Neuropatie tossiche - Docenti.unina.it
Transcription
Neuropatie tossiche - Docenti.unina.it
Scuola di Specializzazione in Medicina del lavoro III anno Neuropatie professionali da solventi ed altri tossici industriali M. Manno Università degli Studi di Napoli Federico II Elementi di fisiologia del SNC • • • • • • • • • Peso 2%, portata card. 14%, consumo O2 18% Sopravvivenza all’anossia 60” Consumo elevato di glucosio BEE Struttura complessa Limitate capacità di compenso funzionale Lipofilicità (25% del peso secco!) Lunghi assoni, trasporto assonale Diversi neurotrasmettitori Classificazione delle neuropatie tossiche professionali • Centrali – – – – – – – Solfuro di carbonio (CS2) Solventi (benzene, toluene, xilene) Alcoli alifatici (metilico, etilico, propilico, ecc.) Pb, Hg, Mg CO Piretroidi Esteri organofosforici • Periferiche – – – – – - N-esano Pb Acrilamide As CS2 Ossido di etilene Diagnosi • Anamnesi • Obiettività • Laboratorio – (indicatori di esposizione e di effetto) • Test funzionali – EMG – Potenziali evocati – EEG • Tecniche d’immagine (TAC, PET, RMN) EMG • Riduzione velocità di conduzione motoria – (danno mielinico) • Aumento latenze distali – (danno assonale) Pb • Encefalopatia acuta e cronica – (bambini, vascolare, atrofia nervo ottico) • Neuropatia periferica – (motoria, n. radiale, “fa le corna”, solo arti superiori, EMG alterato, danno mielinico e assonale) • Colica saturnina • Sempre associata a elevata piombemia – (> 120 ug/100 ml) • Regressione lenta – (6-12 mesi, chelazione con NaEDTA) CO • CO-Hb (dal 20-30% in su, coma a 50% e morte a 70%, ipossia cerebrale) • Confusione, letargia, epilessia, coma • Sintomi circolatori, cardiaci, respiratori Hg • Insonnia, anoressia, sintomi psichici • Tremore (movimenti coreo-atetosici) • Elevata mercuriuria (300-600 ug/L) MeHg (Minamata disease): non di origine professionale BTX (benzene, toluene, xilene) • Assorbimento rapido per inalazione, emivita 48 hr, eliminaz. fino al 50% x esalazione, 30-50% metabolismo epatico (induzione enzimatica?), 0,1% nelle urine immodificato • Euforia -> depressione, cefalea nausea, vertigini, atassia, coma • Aritmie fino a f.v. (sensibilizzazione alle catecolamine endogene) CS2 • Sindrome neuropsichica acuta – (delirio , allucinazioni, suicidio, demenza) • Intoss. cronica – (sintomi neurocomport., polineurite, impotenza, visus) • Polineuropatia assonale (esposizione cronica) • Danno misto: neurologico-vascolare • Arteriosclerosi diffusa – (cardiaca, cerebrale, periferica) • Danno epatico (inibizione P450) Neuropatie periferiche Acrilamide – Assorbimento inalatorio e cutaneo – Subdola (parestesie, debolezza musc., alter. riflessi e sensibilità) – Effetti centrali (atassia, disartria, disturbi sess.) – Assonopatia centripeta (dying back) con rogonfiamento “a corona di rosario” – Effetti cutanei (lesioni bollose al palmo mani) Esteri organofosforici • Sindrome colinergica acuta (recettori muscarinici, nicotinici e centrali) – Scialorrea, rinorrea, bronco-ostru/costrizione, diarrea,dolori addom., bradicardia (s. muscarinici) – Fascicolazioni, paralisi diaframm. (s. nicotinici) – Cefalea, confusione, coma (s. centrali) • Inibizione AChE centrale ed eritrocitaria > 30-40% • Terapia: pralidossime e atropina • Polineuropatia periferica da NTE (danno assonale) n-Esano (MEK, MnBK) • Tipica periferica sensitivo-motoria (danno al SNC dubbio) • Danno assonale per esposizione cronica (polineuropatia dei calzaturieri) • Misura di n-esano ematica o aria espirata o 2,5-esandione nelle urine (metabolita tossico Classi di solventi organici (con esempi) (da White & Proctor, 1997, modificata) Idrocarburi alifatici (n-esano) Idrocarburi alogenati (tetracloruro di carbonio) Alcoli (metanolo) Idrocarburi ciclici (cicloesano) Esteri (etil acetato) Eteri (etil etere) Nitroidrocarburi (etil nitrato) Chetoni (acetone, metiletilchetone) Glicoli (glicole etilenico) Idrocarburi aromatici (benzene, toluene) Aldeidi (acetaldeide) Altri (solfuro di carbonio) Case report Due casi di intossicazione letale acuta Two workers were found dead in a well where they were burying barrels containing solvents and solid chemical waste from a nearby chemical plant… Autopsy