Pathogenetic role of alveolar surfactant depleted by phosgene: Biophysical mechanisms and peak inhalation exposure metrics.

In contrast to water-soluble respiratory tract irritants in their gas phase, the physicochemical properties of 'hydrophilicity' vs. 'lipophilicity' are the preponderant factors that dictate the site of major retention of the gas at the portal of entry. The lipophilic physical properties of phosgene gas facilitate retention in the alveolar region lined with amphipathic pulmonary surfactant (PS). The relationship between exposure and adverse health outcomes is complex, may vary over time, and is dependent on the biokinetics, biophysics, and pool size of PS relative to the inhaled dose of phosgene. Kinetic PS depletion is hypothesized to occur as inhalation followed by inhaled dose-dependent PS depletion. A kinetic model was developed to better understand the variables characterizing the inhaled dose rates of phosgene vs. PS pool size reconstitution. Modeling and empirical data from published evidence revealed that phosgene gas unequivocally follows a concentration x exposure (C × t) metric, independent of the frequency of exposure. The modeled and empirical data support the hypothesis that the exposure standards of phosgene are described best by a C × t time-averaged metric. Modeled data favorably duplicate expert panel-derived standards. Peak exposures within a reasonable range are of no concern.

Derivation of thresholds for inhaled chemically reactive irritants: Searching for substance-specific common denominators for read-across prediction.

Emergency response planning guideline values are used to protect the public when there has been a short-term chemical release. These values serve the purpose of identifying areas where a hazard exists if the concentration of hazardous chemicals is exceeded for the specified exposure duration. This paper focuses on carbonyl chlorides, a class of highly irritant/corrosive chemical intermediates characterized by the reactive moiety R-COCl. Despite their unifying property of reacting with nucleophilic biopolymers/peptides lining the airways of the respiratory tract, their adverse outcome pathway (AOP), in addition to surface area dose, appears to be dominated by their site(s) of major deposition (liquid) or retention (gas) within the respiratory tract. Thus, the physicochemical properties "phase" and "lipophilicity" become more decisive for the AOP than the chemical structure. This complicates the grouping of portal-of-entry irritant chemicals for the read-across prediction of chemicals, especially those with semivolatile properties. Phosgene (COCl2) served as a template to predict emergency response planning levels 2 (non-incapacitating, reversible injury) and 3 (nonlethal) for related chemicals such as SOCl2, formates, and acid chlorides. A rationale and guide to the systematic characterization of uncertainties associated with the lung region, water solubility of the vapor phase, and chemical specificity is given. The approach described in this paper highlights the regional differences and outcomes that are phenotypically described as irritation of the respiratory tract. Especially for such a data-lean group of chemicals, reliable read-across predictions could reduce the uncertainty associated with the derivation of values used for emergency-related risk assessment and management. Likewise, the approach suggested could improve the grouping and categorization of such chemicals, providing a means to reduce animal testing with potentially corrosive chemicals. Overall, the course taken for read-across predictions provided valid estimates as long as emphasis was directed to the physicochemical properties determining the most critical regional injury within the respiratory tract.

Human risk assessment of inhaled irritants: Role of sensory stimulations from spatially separated nociceptors.

Contemporary approaches to human health risk assessment for respiratory tract irritants are variable and controversial. This manuscript provides an in-depth analysis and assessment of the applicability of the classical respiratory depression 50 % (RD50) assay with focus on the Log-linear extrapolation of the non-sensory irritant threshold (RD0 or RD10) relative to the contemporary Point of Departure (POD) U.S.-EPA benchmark approach. Three prototypic volatile chemically reactive irritants are used to exemplify the pros and cons of this alternative approach. These irritants differ in physicochemical properties affecting water-solubility and lipophilicity. Depending on these variables, a vapor may preferentially be retained in the extrathoracic region (ET), the tracheobronchial region (TB), and the pulmonary region (PU); although a smooth transition between these regions occurs at increasingly high concentrations. Each region has its specific nociceptors sensing irritants and regional-specific response to injury. The alternative approach using rats identified the chemical-specific critical region of respiratory tract injury. Statistically derived PODs on ET-TB related sensory irritation provide important information for ET-TB irritants but not for PU irritants. The POD of ET-TB irritants from acute and repeated studies decreased substantially. In summary, statistically derived PODs improve the risk assessment of respiratory tract irritants; however, those from repeated exposures should be given preference to those from acute exposures.

