臺灣博碩士論文加值系統

人類呼吸道過敏性疾病發生率最近幾年有顯著性增加的傾向，而一些環境中的污染原增加，被認為是造成此現象的因素之一。在台灣，施用於田間之農藥種類頗多，同時曾被質疑為一吸入性的環境污染原，但對於農藥是否具造成呼吸道過敏反應之研究卻仍不足。一般而言農藥引發呼吸道過敏反應的作用，可能因其藥劑本身即為呼吸道過敏原(allergen)，亦或具有佐劑(adjuvant)之作用，而對原先已有之呼吸道過敏反應具有增強效應。有鑑於此，本研究擬建立雞卵蛋白(ovalbumin)陽性過敏原以促發小鼠基礎之過敏反應，再以氣管內灌注之方式分別於卵蛋白誘發前或誘發後，投予不同農藥，以評估該類農藥是否更具誘發或促進呼吸道過敏反應，以進一步評估農藥誘發呼吸道過敏反應之風險用。本試驗共評估常用八種藥劑，包括四氯異苯腈(chlorothalonil)、第滅寧(deltamethrin)、丁香油(eugenol)、鋅猛乃浦(mancozeb)、百滅寧(permethrin)、保粒黴素(polyoxin B)、快得寧(quinolate)及鏈黴素(streptomycin)。試驗動物BALB/c小鼠在給予最後一次的攻擊試驗後犧牲。分析血清IgE抗體及肺支氣管沖洗液IL-4及IFN-等細胞激素變化。另一方面，組織切片分別以Luna及PAS染色方法計數呼吸道組織中的嗜酸性球及杯狀細胞的增生。結果顯示，若單獨施用百滅寧、快得寧或鏈黴素時，處理組於呼吸過敏反應相關指標上與對照組相比均有顯著上升。而若再同時以藥劑與陽性過敏原卵蛋白合併處理時，於四氯異苯腈、百滅寧及快得寧等試驗組與單獨處理卵蛋白及單獨處理四氯異苯腈、百滅寧及快得寧試驗組均有提高上述相關呼吸過敏反應指標值。另一方面，為了評估藥劑是否可能導致呼吸道過度反應(airway hyperresponsiveness)，以非侵入式體積氣體描繪器分別投以2.5、5、10及20 mg/ml不同濃度的Methacholine進行呼吸道刺激性反應試驗以評估小鼠呼吸道抗力的水準。結果顯示，四氯異苯腈、百滅寧及鏈黴素等組具有增加Methacholine呼吸道刺激反應試驗中代表呼吸道抗力的Penh值。綜合以上結果顯示，百滅寧、快得寧及鏈黴素等農藥本身於小鼠中即為呼吸道敏感原，並能誘發呼吸道過敏反應，而四氯異苯腈、百滅寧及快得寧等藥劑則具有類似佐劑的作用，可增強卵蛋白所誘發的呼吸道過敏反應。

Respiratory allergic diseases have increased markedly in recent years and several environmental pollutants have been considered as one of the causes of this increase. Pesticides may be one of important environmental inhalable pollutants, however there are few reports of respiratory hypersensitivity by pesticides. Mechanisms on pesticide-induced respiratory hypersensitivity include pesticide by itself as respiratory allergy and acting as an adjuvate to enhance the respiratory hypersensitivity reaction. In view of this, we adopted the protocol that after or before the administration of the positive allergen ovalbumin the test pesticides were instilled intratracheally. The objective of this study was to evaluate the possible roles of pesticide in inducing or enhancing respiratory hypersensitivity reaction to provide the basic information for the risk assessment on respiratory hypersensitivity. Eight suspicious pesticides were evaluated in BALB/C mice, including chlorothalonil, deltamethrin, eugenol, mancozeb, permetrin, polyoxin B, quinolate and streptomycin. The animals were sacrificed 24 hours after the last challenge. The total IgE antibody in serum and cytokine levels of IL-4, IFN- in supernatant of bronchoalveolar lavage fluid were analyzed. Infiltration of eosinophil and hyperplasia of goblet cells in respiratory tract were evaluated by Luna and PAS stain, respectively. Results show that the levels of respiratory allergy associated-indicators in mice treated with permethrin, quimolate or streptomycin were significantly elevated compared to the PBS control group. Cotreatment chlorothalonil, quinolate or permethrin with ovalbumin increased the levels of the respiratory allergy-associated indicators when compared with the group treated with ovalbumin or test pesticide alone. In order to evaluate the pesticide-induced airway hyperresponsiveness, we measured the airway resistant level by unstrained barometric plethysmography with methacholine at concentrations of 2.5, 5, 10 and 20 mg/ml. Results showed that treatment with chlorothalonil, permethrin or streptomycin increased the Penh value in methacholine provocation test compared to the control group (baseline). These data suggest that quinolate, permethrin and streptomycin could be respiratory sensitizers by themselves. Also, chlorothalonil, permethrin and quinolate could serve as an adjuvate to enhance ovalbumin-induced respiratory hypersensitivity reaction.

