Skip to main content

Advertisement

SpringerLink
Log in

The cytotoxicity of jet fuel aromatic hydrocarbons and dose-related interleukin-8 release from human epidermal keratinocytes

  • Molecular Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Many jet fuel aromatic hydrocarbons are known carcinogens with the ability to both readily penetrate the skin with high absorptive flux and cause skin irritation. In order to evaluate the in vitro cutaneous toxicity of individual aromatic hydrocarbons in jet fuels and their potential for inducing skin irritation, we evaluated the LD50, the highest non-cytotoxic (5% mortality) dose (HNTD), and interleukin-8 (IL-8) release activity of nine major jet fuel aromatic hydrocarbons in human epidermal keratinocytes (HEK). LD50 ranged from 1.8 mM (0.03%) for cyclohexylbenzene to 82.9 mM (0.74%) for benzene, with a rank order potency of cyclohexylbenzene >trimethylbenzene ≥xylene >dimethylnaphthalene >ethylbenzene >toluene >benzene. The HNTD values ranged from 0.1 mM (0.001%) for cyclohexylbenzene to 48.2 mM (0.43%) for benzene. Naphthalene and methylnaphthalene could not be ranked in this comparison since their concentrations, presented as percentage saturation, were not comparable to the others presented as solutes in solution. There was a dose-related differential response in IL-8 release at 24 h. Toluene, xylene, trimethylbenzene, cyclohexylbenzene and dimethylnaphthalene significantly decreased IL-8 release at the respective HNTDs, while IL-8 release did not continue to decrease, or significantly increased (cyclohexylbenzene and dimethylnaphthalene), at the LD50. IL-8 significantly increased with both doses of methylnaphthalene and naphthalene. The presence of hexadecane and mineral oil greatly attenuated the cytotoxicity elicited by individual aromatic hydrocarbons in HEK cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2A, B.
Fig. 3.
Fig. 4.
Fig. 5.

Similar content being viewed by others

References

  • Abraham NG (1996) Hematopoietic effects of benzene inhalation assessed by long-term bone marrow culture. Environ Health Perspect 104 [Suppl 6]:1277–1282

  • Aggarwal BB, Puri KJ (1995) Common and uncommon features of cytokines and cytokine receptors: an overview. In: Aggarwal BB, Puri K J (eds) Human cytokines: their role in disease and therapy. Blackwell, Oxford, pp 1–24

  • Allen DG, Riviere JE, Monteiro-Riviere NA (2000) Identification of early biomarkers of inflammation produced by keratinocytes exposed to jet fuels jet A, JP-8, and JP-8(100). J Biochem Mol Toxicol 14:231–237

    Article  CAS  PubMed  Google Scholar 

  • Allen DG, Riviere JE, Monteiro-Riviere NA (2001a) Analysis of interleukin-8 release from normal human epidermal keratinocytes exposed to aliphatic hydrocarbons: delivery of hydrocarbons to cell cultures via complexation with α-cyclodextrin. Toxicol In Vitro 15:663–669

    Article  CAS  PubMed  Google Scholar 

  • Allen DG, Riviere JE, Monteiro-Riviere NA (2001b) Cytokine induction as a measure of cutaneous toxicity in primary and immortalized porcine keratinocytes exposed to jet fuels, and their relationship to normal human epidermal keratinocytes. Toxicol Lett 119:209–217

    Article  CAS  PubMed  Google Scholar 

  • Andrew PJ, Harant H, Lindley IJ (1999) Up-regulation of interleukin-1-β-stimulated interleukin-8 in human keratinocytes by nitric oxide. Biochem Pharmacol 57:1423–1429

    Article  CAS  PubMed  Google Scholar 

  • Barry BW, Harrison SM, Dugard PH (1985) Vapour and liquid diffusion of model penetrants through human skin; correlation with thermodynamic activity. J Pharm Pharmacol 37:226–236

    CAS  PubMed  Google Scholar 

  • Baynes RE, Brooks JD, Riviere JE (2000) Membrane transport of naphthalene and dodecane in jet fuel mixtures. Toxicol Ind Health 16:225–238

    CAS  Google Scholar 

  • Baynes RE, Brooks JD, Budsab K, Smith CE, Riviere JE (2001) Mixture effects of JP-8 additives on the dermal disposition of jet fuel components. Toxicol Appl Pharmacol 175:269–281

    Article  CAS  PubMed  Google Scholar 

  • Boman AS (1996) Irritants—organic solvents. In: van der Valk PGM, Maibach HI (eds) The irritant contact dermatitis syndrome. CRC Press, Boca Raton FL, pp 95–104

  • Borenfreund E, Puerner JA (1985) Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxocol Lett 24:119–124

    Article  CAS  Google Scholar 

  • Brandt HC, Booth ED, de Groot PC, Watson WP (1999) Development of a carcinogenic potency index for dermal exposure to viscous oil products. Arch Toxicol 73:180–188

