Does Haber's law apply to human sensory irritation?

Irritation of the eyes, nose, and throat by airborne chemicals--also referred to as "sensory irritation"--is an important endpoint in both occupational and environmental toxicology. Modeling of human sensory irritation relies on knowledge of the physical chemistry of the compound(s) involved, as well as the exposure parameters (concentration and duration). A reciprocal relationship between these two exposure variables is postulated under Haber's law, implying that protracted, low-level exposures may be toxicologically equivalent to brief, high-level exposures. Although time is recognized as having an influence on sensory irritation, the quantitative predictions of Haber's Law have been addressed for only a handful of compounds in human experimental studies. We have conducted a systematic literature review that includes a semiquantitative comparison of psychophysical data extracted from controlled human exposure studies versus. the predictions of Haber's law. Studies containing relevant data involved exposures to ammonia (2), chlorine (2), formaldehyde (1), inorganic dusts such as calcium oxide (1), and the volatile organic compound 1-octene (1). With the exception of dust exposure, varying exposure concentration has a proportionally greater effect on sensory irritation than does changing exposure duration. For selected time windows, a more generalized power law model (c(n) x t = k) rather than Haber's law per se (c x t = k) yields reasonably robust predictions. Complicating this picture, however, is the frequent observation of intensity-time "plateauing," with time effects disappearing, or even reversing, after a relatively short period, depending on the test compound. The implications of these complex temporal dynamics for risk assessment and standard setting have been incompletely explored to date.     

The use of noncancer endpoints as a basis for establishing a reference concentration for formaldehyde

Published studies involving formaldehyde were selected for quality and relevance for determining whether noncancer endpoints could be used to derive a reference concentration for formaldehyde. Chamber studies provided the highest quality data for determining the presence of eye, nose, or throat irritation at a known level of formaldehyde. Some individuals begin to sense irritation at about 0.5 ppm, 5-20% report eye irritation at 0.5 to 1 ppm, and greater certainty for sensory irritation appears at 1 ppm or greater. These levels of formaldehyde do not appear to impact asthmatics even though these individuals are thought to be more sensitive to irritants. Mild, reversible changes in pulmonary function (forced expiratory volume at 1 s and midexpiratory flow) can occur in sensitized individuals at levels approaching 2 ppm. Studies in the manufacturing setting, while confounded by multiple exposures, provide useful information for setting boundaries for sensory irritation or changes in pulmonary function. Community surveys do not provide the specificity nor sensitivity needed to establish a reference concentration. Histological studies of the nasal mucosa suffer significant methodological and technological shortcomings in addition to issues commonly associated with the design of residential and workplace studies. Based on the review of chamber, community, and workplace studies of human exposures to formaldehyde, it is not possible to identify a specific no observed adverse effect level or lowest observed adverse effect level for formaldehyde. Ranges of exposures associated with acute sensory irritation can be derived and do include sensitive subpopulations. However, given the quality and variability of the data, human studies alone, especially those involving sensory irritation, are not adequate to serve as a reference concentration for estimating risk, or lack thereof, for a lifetime of exposure to formaldehyde. Alternative approaches, such as modeling cellular changes observed in animal studies, may be more useful for quantitative risk assessment of noncancer endpoints and should be used as an adjunct to interpreting human sensory studies.     

Evaluating the human response to chemicals: odor, irritation and non-sensory factors

Although airborne chemicals can directly elicit adverse reactions via stimulation of the olfactory and trigeminal nerves, such as sensory irritation of the mucous membranes of the eyes, nose and throat, an individual's subjective experience is often the result of a complex sequence of events involving those sensory, physiological signals and psychological processes involved in perception, memory and judgment. To evaluate the contribution of these processes, an information-processing model of chemosensory perception is introduced. The model incorporates (1) the perception of odor and trigeminal irritation, and accompanying physiological and somatic changes that follow directly from the encounter with volatile organic compounds (VOCs) in the environment (bottom-up processing), and (2) any physiological/ somatic changes and subjective experiences of irritancy that are influenced by cognitive processes that have been primed by the perception of odor (top-down processing). The model is illustrated with data from our laboratory, and its utility in the context of setting occupational exposure limits is discussed.     

