Alternative Toxicity of Phthalates
Center for Medical Science, International University of Health and Welfare, Kitakanemaru, Ohtawara, Tochigi, Japan
- *Corresponding Author:
- Ken-ichiro Inoue, MD, PhD
Center for Medical Science
International University of Health and Welfare
2600-1, Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan
E-mail: [email protected]
Received date: May 23, 2013; Accepted date: May 27, 2013; Published date: May 30, 2013
Citation: Inoue Ki (2013) Alternative Toxicity of Phthalates. J Clin Toxicol 3:e118. doi: 10.4172/2161-0495.1000e118
Copyright: © 2013 Inoue Ki. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Journal of Clinical Toxicology
Phthalic acid ester plasticizers are widely used in flexible polyvinyl chloride products including vinyl flooring and wall covering, food containers, medical devices, and infant toys. Exposure of the general populations to phthalates is ubiquitous [1,2] and occurs due to the use and/or contact of above mentioned artificial structures. Previously, phthalates were reported to have toxic potential against liver , kidney [4,5], and lung [6-8]. Especially, liver toxicity of phthalates is widely implicated, since phthalates including DEHP are regulators of important transcriptional factors in homeostasis in the liver, i.e. Peroxisome Proliferator-Activated Receptors (PPARs) . As for carcinogenicity and/or mutagenicity, the human database includes researches that infer possible correlation between exposure to phthalates or other chemicals present in polyvinyl chloride-containing products and excess mortality from malignant tumors derived from pancreas [10,11], testicular , respiratory tract [13,14], and breast . On the other hand, the primary human health concern of exposure to phthalates is placed on earlier life exposures and associated risks of reproductive and developmental impacts, in particular in males . Nonetheless, there is a pitfall about their possible potential in toxicity.
The prevalence of allergic disorders has rapidly increased, in particular in developed countries throughout the past several decades  Alternation in environmental factors such as allergen load, infectious disease profile, vaccination, and the environmental adjuvants such as diesel engine-derived particles and so on, rather than genetic factors, is likely to be regarded as the cause of this increase [18,19]. Epidemiologically, environmental risk factors for immunotoxicity on allergy are, at least in part, attributable to environmental pollutants including endocrine disruptors. On the other hand, we and others have experimentally demonstrated that several environmental chemical components such as diesel engine-derived particles (diesel exhaust particles: DEP: they have vast numbers of chemicals around the particles) and nano-leveled particles exacerbate murine atopic allergy models including asthma and dermatitis ones [20-25].
Besides, recently, causal relationship between phthalate exposure and induction, increase, and/or exacerbation of allergic diseases including asthma, dermatitis, and eczema has been implicated, in particular in children [26,28]. Also, we have reported that di-(2- ethylhexyl) phthalate (DEHP), widely used [1.8 million metric tons/ year] among phthalates, potentiates atopic dermatitis-like skin lesions in NC/Nga mice . Further, reportedly, phthalates have been connected to autoimmune disorders such as systemic lupus erythematosus [28,30]. Also, Larsen et al. have shown that DEHP facilitates allergic asthma in BALB/c mice [31,32]. Our present study added the biological evidence that DEHP deteriorate allergen-related inflammation in ICR mice , which had been reported to correlate in epidemiological studies . Also, we provided evidence that this aggravation was concomitant with local production/release of inflammation- and allergy-related molecules such as IL-5, eotaxin, and KC.
In sum, phthaletes have potential to exacerbate allergic pathophysiology, whose adverse impact should list up as alternative toxicity of these chemicals. As well, toxicologists should expand investigation to other environmental chemicals.
- Wittassek M, Wiesmüller GA, Koch HM, Eckard R, Dobler L, et al. (2007) Internal phthalate exposure over the last two decades--a retrospective human biomonitoring study. Int J Hyg Environ Health 210: 319-333.
- Colacino JA, Harris TR, Schecter A (2010) Dietary intake is associated with phthalate body burden in a nationally representative sample. Environ Health Perspect 118: 998-1003.
- Selenskas S, Teta MJ, Vitale JN (1995) Pancreatic cancer among workers processing synthetic resins. Am J Ind Med 28: 385-398.
- Dell L, Teta MJ (1995) Mortality among workers at a plastics manufacturing and research and development facility: 1946-1988. Am J Ind Med 28: 373-384.
- Hardell L, Ohlson CG, Fredrikson M (1997) Occupational exposure to polyvinyl chloride as a risk factor for testicular cancer evaluated in a case-control study. Int J Cancer 73: 828-830.
- Hagmar L, Akesson B, Nielsen J, Andersson C, Linden K, et al. (1990) Mortality and cancer morbidity in workers exposed to low levels of vinyl chloride monomer at a polyvinyl chloride processing plant. American journal of industrial medicine 17: 553-565.