目錄…………………………………………………………………Ⅰ-Ⅲ
表次……………………………………………………………………Ⅳ
圖次……………………………………………………………………Ⅴ
中文摘要……………………………………………………………Ⅵ-Ⅶ
英文摘要……………………………………………………………Ⅷ-Ⅸ
縮寫表…………………………………………………………………Ⅹ
第一章 緒言………………………………………………………1-3
第二章 文獻探討
第一節 農藥之簡介
壹、農業藥物之定義與分類……………………………4-5
貳、目前台灣農業藥物之毒性分類及毒理需求………5-6
第二節 過敏性反應
壹、過敏性反應之分類…………………………………8-9
貳、過敏反應之免疫機制……………………………12-14
參、過敏反應實驗動物模式探討……………………15-18
第三節 呼吸道過敏反應
壹、呼吸道對外來物之免疫反應……………………19-20
貳、呼吸道過敏炎症之機制…………………………21-22
參、農藥與呼吸道過敏反應之關係…………………22-24
第四節 氣喘反應
壹、氣喘反應之機制…………………………………25-26
貳、呼吸道過敏反應與氣喘之關係…………………26-28
參、農藥與氣喘反應之關係…………………………28-29
第五節 本研究之目的………………………………………30
第三章 材料與方法
第一節 試驗材料與供試藥品
壹、供試農藥……………………………………………31
貳、其它試驗用藥品……………………………………31
參、試驗用儀器…………………………………………32
肆、試驗動物…………………………………………32-33
第二節 農藥引發呼吸道過敏反應之評估
壹、試驗農藥劑量選擇及藥劑溶液配置………………33
貳、呼吸道敏感化及攻擊反應試驗………………34
參、肺支氣管沖洗液之製備……………………………37
肆、肺臟之組織病理檢查……………………………37-38
伍、血清中總IgE抗體ELISA測定法………………39
陸、BALF暨培養細胞上清液中總Cytokine測定法39-40
第三節 農藥對呼吸道過敏反應促進作用之探討
壹、呼吸道敏感化及攻擊反應試驗………………40
第四節 以體積氣體描繪器量測農藥對呼吸道過度反應
壹、體積氣體描繪器量測給藥後動物之呼吸功能……42
貳、Methacholine對呼吸道刺激性反應試驗………42-43
第五節 農藥與血清IgE劑量反應關係及時程反應………44
第六節 統計分析方法………………………………………44
第四章 結果
第一節 農藥對呼吸道過敏反應之影響研究
壹、 農藥引發肺臟灌洗液中細胞型態分類之改變…46
貳、 肺臟的病理變化…………………………………47
參、血清中IgE抗體的變化……………………………48
肆、肺沖洗液中細胞激素IL-4及IFN-的變化…49-50
第二節 農藥對呼吸道過敏反應促進作用之探討……55-56
第三節 農藥對呼吸道過度反應之影響………………61-62
第四節 農藥對IgE時程變化及劑量反應關係探討66-67
第五章 討論……………………………………………………69-77
參考文獻……………………………………………………………78-87
附錄…………………………………………………………………88-92表次
頁次
Table 2-1. Classification of pesticides active ingredient used
in Taiwan……………………………………………5
Table 2-2. Toxicology requirements for pesticide registration
in Taiwan………………………………………………7
Table 2-3. Classification of toxicity of pesticides
in mammals (rat)…………………………………………8
Table 2-4. Hypothetical mechanisms for increased production
of IgE in vivo…………………………………………11
Table 4-1. Differential counts of BALF cell………………………50
Table 4-2. Effect of chlorothalonil on OVA induced
respiratory hypersensitivity………………………57
Table 4-3. Effect of deltamethrin on OVA induced
respiratory hypersensitivity………………………57
Table 4-4. Effect of eugenol on OVA induced
respiratory hypersensitivity………………………58
Table 4-5. Effect of mancozeb on OVA induced
respiratory hypersensitivity………………………58
Table 4-6. Effect of polyoxin B on OVA induced
respiratory hypersensitivity………………………59
Table 4-7. Effect of permethrin on OVA induced
respiratory hypersensitivity………………………59
Table 4-8. Effect of quinolate on OVA induced
respiratory hypersensitivity………………………60
Table 4-9. Effect of streptomycin on OVA induced