Inhaled formaldehyde: evaluation of sensory irritation in relation to carcinogenicity

OBJECTIVES: The critical health effects of formaldehyde exposure include sensory irritation and the potential to induce tumours in the upper respiratory tract. In literature, a concentration as low as 0.24 ppm has been reported to be irritating to the respiratory tract in humans. Nasal tumour-inducing levels in experimental animals seem to be 1-2 orders of magnitude larger. In this paper, the subjectively measured sensory irritation threshold levels in humans are discussed in line with findings obtained in animal experiments. In addition, a Benchmark dose (BMD) analysis of sensory irritation was used to estimate response incidences at different formaldehyde concentrations. METHODS: Data on respiratory irritation and carcinogenicity of formaldehyde were retrieved from public literature and discussed. BMD analysis was carried out on human volunteer studies using the US-EPA BMD software. RESULTS: Subjective measures of irritation were the major data found in humans to examine sensory (eye and nasal) irritation; only one study reported objectively measured eye irritation. On a normalized scale, mild/slight eye irritation was observed at levels 1 ppm, and mild/slight respiratory tract irritation at levels 2 ppm. With the BMD software, it was estimated that at a level of 1 ppm, only 9.5% of healthy volunteers experience 'moderate' (i.e., annoying) eye irritation (95% upper confidence limit). An important factor modulating the reported levels of irritation and health symptoms most probably includes the perception of odour intensity. In several studies, the 0-ppm control condition was missing. From the results of the long-term inhalation toxicity studies in experimental animals, a level of 1 ppm formaldehyde has been considered a NOAEL for nasal injury. CONCLUSIONS: Sensory irritation is first observed at levels of 1 ppm and higher. From both human and animal studies, it was concluded that at airborne levels for which the prevalence of sensory irritation is minimal both in incidence and degree (i.e., <1 ppm), risks of respiratory tract cancer are considered to be negligibly low.     

Sensory irritation: risk assessment approaches

Irritation of eyes and upper airways--sensory irritation--is commonly used as a parameter for setting occupational exposure limits and is a common complaint in occupants of non-industrial buildings. Sensory irritation occurs from stimulation of receptors on trigeminal nerves. In general, chemically reactive compounds are more potent than non-reactive congeners. Animal studies allow prediction of sensory irritation effects in humans; the concentration-effect relationships are often steep. In humans, thresholds and suprathreshold effects can be obtained from short-term ( approximately seconds) exposures and from longer exposures ( approximately hours). Sensory irritation may develop over time and odour cues may influence reported sensory irritation symptoms; generally, the slope of the irritant effect is steeper than the slope of odour cues. A best available no-observed-adverse-effect level (NOAEL) should be based on a combined estimate from the three types of study. The NOAEL/5 is considered sufficient to protect individuals not especially sensitive. The present knowledge suggests that especially sensitive individuals may be protected by an additional uncertainty factor (UF) of 2, suggesting a combined UF of 10. In published studies, the combined UF is up to 300, highlighting the need of evidence-based UFs. Combined effects of sensory irritants can be considered additive as a first approximation.     

Sensory irritation response to inhaled aldehydes after formaldehyde pretreatment

Pretreatment of Fischer-344 (F-344) rats with formaldehyde (HCHO) induces significant cross tolerance to the sensory irritation properties of Cl₂. The purpose of this study was to determine if HCHO pretreatment would cause sensory irritation cross tolerance to other inhaled aldehydes. Male F-344 rats, weighing 190 to 210 g, were pretreated with 15 ppm HCHO, 6 hr/day for 9 days, and challenged on the 10th day with a saturated (acetaldehyde, propionaldehyde, and butyraldehyde), unsaturated (acrolein and crotonaldehyde), or cyclic (cyclohexanecarboxaldehyde, 3-cyclohexene-1-carboxaldehyde, and benzaldehyde) aldehyde. The sensory irritation response in these animals was quantified by measuring respiratory rate depression in a head-only inhalation chamber using plethysmographic techniques. Control animals were challenged identically without prior pretreatment. In naive (nonpretreated) animals, the concentration eliciting a 50% decrease in respiratory rate (RD50) was 23 ppm or less for unsaturated aliphatic aldehydes. For cyclic and saturated aliphatic aldehydes, the RD50 ranged from 600 to 1000 ppm and 3000 to 6800 ppm, respectively. Formaldehyde pretreatment resulted in cross tolerance only with acetaldehyde (RD50 increased 3.5-fold) and acrolein (RD50 increased 5-fold). These results indicate that the development of cross tolerance following HCHO pretreatment is not a general phenomenon. Prediction of acceptable concentrations of occupational exposure for the prevention of sensory irritation in humans has been based primarily on RD50 data for mice. Comparison of the RD50 values obtained for rats in this investigation with previously published results for mice varied by over one-half an order of magnitude, thereby disputing the usefulness of data from F-344 rats in setting threshold limit values for the prevention of sensory irritation.     

