1. 1 TRACK 4 : Industrial and Metallic Toxicology A NEW CHALLENGE : ASSESSMENT of Metallic Toxicity Professeur F. DESCHAMPS Dept of Occupational Health (IMTECA) Medicine Faculty REIMS- FRANCE 3 th International Summit on Toxicology CHICAGO Oct 2014

2. 2 INTRODUCTION (Environmental exposure) - Cobalt is a hard lustrous, gray metal - Cobalt is naturally found in rocks, soil, water, plants, animals ….. 3 th International Summit on Toxicology CHICAGO Oct 2014

3. 3 INTRODUCTION (Environmental exposure) - Cobalt is present in trace amounts in human diet - (fish, vegetable, drinking water …) 3 th International Summit on Toxicology CHICAGO Oct 2014

4. 4 PHYSIOLOGY - cobalt is a part of vitamin B 12 (necessary for neurological function, brain function, and blood formation…) - Require for oxygen transport in metabolism 3 th International Summit on Toxicology CHICAGO Oct 2014

5. 5 USES - cobalt containing products include corrosion and heat resistant alloys (metal industries) - hard metal alloy : → cobalt – tungsten - carbide 3 th International Summit on Toxicology CHICAGO Oct 2014

6. 6 OTHER USES - magnet - grinding/ cutting tools - pigments / paint - colored glass - catalyst / batterie - cobalt – coated metal - surgical implants 3 th International Summit on Toxicology CHICAGO Oct 2014

7. 7 OCCUPATIONAL EXPOSURE - hard metal industry - diamond polishing - ceramic industry 3 th International Summit on Toxicology CHICAGO Oct 2014

8. 8 INDUSTRIAL PROCESS ● First step : forming wolfram carbide (WC) from the ore ● WC is then milled to fine powder ● secondly mixed with metallic cobalt (size 1 – 2 mm) 3 th International Summit on Toxicology CHICAGO Oct 2014

9. 9 INDUSTRIAL PROCESS ● mixed powder is pressed to obtain desired shapes ● after heated under pressure to 1000 ° ● this « product » could be drilled ● finelly heated again (1500°C) 3 th International Summit on Toxicology CHICAGO Oct 2014

10. 10 End of the PROCESS ● pieces obtained are ground to very exact shapes ( material is very hard and only diamond grinders can be used) 3 th International Summit on Toxicology CHICAGO Oct 2014

11. 11 Mechanism of cobalt toxicity ● high affinity for sulfhydryl groups ● inhibition of crucial enzymes (oxidative phosphorylation) ● inhibition and competition with calcium binding ● generation of oxygen species ● direct cyto-toxicity 3 th International Summit on Toxicology CHICAGO Oct 2014

12. 12 Effects of cobalt on cells ● inhibit osteoblast function ● reducing alkaline phosphatase activity ● inducing secretion of proteins IL8 and MCP ( osteoblasts) 3 th International Summit on Toxicology CHICAGO Oct 2014

13. 13 Chronic systemic exposure ● accumulation liver ● accumulation Kidney 3 th International Summit on Toxicology CHICAGO Oct 2014

14. 14 Adverse effects of cobalt and pulmonary diseases (intertitial fibrosis) ● tightening of the chest ● cough ● shortness of breath ● fatigue ● production of sputum ● weight loss 3 th International Summit on Toxicology CHICAGO Oct 2014

15. 15 Adverse effects of cobalt ● neurological symptoms → severed headaches → cognitive decline → memory difficulties (remembering names) → poor concentration → depression 3 th International Summit on Toxicology CHICAGO Oct 2014

16. 16 Adverse effects of cobalt ● metal taste in the mouth ● anorexia ● weight loss 3 th International Summit on Toxicology CHICAGO Oct 2014

17. 17 Adverse effects of cobalt ● hearing loss ● visual changes ● arrhythmias and cardiopathy ● endocrine symptoms ( hypothyroïdism …) ● abnormal lymphocyte function 3 th International Summit on Toxicology CHICAGO Oct 2014

18. 18 Adverse effects ● releasing micro particulate metal debris : → development of pseudotumors → hypersensitive reaction → nanoparticles consequences * cytotoxic * genotoxic * immunological (vigilance after long latency) 3 th International Summit on Toxicology CHICAGO Oct 2014

19. 19 Hip prostheses ● conventional total hip prostheses : → metal head → fits into polyethylene cup ( but with time require revision) 3 th International Summit on Toxicology CHICAGO Oct 2014

20. 20 Hip prostheses ● metal on metal bearing (made with cobalt and chromium) ● release a variety of metal ions into : → local tissue → general circulation 3 th International Summit on Toxicology CHICAGO Oct 2014

21. 21 Metal hip assessment ● well fixed (x-rays) ● well aligned implant ● mild osteopenia around acetabular component 3 th International Summit on Toxicology CHICAGO Oct 2014

22. 22 Case report ● 60 years old women ● total hip prosthesis containing cobalt ● three years ago 3 th International Summit on Toxicology CHICAGO Oct 2014

23. 23 Case report clinical symptoms → none symptom 3 th International Summit on Toxicology CHICAGO Oct 2014

24. 24 Case report routinebiomonitoring 1) Blood cobalt level : 3.2 ug/l (non exposed population < 0.6 ug/l) 2) Blood cobalt level : 4.64 ug/l ( three months later) 3) Blood cobalt level increases : 8.29 ug/l ( patient with cobalt hip : 7 ug/l) 3 th International Summit on Toxicology CHICAGO Oct 2014

25. 25 References biomonitoring - Problem from : 60 ug / l (up to 100 times that of physiologic levels) 3 th International Summit on Toxicology CHICAGO Oct 2014

26. 26 Intravenous injection - 40 % eliminated within first 24 hours - 70 % eliminated within one week - 80 % eliminated one month - 90 % eliminated one year 3 th International Summit on Toxicology CHICAGO Oct 2014

27. 27 Treatment of cobalt toxicity - No consensus - To treat the systemic symptoms : * thyroid replacement therapy * beta-blockers * angiotensin-converting……. (no established indication for chelation therapy) 3 th International Summit on Toxicology CHICAGO Oct 2014

28. 28 Conclusion - No current consensus regarding managment of patients with cobalt alloy, hip prostheses and elevated circulating cobalt metal ion levels - Removal of implanted hardware if : * endocrinopathy * cardiopathy ( persistance of neurologic symptoms) - Improved surveillance is needed 3 th International Summit on Toxicology CHICAGO Oct 2014