Inhalation toxicity of cyclic semi-volatile methylsiloxanes: Disentangling the conundrum of phase-specific adaptations from adverse outcomes.

This paper compares the phase-specific inhalation toxicity of the cyclic semi-volatile methylsiloxanes (cVMSs) D4, D5 and D6. The objectives of this paper are to re-analyze information from acute to chronic inhalation studies on rats with these cVMSs to identify the unifying principles of phase-specific toxicity at the portal-of-entry and if they depend on acute, acute-on-chronic or chronic mechanisms. This re-analysis supports the hypothesis that concentrations must be high enough to exceed the vapor saturation at any given temperature for stabilizing the aerosol phase and evoking phase-specific effects at sites of the respiratory tract susceptible to the cVMSs-specific physicochemical properties amphiphilicity and surface tension. In summary, the portal-of-entry effects and related findings appear to be acute in nature and specific to liquid aerosol. The repeated inhalation exposure studies with D4 and D5 up to two years in duration did not reveal chronic aggravations of portal of entry outcomes. Findings at a pulmonary location where amphiphilic surfactant molecules are present appear to be caused by the acute adaptation to deposited dose. Such outcome should better be described as a high-dose liquid aerosol phenomenon imparted by the physicochemical properties "liquid" and "hydrophobic". This calls for a phase-specific human risk characterization of cVMSs.

Phosgene inhalation toxicity: Update on mechanisms and mechanism-based treatment strategies.

Phosgene (carbonyl dichloride) gas is an indispensable high-production-volume chemical intermediate used worldwide in numerous industrial processes. Published evidence of human exposures due to accidents and warfare (World War I) has been reported; however, these reports often lack specificity because of the uncharacterized exposure intensities of phosgene and/or related irritants. These may include liquid or solid congeners of phosgene, including di- and triphosgene and/or the respiratory tract irritant chlorine which are often collectively reported under the umbrella of phosgene exposure without any appreciation of their differences in causing acute lung injury (ALI). Among these irritants, phosgene gas is somewhat unique because of its poor water solubility. This prevents any appreciable retention of the gas in the upper airways and related trigeminal sensations of irritation. By contrast, in the pulmonary compartment, amphiphilic surfactant might scavenge this lipophilic gas. The interaction of phosgene and the surfactant may affect basic physiological functions controlled by Starling's and Laplace's laws, which can be followed by cardiogenic pulmonary edema. The phenotypic manifestations are dependent on the concentration × exposure duration (C × t); the higher the C × t is, the less time that is required for edema to appear. It is hypothesized that this type of edema is caused by cardiovascular and colloid osmotic imbalances to initial neurogenic events but not because of the injury itself. Thus, hemodynamic etiologies appear to cause imbalances in extravasated fluids and solute accumulation in the pulmonary interstitium, which is not drained away by the lymphatic channels of the lung. The most salient associated findings are hemoconcentration and hypoproteinemia. The involved intertwined pathophysiological processes coordinating pulmonary ventilation and cardiopulmonary perfusion under such conditions are complex. Pulmonary arterial catheter measurements on phosgene-exposed dogs provided evidence of 'cor pulmonale', a form of acute right heart failure produced by a sudden increase in resistance to blood flow in the pulmonary circulation about 20 h postexposure. The objective of this review is to critically analyze evidence from experimental inhalation studies in rats and dogs, and evidence from accidental human exposures to better understand the primary and secondary events causing cardiopulmonary dysfunction and an ensuing life-threatening lung edema. Mechanism-based diagnostic and therapeutic approaches are also considered for this form of cardiogenic edema.

