Ototoksične tvari na radnom mjestu: kratak uvid u stanje

Ototoxic chemicals can impair the sense of hearing and balance. Lately, efforts have been intensifi ed to compile evidence-based lists of workplace agents with ototoxic properties. This article gives a rough overview of the latest relevant publications, which confirm that toluene, styrene, and lead should receive particular attention as ototoxic substances at the workplace. Moreover, there is sufficient evidence that occupational exposure to trichloroethylene, mercury, carbon monoxide, and carbon disulfide can affect the ear. Based on the existing information, industrial hygienists should make sure that occupational health professionals and the workforce are made aware of the risks posed by ototoxic substances; support their replacement or new technical measures to reduce exposure; make these substances a part of regular screening, develop tools that can early diagnose chemically induced hearing impairment, and investigate further into the ototoxic properties of these substances. Further research should focus on quantifying the combined effects of ototoxic substances and noise.Ototoksične kemikalije mogu narušiti osjetilo sluha i ravnotežu. Nedavno su uloženi dodatni napori u izradu znanstveno utemeljenih popisa tvari koje su prisutne na radnom mjestu, a koje imaju ototoksična svojstva. Ovaj rad daje kratak uvid u najnovije publikacije objavljene na ovu temu. Usporedba navedenih publikacija potvrđuje da bi toluen, stiren i olovo trebalo razmatrati kao izrazito bitne ototoksične tvari koje postoje na radnom mjestu. Nadalje, postoje dovoljni dokazi koji potvrđuju da ototoksične tvari poput trikloretilena, žive, ugljikova monoksida i disulfida u radnom okruženju mogu oštetiti sluh. Temeljem postojećih informacija stručnjaci u području higijene rada trebali bi upozoravati stručnjake u području medicine rada i same radnike na rizike koje ototoksične tvari predstavljaju; poticati ih na zamjenu takvih tvari ili uvođenje novih mjera za smanjenje izlaganja; uključiti ototoksične tvari u redoviti program praćenja i osmisliti mjere za rano otkrivanje oštećenja sluha zbog izloženosti kemijskim tvarima; dodatno istražiti ototoksična svojstva ovih tvari. Buduća istraživanja trebala bi se usredotočiti na izračun ukupnih učinaka ototoksičnih tvari i buke

Olfactory dysfunction revisited: a reappraisal of work-related olfactory dysfunction caused by chemicals

Abstract Occupational exposure to numerous individual chemicals has been associated with olfactory dysfunction, mainly in individual case descriptions. Comprehensive epidemiological investigations into the olfactotoxic effect of working substances show that the human sense of smell may be impaired by exposure to metal compounds involving cadmium, chromium and nickel, and to formaldehyde. This conclusion is supported by the results of animal experiments. The level of evidence for a relationship between olfactory dysfunction and workplace exposure to other substances is relatively weak

Bitumen (Dampf und Aerosol bei der Heißverarbeitung) : MAK value documentation in German language, 2019 MAK value documentation in German language, 2019

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the classification of bitumen [8052‐42‐4; 64741‐56‐6; 64742‐93‐4] in Carcinogen Category 2 considering all toxicological endpoints. New data allowed a separate assessment of the harmful properties of vapours and aerosols from high‐temperature processing of two bitumen groups. Straight‐Run and Air‐Rectified Bitumen For the derivation of a maximum concentration at the workplace (MAK value), a 2‐year inhalation study in rats exposed to vapours and aerosols from a mixture of straight‐run and air‐rectified bitumen is used. Due to an increased incidence of bronchioalveolar hyperplasia in the lungs and of inflammatory cells in the nasal epithelium, the study resulted in a NOAEC of 6 mg/m3. Taking into account the extrapolation from an animal study and the increased respiratory volume at the workplace compared with the exposure of the animals at rest, a MAK value of 1.5 mg/m3 (sum of vapour and inhalable fraction) is derived for straight‐run and air‐rectified bitumen based on bitumen condensate standard. The MAK value is one‐third of the mean concentration at which three out of 12 inflammation markers are elevated in the sputum of exposed workers. However, the clinical relevance of this finding is unclear and the margin to the MAK value is considered sufficient. The effects on the lung is the most sensitive endpoint, so vapours and aerosols of bitumen are assigned to Peak Limitation Category II with an excursion factor of 2. All in all, the investigated straight‐run and air‐rectified bitumens did not exhibit distinct genotoxic or carcinogenic properties. However, due to the wide range in the chemical composition, harmful emissions of carcinogenic and mutagenic substances during high‐temperature processing cannot be completely excluded. Therefore, vapours and aerosols of straight‐run and air‐rectified bitumens, as commonly used in road paving, are regarded as suspicious carcinogens and classified in Carcinogen Category 3 B. As no data are available for developmental toxicity they are assigned to Pregnancy Risk Group D. Skin contact may contribute significantly to systemic toxicity and the “H” notation is confirmed. Sensitization is not expected from the available data. Oxidized Bitumen There are no inhalation studies available for evaluation of the carcinogenicity of oxidized bitumen (“Roofing Bitumen”). The new animal studies published since 2001 and most of the previous studies show the carcinogenicity of condensates of vapours and aerosols of oxidized bitumens in skin painting studies in mice, so that a significant number of tested oxidized bitumens must be considered carcinogenic. The positive animal experiments on the carcinogenicity are consistent with the results of a genotoxicity study in roofing workers with increased DNA strand break rates. Vapours and aerosols of oxidized bitumen are classified in Carcinogen Category 2. A MAK value could not be derived. Mutations in bacteria and higher levels of benzo[a]pyrene in oxidized bitumen condensates compared to those of straight‐run and air‐rectified bitumen and the systemic availability of inhaled vapours and aerosols of oxidized bitumen support suspicion of germ cell mutagenicity. Therefore, vapours and aerosols of oxidized bitumen are classified in Category 3 B for germ cell mutagens. Skin contact may contribute significantly to systemic toxicity and the “H” notation is confirmed. Sensitization is not expected from the available data

A phosphotyrosine switch regulates organic cation transporters.

Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation

A phosphotyrosine switch regulates organic cation transporters.

Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation