Promises and Risks of Unsaturated Volatile Organic Compounds: Limonene, Pinene, and Isoprene

  • Jin, Kyong-Suk (Food Science Institute, School of Food and Life Science, College of Biomedical Science and Engineering, Inje University) ;
  • Jun, Mi-Ra (Division of Food Science, Dong-A University) ;
  • Park, Min-Ji (Food Science Institute, School of Food and Life Science, College of Biomedical Science and Engineering, Inje University) ;
  • Ok, Seon (Food Science Institute, School of Food and Life Science, College of Biomedical Science and Engineering, Inje University) ;
  • Jeong, Jae-Han (Food Science Institute, School of Food and Life Science, College of Biomedical Science and Engineering, Inje University) ;
  • Kang, Hye-Sook (Food Science Institute, School of Food and Life Science, College of Biomedical Science and Engineering, Inje University) ;
  • Jo, Wan-Keun (Department of Environmental Engineering, Kyungpook National University) ;
  • Lim, Ho-Jin (Department of Environmental Engineering, Kyungpook National University) ;
  • Jeong, Woo-Sik (Food Science Institute, School of Food and Life Science, College of Biomedical Science and Engineering, Inje University)
  • Published : 2008.06.30

Abstract

Limonene, pinene, and isoprene are abundant and ubiquitous volatile organic compounds (VOCs) which are found in various natural products and also produced from various manufacture processes. Limonene and pinene are major components of food additives and household products for enrichment of good flavors and elimination of malodors, and isoprene is a basal motif of monoterpenes such as limonene and pinene. They have shown many beneficial effects such as chemopreventive, chemotherapeutic, and antioxidant activities. Upon certain conditions, however, adverse effects of these compounds on human health have also been reported. Although they do not seem to have acute and severe toxicity to human, they can easily generate secondary organic aerosols (SOAs) when they react with oxygen and/or ozone, which have shown certain toxic effects on experimental animal models as well as on humans. Numerous household and scented products containing limonene, pinene, and isoprene are widely used in these days. However, biological consequences upon exposure to these products are largely unknown. The aim of this review is to summarize and analyze the current understanding on the biological effects of VOCs, in particular limonene, pinene, and isoprene, as well as their SOAs.

Keywords

References

  1. McGarvey DJ, Croteau R. Terpenoid metabolism. Plant Cell 7: 1015-1026 (1995) https://doi.org/10.1105/tpc.7.7.1015
  2. Wagner KH, Elmadfa I. Biological relevance of terpenoids. Overview focusing on mono-, di-, and tetraterpenes. Ann. Nutr. Metab. 47: 95- 106 (2003) https://doi.org/10.1159/000070030
  3. Bell SG, Chen X, Sowden RJ, Xu F, Williams JN, Wong LL, Rao Z. Molecular recognition in (+)-alpha-pinene oxidation by cytochrome P450cam. J. Am. Chem. Soc. 125: 705-714 (2003) https://doi.org/10.1021/ja028460a
  4. Jun M, Jeong WS, Ho CT. Health promoting properties of natural flavor substances. Food Sci. Biotechnol. 15: 329-338 (2006)
  5. Choi H. Headspace analysis of Robus coreanus berry by solid-phase microextraction and its sniffing test by gas chromatopgaphy-olfactometry. Food Sci. Biotechnol. 11: 355-360 (2002)
  6. Choi H, Kim M, Sawamura M. Constituents of the essential oil of Angelica tenuissima, an aromatic medicinal plant. Food Sci. Biotechnol. 10: 557-561 (2001)
  7. Choi H, Sawamura M. Compositions of Citrus tamurana Hort. Ex Tanaka (Hyuganatsu) cold-pressed oil in different sized fruit. Food Sci. Biotechnol. 11: 71-77 (2002)