    CAS  PubMed  Google Scholar 

  • Broddle WD, Dennis MW, Kitchen DN, Vernot EH (1996) Chronic dermal studies of petroleum steams in mice. Fundam Appl Toxicol 30:47–54

    Article  CAS  PubMed  Google Scholar 

  • Brooke I, Cocker J, Delic JI, Payne M, Jones K, Gregg NC, Dyne D (1998) Dermal uptake of solvents from the vapour phase: an experimental study in humans. Ann Occup Hyg 42:531–540

    CAS  PubMed  Google Scholar 

  • Chou CC, Riviere JE, Monteiro-Riviere NA (2002) Differential relationship between the carbon chain-length of jet fuel aliphatic hydrocarbons and their ability to induce cytotoxicity versus interleukin-8 release in human epidermal keratinocytes. Toxicol Sci 69:226–233

    Article  CAS  PubMed  Google Scholar 

  • Committee on Toxicology (1996) Permissible exposure levels for selected military fuel vapors. National Academy Press, Washington DC

  • Corsini E, Galli CL (1998) Cytokines and irritant contact dermatitis. Toxicol Lett 102–103:277–282

    Google Scholar 

  • Corsini E, Galli CL (2000) Epidermal cytokines in experimental contact dermatitis. Toxicology 142:203–212

    Article  CAS  PubMed  Google Scholar 

  • Dahl AR, Damon EG, Mauderly JL, Rothenberg SJ, Seiler FA, McClellan RO (1988) Uptake of 19 hydrocarbon vapors inhaled by F344 rats. Fundam Appl Toxicol 10:262–269

    CAS  PubMed  Google Scholar 

  • Dearman RJ, Kimber I (1999) Cytokine fingerprinting: characterization of chemical allergens. Methods 19:56–63

    Article  CAS  PubMed  Google Scholar 

  • Dudley AC, Peden-Adams MM, EuDaly J, Pollenz RS, Keil DE (2001) An aryl hydrocarbon receptor independent mechanism of JP-8 jet fuel immunotoxicity in Ah-responsive and Ah-nonresponsive mice. Toxicol Sci 59:251–259

    Article  CAS  PubMed  Google Scholar 

  • Effendy I, Loffler H, Maibach HI (2000) Epidermal cytokines in murine cutaneous irritant responses. J Appl Toxicol 20:335–341

    Article  CAS  PubMed  Google Scholar 

  • Freeman JJ, Federici TM, McKee RH (1993) Evaluation of the contribution of chronic skin irritation and selected compositional parameters to the tumorigenicity of petroleum middle distillates in mouse skin. Toxicology 81:103–112

    Article  CAS  PubMed  Google Scholar 

  • Grant GM, Shaffer KM, Kao WY, Stenger DA, Pancrazio JJ (2000) Investigation of in vitro toxicity of jet fuels JP-8 and jet A. Drug Chem Toxicol 23:279–291

    Article  CAS  PubMed  Google Scholar 

  • Harris DT, Sakiestewa D, Robledo RF, Witten M (1997) Immunotoxicological effects of JP-8 jet fuel exposure. Toxicol Ind Health 13:43–55

    CAS  PubMed  Google Scholar 

  • Hood RD, Ottley MS (1985) Developmental effects associated with exposure to xylene: a review. Drug Chem Toxicol 8:281–297

    CAS  PubMed  Google Scholar 

  • Ingram AJ, Phillips JC, Davies S (2000) DNA adducts produced by oils, oil fractions and polycyclic aromatic hydrocarbons in relation to repair processes and skin carcinogenesis. J Appl Toxicol 20:165–174

    Article  CAS  PubMed  Google Scholar 

  • Jepson GW, McDougal JN (1997) Physiologically based modeling of nonsteady state dermal absorption of halogenated methanes from and aqueous solution. Toxicol Appl Pharmacol 144:315–324

    Article  CAS  PubMed  Google Scholar 

  • Kabbur MB, Rogers JV, Gunasekar PG, Garrett CM, Geiss KT, Brinkley WW, McDougal JN (2001) Effect of JP-8 jet fuel on molecular and histological parameters related to acute skin irritation. Toxicol Appl Pharmacol 175:83–88

    Article  CAS  PubMed  Google Scholar 

  • Kalnas J, Teitelbaum DT (2000) Dermal absorption of benzene: implications for work practices and regulations. Int J Occup Environ Health 6:114–121

    CAS  PubMed  Google Scholar 

  • Kezic S, Monster AC, van de Gevel IA, Kruse J, Opdam JJ, Verberk MM (2001) Dermal absorption of neat liquid solvents on brief exposures in volunteers. Am Ind Hyg Assoc J 62:12–18

    CAS  Google Scholar 

  • Larsen CG, Anderson AO, Oppenheim JJ, Matsushima K (1989) Production of interleukin-8 by human dermal fibroblasts and keratinocytes in response to interleukin-1 or tumour necrosis factor. Immunology 68:31–36