respiratory hypersensitivity………………………60
Table 4-10. Penh value of mice treated with ……………63
圖次
頁次
Figure 2-1. Classification of hypersensitivity reaction………………10
Figure 2-2. Inflammation mechanism of respiratory
hypersensitivity…………………………………………11
Figure 3-1. Intratracheal instillation method…………………………35
Figure 3-2. Immunization Ⅰ, experimental design for evaluating
eight pesticides on respiratory hypersensitivity
response by intratracheal instillation………………………36
Figure 3-3. Immunization Ⅱ, experimental design for evaluating
eight pesticides on respiratory hypersensitivity
induced by ovalbumin……………………………………41
Figure 3-4. whole body plethysmography…………………………45
Figure 4-1. The ratio of lung weight by body weight…………51
Figure 4-2. Eosinophil infiltration rate in the lung……………51
Figure 4-3. Histopathological changes of lung
after treatment with pesticides……………………………53
Figure 4-4. Total IgE level in serum.……………………………53
Figure 4-5. Total IL-4 level in BALF.…………………………54
Figure 4-6. Total IFN- level in BALF…………………………54
Figure 4-7. Light micrograph of the bronchiole
with PBS stain………………………………………64
Figure 4-8. The estimation of goblet cell hyperplasia index…65
Figure 4-9. Dose-response of streptomycin
on the serum IgE level…………………………………68
Figure 4-10. Study on the time course of serum IgE level…………68

Arm, J.P. and Lee. T.H. The pathobiology of bronchial asthma. Adv. Immunol. 51, 323-382, 1992.
Atkinson, T.P. and Kaliner, M.A. Anaphylaxis Med. Clin. N. Am. 76, 841—855, 1992.
Bardin, P. G., Johnston, S.L., and Pattemore, P.K. Viruses as ptecipitants of asthma symptoms. II . Physiology and mechanisns. Clin. Exp. Allergy 22, 809-822, 1992.
Basketter, D. A., Roverts, D. W.,Cronin, M., and Scholes, E. W. The value of the local lymph node assay in quantitative structure-activity investigations. Contact Dermatitis 27, 137-142, 1992.
Bergstedt-Lindqvist, S., Moon, H-B., Persson, U., Moller, G., Heusser, C. and Severinson, E. Interleukin 4 instructs uncommitted B lymphocytes to switch to IgG1 and IgE. Eur. J. Immunol. 18, 1073—1077, 1988.
Bessmertny, O. and Pham, T. Antiepileptic hypersensitivity syndrome: clinicians beware and be aware. Curr. Allergy Asthma Rep. 2, 34—39, 2002.
Blanca, M., Posadas, S., Torres, M.J., Leyva, L., Mayorga, C., Gonzalez, L., Juarez, C., Fernandez, J., and Santamaria, L.F. Expression of the skin-homing receptor in peripheral blood lymphocytes from subjects with nonimmediate cutaneous allergic drug reactions. Allergy 55, 998—1004, 2000.
