Insulation fiber deposition in the airways of men and rats. A review of experimental and computational studies.

The typical insulation rock, slag and glass wool fibers are high volume materials. Current exposure levels in industry (generally ≤ 1 fiber/cm3 with a median diameter ∼1 µm and length ≥10 µm) are not considered carcinogenic or causing other types of severe lung effects. However, epidemiological studies are not informative on effects in humans at fiber levels >1 fiber/cm3. Effects may be inferred from valid rat studies, conducted with rat respirable fibers (diameter ≤ 1.5 µm). Therefore, we estimate delivery and deposition in human and rat airways of the industrial fibers. The deposition fractions in humans head regions by nasal (∼0.20) and by mouth breathing (≤0.08) are lower than in rats (0.50). The delivered dose into the lungs per unit lung surface area during a 1-day exposure at a similar air concentration is estimated to be about two times higher in humans than in rats. The deposition fractions in human lungs by nasal (∼0.20) and by mouth breathing (∼0.40) are higher than in rats (∼0.04). The human lung deposition may be up to three times by nasal breathing and up to six times higher by oral breathing than in rats, qualifying assessment factor setting for deposition.

Pulmonary toxicity following exposure to a tile coating product containing alkylsiloxanes. A clinical and toxicological evaluation.

CONTEXT: Coating products are widely used for making surfaces water and dirt repellent. However, on several occasions the use of these products has been associated with lung toxicity. OBJECTIVE: In the present study, we evaluated the toxic effects of an aerosolized tile-coating product. METHODS: Thirty-nine persons, who reported respiratory and systemic symptoms following exposure to the tile-coating product, were clinically examined. The product was analysed chemically and furthermore, the exposure scenario was reconstructed using a climate chamber and the toxicological properties of the product were studied using in vivo and by in vitro surfactometry. RESULTS: The symptoms developed within few hours and included coughing, tachypnoea, chest pain, general malaise and fever. The physical examination revealed perihilar lung infiltrates on chest radiograph and reduced blood oxygen saturation. The acute symptoms resolved gradually within 1-3 days and no delayed symptoms were observed. By means of mass spectrometry and X-ray spectroscopy, it was shown that the product contained non-fluorinated alkylsiloxanes. The exposure conditions in the supermarket were reconstructed under controlled conditions in a climate chamber and particle and gas exposure levels were monitored over time allowing estimation of human exposure levels. Mice exposed to the product developed symptoms of acute pulmonary toxicity in a concentration-and time-dependent manner. The symptoms of acute pulmonary toxicity likely resulted from inhibition of the pulmonary surfactant function as demonstrated by in vitro surfactometry. Among these patients only a partial association between the level of exposure and the degree of respiratory symptoms was observed, which could be because of a high inter-individual difference in sensitivity and time-dependent changes in the chemical composition of the aerosol. CONCLUSION: Workers need to cautiously apply surface coating products because the contents can be highly toxic through inhalation, and the aerosols can disperse to locations remote from the worksite and affect bystanders.

Do indoor chemicals promote development of airway allergy?

UNLABELLED: Allergic asthma has increased worldwide in the industrialized countries. This review evaluates whether the major groups of indoor chemical exposures possess allergy-promoting (adjuvant) effects; formaldehyde was excluded, because of the size of the literature. Volatile organic compounds (VOCs) are used as an example of gases and vapors. The precipitation of asthmatic symptoms by VOC exposures is probably because of VOC levels considerably above typical indoor levels, or VOCs may be a surrogate for exposure to allergens, combustion products or dampness. Indoor particles possessed adjuvant effects in animal studies and allergy-promoting effects in humans. Quaternary ammonium compounds may possess adjuvant effects in animal studies and promoted sensitization in humans in occupational settings. The use of cleaning agents, anionic and non-ionic surfactants are not considered to possess an important adjuvant effect in the general population. Regarding phthalate exposures, results from animal and epidemiological studies were found to be discordant. There is little evidence that the indoor chemicals evaluated possess important adjuvant effects. If buildings are kept clean, dry and free of combustion products, the important question may be would it be profitable to look for lifestyle factors and non-chemical indoor exposures in order to abate airway allergy? PRACTICAL IMPLICATIONS: Indoor chemicals (pollutants) have been accused to promote development of airway allergy by adjuvant effects. In this review, we evaluated the scientific literature and found little support for the supposition that indoor chemicals possess important adjuvant effects. This rises the question: would it be profitable for abatement of airway allergy to look for non-chemical indoor exposures, including lifestyle factors, and exposures to allergens, microorganisms, including vira, and their interactions?

