Although MMAs and DMAs are also known to be toxic, DMAs is more easily excreted in the urine and therefore methylation has generally been considered a detoxification pathway. A collaborative modeling project between epidemiologists, biologists, and mathematicians has the purpose of explaining existing data on methylation in human studies in Bangladesh and also testing, by mathematical modeling, effects of nutritional supplements that could increase As methylation.
  
  
  METHODS
  We develop a whole body mathematical model of arsenic metabolism including arsenic absorption, storage, methylation, and excretion. The parameters for arsenic methylation in the liver were taken from the biochemical literature. The transport parameters between compartments are largely unknown, so we adjust them so that the model accurately predicts the urine excretion rates of time for the iAs, MMAs, and DMAs in single dose experiments on human subjects.
  
  
  RESULTS
  We test the model by showing that, with no changes in parameters, it predicts accurately the time courses of urinary excretion in mutiple dose experiments conducted on human subjects. Our main purpose is to use the model to study and interpret the data on the effects of folate supplementation on arsenic methylation and excretion in clinical trials in Bangladesh. Folate supplementation of folate-deficient individuals resulted in a 14% decrease in arsenicals in the blood. This is confirmed by the model and the model predicts that arsenicals in the liver will decrease by 19% and arsenicals in other body stores by 26% in these same individuals. In addition, the model predicts that arsenic methyltransferase has been upregulated by a factor of two in this population. Finally, we also show that a modification of the model gives excellent fits to the data on arsenic metabolism in human cultured hepatocytes.
  
  
  CONCLUSIONS
  The analysis of the Bangladesh data using the model suggests that folate supplementation may be more effective at reducing whole body arsenic than previously expected. There is almost no data on the upregulation of arsenic methyltransferase in populations chronically exposed to arsenic. Our model predicts upregulation by a factor of two in the Bangladesh population studied. This prediction should be verified since it could have important public health consequences both for treatment strategies and for setting appropriate limits on arsenic in drinking water. Our model has compartments for the binding of arsenicals to proteins inside of cells and we show that these comparments are necessary to obtain good fits to data. Protein-binding of arsenicals should be explored in future biochemical studies.
authors.affiliation: Department of Mathematics, Duke University, 130 Science Drive, Durham, NC 27708, USA. lawley@math.duke.edu
authors.forename: Sean D
authors.initials: SD
authors.lastname: Lawley
authors.forename: Molly
authors.initials: M
authors.lastname: Cinderella
authors.forename: Megan N
authors.initials: MN
authors.lastname: Hall
authors.forename: Mary V
authors.initials: MV
authors.lastname: Gamble
authors.forename: H Frederik
authors.initials: HF
authors.lastname: Nijhout
authors.forename: Michael C
authors.initials: MC
authors.lastname: Reed
mesh_terms: D000818:Animals; D001151:Arsenic / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D001459:Bangladesh; D019587:Dietary Supplements; D005492:Folic Acid / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D007700:Kinetics; D008745:Methylation / Q000187:drug effects; D008954:Models, Biological; D051381:Rats
chemical_list: D005492:Folic Acid; D001151:Arsenic