Özet
Muhammetli S., The Effect of Lead Exposure on Neopterin Levels in Metal
Recycling Industry Workers, Hacettepe University Graduate School of Health
Sciences Pharmacy Department of Pharmaceutical Toxicology Program Master
of Science Thesis, Ankara, 2023. Lead is one of the life-threatening heavy metals that
can be found in detectable concentrationsin different compartments of the human body
after exposure. In industry, lead is widely used in many areas such as battery, metal
and mining. One of the important business lines in which occupational exposure to
toxic metals, mainly lead, may occur isthe “Recycling Sector”. Neopterin is a pteridine
derivative that can be used as an early biomarker in various disorders such as tissue
rejection, human immunodeficiency virus, multi-organ failure, sepsis, and cancer. In
addition to neopterin release, indolamine 2,3-dioxygenase (IDO) enzyme, which plays
a role in the rate-limiting step of the kynurenine pathway, is also induced by cellular
immune activation. In this thesis, the relationship between blood lead levels and
urinary neopterin, biopterin, manganese, cadmium and serum neopterin, kynurenine
and tryptophan concentrations were evaluated in participants working in the recycling
industry. It was found that urinary neopterin, lead, manganese and cadmium levels
changed significantly with the increase in blood lead levels (all; p<0.05). Within the
scope of the thesis, it was determined that exposure to heavy metals, especially lead,
in the recycling sector affects the pteridine and kynurenine pathways.
Künye
1. Demir F. Ağır Metal Toksisitesinin Kanser ile İlişkisi. Gaziosmanpasa J Sci
Res. 2021;10(1):21–9.
2. Akbal A, Reşorlu H, Savaş Y. Ağır Metallerin Kemik Doku Üzerine Toksik
Etkileri. Turk Osteoporoz Derg. 2015;21(1):30–3.
3. Sanders T, Liu Y, Buchner V, Tchounwou PB. Neurotoxic effects and
biomarkers of lead exposure: A review. Rev Environ Health. 2009;24(1):15–
45.
4. Gidlow DA. Lead toxicity. Occup Med (Chic Ill). 2015;65(5):348–56.
5. BAŞ L, DEMET Ö. Çevresel Toksikoloji Yönünden Bazı Ağır Metaller. Çevre
Derg. 1992;5:42–6.
6. Hernberg S. Lead poisoning in a historical perspective. Am J Ind Med.
2000;38(3):244–54.
7. García-Lestón Julia J, Méndez J, Pásaro E, Laffon B. Genotoxic effects of lead:
An updated review. Environ Int. 2010;36(6):623–36.
8. Hodson ME. Heavy metals - Geochemical bogey men? Environ Pollut.
2004;129(3):341–3.
9. Riva MA, Belingheri M, De Vito G, Lucchini R. Bernardino Ramazzini (1633-
1714). J Neurol. 2018;265:2164–5.
10. TATAR ÇP. Kurşun Maruziyetinin İş Sağlığı ve Güvenliği Açısından
Değerlendirilmesi (Akü, Maden ve Metal İşyerlerinde). T.C. ÇALIŞMA VE
SOSYAL GÜVENLİK BAKANLIĞI İŞ SAĞLIĞI VE GÜVENLİĞİ GENEL
MÜDÜRLÜĞÜ; 2014.
11. Aktepe N. Kurşun Ağır Metaline Maruz Kalma Yolları ve Sağlığa Olan
Olumsuz Etkileri. Içinde: Goncagül G, Günaydın E, editörler. Sağlık Bilimleri
Alanında Güncel Araştırmalar. Ankara: Duvar Yayınları; 2020. s. 115–34.
12. ULUSAL GERİ DÖNÜŞÜM STRATEJİ BELGESİ VE EYLEM PLANI 2014-
2017. Ankara; 2017.
13. Caylak E. Lead Toxication and Oxidative Stress in Children and Antioxidant
Effects of Thiol Compounds. Tuberculin Ski Test Child. 2010;10(1):13–23.