Bocquet, H., Bagot, M., and Roujeau, J.C. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin. Cutan. Med. Surg. 15, 250—257, 1996.
Botham, P.A., Rattray, N.J., Woodcock, D.R., Walsh, S.T., Hext, P.M. The induction of respiratory allergy in guinea pigs following intradermal injection of trimellitic anhydride. A comparison with the response to 2, 4-dinitrochlorobenzene. Toxicol. Lett. 47, 25—39, 1989.
Bradley, B.L., Azzawi, M., Jacobson, M., Assoufi, B., Collins, J.V., Irani, A.M., Schwartz, L.B., Durham, S.R., Jeffery, P.K., and Kay, A.B. EosinophilsT-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects with asthma: comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness. J Allergy Clin Immunol. 88, 661—674, 1991.
Britschgi, M., Steiner, U.C., Schmid, S., Depta, J.P., Senti, G., Bircher, A., Burkhart, C., Yawalkar, N., and Pichler, W.J. T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J. Clin. Invest. 107, 1433—1441, 2001.
Brugnolo, F., Annunziato, F., Sampognaro, S., Campi, P., Manfredi, M., Matucci, A., Blanca, M., Romagnani, S., Maggi, E., and Parronchi, P. Highly Th2-skewed cytokine profile of beta-lactam-specific T cells from nonatopic subjects with adverse drug reactions. J. Immunol. 163, 1053—1059, 1999.
Buhl, R., Holroyd, K.J., Mastrangeli, A., Cantin, A.M., Jaffe, H.A., Wells, F.B., Saltini, C., and Crystal, R.G. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet 2, 1294—1298, 1989.
Buehler, E. V. A new method of detecting potential sensitizers using the guinea pig. Toxicol. Appl. Pharmacol. 6, 341-, 1964.
Chong, B.T.Y., Agrawal, D.K., Romero, F.A., and Townley, R.G. Measurement of bronchoconstriction using whole-body plethysmographs: comparison of freely moving versus restrained guinea pigs. J. Pharmacol. Toxicol. Methods 39, 163—168, 1998.
Chung, K. F. and Barnes, P.J. Cytokines in asthma. Thorax 54, 825, 1999.
Coombs, R.R.A. and Gell, P.G.H. Classification of allergic reactions responsible for drug hypersensitivity reactions. In: Coombs, R.R.A., Gells, P.G.H. (Eds.), Clinical Aspects of Immunology, second ed. Davis, Philadelphia, PA, pp. 575—596, 1968.
Copplestone, J. F. The development of the WHO recommended classification of pesticides bt Hazard. Bull. W. H. O. 6, 545-551, 1988.
Crumpton, W.G. Using wetlands for water quality improvement in agricultural watersheds the importance of a watershed scale approach. Water Sci. Technol. 44, 559—564, 2001.
Cumberbatch, M., Dearman, R.J., and Kimber, I. Interleukin 1 and the stimulation of Langerhans cell migration: comparisons with tumour necrosis factor a. Arch. Dermatol. Res. 289, 277—284, 1997.
Dearman, R. J., and kimber, I. Differential stimulation of immune functon by respiratory and contact chimical allergins. Immunol. 72, 563-570, 1991.
Dearman, R.J., Betts, C.J., Humphreys, N., Flanagan, B.F., Gilmour, N.J., Basketter, D.A., and Kimber, I. Chemical Allergy: Considerations for the Practical Application of Cytokine Profiling. Toxicol. Sci. 71, 137-145, 2003.
Dejarnatt, A.C. and Grant, J.A. Basic mechanisms of anaphylaxis and anaphylactoid reactions. Immunol. Allergy Clin. N. Am. 12, 501—515, 1992.
De Silva, O., Basketter, D.A., Barratt, M.D., Corsini, E., Cronin, M.T.D., Das, P.K., Degwert, J., Enk, A., Garrigue, J-L., Hauser, C., Kimber, I., Lepoittevin, J-P., Peguet, J., and Ponec, M. Alternative methods for skin sensitisation testing. The report and recommendations of ECVAM workshop 19. ATLA 24, 683—705, 1996.