Organic compounds in office environments - sensory irritation, odor, measurements and the role of reactive chemistry.

Abstract Sensory irritation and odor effects of organic compounds in indoor environments are reviewed. It is proposed to subdivide volatile organic compounds (VOCs) into four categories: (i) chemically non-reactive, (ii) chemically 'reactive', (iii) biologically reactive (i.e. form chemical bonds to receptor sites in mucous membranes) and (iv) toxic compounds. Chemically non-reactive VOCs are considered non-irritants at typical indoor air levels. However, compounds with low odor thresholds contribute to the overall perception of the indoor air quality. Reported sensory irritation may be the result of odor annoyance. It appears that odor thresholds for many VOCs probably are considerably lower than previously reported. This explains why many building materials persistently are perceived as odorous, although the concentrations of the detected organic compounds are close to or below their reported odor thresholds. Ozone reacts with certain alkenes to form a gas and aerosol phase of oxidation products, some of which are sensory irritants. However, all of the sensory irritating species have not yet been identified and whether the secondary aerosols (ultrafine and fine particles) contribute to sensory irritation requires investigation. Low relative humidity may exacerbate the sensory irritation impact. Practical Implications Certain odors, in addition to odor annoyance, may result in psychological effects and distraction from work. Some building materials continually cause perceivable odors, because the odor thresholds of the emitted compounds are low. Some oxidation products of alkenes (e.g. terpenes) may contribute to eye and airway symptoms under certain conditions and low relative humidity.

Investigation of the adjuvant and immuno-suppressive effects of benzyl butyl phthalate, phthalic acid and benzyl alcohol in a murine injection model.

In a recent study, di-(2-ethylhexyl) phthalate (DEHP) and its metabolite, mono-2-ethylhexyl phthalate, were shown to possess adjuvant effect [Toxicology 169 (2001) 37; Toxicology Letters 125 (2001) 11]. The present study investigates the adjuvant effect of another important commercial phthalate plasticizer, benzyl butyl phthalate (BBP) as well as its degradation products, phthalic acid and benzyl alcohol (BA) in a murine model. The model antigen, ovalbumin (OA), was injected either alone (OA control group), together with one of the test substances (test group) or together with aluminium hydroxide, which served as the positive adjuvant control. The mice were boosted either once or twice with OA before blood was collected and assayed for the content of OA-specific IgE, IgG1 and IgG2a antibodies by ELISA methods. Adjuvant effect was defined as a statistically significant increased antibody level in the test groups compared with the OA control group. Conversely, if the antibody production in a test group was significantly lower than the OA control group, it was deemed to be immunosuppression. This study demonstrated that BBP, in contrast to DEHP, did not possess adjuvant effect. Furthermore, immunosuppression was apparent in the case of BA. The study also demonstrated that if the injections give rise to formation of wounds, it may cause false positive results.

Adjuvant and immuno-suppressive effect of six monophthalates in a subcutaneous injection model with BALB/c mice.