AN EXPOSURE SYSTEM TO STUDY THE EFFECTS OF WATER-SOLUBLE GASES ON PM-INDUCED TOXICITY

Abstract

The Clean Air Act Amendments require the use of oxygenated fuels in the winter months to reduce carbon monoxide levels in areas of the country that exceed national health standards for carbon monoxide. Methyl tertiary butyl ether (MTBE, CAS number 1634–04–4) is the most widely used fuel additive for this purpose. During implementation, people in a few areas of the country reported nose, eye, and throat irritation. Jo evaluate the potential for MTBE to produce symptoms indicative of sensory irritation, mice were tested using a standard bioassay. Concentration-response data obtained from 1-h exposures to MTBE between 300 and 30,000 mglm³ revealed that slight to severe sensory irritation occurred with exposure to all concentrations. At the highest concentration both sensory and pulmonary irritation was observed, indicative of acute lung injury. However, lung lavage protein and lactate deliydrogenase measurements did not support this contention. Respiratory rate was predicted by linear interpolation to be decreased by 50% (RD50) at 16,600 mg/m³ MTBE. Some experts suggest that 3% of the RD50 (in this case 500 mg/m³) would not cause significant sensory (i.e., discomforting) irritation. Since this estimate is at least an order of magnitude greater than typical peak atmospheric exposure levels during refueling, the data would suggest that few healthy individuals would experience sensory irritation during transient exposures to MTBE.     

Evaluation of the Sensory Irritation Test for the Assessment of Occupational Health Risk

Abstract

Many occupational exposure limits (OELs) are based on irritation. A sensory irritation test has been developed based on trigeminal nerve stimulation in the nasal mucosa of rodents which results in a decreased respiratory frequency. The RD₅₀, the concentration inducing a 50% decrease in the respiratory rate, was proposed for the assessment of OELs. The reproducibility within one laboratory appeared to be satisfactory, but interlaboratory differences may be larger. Intra- and interspecies differences were inconsistent. Other effects (pulmonary irritation, toxicity) may interfere with trigeminal nerve stimulation. The effects of mixed and repeated exposures (the occurrence of “sensitization” and “(cross-)tolerance”) are evaluated. Severe toxicity was observed in animals exposed below the RD₅₀ for some compounds. A quantitative evaluation with respect to human data was not possible. The suitability of the test for the assessment of an OEL is doubted. The best purpose will be as an upper range-finding study for subacute or chronic toxicity experiments.     

Does Haber's Law Apply to Human Sensory Irritation?

Irritation of the eyes, nose, and throat by airborne chemicals—also referred to as “sensory irritation”—is an important endpoint in both occupational and environmental toxicology. Modeling of human sensory irritation relies on knowledge of the physical chemistry of the compound(s) involved, as well as the exposure parameters (concentration and duration). A reciprocal relationship between these two exposure variables is postulated under Haber's law, implying that protracted, low-level exposures may be toxicologically equivalent to brief, high-level exposures. Although time is recognized as having an influence on sensory irritation, the quantitative predictions of Haber's Law have been addressed for only a handful of compounds in human experimental studies. We have conducted a systematic literature review that includes a semiquantitative comparison of psychophysical data extracted from controlled human exposure studies versus. the predictions of Haber's law. Studies containing relevant data involved exposures to ammonia (2), chlorine (2), formaldehyde (1), inorganic dusts such as calcium oxide (1), and the volatile organic compound 1-octene (1). With the exception of dust exposure, varying exposure concentration has a proportionally greater effect on sensory irritation than does changing exposure duration. For selected time windows, a more generalized power law model (cⁿ × t = k) rather than Haber's law per se (c × t = k) yields reasonably robust predictions. Complicating this picture, however, is the frequent observation of intensity–time “plateauing,” with time effects disappearing, or even reversing, after a relatively short period, depending on the test compound. The implications of these complex temporal dynamics for risk assessment and standard setting have been incompletely explored to date.     

