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Distributions for time, interspecies and intraspecies extrapolation for deriving occupational exposure limits.

ABSTRACT: This work aimed at improving the empirical database of time (i.e., exposure duration), interspecies and intraspecies extrapolation when deriving occupational exposure limits (OELs). For each extrapolation step, a distribution was derived, which can be used to model the associated uncertainties. For time and interspecies extrapolation, distributions of ratios of dose descriptors were derived from studies of different length or species. National Toxicology Program (NTP) study data were manually assessed, and data from REACH (Registration, Evaluation and Authorisation of Chemicals) registration dossiers were evaluated semi-automatically. Intraspecies extrapolation was investigated by compiling published studies on human toxicokinetic and toxicodynamic variability. A new database was established for toxicokinetic differences in interindividual susceptibility, including many inhalation studies. Using NTP data produced more reliable results than using REACH data. The geometric mean (GM) for time extrapolation subacute/chronic agreed with previous evaluations (GM = 4.11), whereas the GM for subchronic/chronic extrapolation was slightly higher (GM = 2.93) than the GMs found by others. No significant differences were observed between systemically and locally acting substances. Observed interspecies differences confirmed the suitability of allometric scaling, with the derived distribution describing remaining uncertainty. Distributions of intraspecies variability at the 1% and 5% incidence level had medians of 7.25 and 3.56, respectively. When compared with assessment factors (AFs) currently used in the EU, probabilities that these AFs are protective enough span a wide range from 10% to 95%, depending on the extrapolation step. These results help to select AFs in a transparent and informed way and, by allowing to compare protection levels achieved, to harmonise methods for deriving OELs.

SUBMITTER: Dilger M

PROVIDER: S-EPMC9314728 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The twitching motility of bacteria is closely related to environmental adaptability and pathogenic behaviors. Lysobacter is a good genus in which to study twitching motility because of the complex social activities and distinct movement patterns of its members. Regardless, the mechanism that induces twitching motility is largely unknown. In this study, we found that the interspecies signal indole caused Lysobacter to have irregular, random twitching motility with significantly enhanced speed. Deletion of qseC or qseB from the two-component system for indole signaling perception resulted in the disappearance of rapid, random movements and significantly decreased twitching activity. Indole-induced, rapid, random twitching was achieved through upregulation of expression of gene cluster pilE1-pilY11-pilX1-pilW1-pilV1-fimT1 In addition, under conditions of extremely low bacterial density, individual Lysobacter cells grew and divided in a stable manner in situ without any movement. The intraspecies quorum-sensing signaling factor 13-methyltetradecanoic acid, designated L. enzymogenes diffusible signaling factor (LeDSF), was essential for Lysobacter to produce twitching motility through indirect regulation of gene clusters pilM-pilN-pilO-pilP-pilQ and pilS1-pilR-pilA-pilB-pilC These results demonstrate that the motility of Lysobacter is induced and regulated by indole and LeDSF, which reveals a novel theory for future studies of the mechanisms of bacterial twitching activities.IMPORTANCE The mechanism underlying bacterial twitching motility is an important research area because it is closely related to social and pathogenic behaviors. The mechanism mediating cell-to-cell perception of twitching motility is largely unknown. Using Lysobacter as a model, we found in this study that the interspecies signal indole caused Lysobacter to exhibit irregular, random twitching motility via activation of gene cluster pilE1-pilY11-pilX1-pilW1-pilV1-fimT1 In addition, population-dependent behavior induced by 13-methyltetradecanoic acid, a quorum-sensing signaling molecule designated LeDSF, was involved in twitching motility by indirectly regulating gene clusters pilM-pilN-pilO-pilP-pilQ and pilS1-pilR-pilA-pilB-pilC The results demonstrate that the twitching motility of Lysobacter is regulated by these two signaling molecules, offering novel clues for exploring the mechanisms of twitching motility and population-dependent behaviors of bacteria.

Project description:The aim of the investigation was to study if dysfunctions associated to the cochlea or its regulatory system can be found, and possibly explain hearing problems in subjects with normal or near-normal audiograms. The design was a prospective study of subjects recruited from the general population. The included subjects were persons with auditory problems who had normal, or near-normal, pure tone hearing thresholds, who could be included in one of three subgroups: teachers, Education; people working with music, Music; and people with moderate or negligible noise exposure, Other. A fourth group included people with poorer pure tone hearing thresholds and a history of severe occupational noise, Industry. Ntotal?=?193. The following hearing tests were used: - pure tone audiometry with Békésy technique, - transient evoked otoacoustic emissions and distortion product otoacoustic emissions, without and with contralateral noise; - psychoacoustical modulation transfer function, - forward masking, - speech recognition in noise, - tinnitus matching. A questionnaire about occupations, noise exposure, stress/anxiety, muscular problems, medication, and heredity, was addressed to the participants. Forward masking results were significantly worse for Education and Industry than for the other groups, possibly associated to the inner hair cell area. Forward masking results were significantly correlated to louder matched tinnitus. For many subjects speech recognition in noise, left ear, did not increase in a normal way when the listening level was increased. Subjects hypersensitive to loud sound had significantly better speech recognition in noise at the lower test level than subjects not hypersensitive. Self-reported stress/anxiety was similar for all groups. In conclusion, hearing dysfunctions were found in subjects with tinnitus and other auditory problems, combined with normal or near-normal pure tone thresholds. The teachers, mostly regarded as a group exposed to noise below risk levels, had dysfunctions almost identical to those of the more exposed Industry group.

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Distributions for time, interspecies and intraspecies extrapolation for deriving occupational exposure limits.

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