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Neurogenic and Sensitivity to and infiltrates of leukocytes. A number of chemical mediators of inflammation have Environmental Chemicals been identified biochemically. Inflam- mation may be triggered by the immune William J. Meggs system, in which foreign materials interact Department of Emergency Medicine, East Carolina University School of Medicine, with leukocyte receptors created after a Greenville, NC 27858 USA sensitizing exposure to trigger an inflam- matory cascade. Neurogenic inflamma- Neurogenic inflammation as a pathway dis- Sensitivity to environmental chemicals in tion is a well-defined process by which tinct firom iven, immuine-meit- general, and in particular to volatile organ- inflammation is triggered by the nervous ed infla n m pl a piol lei ic chemicals (VOCs) in indoor air, needs system. understadn *~~~~~~~~~~~~~~6a broad cssof eniomn- to be elucidated. The lack of an estab- Early in the study of neurogenic in- al hedth problm resut fro chemical lished mechanism to explain how exposure flammation, chemical stimulation was rec- exposures. Recen press to concentrations of VOCs that are well ognized as a trigger of neurogenic inflam- ing the mediatorsr s, and egulation of the at large can mation. As early as 1910, it was recog- neurogenic inflmmaon is reviewed. Ev- tolerated by population idence for andC tions about "a-ole for produce the array of symptoms seen in nized that the application of mustard oil neuronic inflammation inesablished dts- sensitized individuals has hampered pro- to the conjunctival sac in experimental Orders such as asha rhinits, cnact de¢r- gress in understanding these disorders. models produces inflammation that can be matitis, iriehaah,adremti Over the past few years progress has been blocked by sensory nerve ablation (1,2). arthritis are presented. The:-sicbuiding made in understanding neurogenic in- The neuropeptides (SP), neu- syndrome andm ipl cchemica sivity flammation, chemical irritant receptors, rokinen A (NA), and calcitonin gene-relat- syndrome hawbeen defined as:, c d enti- and the regulation of neurogenic inflam- ed peptide (CGRP) are now known to ...... mation. Here I review these topics, coexist in sensory neurons and to have g: sretdisshe~~~~~~~~~~~~~~.t :Cu t ..... an e.. *. existence of chemical irritant recepton.... emphasizing those aspects that may be potent vasodilatory properties (3-6). the airwaya-nd sknr disc e;ne r applicable to elucidating the mechanism Direct stimulation of sensory nerves pro- enic atin isg from tilai of chemical sensitivity as a disorder of the duces vasodilatation (7,8), which can be of chemical in reeptor is a: possible regulation of neurogenic inflammation. blocked by depletion of substance P with model to explain many of thc aspects of Possible application to specific clinical (9-11). The sensory fibers <:hemicdchemicalse£ies~~~~.sen-sitivities. Key s-Mn. ashm,A entities is discussed, with suggestions for involved in neurogenic inflammation have findoor air puion, mutil~~~~~~~W chmcll se- clinical research to study the association. been identified as C-fibers with a slow siti*ity syndrome,..ur.... inla velocity of 1-2 m/sec (14. neutral endopepdasereacti.:: .:.. .ve.::.:..:....airways:..... :..:.:... dys Neurogenic Inflammation Progress has been made in understand- fiunction sydoe ecieuppier arays Inflammation is an abnormal condition of ing the regulation of neurogenic inflam- dysfu ion sndme, , ssn P, neu- sick building syndrome. Environ Healsh redness, swelling, heat, and pain localized mation (13). A cell-surface enzyme, Perspece 101: 234-238(1993) to a tissue. Histologically, inflammation tral endopeptidase (NEP), downregulates is characterized by edema, vasodilatation, neurogenic inflammation by degradating substance P. In the lung this enzyme is inhibited by cigarette smoke, viral infec- tions, and toluene diisocynate, whereas corticosteroids increase NEP. Neurogenic inflammation is now a well-defined physiological mechanism by which mediators are directly released from sensory nerves to produce-vasodilatation, edema, and other manifestations of in- flammation. The nerve fibers have been identified as slow velocity C-fibers, and the regulation of neurogenic inflammation has been studied. Chemical Irritant Receptors The common chemical sense is a nasal sensation provoked by airborne chemicals which is distinct from taste and smell (14). This sense is experienced as a burn- ing and painfil sensation in the upper air- ways and eyes upon exposure to irritant

Address correspondence to W. J. Meggs, Room Figure 1. Olfaction and the common chemical sense. Olfaction is the sensation of odor, transmitted by 4W54, Brody Building, Department of Emergency cranial nerve 1, the olfactory nerve. The common chemical sense is a sensation of burning and irritation Medicine, East Carolina University School of in the airway, produced by irritant chemicals and transmitted by cranial nerve V, the trigeminal nerve. Medicine, Greenville, NC 27858 USA.

