Do pesticides and manganese affect human health?

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

2. 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

3. Studies on manganese and selected pesticides • Manganese chloride • Maneb • Chlorpyrifos • Combinatory studies • Funded by the Danish EPA Programme for Pesticide Research 2002-2004

4. 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

5. Studies in the project • Manganese (intraperitoneal dosing) 1,22 mg manganese (MnO2)/kg bw/day for 8 or 12 weeks 2,5 mg manganese (MnCl2)/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 (MnCl2)/kg bw/day for 12 weeks 15 chlorpyrifos/kg bw/week for 12 weeks 10 mg maneb/kg bw/week for 12 weeks

6. Manganese concentration(Manganese dosing)

7. Manganese brain concentration(Maneb dosing)

8. Manganese concentrations(Combinatory studies)

9. Concentrations of neurotransmitters(Manganese dosing)

10. Concentration of neurotransmitters(Maneb dosing)

11. Acetylcholinesterase activity(Maneb dosing)

12. Acetylcholinesterase activity(Chlorpyrifos dosing)

13. Concentration of neurotransmitters(Combinatory studies)

14. Acetylcholinesterase activity (Combinatory studies)

15. 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

16. 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

17. 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