The prevalence of allergic airway diseases is rapidly increasing in Western Europe and North America. This increase in disease prevalence may be associated with environmental pollutants. The present study investigated the adjuvant and immuno-suppressive effect of a series of monophthalates which are considered to be important metabolites of commonly used phthalate plasticizers. The effects were studied in a screening model. Ovalbumin (OA), used as the model antigen, was injected subcutaneously in the neck region of BALB/cJ mice with or without one of the test substances, mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBnP), mono-n-octyl phthalate (MnOP), mono-2-ethylhexyl phthalate (MEHP), mono-iso-nonyl phthalate (MiNP) or mono-iso-decyl phthalate (MiDP). The levels of OA-specific IgE, IgG1 and IgG2a in sera were measured by ELISA. Immuno-suppressive effect, defined as a statistically significant reduction in IgE or IgG1 antibody production, was observed with MEHP (1000 microg/ml, IgE and IgG1), MnOP (1000 microg/ml, IgE and IgG1), MiNP (1000 microg/ml, IgE and 10 microg/ml, IgG1) and MiDP (100 microg/ml, IgE and IgG1). Adjuvant effect, defined as a statistically significant increase in IgE or IgG1 antibody level, occurred with MEHP (10 microg/ml, IgE), MnOP (100 microg/ml, and 10 microg/ml, IgG1) and MiNP (100 microg/ml, IgE). No statistically significant immune modulating effect was seen with MBnP and MnBP.

Formation of strong airway irritants in mixtures of isoprene/ozone and isoprene/ozone/nitrogen dioxide.

We evaluated the airway irritation of isoprene, isoprene/ozone, and isoprene/ozone/nitrogen dioxide mixtures using a mouse bioassay, from which we calculated sensory irritation, bronchial constriction, and pulmonary irritation. We observed significant sensory irritation (approximately 50% reduction of mean respiratory rate) by dynamically exposing the mice, over 30 min, to mixtures of isoprene and O3 or isoprene, O3, and NO2. The starting concentrations were approximately 4 ppm O3 and 500 ppm isoprene (+ approximately 4 ppm NO2. The reaction mixtures after approximately 30 sec contained < 0.2 ppm O3. Addition of the effects of the residual reactants and the identified stable irritant products (formaldehyde, formic acid, acetic acid, methacrolein, and methylvinyl ketone) could explain only partially the observed sensory irritation. This suggests that one or more strong airway irritants were formed. It is thus possible that oxidation reactions of common unsaturated compounds may be relevant for indoor air quality.

Chemical and biological evaluation of a reaction mixture of R-(+)-limonene/ozone: formation of strong airway irritants.

The airway irritation of a reaction mixture of R-(+)-limonene and ozone was evaluated by a mouse bioassay in which sensory irritation, bronchoconstriction and pulmonary irritation were measured. Significant sensory irritation (33% reduction of mean respiratory rate) was observed by dynamic exposure of the mice, during 30 min, to a ca. 16 s old reaction mixture of ozone and limonene. The initial concentrations were nominally 4 ppm O3 and 48 ppm limonene. After reaction, the residual O3 was <0.03 ppm. Conventional analytical chemical methods were used to measure the formation of readily identified and stable products. Besides the expected products, 1-methyl-4-acetylcyclohexene (AMCH), 3-isopropenyl-6-oxoheptanal (IPOH), formaldehyde and formic acid, autooxidation products of limonene and a series of compounds including acetone, acrolein and acetic acid, which may or may not be artefacts, were identified. Addition of the sensory irritation effects of the residual reactants and all the identified compounds could not explain the observed sensory irritation effect. This suggests that one or more strong airway irritants were formed. Since limonene is common in the indoor air, and ozone is infiltrated from outdoors and/or produced indoors (e.g., by photocopiers), such oxidation reactions may be relevant for indoor air quality.

Effects of R-(+)- and S-(-)-limonene on the respiratory tract in mice.

