Gunnar Damgård Nielsen

Organic compounds in indoor air - their relevance for perceived indoor air quality?

It is generally believed that indoor air pollution, one way or another may cause indoor air complaints. However, any association between volatile organic compounds (VOCs) concentrations and increase of indoor climate complaints, like the sick-building syndrome symptoms, is not straightforward. The reported symptom rates of, in particular, eye and upper airway irritation cannot generally be explained by our present knowledge of common chemically non-reactive VOCs measured indoors. Recently, experimental evidence has shown those chemical reactions between ozone (either with or without nitrogen dioxide) and unsaturated organic compounds (e.g. from citrus and pine oils) produce strong eye and airway irritating species. These have not yet been well characterised by conventional sampling and analytical techniques. The chemical reactions can occur indoors, and there is indirect evidence that they are associated with eye and airway irritation. However, many other volatile and non-volatile organic compounds have not generally been measured which could equally well have potent biological effects and cause an increase of complaint rates, and posses a health/comfort risk. As a consequence, it is recommended to use a broader analytical window of organic compounds than the classic VOC window as defined by the World Health Organisation. It may include hitherto not yet sampled or identified intermediary species (e.g., radicals, hydroperoxides and ionic compounds like detergents) as well as species deposited onto particles. Additionally, sampling strategies including emission testing of building products should carefully be linked to the measurement of organic compounds that are expected, based on the best available toxicological knowledge, to have biological effects at indoor concentrations. r 2001 Elsevier Science Ltd. All rights reserved.

In vivo Biology and Toxicology of Fullerenes and Their Derivatives

Fullerenes represent a group of nanoparticles discovered in 1985. They are spherical molecules consisting entirely of carbon atoms (C(x)) to which side chains can be added, furnishing compounds with widely different properties. Fullerenes interact with biological systems, for example, by enzyme inhibition, causing phototoxic reactions, being scavengers of reactive oxygen species and free radicals, in addition to being able to initiate free radical reactions. Absorption, distribution and excretion strongly depend on the properties of the side chains. The pristine C(60) has a very long biological half-life, whereas the most water-soluble derivatives are eliminated from the exposed animals within weeks. A long biological half-life raises concern about bioaccumulation and long-term effects. In general, the acute oral, dermal and airway toxicity is low. However, few relevant experimental studies of repeated dose toxicity, reproductive toxicity and carcinogenic effect are available. The data suggest that direct DNA damaging effects are low, but formation of reactive oxygen species may cause inflammation and genetic damage. Apparently, it is dose-dependent whether a beneficial or an adverse effect occurs.

Sensory irritation, pulmonary irritation, and respiratory stimulation by airborne benzene and alkylbenzenes: prediction of safe industrial exposure levels and correlation with their thermodynamic properties.

Abstract The alkylbenzenes, toluene, ethylbenzene, n -propylbenzene, isopropylbenzene, n -butylbenzene, tert -butylbenzene, n -amylbenzene, n -hexylbenzene, and p-tert -butyltoluene were investigated for their property as sensory irritants in mice. The concentrations of these chemicals necessary to depress the respiratory rate by 50% (RD 50 ) due to sensory irritation of the upper respiratory tract were 5300, 4060, 1530, 2490, 710, 760, 230, 125, and 360 ppm, respectively. The potency of the alkylbenzenes increased with chain length. However, the ratio of equipotent concentration/saturated vapor concentration for these alkylbenzenes varied very little. Knowing the vapor pressure enabled prediction of sensory irritation potency up to a chain length of C 6 . As previously suggested ( Y. Alarie, 1981 , Food Cosmet. Toxicol. 19 , 623–626), RD 50 values multiplied by 0.03 gave values for toluene, ethylbenzene, isopropylbenzene, and p-tert -butyltoluene in close agreement with established threshold limit value (TLV) for industrial exposure. No established TLV values exist for the other alkylbenzenes investigated. Using 0.03 RD 50 , acceptable TLVs for n -propylbenzene, n -butylbenzene, tert -butylbenzene, n -amylbenzene, and n -hexylbenzene would be 50, 20, 20, 10, and 5 ppm, respectively. Minimal or no pulmonary irritation was observed with these alkylbenzenes. Benzene was inactive as a sensory irritant or pulmonary irritant up to 8500 ppm. Benzene in particular, and to some extent toluene, stimulated the respiratory rate. The effect was maximum approximately 10 to 20 min after onset of exposure. A model for the sensory irritating action of alkylbenzenes is proposed on the basis of their physical interaction with a receptor protein in a lipid layer.

Nano Titanium Dioxide Particles Promote Allergic Sensitization and Lung Inflammation in Mice

The purpose of this study was to investigate whether photocatalytic TiO2 nanoparticles have adjuvant effect, when administered in combination with ovalbumin (OVA) in mice. Mice were immunized via intraperitoneal injections of OVA, OVA + TiO2 or OVA + Al(OH)3 and challenged with aerosols of OVA. At the end of the study, serum was analysed for content of OVA-specific IgE, IgG1 and IgG2a antibodies, and the bronchoalveolar lavage fluid (BALF) was analysed for content of inflammatory cells and levels of interleukin (IL)-4, IL-5, IL-10 and interferon-γ. The TiO2 particles promoted a Th2 dominant immune response with high levels of OVA-specific IgE and IgG1 in serum and influx of eosinophils, neutrophils and lymphocytes in BALF. The TiO2 particles induced a significantly higher level of OVA-specific IgE than the standard adjuvant Al(OH)3. However, the two substances were comparable regarding the level of eosinophilic inflammation and interleukins present in BALF.

Non-cancer effects of formaldehyde and relevance for setting an indoor air guideline.