Dong, W., Gilmour, M.I., Lambert, A.L., and Selgrade, M.K. Enhanced allergic response to house dust mite by oral exposure to carbaryl in rats. Toxicol. Sci. 44, 63—69, 1998.
Driscoll, K. E., Maurer, J. K., Lindenschmidt, R. C., Romberger, D., Rennerd, S., and Crosby, L. Respiratory tract responses to dust: relationships between dust burden, lung injury, alveolar macrophage fibronectin release, and the development of pulmonary fibrosis. Toxicol. Appl. Pharmacol. 106, 88-101, 1990.
Drorbough, J.E. and Fenn, W.O. A barometric method for measuring ventilation in newborn infants. Pediatrics 16, 81—87, 1955.
Enk, A., Angeloni, V.L., Udey, M.C., and Katz, S.I. An essential role for Langerhans cell-derived IL-1b in the initiation of primary immune responses in the skin. J. Immunol. 150, 3698—3704, 1993.
Finkelman, F.D., Katona, I.M., Urban, J.F. Jr., Holmes, J., Ohara, J., Tung, A.S., Sample, J.V., and Paul, W.E. IL-4 is required to generate and sustain in vivo IgE responses. J. Immunol. 141, 2335—2341, 1988.
Frew, A.J. The immunology of respiratory allergies. Toxicol. Letter 86, 65-72, 1996.
Gerberick, G. F., Cruse, L.W., Ryne, C. A., Hulette, B.C., Chaney, J. G. Skinner, R. A.; Dearman, R. J., and Kimber, I. Use of a B cell marker (B220) to discriminate between allergens and irritants in the local lymph node assay. Toxicol. Sci. 68, 420-428, 2002.
Hamelmann, E., Schwarze, J., Takeda, K., Oshiba, A., Larsen, G.L., Irvin, C.G., and Gelfand, E.W. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156, 766—775, 1997.
Hamelmann, E., Vellat, A. T., Oshiba, A., Kapplert, J. W., Marrack, P., and Gelfand, E. W. Allergic airway sensitization induces T cell activation but not airway hyperresponsiveness in B cell-deficient mice. Proc. Natl. Acad. Sci. 94, 1350-1355, 1997.
Hilton, J., Dearman, R. J., Fielding, D. A., and Kimber, I. Evaluation of the sensitizing potential of eugenol and isoeugenol in mice and guinea pig. J. Appl. Toxicol. 16, 459-464, 1996.
Hotchkiss, J.A., Harkema, J.R., Sun, J.D., and Henderson, R.F. Comparison of acute ozone-induced nasal and pulmonary inflammatory responses in rats. Toxicol. Appl. Pharmacol. 98, 289—302, 1989.
Howard, M. S.; Gary, R.; Sheldon, S, and Roger, K. Immediately and delayed type hypersensitivity to malathion. Ann. Allergy 69, 526-528, 1992.
Hulsmann, A.R., Raatgeep, H.R., den-Hollander, J.C., Bakker, W.H., Saxena, P.R., and de-Jongste, J.C. Permeability of human isolated airways increases after hydrogen peroxide and poly-l-arginine. Am. J. Respir. Crit. Care Med. 153, 841—846, 1996.
Ichinose, T., Takano, H., Miyabara, Y., and Sagai. M. Long-term exposure to diesel exhaust enhances antigen-induced eosinophilic inflammation and epithelial damage in the murine airway. Toxicol. Sci. 44, 70-79, 1998.
Jacques, D. and Genevieve, C. K. Gell and Coombs’s classification: is it still valid? Toxicology 158, 43—49, 2001.
Ishizaka, T., Ishizaka, K., Orange, R.P., and Austen, K.F. Pharmacologic inhibition of the antigen-induced release of histamine and slow reacting substance of anaphylaxis (SRS-A) from monkey lung tissues mediated by human IgE. J. Immunol. 106, 1267-1273, 1971.
Kaneko, S., Shimada, K., Hirouchi, H., Endo, A., Kodama, M., Shinoda, N., Imai, T., and Takiguchi, K. Nasal allergy and air pollution. Otorhinolaryngol. Tokyo 23, 270—279, 1980.