    CAS  PubMed  Google Scholar 

  • Lindl T, Bauer J (1989) Zell- und Gewebekultur: Einfuhrung in die grundlagen sowie ausgehalte methoden und andwendungen, 2nd edn. Fischer, Stuttgart

  • McDougal JN, Pollard DL, Weisman W, Garrett CM, Miller TE (2000) Assessment of skin absorption and penetration of JP-8 jet fuel and its components. Toxicol Sci 55:247–255

    CAS  PubMed  Google Scholar 

  • Monteiro-Riviere NA, Inman AO, Riviere JE (2001) Effects of short-term high-dose and low-dose dermal exposure to jet A, JP-8 and JP-8+100 jet fuels. J Appl Toxicol 21:485–494

    Article  CAS  PubMed  Google Scholar 

  • Nickoloff BJ, Karabin GD, Barker JNWN, Griffiths CEM, Sarma V, Mitra RS, Elder JT, Kunkel SL, Dixit VM (1991) Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-α, in psoriasis. Am J Pathol 138:129–140

    CAS  PubMed  Google Scholar 

  • O'Connor SR, Farmer PB, Lauder I (1999) Benzene and non-Hodgkin's lymphoma. J Pathol 189:448–453

    Article  CAS  PubMed  Google Scholar 

  • Ott RL (1993) An introduction to statistical methods and data analysis, 4th edn. Duxbury Press, Belmont CA, pp 825–831

  • Rhyne BN, Pirone JR, Riviere JE, Monteiro-Riviere NA (2002) The use of enzyme histochemistry in detecting cutaneous toxicity of three topically applied jet fuel mixtures. Toxicol Mech Methods 12:17–34

    Article  CAS  Google Scholar 

  • Ritchie GD, Still KR, Alexander WK, Nordholm AF, Wilson CL, Rossi J, Mattie DR (2001) A review of the neurotoxicity risk of selected hydrocarbon fuels. J. Toxicol Environ Health B Crit Rev 4:223–312

    Article  CAS  Google Scholar 

  • Riviere JE, Brooks JD, Monteiro-Riviere NA, Budsaba K, Smith CE (1999) Dermal absorption and distribution of topically dosed jet fuels Jet-A, JP-8, and JP-8 (100) Toxicol Appl Pharmacol 160:60–75

    Article  Google Scholar 

  • Riviere JE, Qiao G, Baynes RE, Brooks JD, Mumtaz M (2001) Mixture component effects on the in vitro dermal absorption of pentachlorophenol. Arch Toxicol 75:329–334

    Article  CAS  PubMed  Google Scholar 

  • Rogers JV, Gunasekar PG, Garrett CM, McDougal JN (2001) Dermal exposure to m-xylene leads to increasing oxidative species and low molecular weight DNA levels in rat skin. J Biochem Mol Toxicol 15:228–230

    Article  CAS  PubMed  Google Scholar 

  • Seifert M, Sterry W, Effenberger E, Rexin A, Friedrich M, Haeussler-Quade A, Dieter Volk H and Asadullah K (2000) The antipsoriatic activity of IL-10 is rather caused by effects on peripheral blood cells than by a direct effect on human keratinocytes. Arch Dermatol Res 292:164–172

    CAS  PubMed  Google Scholar 

  • Tolbert PE (1997) Oils and cancer. Cancer Causes Control 8:386–405

    Article  CAS  PubMed  Google Scholar 

  • Ullrich SE (1999) Dermal application of JP-8 jet fuel induces immune suppression. Toxicol Sci 52:61-67

    CAS  Google Scholar 

  • Wade LG Jr (1995) Aromatic compounds. In: Wade LG Jr (ed) Organic chemistry. Prentice-Hall, Englewood Cliffs NJ, pp 696

  • Wester RC, Maibach HI (2000) Benzene percutaneous absorption: dermal exposure relative to other benzene sources. Int J Occup Environ Health 6:122–126

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the US Air Force Office of Scientific Research F49620-01-1-0080. The authors wish to thank Alfred Inman and Lauren Gast for their technical assistance.

Author information

Author notes

  1. C. C. Chou

    Present address: National Chung-Hsing University, Taichung, Taiwan

Authors and Affiliations

  1. Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA

    C. C. Chou, J. E. Riviere & N. A. Monteiro-Riviere

Authors
  1. C. C. Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. E. Riviere
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. A. Monteiro-Riviere
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. A. Monteiro-Riviere.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chou, C.C., Riviere, J.E. & Monteiro-Riviere, N.A. The cytotoxicity of jet fuel aromatic hydrocarbons and dose-related interleukin-8 release from human epidermal keratinocytes. Arch Toxicol 77, 384–391 (2003). https://doi.org/10.1007/s00204-003-0461-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-003-0461-z

Keywords

Search

Navigation