  8. Wijaya C, Hadiprodjo I, Apriyantono A. Identification of volatile compounds and key aroma compounds of andaliman fruit (Zanthoxylum acanthopodium DC). Food Sci. Biotechnol. 11: 680-683 (2002)
  9. Choi SI, Chang KM, Lee YS, Kim GH. Antibacterial activity of essential oils from Zanthoxylum piperitum A.P. DC. and Zanthoxylum schinifolium. Food Sci. Biotechnol. 17: 195-198 (2008)
  10. Kwon KD, Jo WK, Lim HJ, Jeong WS. Characterization of emissions composition for selected household products available in Korea. J. Hazard Mater. 148: 192-198 (2007) https://doi.org/10.1016/j.jhazmat.2007.02.025
  11. Marostica M, Mota N, Baudet N, Pastore G. Fungal biotransformation of monoterpenes found in agro-industrial residues from orange and pulp industires into aroma compounds: Screening using solid phase microextraction. Food Sci. Biotechnol. 16: 37-42 (2007)
  12. Rastogi SC, Heydorn S, Johansen JD, Basketter DA. Fragrance chemicals in domestic and occupational products. Contact Dermatitis 45: 221-225 (2001) https://doi.org/10.1034/j.1600-0536.2001.450406.x
  13. Cailleux A, Cogny M, Allain P. Blood isoprene concentrations in humans and in some animal species. Biochem. Med. Metab. B. 47: 157-160 (1992) https://doi.org/10.1016/0885-4505(92)90019-U
  14. Kuzma J, Nemecek-Marshall M, Pollock WH, Fall R. Bacteria produce the volatile hydrocarbon isoprene. Curr. Microbiol. 30: 97- 103 (1995) https://doi.org/10.1007/BF00294190
  15. Sharkey TD. Isoprene synthesis by plants and animals. Endeavour 20: 74-78 (1996) https://doi.org/10.1016/0160-9327(96)10014-4
  16. Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J. Nutr. 129: 775S-778S (1999) https://doi.org/10.1093/jn/129.3.775S
  17. Loreto F, Mannozzi M, Maris C, Nascetti P, Ferranti F, Pasqualini S. Ozone quenching properties of isoprene and its antioxidant role in leaves. Plant Physiol. 126: 993-1000 (2001) https://doi.org/10.1104/pp.126.3.993
  18. DeWitt C, Bebarta V. Botanical solvents. Clin. Occup. Environ. Med. 4: 445-454, v-vi (2004) https://doi.org/10.1016/j.coem.2004.03.003
  19. Falk-Filipsson A, Lof A, Hagberg M, Hjelm EW, Wang Z. d- Limonene exposure to humans by inhalation: Uptake, distribution, elimination, and effects on the pulmonary function. J. Toxicol. Env. Health 38: 77-88 (1993) https://doi.org/10.1080/15287399309531702
  20. Nielsen GD, Larsen ST, Hougaard KS, Hammer M, Wolkoff P, Clausen PA, Wilkins CK, Alarie Y. Mechanisms of acute inhalation effects of (+) and (-)-alpha-pinene in BALB/c mice. Basic Clin. Pharmacol. Toxicol. 96: 420-428 (2005) https://doi.org/10.1111/j.1742-7843.2005.pto_96604.x
  21. Peter H, Wiegand HJ, Filser JG, Bolt HM, Laib RJ. Inhalation pharmacokinetics of isoprene in rats and mice. Environ. Health Persp. 86: 89-92 (1990) https://doi.org/10.2307/3430938
  22. Taalman RD. Isoprene: Background and issues. Toxicology 113: 242-246 (1996) https://doi.org/10.1016/0300-483X(96)03452-X
  23. Matura M, Skold M, Borje A, Andersen KE, Bruze M, Frosch P, Goossens A, Johansen JD, Svedman C, White IR, Karlberg AT. Not only oxidized R-(+)- but also S-(-)-limonene is a common cause of contact allergy in dermatitis patients in Europe. Contact Dermatitis 55: 274-279 (2006) https://doi.org/10.1111/j.1600-0536.2006.00939.x
  24. Sunil VR, Laumbach RJ, Patel KJ, Turpin BJ, Lim HJ, Kipen HM, Laskin JD, Laskin DL. Pulmonary effects of inhaled limonene ozone reaction products in elderly rats. Toxicol. Appl. Pharm. 222: 211-220 (2007) https://doi.org/10.1016/j.taap.2007.05.003
  25. Surratt JD, Lewandowski M, Offenberg JH, Jaoui M, Kleindienst TE, Edney EO, Seinfeld JH. Effect of acidity on secondary organic aerosol formation from isoprene. Environ. Sci. Technol. 41: 5363- 5369 (2007) https://doi.org/10.1021/es0704176
