Biokemijski pristup neurotoksikologiji u medicini rada

Dose-effect and dose-response relationships in occupational neurotoxicology are rarely studied by means of biochemical methods. Some biochemical markers are however available to extrapolate from animal to man and to use in monitoring human exposures. They might be framed in three categories exploring: the delivery of chemicals to the site of action, the modifications of the molecular target induced by chemicals, the biochemical consequences of these modifications. Estimation of absorbed doses in man is possible for virtually every neurotoxic chemical by means of analytical chemistry of body fluids. Protein adducts, as measured in cellular and other blood components, might assess more closely the delivery in vivo, to the site of action. In this way also in viva comparisons across species will be more precise. Examples include haemoglobin adducts, plasma pseudocholinesterase inhibition etc. In addition measurements of blood enzymes involved in the detoxification (e.g. A-esterases and organophosphorus esters) might contribute to assess metabolic capabilities. Once the molecular target of neurotoxicity is known, extrapolations across species are easy to make. Biochemical markers reflecting in vivo the effect at the site of action are available in very few cases, when the same target is accessible in body fluids. In such circumstances the biochemical marker represents an integrated dose/effect index. Examples include Red Blood Cell Acetylcholinesterase and Lymphocyte Neuropathy Target Esterase for acute and delayed neurotoxicity of organophosphorus esters. The understanding of the pathogenesis of a neurotoxic effect might lead to markers reflecting biochemical consequences of the interaction of the chemical with the target. The specificity of the test will dissect the chain of pathogenetic events from secondary consequences. For example, changes of catecholamine metabolism induced by carbon disulphide.U neurotoksikologiji medicine rada rijetko se biokemijskim metodama ispituje odnos doza-učinak kao i doza-odgovor pojedinih spojeva. Pa ipak, neki se biokemijski pokazatelji mogu ekstrapolirati sa životinja na čovjeka te upotrijebiti u praćenju izloženosti ljudi. Oni se mogu podijeliti u tri skupine istraživanja: a) doprema spojeva do mjesta djelovanja, b) modifikacija ciljne molekule uvjetovana spojem, c) biokemijske posljedice ovakove modifikacije. Određivanje apsorbirane doze u čovjeka moguće je za doslovno svaku neurotoksičnu kemikaliju pomoću metoda analitičke kemije tjelesnih tekućina. Spojevi koji se vezuju za proteine, a mjere se u staničnim i drugim dijelovima krvi, mogu dobro ukazati na njihovu pristupačnost in vivo na mjestu djelovanja. Tu spadaju spojevi koji se vezuju na hemoglobin, zatim oni koji inhibiraju pseudokolinesterazu, itd. Uz to mjerenje enzima koji sudjeluju u detoksifikaciji (npr. A-esteraze i organofosforni esteri) može pridonijeti razumijevanju metaboličkih svojstava. Kad je već poznat molekularni cilj neurotoksičnog djelovanja, lako je ekstrapolirati rezultate s drugih životinjskih vrsta. Biokemijski pokazatelji koji odražavaju učinak in vivo na mjestu djelovanja spoja rijetko su dostupni, i to onda kada je ista ciljna molekula prisutna i u tjelesnim tekućinama. U takvim slučajevima biokemijski pokazatelj predstavlja integrirani indeks doza-učinak. Primjeri su za takve pokazatelje acetilkolinesteraza u eritrocitima i NTE (Neuropathy Target Esterase) u limfocitima za akutnu i kasnu neurotoksičnost organofosfornih spojeva. Razumijevanje patogeneze neurotoksičnog djelovanja može dovesti do otkrivanja markera (pokazatelja) koji odražavaju biokemijske posljedice vezivanja spoja sa ciljem. Specifičnim testom moglo bi se razlučiti patogenezu od sekundarnih posljedica. Primjer su za to promjene metabolizma kateholamina djelovanjem ugljik disulfida. Za utvrđivanje biokemijskih pokazatelja koji bi se mogli koristiti u neurotoksikologiji medicine rada potrebno je razumijevanje mehanizma djelovanja. Na taj način bilo bi moguće razriješiti problem toksikokinetike i toksikodinamike spojeva u životinja i u čovjeka

Comunicazione e Linguaggi non verbali Variazioni sul corpo. Pratiche educative, rieducative e terapeutiche

il volume presenta tre percorsi educativi e rieducativi , attraverso il corpo

Blood copper in organophosphate-induced delayed polyneuropathy

Some organophosphorous esters cause a polyneuropathy which becomes clinically evident 2 weeks after a single dose. The pathogenesis involves modifications of a target protein, neuropathy target esterase, in the axons and a selective inhibition of retrograde axonal transport. It was suggested that copper metabolism might also be involved because of increased levels of plasma copper and ceruloplasmin in animals developing this polyneuropathy. Our results do not confirm this observation; treatment of hens with highly neuropathic single doses of two organophosphates (dihexyl-2,2-dichlorovinyl phosphate and mono-o-cresyl diphenyl phosphate) does not affect total and plasma free copper when measured several times during the development of polyneuropathy. We concluded that copper homeostasis is not affected and that copper changes are unlikely to be involved in the pathogenesis of this polyneuropathy

Promotion of organophosphate-induced delayed polyneuropathy by phenylmethanesulfonyl fluoride.

Certain sulfonates, like phenylmethanesulfonyl fluoride (PMSF), carbamates, and phosphinates, when given prior to neuropathic doses of organophosphates such as diisopropyl phosphorofluoridate (DFP), protect hens from organophosphate-induced delayed polyneuropathy (OPIDP). Protection was related to inhibition of the putative target of OPIDP, which is called Neuropathy Target Esterase (NTE). NTE inhibition above 70-80% in the nervous system of hens followed by a molecular rearrangement called aging initiates OPIDP. PMSF and other protective chemicals inhibit NTE but OPIDP does not develop because aging cannot occur. DFP (1 mg/kg sc) inhibited NTE above 70-80% in peripheral nerve and caused OPIDP in hens. Lower doses (0.3 and 0.5 mg/kg sc) caused about 40-60% NTE inhibition and no or marginal OPIDP. Chlorpyrifos (90 mg/kg po) also caused OPIDP. When repeated (30 mg/kg sc daily for 9 days) or single (5-120 mg/kg sc) doses of PMSF were given after either DFP or chlorpyrifos, OPIDP developed in birds treated with nonneuropathic doses of DFP and was more severe in birds treated with chlorpyrifos or higher doses of DFP. PMSF increased NTE inhibition to greater than 90%. Promotion of OPIDP with a single dose of PMSF (120 mg/kg sc) was obtained in birds up to 11 days after a marginally neuropathic dose of DFP (0.5 mg/kg sc). Promotion was also obtained with phenyl N-methyl N-benzyl carbamate (40 mg/kg iv) but not with non-NTE inhibitors in vivo such as paraoxon or benzenesulfonyl fluoride when given at maximum tolerated doses. These results indicate that protection from OPIDP is only one effect of PMSF because promotion of OPIDP is also observed depending upon the sequence of dosing. Either effect is always related to the doses of PMSF, which inhibit NTE