Jürgen Pauluhn

..Some of the many variables and possible artifacts likely to occur in animal inhalation studies are addressed in this paper...

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..Accordingly, the specific pros and cons of the selected animal model, including protocol variables, animal species and strain selected, must be interpreted cautiously in order to arrive at a meaningful extrapolation for humans...

..From that perspective, the determination of mass-based pulmonary lung burdens appears to be amongst the most important and critical nominator of dose and dose-related pulmonary toxicity...

..7 and 4.4 mg m(-3) , respectively, and supports an OEL (time-adjusted chronic occupational exposure level) of 2 mg m(-3) (alveolar fraction)...

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..This is believed to be associated with the higher ventilation of small rodents and with rodent-specific sensory bronchopulmonary defense reflexes...

..Due methodological uncertainties associated with the harsh hydrolysis of biological specimens may be reduced substantially when using incremental pre- to post-shift changes rather than relying solely on absolute data...

..The C x t product in the range of the nonlethal threshold concentration (1008 mg/m3 x min) caused pulmonary injury as indicated by markedly increased protein in BAL. Changes resolved almost entirely within the 4-wk postexposure period...

..6 mg/m3 x min distinct differences to the control existed. Despite the extensively increased airway permeability, histopathology did not provide evidence of lung tissue remodeling or irreversible sequelae...

..Therefore, overnight exposure to the smoke from burning mosquito coils (manufactured in Indonesia) is unlikely to be associated with any unreasonable health risk...

..However, spleens of the 32.4 mg/m3 exposure group exhibited a minimal increase in extramedullary hematopoiesis. Exposure to 9.2 mg/m3 was not associated with any significant effect...

..This supports the conclusion that Wistar rats afford a higher diagnostic resolution than BN rats...

..The content of free NCO per se appears to be a poor predictor of the pulmonary irritant potency of polyisocyanate aerosols...

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..The inhalation studies conducted show unequivocally that acute toxic effects are difficult to produce with this type of product even under rigorous testing conditions...

..Carry-over effects related to erythrotoxicity or Heinz body formation were not observed at any exposure level...

..The no-observed-adverse-effect level (NOAEL) of the 4-wk study was 19.1 mg/m3 and is based on the predominant atrophic changes of the olfactory epithelium and the minimal to borderline erythrocytotoxic effects at 115.1 mg/m3...

..75 l min(-1) per rat exposure port ( approximately 3.75 times the minute volume of young adult rats) to prevent higher CO(2)-concentrations occurring...

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..5 μl PM(respirable)/m³ x agglomerate density, independent on nano- or submicron-sized properties, as a generic no-adverse effect level in both rats and humans...

..05 mg Baytubes/m(3) (time weighted average) is considered to be reasonably protective to prevent lung injury to occur in the workplace environment...

..Thus, the hypothesis of study is verified, namely, common denominators between carbon black and MWCNT do exist...

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..In order to reliably demonstrate retention-related different characteristics in toxicity and fate of poorly soluble (nano)particles postexposure periods of at least 3 months appear to be indispensible...

..In order to prevent indiscriminant testing of such products in bioassays, the development of standardized in vitro alternatives should be considered with high priority...

..e., sampling equipment with different aspiration efficiencies and collection media, improve the judgment whether the results from atmosphere characterization are 'conclusive' or 'inconclusive.'..

..In summary, these data suggest that the vigor of asthma-like responses appear to be more dependent on the inhalation elicitation dose of previously challenged rats rather than the dermal induction dose...

..Accordingly, it is experimentally challenging to articulate a unifying denominator of dose at critical cellular targets in both in vivo and in vitro test systems due to the complex dependence on test material-specific characteristics...

..In summary, this study supports the conclusion that data from rat inhalation studies with these types of isocyanates appear to be more conservative and less variable than the respective data from mice...

..This animal model provides a versatile and robust experimental tool to evaluate and assess at least some features of MDI-related asthma...

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..In all compartments, dosimeters related to higher oligomers of MDI demonstrated low bioavailability, i.e. their recovery was appreciably lower than expected...

..However, it remains unresolved whether the marked effects observed in the topically sensitized rats are more related to a route-of-induction or dose-dependent phenomenon...