234 Environmental Health Perspectives I.,A - M- - - . -ol~, - supported by a combination of animal studies, pharmacological responses of these disorders, and circumstantial evidence. At the current time these associations are somewhat speculative, but there is suffi- cient evidence to justify investigations. It is now known that the neuropeptides of neurogenic inflammation reproduce the pathology of (27), and the role of neurogenic inflammation has been docu- mented in animal models of asthma (28). Barnes (29) has recently reviewed the cur- rent evidence for the role of neurogenic inflammation in asthma and has suggested strategies for reducing neurogenic inflam- mation in this disease. It is increasingly recognized that respiratory irritants such as VOCs and environmental tobacco smoke can exacerbate asthma and rhinitis (30-32). A number of studies have documented an increase in the incidence of asthma in industrialized countries, over both the long Figure 2 Schematc diagram of neurogenic inflammation triggered by chemical irritants. Chemical irri- term and during the 1980s (33). In addi- tants (C) bind chemical irritant receptors on sensory nerves to release substance P (P) and other media- tion, studies during the 1980s established tors from nerve endings. Substance P binds receptors on effector cells to trigger inflammation. Neutral that the American population is exposed to endopeptidase (nep), an enzyme located on the membranes of effector cells, degrades substance P and VOCs in the indoor air (34). downregulates neurogenic inflammation. It is proposed that chemical sensitivity syndromes are disor- The role of neurogenic inflammation ders ofthe regulation of neurogenic inflammation. and chemical irritants in these respiratory Regulation ofNeurogenic disorders and the upregulation of neuro- substances and results from exposure of genic inflammation by inhalant irritants trigeminal nerve endings to the irritants. Inflammation discussed above indicate that there may be The skin and other mucous membranes Neutral endopeptidase degrades substance a relationship between indoor air pollution have similar responses to irritant chemi- P (13). NEP is located on the surfaces of with VOCs and the worsening asthma epi- cals. Recent studies in anosmic subjects cells with substance P receptors, i.e., the demic. Pursuit of this relationship should have separated the common chemical target cells of substance P. Substances that be a research priority. In the past asthma sense from olfaction (15). The common decrease neutral endopeptidase levels was divided into extrinsic asthma, triggered chemical sense and olfaction are depicted increase neurogenic inflammation, while by protein aeroallergens, and intrinsic asth- in Figure 1. There is evidence that pro- substances that increase neutral endopepti- ma of unknown cause. This distinction tein receptors on cell membranes are the dase suppress neurogenic inflammation. was made before the role of neurogenic activation site for chemical irritants. It is Human recombinant NEP suppresses neu- inflammation in asthma was appreciated. thought that sensory nerves act as both rogenic inflammation (18-20). Exogenous It may be that asthma would be better clas- afferent and efferent nerves for neurogenic substances that inhibit NEP include ciga- sified as immunogenic or neurogenic inflammation triggered by chemical irri- rette smoke (21), respiratory viruses (Table 1). The distinction between neuro- tants. In the nose, substance P release has (22-25), and the volatile organic chemical genic and immunologic asthma is limited been verified for exposures to nicotine, toluene diisocyanate (26). to the catalysts because the two types cross capsaicin, ether, formaldehyde, and ciga- over after the release of mediators, in that rette smoke (16,17). Hence, stimulation Possible Roles ofNeurogenic the mediators of neurogenic inflammation of the chemical irritant receptors leads to Inflammation trigger mast cell degranulation, and mast neurogenic