14. Sonçağ A, Yurdakök K. Intrauterin Toksik Ağır Metal Etkilenimi. Çocuk
Sağlığı ve Hast Derg. 2010;53:145–58.
15. Rusyniak DE, Arroyo A, Acciani J, Froberg B, Kao L, Furbee B. Heavy metal
poisoning: management of intoxication and antidotes. Mol Clin Environ
Toxicol. 2010;100:365–96.
16. Wani AL, Ara A, Usmani JA. Lead toxicity: A review. Interdiscip Toxicol.
2015;8(2):55–64.
17. Sipahi H, Girgin G, Palabiyik SS, Tutkun E, Yilmaz OH, Baydar T. Possible
changes of New-Generation inflammation markers with occupational lead
exposure. J Occup Health. 2017;59(4):345–51.
68
18. Cao Y, Skaug MA, Andersen O, Aaseth J. Chelation therapy in intoxications
with mercury, lead and copper. J Trace Elem Med Biol. 2015;31:188–92.
19. Maden M, Köse SI. Biyomarkerlar ve Klinik Kullanımları. Dicle Üniversitesi
Veterinerlik Fakütesi Derg. 2013;2(1):1–8.
20. Henry NL, Hayes DF. Cancer biomarkers. Mol Oncol. 2012;6(2):140–6.
21. Baydar T, Palabıyık S, Şahin G. Neopterin: günümüzün popüler biyogöstergesi
mi? Türkiye Klin. 2009;29(5):1280–91.
22. Hamerlinck FF V. Neopterin : a review. Experimantal Dermatology.
1999;8:167–76.
23. SAKURAI A, GOTO M. Neopterin: Isolation from Human Urine. J Biochem.
1967;61(1):142–5.
24. Schroecksnadel K, Murr C, Winkler C, Wirleitner B, Fuith LC, Fuchs D.
Neopterin to monitor clinical pathologies involving interferon-γ production.
Pteridines. 2004;15(3):75–90.
25. Hoffmann G, Schobersberger W. Neopterin: A mediator of the cellular immune
system. Pteridines. 2004;15(3):107–12.
26. Engin AB, Tuzun D, Sahin G. Evaluation of Pteridine Metabolism in Battery
Workers Chronically Exposed to Lead. Hum Exp Toxicol. 2006;25:353–9.
27. UNEP. Final review of scientific information on lead [Internet]. Available at:
https://wedocs.unep.org/bitstream/handle/20.500.11822/27635/LeadRev.pdf
28. Lead, elemental [Internet]. Available at:
https://pubchem.ncbi.nlm.nih.gov/source/hsdb/231
29. Lead (Element) [Internet]. Available at:
https://pubchem.ncbi.nlm.nih.gov/element/82#section=History
30. LEAD [Internet]. Available at:
https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=0052
31. Ulusal Atık Yönetimi ve Eylem Planı 2023. T.C. Çevre ve Şehircilik Bakanlığı.
2016.
32. King M, Ramachandran V, Prengaman RD, DeVito SC, Breen J, Updated by
Staff. Lead and Lead Alloys. Kirk-Othmer Encycl Chem Technol. 2005;
33. Abadin H, Ashizawa A, Stevens Y-W, Llados F, Diamond G, Sage G, vd.
Toxicological profile for lead. 2020.
34. Casaret L, Klaassen C, Doull J. Toxic effects of metals. Içinde: Klaassen CD,
editör. Casarett & Doull’s Toxicology: The Basic Science of Poisons. Seventh.
Kansas City; 2008. s. 931–81.
35. Lane RE. The Care of the Lead Worker. Br J Ind Med. 1949;6(3):125–43.
36. Needleman H. Lead poisoning. Annu Rev Med. 2004;55(1):209–22.
37. Garza A, Vega R, Soto E. Cellular mechanisms of lead neurotoxicity. Med Sci
Monit. 2006;12(3):57–65.
69
38. Cleveland LM, Minter ML, Cobb KA, Scott AA, German VF. Lead hazards for
pregnant women and children: Part 1. Am J Nurs. 2008;108(10):40–9.