Karol, M.H., Stadler, J., and Magreni, C. Immunotoxicologic evaluation of the respiratory system: animal models for immediate- and delayed-onset pulmonary hypersensitivity. Fund. Appl. Toxicol. 5, 459—472, 1985.
Karol, M. H., Cynthia, G., Robert, G., Orest, T. M., Nancy., S., and Herbert, S. R. Structure-activity relationships and computer-assisted analysis of respiratory sensitization potential Toxicol. Letter 86, 187-191, 1996.
Kephart, D. K., Chinchilli, V. M., Hurd, S. S., and Cherniack, R. M. The organization of the asthma clinical research network: A multicenter, multiprotocol clinical trials team. Controlled Clinical Trials 22, 119-125, 2001.
Khair, O.A., Devalia, J.L., Abdelaziz, M.M., Sapsford, R.J. and Davies, T.J. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and ICAM by cultured human bronchial epithelial cells. Eur. Respir. J. 8, 1451-1457, 1995.
Kimber, I. and Dearman, R.J. Contact hypersensitivity: immunological mechanisms. In: Kimber, I., Maurer, T. (Eds.), Toxicology, 1996. of Contact Hypersensitivity. Taylor and Francis, London, pp. 4—25.
Kimber, I. and Dearman, R.J. Cell and molecular biology of chemical allergy. Clinical Reviews in Allergy and Immunol. 15, 145—168., 1997.
Kimber, I. and Dearman, R.J. T lymphocyte subpopulations and immune responses to chemical allergens. In: Kimber, I., Selgrade, M.K. (Eds.), T. Lymphocyte Subpopulations in Immunotoxicology. Wiley, Chichester, pp. 199—231, 1998.
Kimber, I., Basketter, D.A. and Roggeband, R. Chemical respiratory allergy: classification and labeling. Toxicology 167, 159—162, 2001.
Kimmel, E.C., Whitehead, G.S., Reboulet, J.E., and Carpenter, R.L. Carbon dioxide accumulation during small animal, whole body plethysmography: effects on ventilation, indices of airway function and aerosol deposition. J. Aerosol Med. 15, 37—49, 2002.
Kinet, J. The high affinity receptor for IgE. Curr. Opin. Immunol. 2, 499-505, 1989.
Kita, H., Weiler, D.A., Abu-gazaleh, R., Sanderson, C.J., and Gleich, G.J. Release of granule proteins from eosinophils cultured with IL-5. J. Immunol. 149, 629—635, 1992.
Kopf, M., Le Gros, G., Bachmann, M., Lamers, M.C., Bluethmann, H., and Kohler, G. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362, 245—248, 1993.
Koren, H.S., Devlin, R.B., Graham, D.E., Mann, R., McGee, M.P., Horstman, D.H., Kozumbo, W.J., Becker, S., House, D.E., and McDonnell, W.F. Ozone-induced inflammation in the lower airways of human subjects. Am. Rev. Respir. Dis. 139, 407—415., 1989.
Kossmann, S. and Konieczny, B. Serum immunoglobulin E concentration in workers producing chlorfenvinphos. Przegl Lek. 58, 49—50, 2001.
Krasteva, M. Contact dermatitis. Int. J. Dermatol. 32, 547—560, 1993.
Kung, T.T., Stelts, D., and Zurcher, J.A., Jones, H., Umland, S.P., Kreutner, W., Egan, R.W., and Chapman, R.W. Mast cells modulate allergic pulmonary eosinophilia in mice. Am. J. Respir. Cell Mol. Biol. 12, 404—409, 1995.
Lai, Y. L. and Lee, C.F. Mediators and oxygen radicals in hyperpnea-induced airway constriction of guinea pigs. Lung 178, 213-223, 2000.
Landsteiner, k. and Jacobs, J. Studies on sensitizers of animals with simple chemical compunds. J. Exp. Med. 61,643-656, 1935.
Landsteiner, k. and Chase, M. W. Experiments on transfer of cutaneous sensitivity to simple chemical compounds. Proc. Soc. Exp. Biol. Med. 49, 288-390, 1942.