The effects of airborne R-(+)- and S-(-)- limonene were studied in conscious BALB/c mice by continuous monitoring respiratory rate (f), tidal volume (VT) and mid-expiratory flow rate (VD) during an exposure period of 30 min. Both enantiomers decreasedf from a trigeminal reflex, i.e., due to sensory irritation. The exposure concentration decreasing f by 50% (RD50) in the first 10 min of the exposure period was estimated to be 1,076 ppm for R-(+)-limonene and 1,467 ppm for S-(-)-limonene. Results for sensory irritation of R-(+)-limonene in BALB/c mice and humans are in close agreement. The reported sensory irritation threshold is above 80 ppm in humans while the no-observed-effect level was estimated to be 100 ppm in mice. The enantiomers were devoid of pulmonary irritation or general anesthetic effects with R-(+)-limonene < or =1,599 ppm and S-(-)-limonene < or =2,421 ppm. R-(+)-limonene did not influence VT below 629 ppm. S-(-)-limonene increased VT above 1,900 ppm. Both enantiomers induced a mild bronchoconstrictive effect above 1,000 ppm.

Detergents in the indoor environment - what is the evidence for an allergy promoting effect? Known and postulated mechanisms.

IgE-mediated allergic diseases, such as asthma and rhinitis seem to be increasing in industrialised societies. One possible explanation for this could be the increased use of more effective and aggressive detergents. The surfactants from these could interfere with the sensitisation process in which specific IgE is formed to ubiquitously occurring environmental allergens. Only sparse data exist in relation to surfactants and allergic sensitization. However, it can be speculated that the strong surfactant properties of some of ingredients used in modem detergents may interfere with some of the intricate cellular interactions taking place along the immunological pathways. These include formation of IL-4 and IL-5 producing T helper lymphocytes type 2 and the B-lymphocyte isotype switch, which leads to production of specific IgE. Candidates for experimental studies of such phenomena on the cellular level are proposed.

Study of adjuvant effect of model surfactants from the groups of alkyl sulfates, alkylbenzene sulfonates, alcohol ethoxylates and soaps.

The sodium salts of representatives of anionic surfactants, dodecylbenzene sulfonate (SDBS), dodecyl sulfate (SDS) and coconut oil fatty acids, and a nonionic surfactant, dodecyl alcohol ethoxylate, were studied for adjuvant effect on the production of specific IgE antibodies in mice. The surfactants were injected subcutaneously (sc) in concentrations of 1000, 100, 10 or 1 mg/l, respectively, together with 1 microg of ovalbumin (OVA). In addition, groups of mice received OVA in saline (control group) or in Al(OH)(3) (positive adjuvant control group). After the primary immunization the mice were boosted up to three times with OVA (0.1 microg sc) in saline. OVA-specific IgE antibodies were determined by the heterologous mouse rat passive cutaneous anaphylaxis test. The results were confirmed by a specific ELISA method. After the first booster, the Al(OH)(3) group and the 10 mg/l SDS group showed a statistically significant increase in OVA specific IgE levels. After two boosters, a statistically significant suppression in OVA-specific IgE production occurred with SDS (1000 mg/l), SDBS (1000 and 100 mg/l), coconut soap (1000 mg/l) and the alcohol ethoxylate (10 mg/l). This study suggests that a limited number of surfactants possess an adjuvant effect whereas all surfactants at certain levels can suppress specific IgE production.

Effects of industrial detergents on the barrier function of human skin.

Detergents are involved in the causation of contact dermatitis and in promoting percutaneous absorption of toxic chemicals, but limited information is available to allow an assessment of their relative effects on the skin barrier function. The effect of detergents on skin permeability to water and nickel was examined in an in-vitro model using human skin. Twenty-four of the most widely used detergents were studied. After a two-hour exposure to an aqueous detergent solution, penetration of labeled model compounds was followed for 66 hours. Interindividual variation was substantial, but 12 of the detergents caused statistically significant increases in the penetration of water, nickel, or both. Nonionic detergents were as likely as anionic detergents to have this effect. This study demonstrates that useful information may be obtained by a simple in-vitro method, and that such data may provide a basis for substitution efforts.

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.

Formation of strong airway irritants in terpene/ozone mixtures.