  26. Loza-Tavera H. Monoterpenes in essential oils. Biosynthesis and properties. Adv. Exp. Med. Biol. 464: 49-62 (1999)
  27. Crowell PL, Gould MN. Chemoprevention and therapy of cancer by d-limonene. Crit. Rev. Oncogenesis 5: 1-22 (1994) https://doi.org/10.1615/CritRevOncog.v5.i1.10
  28. Choi H, Min K. Headspace-SPME analysis of citrus hybrid, Hallabong. Food Sci. Biotechnol. 13: 126-129 (2004)
  29. Lee H, Pai T. Chracteristics of cell growth and essential oil accumulation in spearmint cell suspension culture. Food Sci. Biotechnol. 6: 190-192 (1997)
  30. Duetz WA, Bouwmeester H, van Beilen JB, Witholt B. Biotransformation of limonene by bacteria, fungi, yeasts, and plants. Appl. Microbiol. Biot. 61: 269-277 (2003) https://doi.org/10.1007/s00253-003-1221-y
  31. Ishida T. Biotransformation of terpenoids by mammals, microorganisms, and plant-cultured cells. Chem. Biodivers. 2: 569-590 (2005) https://doi.org/10.1002/cbdv.200590038
  32. Al-Saidan SM, Krishnaiah YS, Chandrasekhar DV, Lalla JK, Rama B, Jayaram B, Bhaskar P. Formulation of an HPMC gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing in vitro transdermal delivery of nicorandil. Skin Pharmacol. Physi. 17: 310- 320 (2004) https://doi.org/10.1159/000081117
  33. Phillips MA, Savage TJ, Croteau R. Monoterpene synthases of loblolly pine (Pinus taeda) produce pinene isomers and enantiomers. Arch. Biochem. Biophys. 372: 197-204 (1999) https://doi.org/10.1006/abbi.1999.1467
  34. Lee S, Kim M, Lee S, Ahn Y, Lee H. Inhibitory effects of Cinnamomun cassia bark-derived materials on mushroom tyrosinase. Food Sci. Biotechnol. 9: 330-333 (2000)
  35. Jin Y, Guo L, Veiga MC, Kennes C. Fungal biofiltration of alphapinene: Effects of temperature, relative humidity, and transient loads. Biotechnol. Bioeng. 96: 433-443 (2007) https://doi.org/10.1002/bit.21123
  36. Croteau R, Satterwhite DM, Wheeler CJ, Felton NM. Biosynthesis of monoterpenes. Stereochemistry of the enzymatic cyclizations of geranyl pyrophosphate to (+)-alpha-pinene and (-)-beta-pinene. J. Biol. Chem. 264: 2075-2080 (1989)
  37. Liapi C, Anifantis G, Chinou I, Kourounakis AP, Theodosopoulos S, Galanopoulou P. Antinociceptive properties of 1,8-cineole and betapinene, from the essential oil of Eucalyptus camaldulensis leaves, in rodents. Planta Med. 73: 1247-1254 (2007) https://doi.org/10.1055/s-2007-990224
  38. Stone BG, Besse TJ, Duane WC, Evans CD, DeMaster EG. Effect of regulating cholesterol biosynthesis on breath isoprene excretion in men. Lipids 28: 705-708 (1993) https://doi.org/10.1007/BF02535990
  39. Cailleux A, Moreau X, Delhumeau A, Allain P. Decrease of isoprene concentrations in blood during general anesthesia. Biochem. Med. Metab. B. 49: 321-325 (1993) https://doi.org/10.1006/bmmb.1993.1033
  40. Mukhopadhyay R. Measuring isoprene in breath. Anal. Chem. 79: 2610 (2007) https://doi.org/10.1021/ac071898e
  41. Singh AP, Varshney CK, Singh UK. Seasonal variations in isoprene emission from tropical deciduous tree species. Environ. Monit. Assess. 131: 231-235 (2007) https://doi.org/10.1007/s10661-006-9471-7
  42. Hollingsworth RG. Limonene, a citrus extract, for control of mealybugs and scale insects. J. Econ. Entomol. 98: 772-779 (2005) https://doi.org/10.1603/0022-0493-98.3.772
  43. Lavoue J, Begin D, Geerin M. Technical, occupational health, and environmental aspects of metal degreasing with aqueous cleaners. Ann. Occup. Hyg. 47: 441-459 (2003) https://doi.org/10.1093/annhyg/meg057
  44. Evans DL, Miller DM, Jacobsen KL, Bush PB. Modulation of immune responses in mice by d-limonene. J. Toxicol. Environ. Health 20: 51-66 (1987) https://doi.org/10.1080/15287398709530961