Leong, B. K. J., Coombs, J. K., Sabaitis, C. P., Rop, D. A., and Aaron, C. S. Quantitative morphometric analysis of pulmonary deposition of aerosol particles inhaled via intratracheal nebulization, intratracheal instillation or nose only inhalation in rats. J. Appl. Toxicol. 18, 149-160, 1998.
Maaike van Zijverden, Berit Granum. Adjuvant activity of particulate pollutants in different mouse models. Toxicology 152, 69—77, 2000.
Madden, K.B., Urban, J.F. Jr., Ziltener, H.J., Schrader, J.W., Yamaguchi, Y., Suda, T., Suds, J., Eguchi, M., Miura, Y., Harada, N., Tominaga, A., and Takatsu, K. Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors. J. Exp. Med. 167, 43—56, 1988.
Magnusson, B. and Kligman, A. M. The identification of contact allergens by animal assay. The guinea pig maximization test. J. Invest. Dermatol. 52, 268-276, 1969.
Mariko, K. and Iijima, T. K. Nasal allergy-like symptoms aggravated by ozone exposure in a concentration-dependent manner in guinea pigs Toxicology 199, 73—83, 2004.
Marini, M., Vittori, E., Hollemborg, J., and Mattoli, S. Expression of the potent inflammatory cytokines Gm-CSF I1b and IL-8in bronchial epithelial cells of patients with asthma. J. Allergy Chin. Immunol. 89, 1001-1009, 1992.
Marsha, D. W.; Madison, S. L., Sailstad, D.M., Gavett, S. H., and Selgrade, M. K. Allergen-triggered airway hyperresponsivenessw and lung pathology in mice sensitized with the biopesticide Metarhizium anisopliae. Toxicology 143, 141-154, 2000.
Karol. M. H. Respiratory allergy: what are the uncertainties? Toxicology 181-182, 305-310, 2002.
Metzger, H., Alcaraz, G., Hohman, R., Kinet, J.P., Pribluda, V., and Quarto, R. The receptor with high affinity for immunoglobulin E. Annu. Rev. Immunol. 4, 419-470, 1986.
Mills, P.R., Robert, J., Davies, J. and Devalis, J.A. Airway epithelial cells, cytokines, and pollutants. Am. J. Respir. Cirt. Care Med. 160, 38-43, 1993.
Miyabara, Y., Yanagisawa, R., Shimojo, N., Takano, H., Lim, H.B., Ichinose, T., and Sagai, M. Murine strain differences in airway inflammation caused by diesel exhaust particles. Eur. Respir. J. 11, 291-298, 1998.
Montefort, S., Herbert, C.A., Robinson, C., and Holgate, S.T. The bronchial epithelial as a target for inflammatory attack in asthma. Clip. Exp. Allergy 22, 511-520,1992.
NIOSH. National Occupational Research Agenda. U. S. Department of Health and Human Services, Cincinnati. DHHS Pub No.96-115., 1996.
Park, B. K., Naisbitt, D.J., Gordon, S.F., Kitteringham, N.R., and Pirmohamed, M. Metabolic activation in drug allergies. Toxicology 158, 11—23, 2001.
Pauluhn, J., Petra, E., and Ulrich M. Respiratory hypersensitivity in guinea pigs sensitized to 1,6-hexamethylene diisocyanate (HDI): comparison of results obtained with the monomer and homopolymers of HDI. Toxicology 171, 147—160, 2002.
Platts-Mills, T.A.E., and Carter, M.C. Asthma and indoor exposure to allergens. N. Eng. J. Med. 336, 1382—1384, 1997.
Plaut, M., Pierce, J.H., Watson, C.J., Hanley, H.J., Nordan, R. P., and Paul, W. E. Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI to calcium ionophores. Nature (Lond.) 339, 64-67, 1989.
Poulsen, L. K., Susanne, K. C., and Jinquan, T. Detergents in the indoor environment — what is the evidence for an allergy promoting effect? Known and postulated mechanisms Toxicology 152, 79—85, 2000.