There is considerable recent focus and concern about formaldehyde (FA). We have reviewed the literature on FA with focus on chemosensory perception in the airways and lung effects in indoor environments. Concentrations of FA, both personal and stationary, are on average in the order of 0.05 mg/m(3) or less in Europe and North America with the exception of new housing or buildings with extensive wooden surfaces, where the concentration may exceed 0.1 mg/m(3). With the eye the most sensitive organ, subjective irritation is reported at 0.3-0.5 mg/m(3), which is somewhat higher than reported odour thresholds. Objective effects in the eyes and airways occur around 0.6-1 mg/m(3). Dose-response relationships between FA and lung function effects have not been found in controlled human exposure studies below 1 mg/m(3), and epidemiological associations between FA concentrations and exacerbation of asthma in children and adults are encumbered by complex exposures. Neither experimental nor epidemiological studies point to major differences in susceptibility to FA among children, elderly, and asthmatics. People with personal trait of negative affectivity may report more symptoms. An air quality guideline of 0.1 mg/m(3) (0.08 ppm) is considered protective against both acute and chronic sensory irritation in the airways in the general population assuming a log normal distribution of nasal sensory irritation.

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.

UPPER AIRWAY AND PULMONARY EFFECTS OF OXIDATION PRODUCTS OF (+)- α -PINENE, d -LIMONENE, AND ISOPRENE IN BALB/ c MICE

The oxidation products (OPs) of ozone and the unsaturated hydrocarbons d -limonene, (+)-α -pinene, and isoprene have previously been shown to cause upper airway irritation in mice during 30-min acute exposures. This study evaluated the effects of OPs and the hydrocarbons themselves on the upper airways, the conducting airways, and the lungs over a longer exposure period. The time course of development of effects and the reversibility of effects were investigated; in addition, we assessed possible exacerbation of sensory responses of the airways to the unreacted hydrocarbons. Respiratory parameters in male BALB/ c mice were monitored via head-out plethysmography. Exposures to OPs or hydrocarbons were for 60 min, followed by a 30-min challenge period with air or hydrocarbon, and a 15-min recovery period with air only. Experiments were also performed where limonene/ozone exposures were separated 6 h from the challenge period. Ozone concentration in the reaction mixture was 3.4 ppm, and concentrations of hydrocarbons were 47 ppm (α -pinene), 51 ppm (d -limonene), and 465 ppm (isoprene). Due to reaction, the ozone concentration at the point of exposure was less than 0.35 ppm; exposure to 0.30 ppm ozone for 60 min did not produce effects different from air-exposed control animals. As previously established, upper airway irritation was a prominent effect of OP exposure. In addition, over the longer exposure period we observed the development of airflow limitation that persisted for at least 45 min postexposure. All effects from limonene/ozone exposures were reversible within 6 h. Exposures to OPs did not cause enhanced upper airway irritation during challenge with the hydrocarbons, indicating that a 1-h exposure to OPs did not increase the sensitivity of the upper respiratory system. However, airflow limitation was exacerbated in animals exposed to d -limonene alone immediately following exposure to limonene OPs. These findings suggest that terpene/ozone reaction products may have moderate-lasting adverse effects on both the upper airways and pulmonary regions. This may be important in the context of the etiology or exacerbation of lower airway symptoms in office workers, or of occupational asthma in workers involved in industrial cleaning operations.

Formation of strong airway irritants in a model mixture of (+)-α-pinene/ozone

The airway irritation of (+)-α-pinene, ozone, mixtures thereof, and formaldehyde was evaluated by a mouse bioassay, in which sensory irritation, bronchoconstriction, and pulmonary irritation were measured. The effects are distinguished by analysis of the respiratory parameters. Significant sensory irritation (assessed from reduction of mean respiratory rate) was observed by dynamic exposure of the mice, over a period of 30 min, to a ca. 22 s old reaction mixture of ozone and (+)-α-pinene from a Teflon flow tube. The starting concentrations were 6 ppm and 80 ppm, respectively, which were diluted and let into the exposure chamber. About 10% ozone remained unreacted (0.4 ppm), <0.2 ppm formaldehyde, <0.4 ppm pinonaldehyde, <2 ppm formic acid, and <1 ppm acetic acid were formed. These concentrations, as well as that of the unreacted (+)-α-pinene (51 ppm), were below established no effect levels. The mean reduction of the respiratory rate (30%) was significantly different (p≪0.001) from clean air, as well as from exposure of (+)-α-pinene, ozone, and formaldehyde themselves at the concentrations measured. Addition of the effects of the measured residual reactants and products cannot explain the observed sensory irritation effect. This suggests that one or more strong airway irritants have been formed. Therefore, oxidation reactions of common naturally occurring unsaturated compounds (e.g., terpenes) may be relevant for indoor air quality.

Di-(2-ethylhexyl) phthalate possesses an adjuvant effect in a subcutaneous injection model with BALB/c mice

The prevalence of allergic airway diseases is rapidly increasing in Western Europe and North America and the introduction of anthropogenic chemicals may explain a part of this increase. Recently, our group found that degradation products from several commonly used phthalate plasticizers possess adjuvant activity in an animal model. Mono-2-ethylhexyl phthalate, which is the degradation product of di-(2-ethylhexyl) phthalate (DEHP), was among these substances. These findings prompted the study of the adjuvant activity of the parent compound itself. Thus, DEHP was studied in a model using ovalbumin (OA) as the model antigen. OA was injected subcutaneously in the neck region of BALB/cJ mice with or without DEHP. The levels of OA-specific IgE, IgG1 and IgG2a antibodies in sera were measured by ELISA. Adjuvant effect, defined as a statistically significant increase in antibody level, was observed with IgG1 at a concentration of 2000 microg DEHP/ml after both one and two boosters.

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.