  45. Lim PF, Liu XY, Kang L, Ho PC, Chan YW, Chan SY. Limonene GP1/PG organogel as a vehicle in transdermal delivery of haloperidol. Int. J. Pharm. 311: 157-164 (2006) https://doi.org/10.1016/j.ijpharm.2005.12.042
  46. Krishnaiah YS, Satyanarayana V, Bhaskar P. Influence of limonene on the bioavailability of nicardipine hydrochloride from membranemoderated transdermal therapeutic systems in human volunteers. Int. J. Pharm. 247: 91-102 (2002) https://doi.org/10.1016/S0378-5173(02)00401-5
  47. Krishnaiah YS, Bhaskar P, Satyanarayana V. Formulation and evaluation of limonene-based membrane-moderated transdermal therapeutic system of nimodipine. Drug Deliv. 11: 1-9 (2004) https://doi.org/10.1080/10717540490280372
  48. Krishnaiah YS, Chandrasekhar DV, Rama B, Jayaram B, Satyanarayana V, Al-Saidan SM. In vivo evaluation of limonenebased transdermal therapeutic system of nicorandil in healthy human volunteers. Skin Pharmacol. Physiol. 18: 263-272 (2005) https://doi.org/10.1159/000087607
  49. Zhao K, Singh J. Mechanisms of percutaneous absorption of tamoxifen by terpenes: Eugenol, d-limonene, and menthone. J. Control Release 55: 253-260 (1998) https://doi.org/10.1016/S0168-3659(98)00053-4
  50. Ohara N, Takayama K, Nagai T. Combined effect of d-limonene pretreatment and temperature on the rat skin permeation of lipophilic and hydrophilic drugs. Biol. Pharm. Bull. 18: 439-442 (1995) https://doi.org/10.1248/bpb.18.439
  51. Okabe H, Takayama K, Ogura A, Nagai T. Effect of limonene and related compounds on the percutaneous absorption of indomethacin. Drug Des. Deliv. 4: 313-321 (1989)
  52. Koyama Y, Bando H, Yamashita F, Takakura Y, Sezaki H, Hashida M. Comparative analysis of percutaneous absorption enhancement by d-limonene and oleic acid based on a skin diffusion model. Pharm. Res. 11: 377-383 (1994) https://doi.org/10.1023/A:1018904802566
  53. Igimi H, Tamura R, Toraishi K, Yamamoto F, Kataoka A, Ikejiri Y, Hisatsugu T, Shimura H. Medical dissolution of gallstones. Clinical experience of d-limonene as a simple, safe, and effective solvent. Dig. Dis. Sci. 36: 200-208 (1991) https://doi.org/10.1007/BF01300757
  54. Whysner J, Williams GM. d-Limonene mechanistic data and risk assessment: Absolute species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion. Pharmacol. Therapeut. 71: 127- 136 (1996) https://doi.org/10.1016/0163-7258(96)00065-4
  55. Zhang CF, Yang ZL, Luo JB. Effects of enantiomer and isomer permeation enhancers on transdermal delivery of ligustrazine hydrochloride. Pharm. Dev. Technol. 11: 417-424 (2006) https://doi.org/10.1080/10837450600770163
  56. Crowell PL, Lin S, Vedejs E, Gould MN. Identification of metabolites of the antitumor agent d-limonene capable of inhibiting protein isoprenylation and cell growth. Cancer Chemoth. Pharm. 31: 205-212 (1992) https://doi.org/10.1007/BF00685549
  57. Rastogi SC, Lepoittevin JP, Johansen JD, Frosch PJ, Menne T, Bruze M, Dreier B, Andersen KE, White IR. Fragrances and other materials in deodorants: Search for potentially sensitizing molecules using combined GC-MS and structure activity relationship (SAR) analysis. Contact Dermatitis 39: 293-303 (1998) https://doi.org/10.1111/j.1600-0536.1998.tb05944.x
  58. IARC. Re-evaluation of some organic chemicals, hydrazine, and hydrogen peroxide. Pt 1, pp. 1-315. In: Proceedings of the Working Group on the Evaluation of Carcinogenic Risks to Humans. February 17-24, Lyon, France. International Agency for Research on Cancer, Lyon, France (1998)
  59. Leber AP. Overview of isoprene monomer and polyisoprene production processes. Chem. Biol. Interact 135-136: 169-173 (2001)
