Respiratory Irritant Mixtures

This section is devoted to chemical mixtures that are respiratory irritants. Irritants do not induce immunochemical responses, and irritation in non-sensitized individuals generally leads to slower, less serious respiratory responses and usually requires higher doses of toxicants to produce symptoms than in sensitized people. Irritant-induced inflammation responses (e.g., bronchial hyperactivity) can be severe and prolonged but, by definition, do not result in sensitization of those so exposed. Mixtures of lipo-philes and hydrophiles induce irritant respiratory system responses at concentration levels that are below those for the single chemicals. This phenomenon is well demonstrated by exposures in sick buildings.  

Exposures to sick buildings may stimulate respiratory responses in healthy individuals with no previous history of asthma, allergic rhinitis, chronic respiratory disease, recent acute respiratory illness, or extensive exposure to pollutants. Chemicals typically found in sick buildings arise from carpeting, paint, wood products, cleaners, and other sources. These chemicals are mixtures of lipophilic and hydrophilic chemicals and, with the exception of isocyanates from polyurethane wood finishes, are usually 

The respiratory effects of irritant mixtures are not limited to complex ones such as those just described. Volunteers who were exposed to formaldehyde at concentrations as high as 2.0 pg/m3 (greater than the PEL of 1.2 pg/m3) did not experience lower airway irritation, 8 yet those exposed to mixtures of formaldehyde (Kqw = 0.35) and terpenes (Kqw = 2.42 to 4.83) did exhibit symptoms of lower airway irritation. 9 Additional examples of the effects of respiratory irritant mixtures are presented later in the case study Section (17.7) of this chapter. 

Respiratory irritant mixtures can arise from environmental chemical reactions. For example, ozone reacts rapidly with terpenes under environmental ambient conditions to produce aldehydes, ketones, and carboxylic acids. Several studies that have been carried out demonstrated that reaction of ozone with a-pinene, c/-limonene, and isoprene produce low level concentrations (at or below NOEL levels) of oxidation products and that along with residual ozone and terpenes act as respiratory irritants. 1012 Table 17.3 lists the species typically contained in these mixtures along with their K values. As can be seen, the mixtures contain lipophiles (residual terpenes) and hydrophiles (the reaction products). Similar results have also been reported for environmental reaction of terpenes with ozone and nitrogen dioxide. 9  

Terpenes are widely present in the indoor environment. They are incorporated in cleaners, plastics, adhesives, and other products. Ozone and 

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If nitrogen or sulphur is present in the fuel then the mixture of combustion products may include oxides of these elements. In the absence of excess oxygen incomplete oxidation occurs to produce partially oxidized carbon compounds such as aldehydes, ketones, phenols, and carbon monoxide. Carbon monoxide is extremely toxic and some of the other compounds are respiratory irritants. 

This compound is primarily a toxic lung injurant and is therefore treated in Chap. VII, page 165. In addition to its lung-injurant effect, however, it also exerts a considerable respiratory-irritant action, and for that reason, was used by the Germans in Blue Cross 1" shell in mixture with, and as a solvent for, diphenylcyanarsine. 

Exposures to single toxic chemicals in and around the house produce many well-known identifiable effects in people. An example of such an effect is respiratory irritation following inhalation of chlorine bleach fumes. Often, individuals develop clinical symptoms that are associated with mixtures of chemicals, for example, headache and dizziness following inhalation of paint fumes containing toluene and glycol ethers. 

Particulates are another source of respiratory irritation when inhaled. In urban environments, diesel exhaust particles and fly ash residue from power plant oil combustion are the main contributors of respirable particulates of less than 10 pm diameter (PM 10). These contain mixtures of lipo-philes and hydrophiles including various metals, acid salts, aliphatic hydrocarbons, PAHs, quinones, nitroaromatic hydrocarbons, andaldehydes. 151 Diesel combustion particulates contain large surface areas that can adsorb large quantities of organic compounds and deliver these to respiratory tract tissue. Other inhaled particulates can adhere to lung surfaces and adsorb and bond other vapors that are inhaled, thereby increasing their toxicities. PM2.5 particulates (those with diameters of less than 2.5 pm) that reach the lower respiratory tract as far as the alveoli are more toxic than PM 10 particulates of the same composition. 16 ... 

RADS, as described earlier, requires the onset of symptoms within 24 h of exposure to a high concentration of individual chemical or mixture. Some researchers have reported the onset of RADS following repeated low-dose exposures to respiratory irritants and have labeled the phenomenon low-dose RADS.[46 881 Low-dose RADS apparently bridges the gap between RADS, caused by one-time exposures and OA, which is caused by chronic exposures to affecting chemicals. These observations should not be surprising, since the chemicals known to induce OA and RADS are the very same species that differ only in concentrations of exposure. Low-dose RADS may be considered as being caused by middle level exposures to such chemicals. 