Rajeev V., Maggie L., Madeleine W., Gabriele G., David B. C., and David J. E. The Th2 Lymphocyte Products IL-4 and IL-13 Rapidly Induce Airway Hyperresponsiveness Through Direct Effects on Resident Airway Cells. Am. J. Respir. Cell Mol. Biol. 26, 202-208, 2002.
Rattray, N.J., Botham, P.A., Hext, P.M., Woodcock, D.R., Fielding, I., Dearman, R.J., and Kimber, I. Induction of respiratory hypersensitivity to diphenylmethane-4,4_-diisocyanate (MDI) in guinea pigs. Influence of route of exposure. Toxicology 88, 15—30, 1994.
Riffo-Vasques, Y., Pitchford, S., and Spina, D. Murine models of inflammation: role of CD23. Allergy 55, 21-26, 2000.
Robinson, M. K. and Cruze, C. A. Preclinical skin sensitization resiong of antigistamines. Guinea pig and local lymph node assay responses. Fd. Chem. Toxicol. 34, 495-506, 1996.
Schanker, H.M., Rachelefsky, G., Siegel, S., Kats R., Spector, S., Rohr, A., Rodriquiz, C., Woloshin, K. and Papanek, P. J. Immediately and delayed type hypersensitivity to malathion. Ann. Allergy 69, 526-528, 1992.
Senthilselvan, A., Helen, H., and Dosman, A. Association of asthma with use of pesticides. Am. Rev. Respi. Dis.146, 884-887, 1992.
Sharma, R.P. and Reddy, R.V. Toxic effects of chemicals on the immune system. In: Haley, T.J., Berndt, W.O. (Eds.), Handbook of Toxicology. Hemisphere Publishing Corp., Philadelphia, pp. 555—591, 1987.
Shishikura, T., Yamada, M., Oguro, K., Tamaki, N., and Kosugi, T. Induction of airway hyperresponsiveness in allergic rats. Int. J. Tiss. Reac. 12, 341-346, 1990.
Swain, S.L., Weinberg, A.D., English, M., and Huston, G. IL-4 directs the development of Th2-like helper effectors. J. Immunol. 145, 3796—3806, 1990.
Takahiko, S., Masato, T., Hisamitsu, N., and Niikawa, M. Augmentation of allergic reactions by several pesticides. Toxicology 126, 41—53, 1998.
Van Oosterhaut, A.J.M., van Ark, I., Hofman, G., Van Der Linde, H.J., Fattah, D., and Nijkamp, F.P. Role of interleukin-5 and substance P in development of airway hyperreactivity to histamine in guinea-pigs. Eur. Respir. J. 9, 493—499, 1996.
Vohr, H. W., Pauluhn, J., and Ahr, H. J. Respiratory hypersensitivity to trimellitic anhydride in brown Norway rats: evidence for different activation pattern of immune cells following topical and respiratory induction. Arch. Toxicol. 76, 538-544, 2002.
Wardlaw, A.J., Dunnette, S., Gleich, G.J., Collins, J.V., and Kay, A.B. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma: relationship to bronchial hyperreactivity. Am. Rev. Respir. Dis. 137, 62—69, 1988.
Wasserman, S. and D.L. Marquardt. Anaphylaxis. In Allergy: Principles and Practice. E. Middleton, Jr., C.E. Reed, E.F. Ellis, N.F. Adkinson, Jr., and J.W. Yuninger eds. 2nd ed. Mosby, St. Louis. pp. 1365-1376, 1988.
Wax, P. M. and Hoffman, R.S. Fatality associated with inhalation of a pyrethrin shapoo. Clin. Toxicol. 32, 457-460, 1994.
Weiner A. Bronchial asthma due to organic phosphate insecticide. Ann. Allergy 19, 397-401, 1961.
Weller, P.F. The immunology of eosinophils. N. Engl. J. Med. 324, 1110—1118, 1991.
Wenzel, S.E., Szefler, S.J., Leung, D.Y., Sloan, S.I., Rex, M.D. and Martin, R.J. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am. J. Respir. Crit. Care Med. 156, 737—743, 1997.
Wills-Karp, M. Immunologic basis of antigen-induced aitway hyperresponsiveness. Annu. Rev. Immunol. 17, 255-, 1999.