  60. Turner C, Spanel P, Smith D. A longitudinal study of breath isoprene in healthy volunteers using selected ion flow tube mass spectrometry (SIFT-MS). Physiol. Meas. 27: 13-22 (2006) https://doi.org/10.1088/0967-3334/27/1/002
  61. Salerno-Kennedy R, Cashman KD. Potential applications of breath isoprene as a biomarker in modern medicine: A concise overview. Wien. Klin. Wochenschr. 117: 180-186 (2005) https://doi.org/10.1007/s00508-005-0336-9
  62. McGrath LT, Patrick R, Silke B. Breath isoprene in patients with heart failure. Eur. J. Heart Fail. 3: 423-427 (2001) https://doi.org/10.1016/S1388-9842(01)00128-3
  63. Karl T, Prazeller P, Mayr D, Jordan A, Rieder J, Fall R, Lindinger W. Human breath isoprene and its relation to blood cholesterol levels: New measurements and modeling. J. Appl. Physiol. 91: 762- 770 (2001) https://doi.org/10.1152/jappl.2001.91.2.762
  64. Nelson N, Lagesson V, Nosratabadi AR, Ludvigsson J, Tagesson C. Exhaled isoprene and acetone in newborn infants and in children with diabetes mellitus. Pediatr. Res. 44: 363-367 (1998) https://doi.org/10.1203/00006450-199809000-00016
  65. Foster WM, Jiang L, Stetkiewicz PT, Risby TH. Breath isoprene: Temporal changes in respiratory output after exposure to ozone. J. Appl. Physiol. 80: 706-710 (1996) https://doi.org/10.1152/jappl.1996.80.2.706
  66. Lechner M, Moser B, Niederseer D, Karlseder A, Holzknecht B, Fuchs M, Colvin S, Tilg H, Rieder J. Gender and age specific differences in exhaled isoprene levels. Respir. Physiol. Neuro. 154: 478-483 (2006) https://doi.org/10.1016/j.resp.2006.01.007
  67. Lirk P, Bodrogi F, Raifer H, Greiner K, Ulmer H, Rieder J. Elective haemodialysis increases exhaled isoprene. Nephrol. Dial. Transpl. 18: 937-941 (2003) https://doi.org/10.1093/ndt/gfg049
  68. Diskin AM, Spanel P, Smith D. Time variation of ammonia, acetone, isoprene, and ethanol in breath: A quantitative SIFT-MS study over 30 days. Physiol. Meas. 24: 107-119 (2003) https://doi.org/10.1088/0967-3334/24/1/308
  69. Capodicasa E, Trovarelli G, Brunori F, Vecchi L, Carobi C, De M, Pelli MA, Buoncristiani U. Lack of isoprene overproduction during peritoneal dialysis. Perit. Dial. Int. 22: 48-52 (2002)
  70. Trovarelli G, Brunori F, De Medio GE, Timio M, Lippi G, Pelli MA, Capodicasa E. Onset, time course, and persistence of increased haemodialysis-induced breath isoprene emission. Nephron 88: 44- 47 (2001) https://doi.org/10.1159/000045958
  71. McGrath LT, Patrick R, Mallon P, Dowey L, Silke B, Norwood W, Elborn S. Breath isoprene during acute respiratory exacerbation in cystic fibrosis. Eur. Respir. J. 16: 1065-1069 (2000) https://doi.org/10.1034/j.1399-3003.2000.16f08.x
  72. Capodicasa E, Trovarelli G, De Medio GE, Pelli MA, Lippi G, Verdura C, Timio M. Volatile alkanes and increased concentrations of isoprene in exhaled air during hemodialysis. Nephron 82: 331- 337 (1999) https://doi.org/10.1159/000045448
  73. Chen J, Lu M, Jing Y, Dong J. The synthesis of L-carvone and limonene derivatives with increased antiproliferative effect and activation of ERK pathway in prostate cancer cells. Bioorg. Med. Chem. 14: 6539-6547 (2006) https://doi.org/10.1016/j.bmc.2006.06.013
  74. Crowell PL, Siar Ayoubi A, Burke YD. Antitumorigenic effects of limonene and perillyl alcohol against pancreatic and breast cancer. Adv. Exp. Med. Biol. 401: 131-136 (1996)
  75. Crowell PL, Chang RR, Ren ZB, Elson CE, Gould MN. Selective inhibition of isoprenylation of 21-26 kDa proteins by the anticarcinogen d-limonene and its metabolites. J. Biol. Chem. 266: 17679-17685 (1991)
  76. Ji J, Zhang L, Wu YY, Zhu XY, Lv SQ, Sun XZ. Induction of apoptosis by d-limonene is mediated by a caspase-dependent mitochondrial death pathway in human leukemia cells. Leuk. Lymphoma. 47: 2617-2624 (2006) https://doi.org/10.1080/00268970600909205