39. CDC. Preventing lead poisoning in children. 1991.
40. Winneke G, Brockhaus A, Ewers U, Krämer U, Neuf M. Results from the
European multicenter study on lead neurotoxicity in children: Implications for
risk assessment. Neurotoxicol Teratol. 1990;12(5):553–9.
41. Hu H, Aro A, Payton M, Korrick S, Sparrow D, Weiss ST, vd. The relationship
of bone and blood lead to hypertension: The normative aging study. Jama.
1996;275(15):1171–6.
42. Batuman V. Lead Nephropathy, Gout and Hypertension. Am J Med Sci.
1993;305(4):241–7.
43. Schwartz J. Lead, blood pressure, and cardiovascular disease in men. Arch
Environ Health. 1995;50(1):31–7.
44. Nash D, Lustberg M, Sherwin RW, Rubin RJ, Kaufmann RB, Silbergeld EK.
Blood Lead, Blood Pressure, and Hypertension in Perimenopausal and
Postmenopausal Women. 2003;289(12):1523–32.
45. Rothenberg SJ, Kondrasho V, Manalo M, Jiang J, Cuellar R, Garcia M, vd.
Increases in hypertension and blood pressure during pregnancy with increased
bone lead levels. Am J Epidemiol. 2002;156(12):1079–87.
46. Dietert RR, Lee JE, Hussain I, Piepenbrink M. Developmental
immunotoxicology of lead. Toxicol Appl Pharmacol. 2004;198(2):86–94.
47. Karmaus W, Brooks KR, Nebe T, Witten J, Obi-Osius N, Kruse H. Immune
function biomarkers in children exposed to lead and organochlorine
compounds: A cross-sectional study. Environ Heal A Glob Access Sci Source.
2005;4:1–10.
48. Goyer RA. Mechanisms of lead and cadmium nephrotoxicity. Toxicol Lett.
1989;46(1–3):153–62.
49. Borja-Aburto VH, Hertz-Picciotto I, Lopez MR, Farias P, Rios C, Blanco J.
Blood lead levels measured prospectively and risk of spontaneous abortion. Am
J Epidemiol. 1999;150(6):590–7.
50. McClain RM, Becker BA. Teratogenicity, fetal toxicity, and placental transfer
of lead nitrate in rats. Toxicol Appl Pharmacol. 1975;31(1):72–82.
51. Rousseau MC, Straif K, Siemiatycki J. IARC carcinogen update. Environ
Health Perspect. 2005;113(9):580–3.
52. Cocco P, Dosemeci M, Heineman EF. Brain Cancer and Occupational Exposure
to Lead. J Occup Environ Med. 1998;40(11):937–42.
53. Anttila A, Heikkila P, Pukkala E, Nykyri E, Kauppinen T, Hernberg S, vd.
Excess lung cancer among workers exposed to lead. Scand J Work Environ
Heal. 1995;21(6):460–9.
54. Patra RC, Rautray AK, Swarup D. Oxidative stress in lead and cadmium
toxicity and its amelioration. Vet Med Int. 2011;2011.
70
55. Pounds JG, Long GJ, Rosen JF. Cellular and molecular toxicity of lead in bone.
Environ Health Perspect. 1991;91:17–32.
56. Vahter M, Berglund M, Åkesson A, Lidén C. Metals and women’s health.
Environ Res. 2002;88(3):145–55.
57. Kianoush S, Sadeghi M, Balali-Mood M. Recent advances in the clinical
management of lead poisoning. Acta Med Iran. 2015;53(6):327–36.
58. Januzzi AT. Mesleki Kurşun Maruziyetine Bağlı DNA Hasarlarının
Değerlendirilmesi. İstanbul Üniversitesi Sağlık Bilimleri Estitüsü; 2013.
59. Sachdeva C, Thakur K, Sharma A, Sharma KK. Lead: Tiny but Mighty Poison.
Indian J Clin Biochem. 2018;33(2):132–46.
60. Laraque D, Trasande L. Lead Poisoning : Century Challenges. Pediatr Rev.
2005;26(12).
