title: Modeling U-shaped dose-response curves for manganese using categorical regression.
abstract: Manganese is an essential nutrient which can cause adverse effects if ingested to excess or in insufficient amounts, leading to a U-shaped exposure-response relationship. Methods have recently been developed to describe such relationships by simultaneously modeling the exposure-response curves for excess and deficiency. These methods incorporate information from studies with diverse adverse health outcomes within the same analysis by assigning severity scores to achieve a common response metric for exposure-response modeling.
  
  
  
  We aimed to provide an estimate of the optimal dietary intake of manganese to balance adverse effects from deficient or excess intake.
  
  
  
  We undertook a systematic review of the literature from 1930 to 2013 and extracted information on adverse effects from manganese deficiency and excess to create a database on manganese toxicity following oral exposure. Although data were available for seven different species, only the data from rats was sufficiently comprehensive to support analytical modelling. The toxicological outcomes were standardized on an 18-point severity scale, allowing for a common analysis of all available toxicological data. Logistic regression modelling was used to simultaneously estimate the exposure-response profile for dietary deficiency and excess for manganese and generate a U-shaped exposure-response curve for all outcomes.
  
  
  
  Data were available on the adverse effects of 6113 rats. The nadir of the U-shaped joint response curve occurred at a manganese intake of 2.70mg/kgbw/day with a 95% confidence interval of 2.51-3.02. The extremes of both deficient and excess intake were associated with a 90% probability of some measurable adverse event.
  
  
  
  The manganese database supports estimation of optimal intake based on combining information on adverse effects from systematic review of published experiments. There is a need for more studies on humans. Translation of our results from rats to humans will require adjustment for interspecies differences in sensitivity to manganese.
authors.affiliation: Risk Sciences International, 55 Metcalfe Street, Suite 700, K1P 6L5, Ottawa, Canada. Electronic address: bmilton@risksciences.com.
authors.forename: Brittany
authors.initials: B
authors.lastname: Milton
authors.affiliation: Risk Sciences International, 55 Metcalfe Street, Suite 700, K1P 6L5, Ottawa, Canada; R. Samuel McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, 850 Peter Morand Crescent, Room 119, Ottawa, K1G 3Z7, Canada; School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krewski
authors.affiliation: Risk Sciences International, 55 Metcalfe Street, Suite 700, K1P 6L5, Ottawa, Canada; R. Samuel McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, 850 Peter Morand Crescent, Room 119, Ottawa, K1G 3Z7, Canada.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Mattison
authors.affiliation: Risk Sciences International, 55 Metcalfe Street, Suite 700, K1P 6L5, Ottawa, Canada; R. Samuel McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, 850 Peter Morand Crescent, Room 119, Ottawa, K1G 3Z7, Canada.
authors.forename: Nataliya A
authors.initials: NA
authors.lastname: Karyakina
authors.affiliation: Risk Sciences International, 55 Metcalfe Street, Suite 700, K1P 6L5, Ottawa, Canada.
authors.forename: Siva
authors.initials: S
authors.lastname: Ramoju
authors.affiliation: Risk Sciences International, 55 Metcalfe Street, Suite 700, K1P 6L5, Ottawa, Canada; R. Samuel McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, 850 Peter Morand Crescent, Room 119, Ottawa, K1G 3Z7, Canada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shilnikova
authors.affiliation: R. Samuel McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, 850 Peter Morand Crescent, Room 119, Ottawa, K1G 3Z7, Canada; School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Birkett
authors.affiliation: School of Mathematics and Statistics, 1125 Colonel By Drive, 4302 Herzberg Laboratories, 5215HP, Carleton University, Ottawa, K1S 5B6, Canada.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Farrell
authors.affiliation: International Manganese Institute, 17 rue Duphot, 75001 Paris, France.
authors.forename: Doreen
authors.initials: D
authors.lastname: McGough
mesh_terms: D000818:Animals; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016015:Logistic Models; D008345:Manganese / Q000633:toxicity*; D020149:Manganese Poisoning / Q000209:etiology; D051381:Rats
chemical_list: D008345:Manganese
keywords: Categorical regression; Deficiency; Excess; Manganese toxicity; U-shaped dose-response curve