inflammation. The relation- Neurogenic inflammation may play a role cell mediators stimulate peripheral nerves. ship among chemical irritants, sensory in a variety of disorders, from asthma and This "bidirectional regulatory circuit" has nerves, substance P, and NEP is summa- rhinitis to headache, rheumatoid recently been reviewed (35). rized in Figure 2. arthritis, and . Such a role is This crossover phenomenon does not mean that neurogenic inflammation and immunologic inflammation are clinically Table 1. Immunogenic versus neurogenic asthma identical in all cases. In the upper airways Immunogenic Neurogenic and skin, the initial complaint associated Triggered by Protein aeroallergens Volatile organic chemicals with exposure to chemical irritants is burn- Interacting with IgE antibody Chemical irritant receptors ing or pain, whereas itching is the initial Located on Mast cells Sensory nerve C-fibers complaint associated with immune-medi- It be there is Releasing Histamine, leukotrienes, Neuropeptides: substance P, ated exposures. may that prostoglandins, chemotactic neurokinen A, calcitonin individual variability in the degree to factors gene-related peptide which crossover is clinically manifested. Stimulating Sensory nerve C-fibers Mast cell degranulation The two mechanisms might be differenti- ated by testing patients with challenging Producing Bronchial inflammation Bronchial inflammation doses of antigens and nonallergenic chemi- Manifesting as Asthma Asthma cal irritants while monitoring clinical

Volume 101, Number3, August 1993 235 --i S MI I I lI I symptoms and measuring mediators. This fibers in rheumatoid arthritis, and neuro- Reactive upper-airways dysfunction research would best be carried out by genic inflammation may play a role i9 this syndrome (RUDS) also follows a chemical studying upper airway responses, as nasal disorder. Zimmerman has suggested that exposure, and there is persistent chronic washings can be easily obtained for quanti- neurogenic inflammation may play a role rhinitis. The chief complaint of patients fying mediators. in fibromyalgia (44. with RUDS is chemical sensitivity (47). Another disorder that increased signifi- Unlike patients with RADS, medical atten- cantly during the 1980s is migraine head- Role ofNeurogenic Inflammation in tion is not sought on the day of exposure, aches (36). Headache is an early and con- Chemical Sensitivity Syndromes which probably reflects the fact that sistent consequence of exposure to VOCs. "Sick building syndrome" (SBS) is a term breathing is compromised in RADS but On the basis of pharmaceutical responses used to designate an outbreak of illness not in RUDS. Preliminary study of the of migraine and animal experiments, associated with indoor air contaminants in nasal mucosa found lymphocytic infil- Nicolodi and Sicuteri proposed that neuro- new and tightly sealed buildings. Symp- trates, and electron microscopy has shown genic inflammation plays a role in the toms include irritation of the eyes, nose, thickening of the basement membrane and pathophysiology of migraine headaches and throat, skin irritation, and neurotoxic desquamation of the respiratory epithelium (37). Silberstein argued that both tension symptoms including mental fatigue and (48). headaches and migraine may be generated difficulty concentrating (43). The syn- There are many similarities between by neurogenic inflammation (38). Buzzi drome is an acquired disorder with onset SBS, MCS, RADS, and RUDS (Fig. 3). In and Moskowitz demonstrated that stimula- related to moving into a new or renovated each snydrome, a high-dose exposure tion of trigeminal sensory fibers leads to building, and there is wide individual vari- induces the syndrome, and subsequent changes consistent with those of migraine ability in onset and symptoms after expo- exacerbations are associated with low-level in a rat model, and these changes can be sure. exposures. SBS and MCS include symp- blocked by the antimigraine drugs suma- Multiple chemical sensitivity