Not all mixtures that are toxic to the respiratory system are mixtures of lipophiles and hydrophiles. In some instances, irritant chemicals react to produce more toxic species. Chloramine-induced pneumonitis from the mixing of household ammonia and bleach is an example of this phenomenon. 100 101 Household ammonia cleaner is usually a 5-10% aqueous solution of ammonia. Household bleach is generally a 5.25% solution of sodium hypochlorite. At these concentrations, these chemicals alone act as respiratory irritants. When mixed together, however, they react to form monochloroamine, dichloroamine, and trichloroamine as shown in Fig. 17.1. Chloramines are far more toxic than either hypochlorite or ammonia and are capable of producing inflammation and edema of the respiratory system. Case 14 is an example of the toxicity of chloramines. 

The continuing worldwide increase in respiratory disease corresponds to increases in the release of chemicals into the atmosphere. Respiratory irritation, sensitization, asthma, RADS, and lung cancer can be attributed to numerous single chemicals whose toxicological properties are, for the most part, well known. Many unexplained incidences of respiratory disease cannot be attributed to single chemical exposures, but have been shown to occur when exposures are to chemical mixtures that are composed of at least one lipophile and one hydrophile. The sources of such mixtures include diesel exhausts, tobacco smoke, carpet emissions, paint fumes, and cleaning products. Prevention of chemically induced respiratory diseases should include limiting exposures to these chemical mixtures. 

Stoddard solvent is a petroleum distillate mixture of C7-C12 hydrocarbons, approximately 80-90% aliphatics (30-50% linear and branched alkanes, and 30-40% cyclic alkanes) and 10-20% aromatics (not PAHs). It is similar to white spirits, which is also included in the toxicological profile on Stoddard solvent (ATSDR 1995b). For additional detail, see Section 3.2 and Table E-2.b. Data regarding the health effects of Stoddard solvent in either humans or animals are limited and were judged inadequate for MRL development. Upper respiratory irritant effects were seen in animals exposed by inhalation for acute and intermediate durations these appear to be the most sensitive effects by the inhalation route. Male rat nephropathy has been reported in intermediate inhalation studies, but is not considered relevant to human health. No oral studies were located. Information on the potential carcinogenicity of Stoddard solvent is inadequate. 

Inhalation Exposure. Only one inhalation MRL, a chronic MRL for //-hexane, is available for this combined fraction this is listed in Table 6-8. //-Hexane produces a characteristic peripheral nephropathy in humans and animals the chronic MRL is based on this effect in humans. Commercial hexane, which contains //-hexane plus other C6 branched chain and cyclic alkanes (see Table 6-8), also has been shown to cause this effect in animals, due to its content of //-hexane (IRDC 1981) (see Section 6.2.4.1). The non n-hexane portion of the mixture does not. In addition, the non //-hexane constituents of this combined fraction do not appear to cause peripheral neuropathy when tested singly although, like //-hexane, they do cause neurological effects (depression of the central nervous system). //-Hexane and commercial hexane are respiratory irritants. Commercial hexane has undergone extensive recent testing as part of an EPA Test Rule under TSCA Section 4. However, until the database for commercial hexane can be more fully evaluated, the chronic MRL for //-hexane has been determined to be the most appropriate surrogate for a health guidance value for this fraction. 

The tolylene diisocyanate isomer mixtures melt in the range 5—15°C and are therefore usually encountered as liquids tolylene 2,4-diisocyanate is a solid, m.p. 22°C. Tolylene diisocyanates are respiratory irritants and require careful handling. Of the various products described above, the 80 20 isomer mixture is the cheapest and is widely used, particularly in the production of flexible foams. The other products find use when enhanced or reduced reactivity is desired for steric reasons, the 4-isocyanato group is considerably more reactive than either the 2- or 6-isocyan to group. 

The authors were unable to find any other similar case report in the literature. TDI is a known respiratory irritant and sensitizer, but is not known to attack the CNS in low concentrations [129, 130]. The low-level exposures to the other solvents could also not account for the observed neurotoxic effects. Clearly, this painter was exposed to a mixture of several hpophiles and hydrophiles that produced this previously unknown effect. 

The effects of this mixture of gases are insidious several hours may elapse before lung iiTitation develops. It is feebly irritant to the upper respiratory tract due to its relatively low solubility. 

Halothane (Fluothane) is a volatile liquid given by inhalation for induction and maintenance of anesthesia Induction and recovery from anesthesia are rapid, and the depth of anesthesia can be rapidly altered. Halothane does not irritate the respiratory tract, and an increase in tracheobronchial secretions usually does not occur. Halothane produces moderate muscle relaxation, but skeletal muscle relaxants may be used in certain types of surgeries. This anesthetic may be given with a mixture of nitrous oxide and oxygen. 

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