  77. Lu XG, Zhan LB, Feng BA, Qu MY, Yu LH, Xie JH. Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by d-limonene. World J. Gastroentero. 10: 2140-2144 (2004) https://doi.org/10.3748/wjg.v10.i14.2140
  78. Raphael TJ, Kuttan G. Effect of naturally occurring monoterpenes carvone, limonene, and perillic acid in the inhibition of experimental lung metastasis induced by B16F-10 melanoma cells. J. Exp. Clin. Canc. Res. 22: 419-424 (2003)
  79. Parija T, Das BR. Involvement of YY1 and its correlation with cmyc in NDEA induced hepatocarcinogenesis, its prevention by dlimonene. Mol. Biol. Rep. 30: 41-46 (2003) https://doi.org/10.1023/A:1022207630482
  80. Tsuda H, Ohshima Y, Nomoto H, Fujita K, Matsuda E, Iigo M, Takasuka N, Moore MA. Cancer prevention by natural compounds. Drug Metab. Pharmacokinet. 19: 245-263 (2004) https://doi.org/10.2133/dmpk.19.245
  81. Wei A, Shibamoto T. Antioxidant activities and volatile constituents of various essential oils. J. Agr. Food Chem. 55: 1737-1742 (2007) https://doi.org/10.1021/jf062959x
  82. Fraternale D, Giamperi L, Bucchini A, Ricci D. Essential oil composition and antioxidant activity of aerial parts of Grindelia robusta from central Italy. Fitoterapia 78: 443-445 (2007) https://doi.org/10.1016/j.fitote.2007.04.011
  83. Barra A, Coroneo V, Dessi S, Cabras P, Angioni A. Characterization of the volatile constituents in the essential oil of Pistacia lentiscus L. from different origins and its antifungal and antioxidant activity. J. Agr. Food Chem. 55: 7093-7098 (2007) https://doi.org/10.1021/jf071129w
  84. Akutsu H, Kikusui T, Takeuchi Y, Mori Y. Effects of alpha-pinene odor in different concentrations on stress-induced hyperthermia in rats. J. Vet. Med. Sci. 65: 1023-1025 (2003) https://doi.org/10.1292/jvms.65.1023
  85. Zhou JY, Tang FD, Mao GG, Bian RL. Effect of alpha-pinene on nuclear translocation of NF-kappa B in THP-1 cells. Acta Pharmacol. Sin. 25: 480-484 (2004)
  86. Loreto F, Velikova V. Isoprene produced by leaves protects the photosynthetic apparatus against ozone damage, quenches ozone products, and reduces lipid peroxidation of cellular membranes. Plant Physiol. 127: 1781-1787 (2001) https://doi.org/10.1104/pp.010497
  87. Singsaas EL, Lerdau M, Winter K, Sharkey TD. Isoprene increases thermotolerance of isoprene-emitting species. Plant Physiol. 115: 1413-1420 (1997) https://doi.org/10.1104/pp.115.4.1413
  88. Siwko ME, Marrink SJ, de Vries AH, Kozubek A, Schoot Uiterkamp AJ, Mark AE. Does isoprene protect plant membranes from thermal shock? A molecular dynamics study. Biochim. Biophys. Acta 1768: 198-206 (2007) https://doi.org/10.1016/j.bbamem.2006.09.023
  89. Logan BA, Monson RK, Potosnak MJ. Biochemistry and physiology of foliar isoprene production. Trends Plant Sci. 5: 477- 481 (2000) https://doi.org/10.1016/S1360-1385(00)01765-9
  90. Velikova V, Pinelli P, Pasqualini S, Reale L, Ferranti F, Loreto F. Isoprene decreases the concentration of nitric oxide in leaves exposed to elevated ozone. New Phytol. 166: 419-425 (2005) https://doi.org/10.1111/j.1469-8137.2005.01409.x
  91. Karlberg AT, Boman A, Melin B. Animal experiments on the allergenicity of d-limonene-the citrus solvent. Ann. Occup. Hyg. 35: 419-426 (1991) https://doi.org/10.1093/annhyg/35.4.419
  92. Larsen ST, Hougaard KS, Hammer M, Alarie Y, Wolkoff P, Clausen PA, Wilkins CK, Nielsen GD. Effects of R-(+)- and S-(-)-limonene on the respiratory tract in mice. Hum. Exp. Toxicol. 19: 457-466 (2000) https://doi.org/10.1191/096032700682694233
  93. Hard GC, Whysner J. Risk assessment of d-limonene: An example of male rat-specific renal tumorigens. Crit. Rev. Toxicol. 24: 231- 254 (1994) https://doi.org/10.3109/10408449409021607
