Exhaled nitric oxide (eNO) is a biological mediator in human lungs and can be measured easily in exhaled air. Increasing eNO concentrations after specific inhalation testing (SIT) have been described for subjects with occupational asthma. Nevertheless, interpreting eNO concentrations after SIT is still a challenge because eNO concentrations depend on various confounding factors. In this study, 24 women and 43 men with suspected occupational asthma were examined by a questionnaire, physical examination, routine laboratory testing, skin prick testing (atopy: at least one wheal reaction >3 mm), lung function including methacholine testing, and SIT with various occupational allergens. Exhaled NO was measured before SIT (t0), 2 h (t1) and 20-22 h (t2) afterwards (NIOX Flex, Aerocrine, Sweden). At baseline we observed significantly lower eNO concentrations in smokers than in non-smokers and in non-atopics than in atopics (significant only in SIT non-responders). In the SIT non-responders (n = 45), eNO concentrations showed no change after SIT (t0: 16.0, t1: 12.3, t2: 16.0 ppb). In the SIT responders (n = 22), eNO was elevated significantly at t2 (t0: 22.9, t1: 19.9, t2: 42.0 ppb). In addition to positive responder status and measuring time, missing atopy and exposure to isocyanates were the essential factors leading to increased eNO concentrations. We conclude that the measurements of eNO after SIT may provide valuable information concerning the allergenic status of a patient.
[Show abstract][Hide abstract] ABSTRACT: Toluene diisocyanate (TDI), a known human asthmagen, was investigated in skin-sensitized Brown Norway rats for its concentration x time (Cxt)-response relationship on elicitation-based endpoints. The major goal of study was to determine the elicitation inhalation threshold dose in sensitized, re-challenged Brown Norway rats, including the associated variables affecting the dosimetry of inhaled TDI-vapor in rats and as to how these differences can be translated to humans. Attempts were made to duplicate at least some traits of human asthma by using skin-sensitized rats which were subjected to single or multiple inhalation-escalation challenge exposures. Two types of dose-escalation protocols were used to determine the elicitation-threshold Cxt; one used a variable C (Cvar) and constant t (tconst), the other a constant C (Cconst) and variable t (tvar). The selection of the “minimal irritant’ C was based an ancillary pre-studies. Neutrophilic granulocytes (PMNs) in bronchoalveolar lavage fluid (BAL) were considered as the endpoint of choice to integrate the allergic pulmonary inflammation. These were supplemented by physiological measurements characterizing nocturnal asthma-like responses and increased nitric oxide in exhaled breath (eNO). The Cconst x tvar regimen yielded the most conclusive dose-response relationship as long C was high enough to overcome the scrubbing capacity of the upper airways. Based on ancillary pre-studies in naïve rats, the related human-equivalent respiratory tract irritant threshold concentration was estimated to be 0.09 ppm. The respective 8-hour time-adjusted asthma-related human-equivalent threshold Cxt-product (dose), in ‘asthmatic’ rats, was estimated to be 0.003 ppm. Both thresholds are in agreement of the current ACGIH TLV® of TDI and published human evidence. In summary, the findings from this animal model suggest that TDI-induced respiratory allergy is likely to be contingent on two interlinked, sequentially occurring mechanisms: first, dermal sensitizing encounters high enough to cause systemic sensitization. Second, when followed by inhalation exposure(s) high enough to initiate and amplify an allergic airway inflammation, then a progression into asthma may occur. This bioassay requires an in-depth knowledge on respiratory tract dosimetry and irritation of the involved test substance to clearly understand the dosimetry causing C- and/or Cxt-dependent respiratory tract irritation and eventually asthma.
[Show abstract][Hide abstract] ABSTRACT: This paper summarizes are range of experimental data central to developing a science-based approach to hazard identification for monomeric and polymeric aliphatic 1,6-hexamethylene diisocyanate (HDI). The dose-response of HDI-induced pulmonary responses in naïve or dermally sensitized rats after one or several inhalation priming exposures was examined in the Brown Norway (BN) rat asthma model. Emphasis was directed to demonstrate the need and difficulty in selecting an appropriate pulmonary dose when much of the inhaled chemical-ly reactive vapor may concentration-dependently be retained in the upper airways of obligate nose-breathing rats. The course taken acknowledges the experimental challenges in identify-ing an elicitation threshold for HDI-monomer near or above the saturated vapor concentration or in the presence of a HDI-polymer aerosol. The inhalation threshold dose on elicitation was determined based on a fixed concentration (C) x variable exposure duration (t) protocol for improving inhalation dosimetry of the lower airways. Neutrophilic granulocytes (PMN) in bronchoalveolar lavage fluid (BAL) in equally inhalation primed naïve and dermally sensitized rats were used to define the inhalation elicitation threshold C x t. Sensitized rats elaborated markedly increased PMN challenged sensitized rats relative to equally challenged naïve rats at 5625 mg HDI/m³ x min (75 mg/m³ for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m³ x min. By applying adjustment factors accounting for both inter-species dif-ferences in inhalation dosimetry and intra-species susceptibility, the workplace human-equivalent threshold C x t was estimated to be in the range of the current ACGIH TLV® of HDI. Thus, this rat ‘asthma’ model was suitable to demonstrate elicitation thresholds for HDI-vapor after one or several inhalation priming exposures and seems to be suitable to derive occupational exposure values (OELs) for diisocyanates in general.
Gabriela R Oates, Irena Stepanikova, Stephanie Gamble, Hector H Gutierrez, William T Harris
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