61. Wachter H, Fuchs D, Hausen A, Reibnegger G, Werner ER, Werner-Felmayer
G. Neopterin. Biochemistry—methods—clinical application. 1992.
62. Fuchs D, Weiss G, Reibnegger G, Wachter H. The role of neopterin as a monitor
of cellular immune activation in transplantation, inflammatory, infectious, and
malignant diseases. Crit Rev Clin Lab Sci. 1992;29(3–4):307–44.
63. Sucher R, Schroecksnadel K, Weiss G, Margreiter R, Fuchs D, Brandacher G.
Neopterin, a prognostic marker in human malignancies. Cancer Lett.
2010;287:13–22.
64. Fuchs D, Weiss G, Wachter H. Neopterin, Biochemistry and Clinical Use as a
Marker for Cellular Immune Reactions. Int Arch Allergy Immunol.
1993;101:1–6.
65. Fuchs D, Stahl-Hennig C, Gruber A, Murr C, Hunsmann G, Wachter H.
Neopterin - its clinical use in urinalysis. Kidney Interational Suppl. 1994;47:8–
11.
66. Berdowska A, Zwirska-Korczala K. Neopterin measurement in clinical
diagnosis. J Clin Pharm Ther. 2001;26(5):319–29.
67. Ceyhan AM, Yildirim M, Ceyhan BM, Sütçü R. Psoriasisde serum neopterin ve
TNF-α düzeyleri ve hastalik şiddeti ile ı̇lişkisi. Turkderm Deri Hast ve Frengi
Ars. 2012;46(1):7–10.
68. Baydar T, Yuksel O, Sahin TT, Dikmen K, Girgin G, Sipahi H, vd. Neopterin
as a prognostic biomarker in intensive care unit patients. J Crit Care [Internet].
2009;24(3):318–21. Available at: http://dx.doi.org/10.1016/j.jcrc.2008.06.013
69. Sahin T, Yuksel O, Girgin G, Sipahi H, Dikmen K, Azili C, vd. Is neopterin
level a predictive and differential biomarker in patients with thyroid disorders?
J Endocrinol Invest. 2009;32:147–9.
70. Yuksel O, Sahin T, Girgin G, Sipahi H, Dikmen K, Samur O, vd. Neopterin,
catalase and superoxide dismutase in females with benign and malignant breast
tumors. Pteridines. 2007;18(4):132–8.
71. Müller MM, Curtius HC, Herold M, Huber CH. Neopterin in clinical practice.
71
Clin Chim Acta. 1991;201(1–2):1–16.
72. 6-Biopterin [Internet]. Available at:
https://www.sigmaaldrich.com/TR/en/product/sigma/b2517
73. Maršálek P, Svoboda M, Smutná M, Blahová J, Večerek V. Neopterin and
biopterin as biomarkers of immune system activation associated with castration
in piglets. J Anim Sci. 2011;89(6):1758–62.
74. Uçar T. Fabry Hastalarında Serum Neopterin, Biopterin, Triptofan ve Kinürenin
Düzeylerinin Araştırılması. İstanbul Üniversitesi; 2022.
75. Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis.
2009;32(3):457.
76. Girgin G, Baydar T, Sahin TT, Palabiyik SS, Sipahi H, Yuksel O, vd. Urinary
Biopterin Levels and Blood Dihydropteridine Reductase Activities in Patients
with Thyroid and Breast Disorders. Pteridines. 2010;21:72–8.
77. Richard DM, Dawes MA, Mathias CW, Acheson A, Hill-Kapturczak N,
Dougherty DM. L-tryptophan: Basic metabolic functions, behavioral research
and therapeutic indications. Int J Tryptophan Res. 2009;2(1):45–60.
78. Sainio EL, Pulkki K, Young SN. L-Tryptophan: Biochemical, nutritional and
pharmacological aspects. Amino Acids. 1995;21–47.
79. L-Tryptophan [Internet]. Available at:
https://www.sigmaaldrich.com/TR/en/substance/ltryptophan2042373223
80. L-Kynurenine [Internet]. Available at:
https://www.sigmaaldrich.com/TR/en/product/sigma/k8625
81. Gürcü S. Dı̇yabet hastalarinda pterı̇dı̇nlerı̇n ve ı̇lgı̇lı̇ yolaklarin
değerlendı̇rı̇lmesı̇. Hacettepe Üniversitesi; 2018.