Effects of methacrolein on the respiratory tract in mice

The acute respiratory effects of airborne exposure to methacrolein were studied in a recent refinement of the standard test method with mice (ASTM, 1984. American Society for Testing and Materials, Philadelphia). Irritation of the upper respiratory tract caused a concentration-dependent decrease in the respiratory rate of 2-26 ppm methacrolein. In this range, only a minor airflow limitation occurred in the lower respiratory tract, suggesting that the main effect of methacrolein is sensory irritation. During exposure, the sensory irritation response maintained the same level, i.e. no desensitisation occurred. The concentration 10.4 ppm methacrolein reduced the respiratory rate by 50% (RD50). The extrapolated threshold for the respiratory depressing effect, RD0, was 1.3 ppm. The sensory irritation effect of methacrolein was compared with results from closely related compounds in order to elucidate the mechanism of the interaction between methacrolein and the sensory irritant receptor.     

Airway effects of repeated exposures to ozone-initiated limonene oxidation products as model of indoor air mixtures

Repeated low-level indoor air exposure to volatile organic compounds (VOCs) may influence the reporting of sensory irritation in the eyes and airways. The ozone-initiated reaction products of limonene, an abundant VOC, were used as a model of indoor air mixtures to study upper airway (sensory) irritation, bronchoconstrictive and alveolar level effects after repeated exposures. Mice were exposed 1 h/day for 10 consecutive days to: air, limonene (52 ppm/289 mg/m³); ozone (0.1 ppm/0.2 mg/m³); a reaction mixture of limonene (52 ± 8 ppm) and ozone (0.5, 2.5 and 3.9 ppm) resulting in ∼0.05 ppm residual ozone. Neither the limonene nor the ozone exposures alone showed consistent effects on the respiratory parameters. In the limonene/ozone groups, the respiratory rate decreased concentration-dependently with an extrapolated no-effect-level of ∼0.3 ppm admixed ozone. Both sensory irritation and airflow limitation were conspicuous effects of the mixtures; sensory irritation appeared rapidly and airflow limitation developed slowly during each exposure. The effects of these parameters did not change with increasing number of exposures. No firm conclusion could be drawn about alveolar level effects. Cells in bronchoalveolar lavage were unchanged irrespective of exposure to air, ozone, and limonene with and without ozone. In conclusion, the study indicated that repeated exposures to ozone-initiated limonene mixtures did not cause sensitization of sensory irritation and airflow limitation. Bronchoalveolar lavage after exposures to ozone, and limonene with and without ozone, respectively, did not show airway inflammation.     

An Analysis of Human Response to the Irritancy of Acetone Vapors

Studies on the irritative effects of acetone vapor in humans and experimental animals have revealed large differences in the lowest acetone concentration found to be irritative to the respiratory tract and eyes. This has brought on much confusion in the process of setting occupational exposure limits for acetone. A literature survey was carried out focusing on the differences in results between studies using subjective (neuro)behavioral methods (questionnaires) and studies using objective measurements to detect odor and irritation thresholds.

A critical review of published studies revealed that the odor detection threshold of acetone ranges from about 20 to about 400?ppm. Loss of sensitivity due to adaptation and/or habituation to acetone odor may occur, as was shown in studies comparing workers previously exposed to acetone with previously unexposed subjects. It further appeared that the sensory irritation threshold of acetone lies between 10,000 and 40,000?ppm. Thus, the threshold for sensory irritation is much higher than the odor detection limit, a conclusion that is supported by observations in anosmics, showing a ten times higher irritation threshold level than the odor threshold found in normosmics. The two-times higher sensory irritation threshold observed in acetone-exposed workers compared with previously nonexposed controls can apart from adaptation be ascribed to habituation. An evaluation of studies on subjectively reported irritation at acetone concentrations <1000?ppm shows that perception of odor intensity, information bias, and exposure history (i.e., habituation) are confounding factors in the reporting of irritation thresholds and health symptoms.