..Comparison of MDI with its corresponding amine support that the analytes determined stem from conjugated MDI rather than in vivo hydrolyzed MDI...

..Repeated short-term inhalation exposures to mildly irritant concentrations (but low doses) of chemical asthmagens may be of higher concern than topical exposures...

..This supports the conclusion that the predominant response to inhaled MWCNT is principally related to the assemblage structure and not catalyst impurities (if in the range of < or = 0.5%)...

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..It is concluded that pulmonary irritation caused by polyisocyanate aerosols can readily be quantified in an acute rat bioassay by the analysis of total protein in BALF...

..In the case that threshold is exceeded, the secondary compensatory chronic response may then cause additional superimposed types of chronic pathologies...

..Taking into account the respective differences in exposure intensities, the comparison of elicitation thresholds of BN rats sensitized by inhalation or skin exposure did not demonstrate essential differences...

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..In summary, with respect to induction of allergy and asthma, the data presented here suggest that the homopolymeric forms of HDI appear to be less potent asthmagens, if any, than monomeric HDI...

..e., results obtained from integrating dosimeters of exposure need to be verified by adequate air monitoring...

..This paper addresses major developments in the discipline of inhalation toxicology with particular emphasis on the state-of-the-art testing of complex mixtures...

..In spite of using maximal technically attainable concentrations, it appears to be experimentally challenging to deliver such nucleophiles to the lower respiratory tract at high dosages...

..This study demonstrates some of the pitfalls that can occur in context with route-to-route extrapolations and reinforces many of the concerns related to such extrapolations...

..Accordingly, the muscular deficits elicited by high concentrations of propineb are viewed to be secondary effects in an animal species likely to be more susceptible to this type of change than humans (Pauluhn & Rosenbruch, 2003)...

..However, owing to their higher ventilation, under such conditions the pups may receive dosages at least double those of the dams...

..e., whether a dynamic or (quasi)static mode of exposure is chosen. Inappropriate timing of the sampling of biological specimens may lead to the underestimation of effects, especially in whole-body exposed animals...

..Also with systemically acting agents caution is advised to perform simple route-to-route extrapolations in the absence of a detailed pharmacokinetic understanding and knowledge of the critical toxophoric moieties...

..In summary, triphosgene-induced lung injury patterns are different from that of phosgene and diphosgene. More research is needed to close the substantial data gaps of triphosgene...

..In summary, it appears that respirable PMDI aerosol interacts with pulmonary surfactant, which, in turn, may stimulate type II pneumocytes to increase their production of surfactant and to proliferate...

..9 mg/m(3). With respect to changes of early markers of pulmonary epithelial barrier dysfunction, approximately 3 mg HDI-IC/m(3) was considered to be the threshold concentration for acute pulmonary irritation...

..97 mg/m(3). Further study is needed to clarify whether the pulmonary response observed at this exposure level is consistent with an adaptive or an early adverse effect...

..7 mg/m3 and appears to be related a dysfunction of pulmonary surfactant. Nonprotein sulfhydryl constituents appear to play a role as portal-of-entry specific modifying factors...

..Furthermore, it appears that particles in the range of approximately 2-6 microm evoke more consistent respiratory response upon challenge exposure than particles in the 1-2 microm range...

..The no-observable-adverse-effect levels (NOAELs) of both the 3- and 13-wk studies were in the range of 3-4 mg/m(3). Appreciable differences between the two types of polyisocyanates were not observed...

..Positive control groups exhibited significant increases in MN-PCE. In summary, monomeric MDI aerosol did not induce cytogenetic damage in Brown-Norway rats when investigated according to current testing guidelines...

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..Overall, challenge exposures with this type of irritant aerosol appear to evoke more consistent effects when the MMAD is in the range of approximately 2 rather than approximately 5 microm...

..1 mg/m(3) air and that of the 1-wk study was 38.2 mg/m(3) air. This difference in NOAELs is considered to be related to the selection of exposure concentrations rather than cumulative toxicity...

..Collectively, this study supports the view held that polymeric alpha, omega-diamines appear to be potent pneumotoxicants...