results brain lung lung kidney liver Laboratory findings Where was CO coming from? Remarks 1. High CO-Hb levels are likely to have contributed significantly to acute DCM neurotoxicity (bioactivation) 2. CO-Hb may be used as a biomarker of exposure in subjects exposed to DCM (biomonitoring) Content • Role of bioactivation in neurotoxicity – individual chemicals – neurotoxicants’ interactions • Biomonitoring of neurotoxicants – Biomarkers of exposure, effect, susceptibility – New biomarkers (CYP) • Final remarks Part 1 • Bioactivation of neurotoxicants A - Bioactivation-dependent Neurotoxicants Examples: • n-Hexane (periferal polyneuropathy) • OP (periferal polyneuropathy) • Acrylamide (cell & axon degeneration) activation CYP2B detoxication Interestingly… • Liver CYP enzyme inducers (PB) decrease rather than increase MePA toxicity! Why? OP bioactivation is tissue- and enzyme-specific • Metabolic activation of Me-Parathion to Me-Paraoxon in the brain is likely to be more relevant for toxicity than activation in the liver. • CYP2B, but not CYP1A, may be responsible for Me-Parathion activation in the brain. activation detoxication B - Bioactivation-independent Neurotoxicants Examples: • Pyrethroids (CNS excitatory neurotoxicity) • CO, CN (cytotoxic hypoxia) • Pb (CNS & PNS damage) CYP Esterases Evidence indicating metabolism as a protecting factor against pyrethroid neurotoxicity* • Compounds inhibiting esterases or CYP-dependent monooxygenases increase pyrethroid toxicity. • Products of pyrethroid biotransformation exhibit a lower acute toxicity than the parent compounds. • Pyrethroids do not accumulate and, in general, have no chronic toxicity. * although some pyrethroid metabolites have shown estrogenic properties in vitro (McCarthy et al., 2006) C - Neurotoxicants’ interactions By mechanism: • • • toxicokinetic biotransformation toxicodynamic By type of effect: • • increased toxicity decreased toxicity (therapeutic) detoxication activation Acute methanol poisoning • 1-2 hrs Dizziness • 6-24 hrs Vomiting, abdominal pain, visual impairment, dispnoea • 24-72 hrs Unconsciousness, coma, death Solvent toxicity Ocular damage Acidosis Methanol bioactivation Treatment of acute methanol intoxication • ethanol i.v. administration • treatment of acidosis • dialisis Inhibition of methanol activation by ethanol Part 2 • Biomonitoring of neurotoxicants , Use, target organ, mechanism, biomarker(s) and BEI of some occupational neurotoxicants Chemical Use Target Mechanism Biomarker BEI (ACGIH 2005) Pb Paint, plastic, batteries PNS/CNS Peripheral neuropathy with segmental demyelination Blood Pb 30 ug/100 mL n-hexane Solvent in shoe manufacturing PNS/CNS Axonopathy due to cross linking 2,5-hexandione in urine 0,4 mg/L Hg Cl production CNS Extrapiramidal syndrome Blood Hg Urine Hg 15ug/L 35ug/g creat. As Insecticide PNS/CNS Encefalopathy (acute), peripheral neuropathy (chronic) As in urine 35 ug As/L Mg Dry battery, alloys CNS Degeneration of striatum/globus pallidus - - CS2 Artificial fibres, laboratory PNS/CNS Axonal degen. (vascular damage) TTCA in urine 5 mg/g creat. Use, target organ, mechanism, biomarker(s) and BEI of some occupational neurotoxicants (2) Chemical Use Target Mechanism Biomarker BEI (ACGIH 2005) OP (Parathion) Pesticide CNS AChE inibhition p-nitrophenol in 0,5 mg/g creat., (70%) CO urine, (RBC AChE activ.) Incomplete combustion CNS Cerebral hypoxia COHb, CO in expired air 3,5% COHb, 20 ppm Minerals separation CNS Cytochrome oxidase inhib., Hypoxia Thiocyanate in blood - Manufacture of paper products PNS/CNS Axonal degeneration Mercapturic acids in urine - Dry Cleaning PNS trigeminal neuropathy TCA in urine TCE in blood 80 mg/L 2 mg/l Insecticide PNS/CNS Sodium channel block Ester hydrolysis/ oxid./conjug. prod.s - Solvent CNS Cerebral hypoxia, oedema DCM in urine, (COHb) 0,3 mg/L (3.5%) (DCM metab.) Cyanide ACRYLAMIDE TCE PYRETHROIDS DCM New biomarkers of exposure, effect and susceptibility to neurotoxicants • CYP2E1 geno- and phenotype as new potential biomarkers in subjects exposed to neurotoxicants Apoprotein, haem and substrate in a CYP structure Protocol of CYP2E1 phenotyping in vivo by the CHZ test • no alcohol