  94. Wainman T, Zhang J, Weschler CJ, Lioy PJ. Ozone and limonene in indoor air: A source of submicron particle exposure. Environ. Health Persp. 108: 1139-1145 (2000) https://doi.org/10.1289/ehp.001081139
  95. Karlberg AT, Magnusson K, Nilsson U. Air oxidation of d-limonene (the citrus solvent) creates potent allergens. Contact Dermatitis 26: 332-340 (1992) https://doi.org/10.1111/j.1600-0536.1992.tb00129.x
  96. Li TH, Turpin BJ, Shields HC, Weschler CJ. Indoor hydrogen peroxide derived from ozone/d-limonene reactions. Environ. Sci. Technol. 36: 3295-3302 (2002) https://doi.org/10.1021/es015842s
  97. Kleno J, Wolkoff P. Changes in eye blink frequency as a measure of trigeminal stimulation by exposure to limonene oxidation products, isoprene oxidation products, and nitrate radicals. Int. Arch. Occ. Env. Hea. 77: 235-243 (2004) https://doi.org/10.1007/s00420-003-0502-1
  98. Nojgaard JK, Christensen KB, Wolkoff P. The effect on human eye blink frequency of exposure to limonene oxidation products and methacrolein. Toxicol. Lett. 156: 241-251 (2005) https://doi.org/10.1016/j.toxlet.2004.11.013
  99. Foti C, Zambonin CG, Conserva A, Casulli C, D'Accolti L, Angelini G. Occupational contact dermatitis to a limonene-based solvent in a histopathology technician. Contact Dermatitis 56: 109-112 (2007) https://doi.org/10.1111/j.1600-0536.2007.00995.x
  100. Wakelin SH, McFadden JP, Leonard JN, Rycroft RJ. Allergic contact dermatitis from d-limonene in a laboratory technician. Contact Dermatitis 38: 164-165 (1998)
  101. Karlberg AT, Dooms-Goossens A. Contact allergy to oxidized dlimonene among dermatitis patients. Contact Dermatitis 36: 201-206 (1997) https://doi.org/10.1111/j.1600-0536.1997.tb00270.x
  102. Topham EJ, Wakelin SH. d-Limonene contact dermatitis from hand cleansers. Contact Dermatitis 49: 108-109 (2003)
  103. Lee JA, Budgin JB, Mauldin EA. Acute necrotizing dermatitis and septicemia after application of a d-limonene-based insecticidal shampoo in a cat. J. Am. Vet. Med. Assoc. 221: 258-262, 239-240 (2002) https://doi.org/10.2460/javma.2002.221.258
  104. Singh HP, Batish DR, Kaur S, Arora K, Kohli RK. Alpha-pinene inhibits growth and induces oxidative stress in roots. Ann. Bot. - London 98: 1261-1269 (2006) https://doi.org/10.1093/aob/mcl213
  105. Kasanen JP, Pasanen AL, Pasanen P, Liesivuori J, Kosma VM, Alarie Y. Stereospecificity of the sensory irritation receptor for nonreactive chemicals illustrated by pinene enantiomers. Arch. Toxicol. 72: 514-523 (1998) https://doi.org/10.1007/s002040050536
  106. Rosenberg C, Liukkonen T, Kallas-Tarpila T, Ruonakangas A, Ranta R, Nurminen M, Welling I, Jappinen P. Monoterpene and wood dust exposures: Work-related symptoms among Finnish sawmill workers. Am. J. Ind. Med. 41: 38-53 (2002) https://doi.org/10.1002/ajim.10033
  107. Eriksson KA, Levin JO, Sandstrom T, Lindstrom-Espeling K, Linden G, Stjernberg NL. Terpene exposure and respiratory effects among workers in Swedish joinery shops. Scand. J. Work Env. Hea. 23: 114-120 (1997) https://doi.org/10.5271/sjweh.188
  108. Falk AA, Hagberg MT, Lof AE, Wigaeus-Hjelm EM, Wang ZP. Uptake, distribution, and elimination of alpha-pinene in man after exposure by inhalation. Scand. J. Work Env. Hea. 16: 372-378 (1990) https://doi.org/10.5271/sjweh.1771
  109. Pellizzari ED, Hartwell TD, Harris BS 3rd , Waddell RD, Whitaker DA, Erickson MD. Purgeable organic compounds in mother's milk. Bull. Environ. Contam. Tox. 28: 322-328 (1982) https://doi.org/10.1007/BF01608515
  110. Librando V, Tringali G. Atmospheric fate of OH initiated oxidation of terpenes. Reaction mechanism of alpha-pinene degradation and secondary organic aerosol formation. J. Environ. Manage. 75: 275- 282 (2005) https://doi.org/10.1016/j.jenvman.2005.01.001