In conclusion, subjective measures alone are inappropriate for establishing sensory irritation effects and sensory irritation threshold levels of odorants such as acetone. Clearly, the sensory irritation threshold of acetone should be based on objective measurements.     

Structure-activity relationship of a series of sensory irritants.

The relative potencies for a series of sensory irritants, with structures based on toluene, were determined by measuring the airborne concentrations that caused a 50% decrease in respiratory rate in Swiss-Webster mice. This concentration is referred to as the RD50. Toluene, a relatively nonirritating compound, and compounds with chlorine, two chlorines, bromine, and iodine atoms substituted on the alpha carbon of toluene were tested. The RD50s for these compound types were determined to be 4900, 27, 27, 5.2, and 4.3 ppm, respectively. In addition, compounds with chlorine substituted at the ortho, meta, and para positions on the toluene ring were also tested. The RD50s were determined to be 4.9, 13, and 14 ppm, respectively. The structure-activity relationships of the compounds studied are explained by a model (Abraham et al., 1990; Nielsen and Alarie, 1982) that relates the interaction of sensory irritants with a receptor protein in a lipid bilayer. The trends in the RD50s, and thus sensory irritation, for the compounds studies are related to the development of a partial positive charge on the toluene alpha carbon by the positioning of a ring chlorine and the bond dissociation energies of the alpha carbon-halogen bond for the iodo, bromo, and chloro isomers of benzyl halide.     

An analysis of human response to the irritancy of acetone vapors

Studies on the irritative effects of acetone vapor in humans and experimental animals have revealed large differences in the lowest acetone concentration found to be irritative to the respiratory tract and eyes. This has brought on much confusion in the process of setting occupational exposure limits for acetone. A literature survey was carried out focusing on the differences in results between studies using subjective (neuro)behavioral methods (questionnaires) and studies using objective measurements to detect odor and irritation thresholds. A critical review of published studies revealed that the odor detection threshold of acetone ranges from about 20 to about 400 ppm. Loss of sensitivity due to adaptation and/or habituation to acetone odor may occur, as was shown in studies comparing workers previously exposed to acetone with previously unexposed subjects. It further appeared that the sensory irritation threshold of acetone lies between 10,000 and 40,000 ppm. Thus, the threshold for sensory irritation is much higher than the odor detection limit, a conclusion that is supported by observations in anosmics, showing a ten times higher irritation threshold level than the odor threshold found in normosmics. The two-times higher sensory irritation threshold observed in acetone-exposed workers compared with previously nonexposed controls can apart from adaptation be ascribed to habituation. An evaluation of studies on subjectively reported irritation at acetone concentrations < 1000 ppm shows that perception of odor intensity, information bias, and exposure history (i.e., habituation) are confounding factors in the reporting of irritation thresholds and health symptoms. In conclusion, subjective measures alone are inappropriate for establishing sensory irritation effects and sensory irritation threshold levels of odorants such as acetone. Clearly, the sensory irritation threshold of acetone should be based on objective measurements.     