Estimation of time to compromised tenability in fires: is it time to change paradigms?

The ISO standard 13571 estimates the time to the compromised tenability of people in enclosed fires. This is understood as the time which must be available for the structural design to pass an evacuation, or an escape paradigm for the evacuation of burning buildings. As with all emergency response planning values, such once-in-a-lifetime events cannot readily be validated side-by-side. Consequently, risk assessors must refer to animal-based reference data fitting the scenario of concern closely. The analysis detailed in this paper used the concentration × time (Cxt)-matrix of point of departures (PODs) from rats acutely exposed to carbon monoxide (CO), which is amongst the most abundant toxic fire gases. The objective of the analysis was to clarify whether the time- and effect-adjusted nonlethal threshold concentration LCt01 × 1/3 from acute rat inhalation studies is suited to model thresholds characterizing any 'impairment of escape' in humans. Modeled outcomes are compared with published reference data from human volunteers exposed at the similar C × t's of CO at 800 ppm × 1-h and 100 ppm × 8-h. These exposure durations match the maximum escape duration of 1-h considered in the ISO standard 13571 and standards enforcing occupational exposure limits of 8-h duration. The reference PODs indicative of 'impairment of escape' in healthy adults relied on C × t's below those eliciting any loss of motor function or psychoneurological functions. The comparison of the LCt01 × 1/3 based modeled outcomes from rats match favorably with the effect-based PODs from humans. Consistent with published evidence from humans, carboxyhemoglobin (COHb) saturation-a biomarker of exposure rather than of effect-failed to reliably predict effect-based outcomes. Unlike the LCt01 × 1/3 threshold approach, the COHb-based median approach used by ISO TS 13571 is inconsistent with human evidence and both over- and under-estimates the CO-related potency for causing incapacitation at non-toxic and critically-toxic C × 's, respectively. In summary, it seems timely that the ISO TS 13571 standard pays attention to scientific progress in relevant toxicity information and refinements to scientific methods shown to adequately predict human risks.

Concentration × time analyses of sensory irritants revisited: Weight of evidence or the toxic load approach. That is the question.

The toxic effects resulting from inhalation exposure depend on both the concentration (C) of the inhaled substance and the exposure duration (t), including the assumptions that the exposure-limiting toxic effect is linearly linked with the accumulated C × t (inhaled dose), and detoxification or compensatory responses diminishing this dose are negligible. This interrelationship applies for both constant and fluctuating concentrations and is usually expressed by the toxic load equation Cn × t = constant effect (k). The toxic load exponent 'n' is derived from both C- and t-dependent exponents with Cb2×tb3 = k with n = b2/b3. This model is taken as a fundamental basis for assessing the acute hazard posed by atmospheric releases of noxious substances, whether deliberate or accidental. Despite its universal use, especially for inhaled irritants, the toxicological significance of this mathematical construct is still discussed controversially. With n = 1 this equation is called Haber's rule. The underlying assumption is that the exposure-based calculated and the actually inhaled Cb2×tb3 are identical. Unlike the calculated dose, the latter is dependent on the test species and its t-dependent change in respiratory minute volume (MV). The retention patterns of inhaled irritant vapors may differ in obligate nasal breathing rodents and oronasally breathing humans as well. Thus, due to the interdependence of n on both C, t and k, this mathematical construct generates a bioassay-specific 'n' which can hardly be considered as human-equivalent, especially following exposure to sensory irritants known to elicit reflex-related changes in MV. The C- and t-dependent impact on Cn × t = k was analyzed with the sensory irritant n-butyl monoisocyanate and compared with t-dependent changes elicited by highly, moderately, and poorly water-soluble sensory irritants ammonia, toluene diisocyanate, and phosgene, respectively. This comparison reveals that n depends on several factors: In cases where MV is instantly and plateau-like depressed with onset of exposure, n appears to be most dependent on Cb2 × MV whereas for a similar slower time-dependent response n becomes more dependent on MV × tb3. For any ensuing risk characterization that focuses on acute non-lethal threshold Cb2 × tb3's, the sensory irritation-related depression in MV must be known to arrive at meaningful conclusions. In summary, both Cn- and t-dependent dosimetry-related pitfalls may occur in acute bioassays on rodents following inhalation exposure to irritants. These must be identified and dealt with judiciously prior to translation to apparently similar human exposures. By default, extrapolations from one duration to another should start with that Cn × t eliciting the least depression in MV with n = 1.