for 3 days before test • overnight fasting • time 0: 500 mg Chlorzoxazone p.o. • after 2 hrs: Blood sampling and serum storage • h.p.l.c. analysis and 6-OH-CHZ to CHZ ratio calculation + ethanol - ethanol 1. CYP2E1 phenotype as a biomarker of exposure (or effect?) to neurotoxicants • CYP2E1 enzymatic activity inhbition in vivo in subjects exposed to a mixture of neurotoxic solvents + solvents 2. CYP2E1 mRNA as a biomarker of effect by neurotoxicants • CYP2E1 mRNA expression was assessed in vivo in subjects exposed to toluene Environmental Health Perspectives Volume 114, Number 4, April 2006 Occupational Toluene Exposure Induces Cytochrome P450 2E1 mRNA Expression in Peripheral Lymphocytes Ania Mendoza-Cantú, Fabiola Castorena-Torres, Mario Bermúdez de León, Bulmaro Cisneros, Lizbeth López-Carrillo, Aurora E. Rojas-García, Alberto Aguilar-Salinas, Maurizio Manno, and Arnulfo Albores AIM OF THE STUDY The effects of occupational exposure to toluene on the induction of CYP2E1 were investigated in workers of the printing industry by measuring: a) CYP2E1 mRNA expression in peripheral lymphocytes and b) the 6-OH-CHZ/CHZ metabolic ratio Expected sequence of events following toluene exposure Toluene Exposure CYP2E1 mRNA expression CYP2E1 enzymatic activity (CHZ metabolic ratio) Preliminary conclusions from the toluene study • CYP2E1 mRNA expression in lymphocytes, but not CYP 2E1 activity in vivo (CHZ ratio), may be a promising biomarker of effect in workers exposed to low, but not very low, levels of toluene. • CYP 2E1 activity was correlated with hippuric acid levels in urine but not with CYP mRNA expression in lymphocytes. • The relationship between mRNA expression and CYP 2E1 activity remains to be clarified. Possible reasons for the lack of correlation between mRNA expression and CYP2E1 enzymatic activity (CHZ ratio) • mRNA expression not effective for new enzyme synthesis • other individual factors may affect enzyme activity (genotype, diet, etc.) • coexposure to other CYP2E1 substrates 3. CYP2E1 genotype as a biomarker of susceptibility to neurotoxicants • CYP2E1 DRA polymorphism omozygote genotype in subjects exposed to n-hexane CYP2E1 polymorphism may be an important susceptibility factor in n-hexane toxicity Biomarkers, 11: 65-69, 2006 “Association between metabolic gene polymorphisms and susceptibility to peripheral nerve damage in workers exposed to n-hexane: a preliminary study.” Zhang Y, Liu Q, Liu Q, Duan H, Cheng J, Jiang S, Huang X*, Leng S, He F, Zheng Y. National Institute for Occupational Health and Poison Control, Chinese Centre for Disease Control and Prevention, Beijing, China. *Shenzhen Institute of Health Inspection, Shenzhen, China Distribution of CYP2E1 Dra homozygous mutations in workers exposed to n-hexane in a printing factory and with (Cases) or without (Controls) periferal polyneuropathy symptoms Genotype Cases (CYP2E1 Dra polymorphism) (n =22) Homozygotes 18,2 % (n = 163) Statistical significance 3,7 % p = 0.015 Controls Should homozygotes for CYP2E1 Dra polymorphism be prevented from exposure to n-hexane? Valutazione clinica in caso di sospetta neurotossicità da solventi (da White & Proctor, 1997, modificata) 1. Questionario o anamnesi – storia lavorativa (qualitativa) – descrizione dell’esposizione (quali-quantitativa) – Sintomi 2. Esame clinico – esame neurologico generale (SNC e SNP) – valutazione di specifiche funzioni sensitivo-motorie e dei riflessi 3. Esami neurofisiologici e radiologici – – – – – – conduzione nervosa elettromielogramma potenziali evocati PET TAC risonanza magnetica 4. Test neurocomportamentali – funzione cognitiva – funzione motoria – umore e personalità Diagnosi eziologica in caso di sospetta neurotossicità cronica da solventi 1. Segni, sintomi ed esami funzionali compatibili con neuropatia da solventi 2. Esposizione documentata e significativa a solventi neurotossici 3. Assenza di altre patologie o fattori di rischio Final remarks Understanding the pathways of neurotoxicants’ bioactivation may be important: • to understand their mechanism of action • to perform a more rational biological monitoring • to treat and prevent their clinical effects [email protected]