syn- toms involving more than one organ sys- triptan and dihydroergotamine (39). drome (MCS) is a related syndrome with tem, with the respiratory mucosal and cen- Hardebo has pointed out that the postulate onset related to an environmental expo- tral nervous system being prominently that neurogenic inflammation mediates sure, most commonly a solvent or pesti- involved. The major difference between migraine provides a rational explanation cide. After the initial exposure, individu- SBS and MCS is that SBS refers to a cluster for why antagonists are effective als become sensitive to low-level chemical of cases associated with a building, while in treating migraine (40). Challenge stud- exposures with symptoms involving more MCS patients have more generalized com- ies with VOCs on migraine patients, with than one organ system. Though this syn- plaints. RADS and RUDS have prominent and without specific pharmacological drome was de-scribed four decades ago airway involvement, with the difference blockage of relevant receptors, is needed to (44.45), it re-mains highly controversial. between the two being that RADS involves elucidate the role of neurogenic inflamma- Reactive airways dysfunction syn- the lower airway (asthma), and RUDS tion and chemical irritants in migraine. drome (RADS) is an asthmalike illness involves the upper airway (rhinitis). In one A comparison of neuropeptide staining that develops within minutes to hours small series, 100% of patients with RUDS in the synovium of patients with rheuma- after an acute exposure to dust, smoke, or had extra-airway manifestations and met toid arthritis, osteoarthritis, and controls solvent. There is persistent bronchial the Cullen case definition (49) for MCS. found weaker staining in the nerve fila- hyperreactivity with positive methacholine These syndromes may be related at a ments of the rheumatoid arthritis group challenge. The asthma becomes chronic deeper level. All of these illnesses may be (41). The authors suggest that this weaker after the initial exposure and can be diffi- disorders of the regulation of neurogenic staining is evidence of release from nerve cult to treat (46). inflammation. The inducing exposure may alter the respiratory mucosa in one or more ways. The regulation ofneurogenic inflam- mation may be disturbed by the depletion of NEP or other enzymes, which would result in a heightened response to subse- quent exposures. The desquamation of the respiratory epithelium seen in RUDS may remove a barrier to chemical irritants, so that chemical irritants may reach and trig- ger the irritant receptors at lower concen- trations. Patients with these illnesses complain of symptoms in organ systems in addition to the airways, and some patients have no air- ways symptoms at all. Mechanisms to explain how airway irritants can trigger sys- temic symptoms must be considered. First, it is common for inflammatory illnesses pri- marily arising in one organ or tissue to pro- duce systemic manifestations (e.g., the extra-articular manifestations of rheuma- toid arthritis and the systemic manifesta- tions of Crohn's disease). Viral infections Figure 3. Chemical sensitivity syndromes. The multiple chemical sensitivity syndrome (MCS), sick build- ing syndrome (SOS), reactive airways dysfunction syndrome (RADS), the reactive upper airways dysfunc- of the upper airway produce systemic tion syndrome. (RUDS) have many features in common. These syndromes may all be disorders of the reg- symptoms, including myalgias, fever, ulation of neurogenic inflammation. fatigue, and malaise.