The American Society for Testing and Materials (ASTM) mouse bioassay, which quantifies airway irritation from reduction in the respiratory rate, was used to find evidence for the formation of highly irritating substances in reactions of ozone with terpenes (common indoor volatile organic compounds (VOCs)). No-observed-effect-levels (NOELs) and concentration-effect relationships were established for ozone, (+)-alpha-pinene and R-(+)-limonene, isoprene, and some of their major reaction products. Reaction mixtures of excess terpene and ozone considerably below their NOEL concentrations resulted in significant upper airway irritation. The reduction of the respiratory rate was from 30% to about 50%, lowest for the alpha-pinene and highest for the isoprene mixture. Chemical analysis of reaction mixtures by conventional methods showed that readily identified stable products and residual reactants at the concentrations found could not account for the observed reductions of the respiratory rate, assuming additivity of the reaction products. The results suggest that, in addition to known irritants (formaldehyde, acrolein, methacrolein, methyl vinylketone), one or more strong airway irritant(s) of unknown structure(s) were formed. Future indoor air quality (IAQ) guidelines for unsaturated VOCs (e.g., terpenes) and their emission from building products may require the consideration of reactions with oxidants, like ozone. Similarly, effects of ozone-emitting equipment should be re-evaluated.

Acute airway effects of formaldehyde and ozone in BALB/c mice.

1. Concentration and time-effect relationships of formaldehyde and ozone on the airways were investigated in BALB/c mice. The effects were obtained by continuous monitoring of the respiratory rate, tidal volume, expiratory flow rate, time of inspiration, time of expiration, and respiratory patterns. 2. With concentrations up to 4 p.p.m., formaldehyde showed mainly sensory irritation effects of the upper airways that decrease the respiratory rate from a trigeminal reflex. The no-effect level (NOEL) was about 0.3 p.p.m. This value is close to the human NOEL, which is about 0.08 p.p.m. 3. Ozone caused rapid, shallow breathing in BALB/c mice. Later on, the respiratory rate decreased due to another vagal response that indicated an incipient lung oedema. The NOEL in mice was about 1 p.p.m. during 30 min of ozone exposure. No major effect occurs in resting humans at about 0.4 p.p.m. 4. Thus, the upper airway irritant, formaldehyde, and the deep lung irritant, ozone, showed the same types of respiratory effects in humans and in BALB/c mice. Also, the sensitivity was nearly identical. Continuous monitoring of respiratory effects in BALB/c mice, therefore, may be a valuable method for the study of effects of other environmental pollutants, which, however, should be confirmed in further studies.

Absorption and retention of nickel from drinking water in relation to food intake and nickel sensitivity.

Two studies were performed to examine the influence of fasting and food intake on the absorption and retention of nickel added to drinking water and to determine if nickel sensitization played any role in this regard. First, eight nonallergic male volunteers fasted overnight before being given nickel in drinking water (12 micrograms Ni/kg) and, at different time intervals, standardized 1400-kJ portions of scrambled eggs. When nickel was ingested in water 30 min or 1 h prior to the meal, peak nickel concentrations in serum occurred 1 h after the water intake, and the peak was 13-fold higher than the one seen 1 h after simultaneous intake of nickel-containing water and scrambled eggs. In the latter case, a smaller, delayed peak occurred 3 h after the meal. Median urinary nickel excretion half-times varied between 19.9 and 26.7 h. Within 3 days, the amount of nickel excreted corresponded to 2.5% of the nickel ingested when it was mixed into the scrambled eggs. Increasing amounts were excreted as the interval between the water and the meal increased, with 25.8% of the administered dose being excreted when the eggs were served 4 h prior to the nickel-containing drinking water. In the second experiment, a stable nickel isotope, 61Ni, was given in drinking water to 20 nickel-sensitized women and 20 age-matched controls, both groups having vesicular hand eczema of the pompholyx type. Nine of 20 nickel allergic eczema patients experienced aggravation of hand eczema after nickel administration, and three also developed a maculopapular exanthema. No exacerbation was seen in the control group. The course of nickel absorption and excretion in the allergic groups did not differ and was similar to the pattern seen in the first study, although the absorption in the women was less. A sex-related difference in gastric emptying rates may play a role. Thus, food intake and gastric emptying are of substantial significance for the bioavailability of nickel from aqueous solutions.