82. Abd El-Fattah EE. IDO/kynurenine pathway in cancer: possible therapeutic
approaches. J Transl Med. 2022;20(1):1–13.
83. King NJC, Thomas SR. Molecules in focus: Indoleamine 2,3-dioxygenase. Int
J Biochem Cell Biol. 2007;39(12):2167–72.
84. Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance:
Immunosuppression by starvation? Immunol Today. 1999;20(10):469–73.
85. Obara-Michlewska M. The tryptophan metabolism, kynurenine pathway and
oxidative stress – implications for glioma pathobiology. Neurochem Int.
2022;158.
86. Davis I, Liu A. What is the tryptophan kynurenine pathway and why is it
important to neurotherapeutics? Expert Rev Neurother. 2015;15(7):719–21.
87. Schröcksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan
metabolism in chronic immune activation. Clin Chim Acta. 2006;364(1–2):82–
90.
88. Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, vd.
CSF concentrations of brain tryptophan and kynurenines during immune
stimulation with IFN-α: Relationship to CNS immune responses and
72
depression. Mol Psychiatry. 2010;15(4):393–403.
89. Geng J, Liu A. Heme-dependent dioxygenases in tryptophan oxidation. Arch
Biochem Biophys. 2014;544:18–26.
90. Mándi Y, Vécsei L. The kynurenine system and immunoregulation. J Neural
Transm. 2012;119:197–209.
91. Kayaoğlu MY, Girgin G, Solmaz İ, Baydar T, Anlar B. Urine neopterin in
childhood acute demyelinating diseases: Potential for differential diagnosis.
Mult Scler Relat Disord. 2022;59(103662).
92. Girgin G, Palabıyık-Yücelik SS, Sipahi H, Kılıçarslan B, Ünüvar S, Tutkun E,
vd. Mercury exposure, neopterin profile, and tryptophan degradation in dental
technicians. Pteridines. 2022;33:32–8.
93. Sabuncuoğlu S, Öztaş Y, Yalçınkaya A, Ünal S, Baydar T, Girgin G. The
increased neopterin content in turkish pediatric patients with sickle cell anemia.
Ann Hematol. 2020;99:41–7.
94. Gürcü S, Girgin G, Yorulmaz G, Kılıçarslan B, Efe B, Baydar T. Neopterin and
biopterin levels and tryptophan degradation in patients with diabetes. Sci Rep.
2020;10.
95. Başaran N, Ündeğer Ü. Effects of lead on immune parameters in occupationally
exposed workers. Am J Ind Med. 2000;38(3):349–54.
96. Cavaleri D, Bartoli F, Capogrosso, Chiara A. Guzzi P, Moretti F, Riboldi I,
Misiak B, vd. Blood concentrations of neopterin and biopterin in subjects with
depression: A systematic review and meta-analysis. Prog Neuro Psychopharmacology Biol Psychiatry. 2023;120.
97. Mourad B, Teleb H. ALTERATION OF THE IMMUNE FUNCTIONS
AMONG WORKERS OF SECONDART ALUMINUM SMELTING. Egypt J
Occup Med. 2023;47(1):19–34.
98. Ahmad I, Khan B, Khan S, Khan MT, Schwab AP. Assessment of lead exposure
among automobile technicians in Khyber Pakhtunkhwa, Pakistan. Sci Total
Environ. 2018;633:293–9.
99. Himani G, Kumar R, Ansari JA, Mahdi AA, Sharma D, Karunanand B, vd.
Blood Lead Levels in Occupationally Exposed Workers Involved in Battery
Factories of Delhi-NCR Region: Effect on Vitamin D and Calcium Metabolism.
Indian J Clin Biochem. 2020;35(1):80–7.
100. Basit S, Karim N, Munshi AB. Occupational lead toxicity in battery workers.
Pakistan J Med Sci. 2015;31(4):775–80.