236 Environmental Health Perspectives -. A I - I e Exp Physiol 6:339-354(1913). 3. Tanaka DT, Grunstein MM. Vasoactive *....~~~~~~~~~~~~~~~~~~~~~~W ll '' O d_vie hsis an....p.o. Wlli~O fte'is andfe effects of substance P on isolated rabbit pul- :. l. .a 1 S *x. U.n.|V~~~~~~~~~~~~~~~~~~~~~~~~~~~4 monary artery. J Appi Physiol 58:1291(1985). X:d..ce n e Misa n 4. Foreman JC. Peptides and neurogenic inflam- ~~~~~~~~~~~~~~~~~~~~~...... mation. Br Med Bull 43:386(1987). r;._...... ~ ~~...... 5. Lundberg JM, Lundblad L, Martling CR, Saria ...... ~~~~~~~~~~~~~~~~~~~~~~~~: ... _...... duc1 * ;f6-s ot a''- Be{¢loly r gSs .P Z.n::.: t.th. r' A, Stjarne P, Anggard A. Coexistence ofmulti- ~~~~~~~~~~~~~~~~~~~~.i ple peptides and classic transmitters in airway * .$c.e.n.ces,iicha-ored*.e.bo....a.k...::M.#fVm.~~~~~~~~~~~~~~~~~~~~~~~~...... neurons. Am Rev Respir Dis 136:16(1987). ..~~~~~~~~~~~~~~~~~~~~~~~~~~~~~. .1::.:re: 6. Uddman R, Grunditz T, Larsson A, Sundler F. Sensory innervation of the ear drum and mid- dle ear mucosa. Cell Tissue Res 252:141 (1988). 7. Hinsey JC and Gasser HS. The component of the dorsal root mediating vasodilatation and the Sherrington contracture. Am J Physiol Both the mediators and regulators of by environmental chemicals such as ciga- 92:679(1930). inflammation may be released from the site rette smoke and solvents. Hence, any dis- 8. Jancso-Gabor, A., Szolcsany J. Action of rare of inflammation and affect distant sites. order mediated by neurogenic inflamma- earth metal complexes on neurogenic as well as Two important regulators of inflamma- tion can potentially be exacerbated by on bradykinin induced inflammation. J Pharm Pharmacol 22:366:135(1970). tion, interleukin 1 and interleukin 2, sup- environmental chemicals. Study of the 9. Gasparovic I, Hadzovic S, Hukovic S, Stern P. press central nervous system activity hypothesis that chemical sensitivity syn- Contribution to the theory that substance P (50,51). Another possibility is that some dromes such as SBS and MCS may result has a transmitter role in sensitive pathways. form of neural switching may take place. from neurogenic inflammation arising Med Exp 10:155-159(1964). That is, triggering of chemical irritant from stimulation of irritant receptors by 10. Gazelius B, Brodin E, Olgart L, Panopoulos P. receptors in one organ could lead to an environmental chemicals may lead to an Evidence that substance P is a mediator of antidromic vasodilatation using somatostatin as efferent signal traveling to another site understanding of these disorders. It is of a release inhibitor. Acta Physiol Scand 113: through an aberrant or conditioned cross- interest that the symptoms of headache, 155-159(1981). ing of the pathways. A combination of myalgia, arthralgias and arthritis, and air- 11. Chahl LA. Antidromic vasocilatation and neu- these two mechanisms may be operative. way symptoms reported by MCS patients rogenic inflammation. Pharmacol Ther 37: The hypothesis that neurogenic inflam- overlap with those disorders for which a 275-300(1988). mation is the mechanism of chemical sen- role for neurogenic inflammation has been 12. Ehrlanger J, Glasser HJ. The action potential in fibers ofslow conduction in spinal roots and sitivity syndromes is amenable to scientific reported. somatic nerves. Am J Physiol 90:338-339 study. Biopsies of the airways ofchemical- The hypothesis that neurogenic inflam- (1929). ly sensitive individuals should be abnor- mation triggered by environmental chemi- 13. Nadel JA. Neutral endopeptidase modulates mal, with signs of inflammation. Im- cals plays a role in human health is amen- neurogenic inflammation. Eur Respir J 4: munofluorescent monoclonal antibodies able to scientific study. Research should 745-754(1991). could be used to detect NEP, which focus on noninvasive methods for detect- 14. Nielsen GD. Mechanisms of activation of the sensory irritant receptor by airborne chemicals. should be decreased, and substance P, ing biomarkers of neurogenic inflamma- Crit Rev Toxicol 21:183-208(1991). which should be elevated relative to con- tion. Are there degradation products of 15. Cometto-Muniz JE, Cain WS. Thresholds for trols. Nasal washings should contain substance P or other mediators of neuro- odor and nasal pungency. Physiol Behav increased levels of the mediators of neuro- genic inflammation that are elevated in the 48:719-725(990). genic inflammation relative to controls, urine or serum of patients