Danmarks Fødevareforskning Do pesticides and manganese affect human health? Henrik Rye Lam Department of Toxicology and Risk Assessment Danish Institute for Food Safety

Danmarks Fødevareforskning Do pesticides and manganese affect human health? Acute, high dose pesticide exposure affects human health Long term, low dose pesticide exposure seems linked to increased risk for Parkinson´s disease Manganese affects human health There is a potential for combinatory effects of manganese and pesticides when co-exposed

Danmarks Fødevareforskning Studies on manganese and selected pesticides Manganese chloride Maneb Chlorpyrifos Combinatory studies Funded by the Danish EPA Programme for Pesticide Research

Danmarks Fødevareforskning Working hypotheses There are combinatory effects between neurotoxicity induced by manganese and certain pesticides Underlying mechanisms and their combinatory effects can be illuminated by neurochemical, morphological, and immunohistochemical methods by use of the rat as the model

Danmarks Fødevareforskning Studies in the project Manganese (intraperitoneal dosing) 1,22 mg manganese (MnO 2 )/kg bw/day for 8 or 12 weeks 2,5 mg manganese (MnCl 2 )/kg bw/day for 8 or 12 weeks Maneb (intraperitoneal dosing) 7,5, 15 or 30 mg maneb/kg bw/week for 12 weeks Chlorpyrifos (subcutaneous dosing) 2,5, 15 or 30 mg chlorpyrifos/kg bw/week for 12 weeks Combinatory studies 2,5 mg manganese (MnCl 2 )/kg bw/day for 12 weeks 15 chlorpyrifos/kg bw/week for 12 weeks 10 mg maneb/kg bw/week for 12 weeks

Danmarks Fødevareforskning Manganese concentration (Manganese dosing)

Danmarks Fødevareforskning Manganese brain concentration (Maneb dosing)

Danmarks Fødevareforskning Manganese concentrations (Combinatory studies)

Danmarks Fødevareforskning Concentrations of neurotransmitters (Manganese dosing)

Danmarks Fødevareforskning Concentration of neurotransmitters (Maneb dosing)

Danmarks Fødevareforskning Acetylcholinesterase activity (Maneb dosing)

Danmarks Fødevareforskning Acetylcholinesterase activity (Chlorpyrifos dosing)

Danmarks Fødevareforskning Concentration of neurotransmitters (Combinatory studies)

Danmarks Fødevareforskning Acetylcholinesterase activity (Combinatory studies)

Danmarks Fødevareforskning Key conclusions Manganese dosing increases the brain manganese concentration Maneb dosing increases the brain manganese concentration Co-exposure to manganese and maneb increases the brain manganese concentration in an additive manner and thereby potentially increases the risk for developing Parkinson´s disease Chlorpyrifos dosing reduces the activity of brain acetylcholinesterase Manganese, chlorpyrifos, maneb and their combinations affect basic neurochemical parameters that are early indications of neurotoxicity

Danmarks Fødevareforskning Perspectives Because: Many epidemiological studies document increased risk of developing Parkinsons disease when exposed to manganese and pesticides Several cases report development of Parkinson´s disease when occupationally exposed to maneb Inhalation of manganese can induce parkinsonism There is a need for future studies that can illuminate or even document the potential for combinatory effects of manganese and pesticides to obtain increased protection and health

Danmarks Fødevareforskning Ole Ladefoged, Erik Huusfeldt Larsen, Brian Svend Nielsen, and Henrik Rye Lam acknowledge: Technical staff Amer Mujezinovic, Annette Landin, Kai Vest, Lena Kristensen, Trine Gejsing, Vibeke Kegel, Vibeke Kjær, Birgitte Koch Herbst, Karen Bielefeldt Pedersen, Lisbeth Philkjær Christensen, Animal caretakers Colaborating parteners Prof. Michael Aschner, Wake Forest University, NC, USA Prof. Poul Henning Jensen, Aarhus Universitet PhD Karina Petersen, Lundbeck