A theoretical approach to the Ferguson principle and its use with non-reactive and reactive airborne chemicals.

The Ferguson principle has been widely used in toxicology to separate or indicate possible mechanisms for acute toxic effects of chemicals. However, this principle has never been adequately tested because of the lack of a database containing a sufficient number of both types of chemicals, non-reactive and reactive, that the Ferguson principle purports to separate. Such a database is now available. In this report a theoretical framework for the Ferguson principle is presented, regarding one of the acute toxicological effects of volatile airborne chemicals: sensory irritation. Previously obtained results on series of non-reactive and reactive chemicals are then used to demonstrate that the Ferguson principle can be extended to reactive chemicals by adding chemical reactivity descriptors to the physicochemical descriptors required by the Ferguson principle. This approach can be successful, provided that specific chemical reactivity mechanisms can be identified for the reactive chemicals of concern. The findings suggest that it is possible to replace the empirical Ferguson principle by formal mechanistic equations which will provide a better foundation for the understanding of the mechanisms by which airborne sensory irritants exert their action.

Respiratory effects in mice exposed to airborne emissions from Stachybotrys chartarum and implications for risk assessment.

Stachybotrys chartarum, a mycotoxin producing mould found in some damp buildings, was grown in aluminum dishes in closed exposure chambers. The loading factor, 5.12 m2/m3, corresponded to 2.8 times the loading in a normal room with all surfaces covered by mould. Sensory irritation, bronchoconstriction and pulmonary irritation effects were investigated using a sensitive mouse bioassay in which the airway reactions were measured plethysmographically. Little effect was seen from the vapours in agreement with the predicted effects of the low concentrations of volatile organic compounds measured. Even under the influence of an airflow about four times that measured in normal buildings, the concentration of liberated spores and other particles was very low, corresponding to the biological effects observed, and probably reflecting the high water content of the substrate. These results demonstrate that many factors are important for the transport of biologically active mould metabolites from building material to occupants and that no direct relationship may exist between immediate biological effects and surface area covered with mould. Therefore, risk assessments should be based on estimated effects of emitted vapours, effects of liberated particles, e.g. sensitization potentials of the mould spores and effects of the generated metabolites (mycotoxins).

Structure-activity relationships of volatile organic chemicals as sensory irritants.

We used a database of 145 volatile organic chemicals for which the sensory irritation potency (RD50) has been reported in mice. Chemicals were first separated into two groups: nonreactive and reactive, using Ferguson's rule. This rule suggests that nonreactive chemicals induce their effect via a physical (p) mechanism (i.e., weak forces or interactions between a chemical and a biological receptor). Therefore, appropriate physicochemical descriptors can be used to estimate their potency. For reactives, a chemical (c) mechanism (i.e., covalent bonding with the receptor) would explain their potency. All chemicals were also separated on the basis of functional groups and subgroups into 24 classifications. Our results indicated that the potency of nonreactive chemicals, regardless of their chemical structure, can be estimated using a variety of physicochemical descriptors. For reactive chemicals, we identified five basic reactivity mechanisms which explained why their potency was higher than that estimated from physicochemical descriptors. We concluded that Ferguson's proposed rule is adequate initially to classify two separate mechanisms of receptor interactions, p vs c. Several physicochemical descriptors can be used to estimate the potency of p chemicals, but chemical reactivity descriptors are needed to estimate the potency for c chemicals. At present, this is the largest database for nonreactive-reactive chemicals in toxicology. Because of the wide variety of c chemicals presented, a semi-quantitative estimate of the potency of new, or not previously evaluated, c chemicals can be arrived at via comparison with those presented and the basic chemical reactivity mechanisms presented.