with activation 16. Lundblad L. Protective reflexes and vascular and the levels should increase after chemi- of this system? Are there evoked potentials effects in the nasal mucosa elicited by activa- tion of capsaicin-sensitive substance P im- cal challenge in patients but not controls. or nerve conduction parameters that can munoreactive trigeminal neurons. Acta Physiol Heightened neuronal firing of sensory be used to detect activation of neurogenic Scand 529(suppl) (1984). fibers should occur after chemical chal- inflammation? Two groups of patients 17. Lundberg JM, Lundbblad L, Saria A, Angaard lenges. should be studied with challenge tests: A. Inhibition ofcigarette smoke-induced oede- patients with disorders in which neuro- ma in the nasal mucosa by capsaicin pretreat- Discussion genic inflammation is suspected to play a ment and a substance P antagonist. Naunyn- Schmiedebergs Arch Pharmakol 326: 181 Neurogenic inflammation leads to inflam- role (i.e., asthma, rhinitis, migraine, (1984). mation independent of the immune sys- rheumatoid arthritis, fibromyalgia) and 18. Kohrogi H, Nadel JA, Malfroy B, Gorman C, tem. Polypeptide mediators are stored in patients with chemical sensitivity syn- Bridenbaugh R, Patton JS, Borson DB. nerve endings and released when irritant dromes. These patients should be isolated Recombinant human enkephalinase (neutral receptors on nerves are stimulated by from VOCs in a specially constructed din- endopeptidase) prevents cough induced by chemicals. The role of neurogenic inflam- ical research unit and monitored for reso- tachykinins in awake guinea pigs. J Clin Invest 84:781-786(1989). mation in a number of inflammatory con- lution of their symptoms. Chemical chal- 19. Iwamoto I, Ueki IF, Borson DB, Nadel JA. ditions is currently under investigation. lenges should be conducted while patients Neutral endopeptidase modulates tachykinin- There is strong evidence that neurogenic are monitored for provoked symptoms. induced increase in vascular permeability in inflammation is operative in asthma and Biomarkers of neurogenic inflammation guinea pig skin. Int Arch Allergy Appl Im- rhinitis..There is circumstantial evidence should be measured throughout the course munol 88:288-293(1989). that neurogenic inflammation may play a ofthese challenges. 20. Rubenstein I, Iwamoto I, Ucki IF, Borson DB, Nadel JA. Recombinant neutral endopeptidase role in migraine headache. Evidence for a attenuates substance P induced plasma extrava- role in rheumatoid arthritis and fibromyal- REFERENCES sation in the guinea pig skin. Int Arch Allergy gia is not as compelling at this time. The 1. Bruce AN. Uber die Beziehung der Sensiblen Appl Immunol 91:232-238(1990). significance of these associations for envi- Nervenendigungen zum Enzundungsvorgang. 21. Dusse DJ, Djokic TD, Borson DB, Nadel JA. ronmental health is that neurogenic in- Arch Exp Pathol Pharmakol 63:424(1910). Cigarette smoke induces bronchoconstrictor flammation can be triggered in the airways 2. Bruce AN. Vaso-dilatory axon reflexes. Q J hyperresponsiveness in substance P and inacti-

Volume 101, Number 3, August 1993 237 1- -. 4j - vates airway neutral endopeptidases in the 31. Stankus RP, Menon PK, and Rando RJ, Air '87: Proceedings of the IV international guinea pig. Possible role of free radicals. J Glindmeyer H, Salvaggio JE, and Lehrer SB. conference on indoor air quality and climate, Clin Invest 84:900-906(1989). Cigarette smoke sensitive asthma: chalienge vol 2 (Sefert B, Esdorn H, Fischer M, eds), 22. Jacobi DB, Tamaoki J, Borso DB, and Nadel studies. J Allergy Clin Immunol 82:331-338 Berlin:Institute for Water, Soil, and Air JA. Influenza infection causes airway hyperre- (1988). Hygiene, 1987;469-473. sponsiveness by decrcasing enkephalinase. J 32. Meggs WJ. Health effects of indoor air pollu- 44. Randolph TG. Human ecology and suscepti- Appl Physiol 64:2653-2658(1988). tion. NC Med J 53:354-358(1992). bility to the chemical environment. Spring- 23. Dusser DJ, Jacoby DB, Djokic TD, 33. Weiss KD, Wagener DK Asthma surveillance field, Illinois: C. C. Thomas, 1962. Rubenstein I, Borson DB, and Nadel JA. in the United States: a review of current trends 45. Tabershaw IR, Cooper WC. Sequelae of acute Virus induces airway hyperresponsivenss to and knowledge gaps. Chest 98(suppl 5):1795- organic phosphate poisoning. J Occup Med tachykinins: role of neutral endopeptidase. J 1845(1990). 