  111. Stanier CO, Pathak RK, Pandis SN. Measurements of the volatility of aerosols from alpha-pinene ozonolysis. Environ. Sci. Technol. 41: 2756-2763 (2007) https://doi.org/10.1021/es0519280
  112. National Toxicology Program. Isoprene. Rep. Carcinog. 10: 141- 143 (2002)
  113. Lynch J. Occupational exposure to butadiene, isoprene, and chloroprene. Chem. Biol. Interact. 135-136: 207-214 (2001)
  114. Gervasi PG, Citti L, Del Monte M, Longo V, Benetti D. Mutagenicity and chemical reactivity of epoxidic intermediates of the isoprene metabolism and other structurally related compounds. Mutat. Res. 156: 77-82 (1985) https://doi.org/10.1016/0165-1218(85)90009-6
  115. National Toxicology Program. NTP toxicology and carcinogenesis studies of isoprene (CAS No. 78-79-5) in F344/N rats (inhalation studies). Natl. Toxicol. Program. Tech. Rep. Ser. 486: 1-176 (1999)
  116. Melnick R. NTP technical report on the toxicity studies of isoprene (CAS No. 78-79-5) administered by inhalation to F344/N rats and B6C3F1 mice. Toxic. Rep. Ser. 31: 1-G5 (1995)
  117. Peter H, Wiegand HJ, Bolt HM, Greim H, Walter G, Berg M, Filser JG. Pharmacokinetics of isoprene in mice and rats. Toxicol. Lett. 36: 9-14 (1987) https://doi.org/10.1016/0378-4274(87)90035-X
  118. Bond JA, Bechtold WE, Birnbaum LS, Dahl AR, Medinsky MA, Sun JD, Henderson RF. Disposition of inhaled isoprene in B6C3F1 mice. Toxicol. Appl. Pharmacol. 107: 494-503 (1991) https://doi.org/10.1016/0041-008X(91)90312-3
  119. Wilkins CK, Clausen PA, Wolkoff P, Larsen ST, Hammer M, Larsen K, Hansen V, Nielsen GD. Formation of strong airway irritants in mixtures of isoprene/ozone and isoprene/ozone/nitrogen dioxide. Environ. Health Perspect. 109: 937-941 (2001) https://doi.org/10.1289/ehp.01109937
  120. Rohr AC, Shore SA, Spengler JD. Repeated exposure to isoprene oxidation products causes enhanced respiratory tract effects in multiple murine strains. Inhal. Toxicol. 15: 1191-1207 (2003) https://doi.org/10.1080/08958370390229870
  121. Claeys M, Graham B, Vas G, Wang W, Vermeylen R, Pashynska V, Cafmeyer J, Guyon P, Andreae MO, Artaxo P, Maenhaut W. Formation of secondary organic aerosols through photooxidation of isoprene. Science 303: 1173-1176 (2004) https://doi.org/10.1126/science.1092805
  122. Doyle M, Sexton KG, Jeffries H, Bridge K, Jaspers I. Effects of 1,3-butadiene, isoprene, and their photochemical degradation products on human lung cells. Environ. Health Perspect. 112: 1488-1495 (2004) https://doi.org/10.1289/ehp.7022
  123. Grassmann J. Terpenoids as plant antioxidants. Vitam. Horm. 72: 505-535 (2005) https://doi.org/10.1016/S0083-6729(05)72015-X
  124. Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol. 71: 1397- 1421 (2006) https://doi.org/10.1016/j.bcp.2006.02.009
  125. Karlberg AT, Basketter D, Goossens A, Lepoittevin JP. Regulatory classification of substances oxidized to skin sensitizers on exposure to air. Contact Dermatitis 40: 183-188 (1999) https://doi.org/10.1111/j.1600-0536.1999.tb06030.x
  126. Windholz M, Budavari S, Stroumtsos LY, Fertig MN. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 9th ed. Merck & Co., Inc., Rahway, NJ, USA. p. 7248 (1976)
  127. Tamas G, Weschler CJ, Toftum J, Fanger PO. Influence of ozonelimonene reactions on perceived air quality. Indoor Air 16: 168- 178 (2006) https://doi.org/10.1111/j.1600-0668.2005.00413.x
  128. Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, Morozzi G. DNA-damaging ability of isoprene and isoprene mono-epoxide (EPOX I) in human cells evaluated with the comet assay. Mutat. Res. 629: 7-13 (2007) https://doi.org/10.1016/j.mrgentox.2006.12.007