Phosgene-induced lung edema: Comparison of clinical criteria for increased extravascular lung water content with postmortem lung gravimetry and lavage-protein in rats and dogs.

Phosgene-induced acute lung injury (ALI) is characterized by a concentration x time (Cxt)-dependent increased pulmonary vascular permeability, phenotypically manifested as potentially life-threatening acute lung edema. In contemporary animal bioassays, the quantification of protein in bronchoalveolar lavage fluid (BAL) is taken as an unequivocal endpoint suggestive of disruption of alveolar barrier function. However, extravasated protein can only be a surrogate endpoint for assessing the extravascular fluid dynamics of the lung. This pathophysiological hallmark of ALI is diagnosed and quantified in vivo in humans by assessing the accumulation of excess extravascular lung water (EVLW). The Point of Departure (POD) of the Cxt relationship of this adverse outcome pathway should also constitute the basis for setting safe occupational and emergency response values. Unlike the EVLW approach, toxicology-based animal models utilize postmortem analyses of total protein in BAL and lung weights as the basis for human risk assessment. With either approach, it remains difficult to unequivocally evaluate pulmonary edema in terms of etiopathology and specificity, i.e., cardiogenic and hydrostatic versus increased permeability edema. The objective of this paper is to retrospectively analyze the clinical scoring of the severity grades of in vivo EVLWs from humans with the respective postmortem biomarkers BAL protein and collagen versus wet lung weights in rats and dogs exposed by inhalation to phosgene gas. Despite the different methodological approaches taken in humans and animals, the EVLW-based predicted thresholds for the onset of pulmonary edema and potentially life-threatening severe pulmonary edema were in remarkable agreement. Data from dogs appear to more aptly reflect the human etiopathology and should be given preference over data from rodents. Especially in rats, elevations in BAL protein may lead to a marked overestimation of the edematous potency of phosgene due to secreted protein into airways. In summary, increased lung weight in rats and dogs scaled favorably with the human-EVLW and was shown to be the biomarker of choice for the scaling lung edema. Caution is advised when using BAL protein in isolation as a surrogate endpoint of pulmonary edema.

Nano-oleanolic acid alleviates metabolic dysfunctions in rats with high fat and fructose diet.

Obesity, diabetes and related metabolic disorders are among the top prevalent metabolism-related diseases with increasing threat to human health throughout the world. Oleanolic acid (OA) is a natural triterpenoid and an aglycone of many saponins possessing anti-diabetic, antioxidant, hypolipidemic and anti-inflammatory activities. A nano-formulation of OA was recently developed to evaluate the efficiency of nano-OA in the treatment of insulin-resistance and metabolic disorders in high fat and fructose (HFF) diet-fed rats. This study further identified that nano-OA could reduce the increase of body weights, serum insulin, insulin sensitivity index, serum triglycerides, and cholesterol in HFF-fed rats. In consistence, nano-OA was able to attenuate HFF diet-induced lipid accumulation in the liver and improve the structural integrity of mitochondria and endoplasmic reticulum in liver and pancreas in animals fed with HFF diet. In addition, nan-OA can efficaciously mitigate the increase of levels of malondialdehyde (MDA) and nitric oxide (NO), and serum superoxide dismutase (SOD) and catalase (CAT) activities in blood samples. The beneficial effects of nano-OA was further evidenced to be superior to OA formulated in arabic gum and rosiglitazone treatment. Together, this study provides the evidence that nano-OA can effectively improve HFF diet-induced metabolic dysfunctions in rats by improving its bioavailability and pharmacodynamic properties and thus nano-OA may be a potentially efficient agent to treat obesity-related diabetes and metabolic disorders.