8:5-19(1966). Appl Physiol 67:1504-1511(1989). 34. Wallace LA. Recent field studies of personal 46. Brooks SM, Weiss MA, and Bernstein IL. 24. Borson DB, Brokaw JJ, Sekizawa K, and indoor exposures to environmental pollu- Reactive airways dysfunction syndrome McDonald DM, and Nadel JA. Neutral tants. Ann NYAcad Sci 641:7-16(1992). (RADS): persistent asthma syndrome after high endopeptidase and neurogenic inflammation in 35. Lewis RM. Bidirectional regulatory circuit level irritant exposurc. Chest 88:376-384 rats with respiratory infections. J Appl Physiol between the immune and neuroendocrine sys- (1985). 66:2653-2658(1989). tems. Year Immunol 4:241-252(1989). 47. Meggs WJ, Cleveland CH. Rhinolaryngo- 25. Piedimonte G, Nadel JA, Umeno E, 36. Anonymous. Prevalence of chronic migraine scopic findings in the multiple chemical sensi- McDonald DM. Sendai virus infection poten- headaches-United States, 1980-1989. tivity syndrome. Arch Environ Health 48: tiates neurogenic inflammation in the rat tra- MMWR 40:337-338(1991). 14-18(1993). chea. J Appl Physiol 68:754-760(1990). 37. Nicolodi M, Sicuteri F. Links between head- 48. Meggs WJ, Cleveland CH, Metzger WJ, 26. Sheppard D, Thompson JE, Scypinski L, ache mechanisms and new medications. Clin J Larkin E, Albernaz M. Reactive upper-airways Dusser D, Nadel JA, Borson DB. Toluene Pain 7(suppl):S64-71(1991). dysfunction syndrome (RUDS): a form of diisocyanate increases airway responsiveness to 38. Silberstein SD. Advances in understanding the chemical irritant rhinitis following an acute substance P and decreases airway enkephali- pathophysiology of headache. Neurology 42 exposure. J Allergy Clin Immunol 89:145 nase. J Clin Invest 81:1111-1115(1988). (suppl 2):6-10(1992). (1992). 27. Barnes PJ. Neurogenic inflammation in air- 39. Buzzi MG, Moskowitz MA. The trigemino- 49. Cullen MR The worker with chemical sensi- ways. Int Arch Allergy Appl Immunol 94: vascular system and migraine. Pathol Biol tivities: an overview. State Art Rev Occup 303-309(1991). 40:313-317(1992). Med 2:655-661(1987). 28. Lundberg JM, Saria A, Lundberg L, Anggard 40. Harbedo, J. A cortical excitatory wave may 50. Obal F Jr, Opp M, Cady AB, Johannsen L, A, Martling C-R, Thesodorsson-Norheim E, cause both the aura and the headache of Postlethwaite AE, Poppleton H, Seyer JE, and Stjarne P, Hokfelt TG. Bioactive peptides in migraine. Cephalalgia 12:75-80(1992). Krueger JM. Interleukin 1 alpha and intcr- capsaicin-sensitive C-fiber afferents of the air- 41. Gronblad M, Konttinen YT, Korkala 0, Liesi leukin 1 beta fragments are somnogenic. Am J ways: functional and pathophysiological impli- P, Hukkanen M, Polak JM. Neuropeptides in Physiol 259:R439-446(1990). cations. In: The airways neural control in synovium of patients with rheumatoid arthritis 51. De Sarro GB, Masuda Y, Ascioti C, Andino health and disease (Kaliner MA, Barnes RJ, and osteoarthritis. J Rheum 15:1807-1810 MG, and Nistico G. Behavioral and ECG eds). New York:Marcel Dekker, 1987; (1988). spectrum changes induced by intracerebral 417-445. 42. Zimmerman M. Pathophysiologic mecha- infusion of interferons and interleukin 2 in rats 29. Barnes PJ. Neurogenic inflammation and asth- nisms of fibromyalgia. Clin J Pain 7 (suppl are antagonized by naloxone. Neuropharma- ma. J Asthma 29:165-180 (1992). 1):S8-15, 1991 cology 29:167-179(1990). 30. Shim C, Williams MH, Jr. Effect of odors in 43. Molhave L. The sick buildings-a subpopula- asthma. Am J Med 80:18-22(1986). tion among the problem buildings. In: Indoor

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238 Environmental Health Perspectives