Sensory irritation as a basis for setting occupational exposure limits

There is a need of guidance on how local irritancy data should be incorporated into risk assessment procedures, particularly with respect to the derivation of occupational exposure limits (OELs). Therefore, a board of experts from German committees in charge of the derivation of OELs discussed the major challenges of this particular end point for regulatory toxicology. As a result, this overview deals with the question of integrating results of local toxicity at the eyes and the upper respiratory tract (URT). Part 1 describes the morphology and physiology of the relevant target sites, i.e., the outer eye, nasal cavity, and larynx/pharynx in humans. Special emphasis is placed on sensory innervation, species differences between humans and rodents, and possible effects of obnoxious odor in humans. Based on this physiological basis, Part 2 describes a conceptual model for the causation of adverse health effects at these targets that is composed of two pathways. The first, “sensory irritation” pathway is initiated by the interaction of local irritants with receptors of the nervous system (e.g., trigeminal nerve endings) and a downstream cascade of reflexes and defense mechanisms (e.g., eyeblinks, coughing). While the first stages of this pathway are thought to be completely reversible, high or prolonged exposure can lead to neurogenic inflammation and subsequently tissue damage. The second, “tissue irritation” pathway starts with the interaction of the local irritant with the epithelial cell layers of the eyes and the URT. Adaptive changes are the first response on that pathway followed by inflammation and irreversible damages. Regardless of these initial steps, at high concentrations and prolonged exposures, the two pathways converge to the adverse effect of morphologically and biochemically ascertainable changes. Experimental exposure studies with human volunteers provide the empirical basis for effects along the sensory irritation pathway and thus, “sensory NOAEC_human” can be derived. In contrast, inhalation studies with rodents investigate the second pathway that yields an “irritative NOAEC_animal.” Usually the data for both pathways is not available and extrapolation across species is necessary. Part 3 comprises an empirical approach for the derivation of a default factor for interspecies differences. Therefore, from those substances under discussion in German scientific and regulatory bodies, 19 substances were identified known to be human irritants with available human and animal data. The evaluation started with three substances: ethyl acrylate, formaldehyde, and methyl methacrylate. For these substances, appropriate chronic animal and a controlled human exposure studies were available. The comparison of the sensory NOAEC_human with the irritative NOAEC_animal (chronic) resulted in an interspecies extrapolation factor (iEF) of 3 for extrapolating animal data concerning local sensory irritating effects. The adequacy of this iEF was confirmed by its application to additional substances with lower data density (acetaldehyde, ammonia, n-butyl acetate, hydrogen sulfide, and 2-ethylhexanol). Thus, extrapolating from animal studies, an iEF of 3 should be applied for local sensory irritants without reliable human data, unless individual data argue for a substance-specific approach.     

Evaluation of the sensory irritation test for the assessment of occupational health risk.

Many occupational exposure limits (OELs) are based on irritation. A sensory irritation test has been developed based on trigeminal nerve stimulation in the nasal mucosa of rodents which results in a decreased respiratory frequency. The RD50, the concentration inducing a 50% decrease in the respiratory rate, was proposed for the assessment of OELs. The reproducibility within one laboratory appeared to be satisfactory, but interlaboratory differences may be larger. Intra- and interspecies differences were inconsistent. Other effects (pulmonary irritation, toxicity) may interfere with trigeminal nerve stimulation. The effects of mixed and repeated exposures (the occurrence of "sensitization" and "(cross-)tolerance") are evaluated. Severe toxicity was observed in animals exposed below the RD50 for some compounds. A quantitative evaluation with respect to human data was not possible. The suitability of the test for the assessment of an OEL is doubted. The best purpose will be as an upper range-finding study for subacute or chronic toxicity experiments.     

Sensory irritation potential of selected nasal tumorigens in the rat

Several important chemicals, including formaldehyde, 1,4-dichloro-2-butene, bis-chloromethyl ether, hexamethylphosphoramide, and epichlorohydrin have been shown to produce nasal tumours in rats following repeated or continuous inhalation exposures. Some of these compounds are respiratory irritants. To determine whether there is a correlation between the ability of a chemical to produce sensory irritation and to elicit nasal tumours, the atmospheric concentration causing a 50% decrease in the respiratory rate (RD50) of male rats was determined. Three other nasal tumorigens, dimethylcarbamoyl chloride, 2,3,4-trichloro-1-butene and 1,2-ethoxy-3-phenoxypropane, were also studied. No correlation between sensory irritation potency and nasal tumorigenic potential was observed. The most potent nasal tumorigen hexamethylphosphoramide, which produces tumours in rats following 12 months' continuous exposure to 50 ppb, failed to cause any decrease in respiratory rate when tested at 351 ppm (an aerosol exposure level which exceeds atmospheric saturation by approximately ten times).     

Human exposure to acrolein: Time-dependence and individual variation in eye irritation

The aim of the study was to examine the time dependence on sensory irritation detection following exposure to threshold levels of acrolein, in humans. The exposures occurred in an exposure chamber and the subjects were breathing fresh air through a mask that covered the nose and mouth. All participants participated in four exposure conditions, of which three consisted of a mixture of acrolein and heptane and one of only heptane. Exposure to acrolein at a concentration half of the TLV-C lead to sensory irritation. The perceived sensory irritation resulted in both increased detectability and sensory irritation after about 6.8 min of exposure in 58% of the participants. The study confirm the previously suggested LOAEL of about 0.34 mg/m³ for eye irritation due to acrolein exposure. The sensory irritation was still significant 10 min after exposure. These results have implications for risk assessment and limit setting in occupational hygiene.