Re-defining kinetic lung overload: Time for new paradigms.

This paper compares two previously published 13-week inhalation studies with poorly soluble, low-toxicity particles (PSLTs) in rats to identify the unifying key metric of kinetic lung overload. The PSLTs compared are Multi-Walled Carbon Nanotubes (MWCNT) and black iron oxide (Fe3O4, magnetite). Their material densities and related displacement volumes differ approximately 30-fold. This offers an opportunity for analyzing the impact of the PSLT-density of agglomerates on endpoints currently conceived to be involved in kinetic lung overload. Corpuscular volumes and counts of cells retrieved by bronchoalveolar lavage (BAL) are analyzed to interrelate modeled cumulative lung burdens of solid aerosol to predict the no observed adverse effect concentration (NOAEC) and range of conditions causing various degrees of kinetic lung overload up to and beyond the maximum tolerated cumulative dose (MTD). Both descriptors are a reflection of accumulated lung burdens and, by design, bracket repeated exposure inhalation studies with PSLTs. This comparative analysis of high- and low-density PSLTs reveals that the leading adverse outcome pathway (AOP) is caused by a markedly increased pool-size of BAL-cells rather than any increased corpuscular volume of cells. The overload-related increased pool-size of BAL-cells is shown to be the dependent variable for the prorated increased elimination half-time of PSLTs. This interrelationship was used to predict the exposure concentrations for attaining a NOAEC and MTD of guideline-based repeated exposure inhalation studies with PSLTs. Earlier approaches suggesting a loss of the migratory capabilities of particle-laden, enlarged alveolar macrophages to be the cause for any increased elimination half-time of PSLTs could not be confirmed. In summary, kinetic modeling provides a versatile means to predict the cornerstones of repeated inhalation studies with PSLTs on rats. Such possibilities leverage adjustment of studies from different sources to identical degrees of kinetic overload. They also facilitate and foster AOP-facilitated read-across approaches. The course taken enables risk assessors to better differentiate lung pathologies caused by generic lung overload and substance-specific pathologies.

Fate of inhaled Nano-CeO2 revisited: Predicting the unpredictable.

This paper compares the pulmonary kinetics of inhaled nano-CeO2 from two published repeated inhalation studies of 13-week duration in rats. This database was used to predict the outcome of a 2-year chronic inhalation study with a focus on the no observed adverse effect level (NOAEL) and range of conditions causing kinetic lung overload up to and beyond the maximum tolerated dose (MTD). Modeling identified nano-CeO2 to be typical poorly soluble, low-toxicity particles (PSLTs), although even partial dissolution may lead to interactions with pulmonary surfactant, eventually resulting in pulmonary phospholipidosis and fibrosis. An earlier model published in 2011 to surpass and replace the traditional Morrow approach focused on kinetic lung overload to simulate the pulmonary fate of inhaled micron-sized PSLT in rats. By misunderstanding or inaction, this earlier model was overlooked as a better hypothesis-based model for dosimetry selection of long-term inhalation studies with the aim of reducing study repetition and animal numbers. While it appears that the primary adverse pathway of the earlier model also applies to nano-CeO2, the updated model proposed here also accounts for phospholipid-like additional volume loads. Data from a heralded 2-year inhalation study in rats are not yet available, but the study was traditionally modeled to predict the toxicological NOAEL and MTD hallmarks. When completed, this study's data will clarify whether the advanced 21st century modeling proposed here may be more advantageous for design and execution of inhalation studies, compared to simplistic and outdated gross overload models.

Upper respiratory tract nociceptor stimulation and stress response following acute and repeated Cyfluthrin inhalation in normal and pregnant rats: Physiological rat-specific adaptions can easily be misunderstood as adversities.

This paper reviews the results from past regulatory and mechanistic inhalation studies in rats with the type II pyrethroid Cyfluthrin. Apart from many chemical irritants, Cyfluthrin was shown to be a neuroexcitatory agent without any inherent tissue-destructive or irritant property. Thus, any Cyfluthrin-induced neuroexcitatory afferent sensory stimulus from peripheral nociceptors in the upper respiratory tract is likely to be perceived as a transient stimulus triggering annoyance and/or avoidance by both rats and humans. However, while thermolabile rats respond to such stresses reflexively, homeothermic humans appear to respond psychologically. With this focus in mind, past inhalation studies in rats and human volunteers were reevaluated and assessed to identify common denominators to such neuroexcitatory stimuli upon inhalation exposure. This analysis supports the conclusion that the adaptive physiological response occurring in rats secondary to such chemosensory stimuli requires inhalation exposures above the chemosensory threshold. Rats, a species known to undergo adaptively a hibernation-like physiological state upon environmental stresses, experienced reflexively-induced bradypnea, bradycardia, hypothermia, and changes in acid-base status during inhalation exposure. After cessation of the sensory stimulus, rapid recovery occurred. Physiological data of male and female rats from a 4-week repeated inhalation study (exposure 6-h/day, 5-times/week) were used to select concentration for a 10-day developmental inhalation toxicity study in pregnant rats. Maternal hypothermia and hypoventilation were identified as likely cause of fetal and placental growth retardations because of a maternal adaptation-driven reduced feto-placental transfer of oxygen. In summary, maternal reflex-hypothermia, reduced cardiac output and placental perfusion, and disruption of the gestation-related hyperventilation are believed to be the maternally mediated causes for developmental impairments. Thus, inhaled chemosensory substances may appear to be more toxic in rats than they will be in humans because the thermoregulatory response of rats to such stimuli can cause profound physiological adaptions that can easily be misunderstood as adversities in conventional inhalation studies in small rodents. The afferent threshold triggering such outcomes in rodents translate to perceptions of annoyance in humans. Consequently, hazard characterization and human risk assessment need to be focused on the chemosensory threshold rather than endpoints occurring downstream to rodent-specific homeostasis.

Phosgene-induced acute lung injury (ALI): differences from chlorine-induced ALI and attempts to translate toxicology to clinical medicine.

BACKGROUND: Phosgene (carbonyl dichloride) gas is an indispensable chemical inter-mediate used in numerous industrial processes. There is no clear consensus as to its time- and inhaled-dose-dependent etiopathologies and associated preventive or therapeutic treatment strategies. METHODS: Cardiopulmonary function was examined in rats exposed by inhalation to the alveolar irritant phosgene or to the airway irritant chlorine during and following exposure. Terminal measurements focused on hematology, protein extravasation in bronchoalveolar lavage (BAL), and increased lung weight. Noninvasive diagnostic and prognostic endpoints in exhaled breath (carbon dioxide and nitric oxide) were used to detect the clinically occult stage of pulmonary edema. RESULTS: The first event observed in rats following high but sublethal acute exposure to phosgene was the stimulation of alveolar nociceptive vagal receptors. This afferent stimulation resulted in dramatic changes in cardiopulmonary functions, ventilation: perfusion imbalances, and progressive pulmonary edema and phospholipoproteinosis. Hematology revealed hemoconcentration to be an early marker of pulmonary edema and fibrin as a discriminating endpoint that was positive for the airway irritant chlorine and negative for the alveolar irritant phosgene. CONCLUSIONS: The application of each gas produced typical ALI/ARDS (acute lung injury/acute respiratory distress syndrome) characteristics. Phosgene-induced ALI showed evidence of persistent apnea periods, bradycardia, and shifts of vascular fluid from the peripheral to the pulmonary circulation. Carbon dioxide in expired gas was suggestive of increased ventilation dead space and appeared to be a harbinger of progressively developing lung edema. Treatment with the iNOS inhibitor aminoguanidine aerosol by inhalation reduced the severity of phosgene-induced ALI when applied at low dose-rates. Symptomatic treatment regimens were considered inferior to causal modes of treatment.

Kinetic modeling of the retention and fate of inhaled cerium oxide nanoparticles in rats: The cumulative displacement volume of agglomerates determines the outcome.

This paper compares the pulmonary kinetics of inhaled nano-CeO2 from published repeated inhalation studies of 1-, 4-, 13-, and 52-week duration using a previously published kinetic model to simulate the pulmonary kinetics of inhaled micron-sized poorly soluble, low toxicity particles (PSPs) in rats. This comparative analysis demonstrates that the kinetic hallmarks characterizing lung overload-related pulmonary inflammation are indistinguishable for PSPs and agglomerated nano-CeO2. Unlike PSPs, nano-CeO2 appears to dissolve within the lung as long as tissue saturation has not been attained. When saturation is reached, the accumulated retained particle displacement volume becomes the prominent unifying factor interrelating the retained volumetric particle dose and pulmonary inflammogenicity observed in inhalation studies of 1- to 52-weeks duration. In summary, the pulmonary kinetics of nano-CeO2 inhaled as micron-sized agglomerates exhibit kinetic and toxicological profiles similar to micron-sized PSPs. The coherence of modeled and empirical outcomes supports the hypothesis that the leading metric of pulmonary toxicity is the displacement volume of accumulated aggregated particles. Whereas agglomerated nano-CeO2 particles follow the typical kinetic of lung overload, evidence of dissolution of nano-CeO2 demonstrates a much shorter elimination half-time of t1/2 = 17 days. Thus, kinetic modeling approaches appear to not only deliver the highest degree of integrated mechanistic information, it also provides a validating feed-back loop to verify/refute the starting hypothesis of inhalation studies.

Risk assessment in combustion toxicology: Should carbon dioxide be recognized as a modifier of toxicity or separate toxicological entity?

To characterize the accumulated hazards associated with the inhalation of gases typical of combustion products, a time-integrated value known as the fractional effective dose (FED) is used. This FED is maintained by the International Organization for Standardization (ISO) and made publicly available as the Standard ISO 13571. The current FED calculation related to asphyxiant gases is based on non-human primate data to estimate the 50% probability of humans to be incapacitated or not being able to execute any escape paradigm from fires. The objective of this paper was to compare two to calculate FEDs of the most common mixture of asphyxiant fire gases CO, HCN, and CO2. The first was based on the current ISO 13571 (draft) standard, the alternative second method applied the conceptual principles established for the derivation of Acute Emergency Response Planning Guideline values. The alternative approach applied one third of the non-lethal threshold concentration (LC01) as the most suitable and robust Point of Departure (POD) to estimate the threshold characterizing 'impairment of escape' in the absence of post-exposure mortality. The hyperventilation correction factor for CO2 of ISO 13571 was replaced by a separate term that accounts for the inherent acute toxicity of CO2. This analysis supports the conclusion that the current ISO 13571 standard misjudges the impact of the acute toxicity elicited by concentrations of CO2 exceeding ≈6%. While underestimating the hazards attributable to CO2, the hyperventilation adjustment factor suggested by this standard is biased to markedly overestimate the hazards assigned to CO and HCN in fire effluents.

Developing a framework for assessing chemical respiratory sensitization: A workshop report.

Respiratory tract sensitization can have significant acute and chronic health implications. While induction of respiratory sensitization is widely recognized for some chemicals, validated standard methods or frameworks for identifying and characterizing the hazard are not available. A workshop on assessment of respiratory sensitization was held to discuss the current state of science for identification and characterization of respiratory sensitizer hazard, identify information facilitating development of validated standard methods and frameworks, and consider the regulatory and practical risk management needs. Participants agreed on a predominant Th2 immunological mechanism and several steps in respiratory sensitization. Some overlapping cellular events in respiratory and skin sensitization are well understood, but full mechanism(s) remain unavailable. Progress on non-animal approaches to skin sensitization testing, ranging from in vitro systems, -omics, in silico profiling, and structural profiling were acknowledged. Addressing both induction and elicitation phases remains challenging. Participants identified lack of a unifying dose metric as increasing the difficulty of interpreting dosimetry across exposures. A number of research needs were identified, including an agreed list of respiratory sensitizers and other asthmagens, distinguishing between adverse effects from immune-mediated versus non-immunological mechanisms. A number of themes emerged from the discussion regarding future testing strategies, particularly the need for a tiered framework respiratory sensitizer assessment. These workshop present a basis for moving towards a weight-of-evidence assessment.

Acute inhalation toxicity of carbon monoxide and hydrogen cyanide revisited: Comparison of models to disentangle the concentration × time conundrum of lethality and incapacitation.

Contemporary emergency response planning guidelines are stratified to consider the threshold for serious toxicity and/or impairment of escape, relative to the potentially lethal level above this threshold and the lower level at which individuals should not experience or develop effects more serious than mild irritation. While harmonized testing guidelines and risk assessment paradigms are available for the quantification of thresholds for lethality or establishing no adverse effect levels, the quantification of 'impairment of escape' appears to be a more elusive goal. Approaches were explored in context with CO and HCN in past experimental combustion toxicology studies to estimate the time available for escape. This point of departure (POD) was compared with the non-lethal threshold (LC01) and one third thereof from published recent acute inhalation studies in rats examining the Cxt-matrix of both CO and HCN. The findings from this analysis suggest that the rat delivers the most consistent data. However, it remains challenging yet to bridge the behavioral variables of human behavior typical of escape to any surrogate animal model. For the asphyxiant gases examined, the PODs characterizing 'impairment of escape' were difficult to distinguish from those indicative of impending death. No specific modeled carboxyhemoglobin (COHb) level could be linked to onset of incapacitation. In summary, the higher ventilation of rats (kg body weight adjusted) renders this species even more susceptible than heavy breathing humans. LCt01 × 1/3 values derived from the comprehensive Cxt matrix of rat inhalation studies are considered to be most suitable and robust to estimate the human equivalent threshold (POD) of 'impairment of escape'.

Transfluthrin: comparative efficacy and toxicity of reference and generic versions.

Stringent requirements are in place for the evaluation and registration of new compounds with biocidal or pesticidal activities. However, the registration requirements for established compounds from new suppliers or for established compounds produced by a different manufacturing process have been less clear and ambiguity exists as to how 'equivalence of health hazards' can unequivocally be demonstrated analytically and by toxicological assays. The case presented in this analysis focuses on the chiral pyrethroid transfluthrin (TFL) synthesized by esterification of an acid chloride and alcoholic moiety. According to any modifications of the process of synthesis and purification, new potentially highly toxic and yet chemically reactive impurities in low concentrations (<0.1%) may be formed. Amongst these, that with the structural alert 'organic acid anhydride' was given heightened concern as the most potent putative toxicologically significant impurity. The course taken in this analysis focused on the comparison of reference TFL with commercialized generic TFL from two alternative manufacturing sources in India and China. Despite their apparent high racemic purity, TFLs from generic sources were biologically less effective, genotoxic in the Ames' assay, demonstrated sensory lung irritation and lung/skin sensitization in specialized bioassays. While the off-patent reference TFL was unequivocally negative in all assays (anhydride content not detectable, LOQ <0.01%), positive results with high batch-to-batch variability were a frequent outcome in generic TFLs. Tier I analytical assays failed to detect this relevant impurity in the absence of impurity-specific optimized analytical procedures. This finding suggests that a well-balanced combined approach of analytical and toxicological assays provides the best means to assure that all critical impurities are identified and accounted for. Similarly, putative 'structural alert'-based toxicity tests proved to be more predictive than any indiscriminant battery of standard bioassays commonly applied to demonstrate equivalence, such as acute oral/dermal toxicity and/or eye/skin irritation assays.