- Riboli E, Bai E, Berrino F, Merisi A (1983) Mortality from lung cancer in an acetylene and phthalic anhydride plant. A case-referent study. Scand J Work Environ Health 9: 455-462.
- Hineman EF, Olsen JH, Pottern LM, Gomez M, Raffn E, Blair A (1992) Occupational risk factors for multiple myeloma among Danish men. Cancer causes & control 3: 555-568.
- David RM, Moore MR, Finney Dc, Guest D (2000) Chronic toxicity of di(2-ethylhexyl)phthalate in mice. Toxicol Sci 58: 377-385.
- David RM, Moore MR, Finney DC, Guest D (2000) Chronic toxicity of di(2-ethylhexyl)phthalate in rats. Toxicol Sci 55: 433-443.
- Wilson VS, Blystone CR, Hotchkiss AK, Rider CV, Gray LE Jr (2008) Diverse mechanisms of anti-androgen action: impact on male rat reproductive tract development. Int J Androl 31: 178-187.
- Karle VA, Short BL, Martin GR, Bulas DI, Getson PR, et al. (1997) Extracorporeal membrane oxygenation exposes infants to the plasticizer, di(2-ethylhexyl)phthalate. Crit Care Med 25: 696-703.
- Ward JM, Peters JM, Perella CM, Gonzalez FJ (1998) Receptor and nonreceptor-mediated organ-specific toxicity of di(2-ethylhexyl)phthalate (DEHP) in peroxisome proliferator-activated receptor alpha-null mice. Toxicol Pathol 26: 240-246.
- Rosen MB, Abbott BD, Wolf DC, Corton JC, Wood CR, et al. (2008) Gene profiling in the livers of wild-type and PPARalpha-null mice exposed to perfluorooctanoic acid. Toxicol Pathol 36: 592-607.
- Doelman CJ, Borm PJ, Bast A (1990) Plasticisers and bronchial hyperreactivity. Lancet 335: 725.
- Grosse Y, Baan R, Secretan-Lauby B, El Ghissassi F, Bouvard V, et al. (2011) Carcinogenicity of chemicals in industrial and consumer products, food contaminants and flavourings, and water chlorination byproducts. Lancet Oncol 12: 328-329.
- Beasley R, Ellwood P, Asher I (2003) International patterns of the prevalence of pediatric asthma the ISAAC program. Pediatr Clin North Am 50: 539-553.
- Etzel RA (2003) How environmental exposures influence the development and exacerbation of asthma. Pediatrics 112: 233-239.
- Strachan DP (2000) The role of environmental factors in asthma. Br Med Bull 56: 865-882.
- Hiyoshi K, Takano H, Inoue KI, Ichinose T, Yanagisawa R, et al. (2005) Effects of phenanthraquinone on allergic airway inflammation in mice. Clin Exp Allergy 35: 1243-1248.
- Koike E, Yanagisawa R, Sadakane K, Inoue K, Ichinose T, et al. (2010) Effects of diisononyl phthalate on atopic dermatitis in vivo and immunologic responses in vitro. Environ Health Perspect 118: 472-478.
- Takano H, Yoshikawa T, Ichinose T, Miyabara Y, Imaoka K, et al. (1997) Diesel exhaust particles enhance antigen-induced airway inflammation and local cytokine expression in mice. Am J Respir Crit Care Med 156: 36-42.
- Yanagisawa R, Takano H, Inoue KI, Ichinose T, Sadakane K, et al. (2006) Components of diesel exhaust particles differentially affect Th1/Th2 response in a murine model of allergic airway inflammation. Clin Exp Allergy 36: 386-395.
- Inoue K, Takano H, Hiyoshi K, Ichinose T, et al. (2007) Naphthoquinone enhances antigen-related airway inflammation in mice. Eur Respir J 29: 259-267.
- Inoue K, Koike E, Takano H, Yanagisawa R, Ichinose T, et al. (2009) Effects of diesel exhaust particles on antigen-presenting cells and antigen-specific Th immunity in mice. Exp Biol Med (Maywood) 234: 200-209.
- Kolarik B, Naydenov K, Larsson M, Bornehag CG, Sundell J (2008) The association between phthalates in dust and allergic diseases among Bulgarian children. Environ Health Perspect 116: 98-103.
- Bornehag CG, Sundell J, Weschler CJ, Sigsgaard T, Lundgren B, et al. (2004) The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study. Environ Health Perspect 112: 1393-1397.
- Potera C (2005) Phthalate linked to lupus in mice. Environ Health Perspect 113: A809.
- Takano H, Yanagisawa R, Inoue K, Ichinose T, Sadakane K, et al. (2006) Di-(2-ethylhexyl) phthalate enhances atopic dermatitis-like skin lesions in mice. Environ Health Perspect 114: 1266-1269.
- Lim SY, Ghosh SK (2005) Autoreactive responses to environmental factors: 3. Mouse strain-specific differences in induction and regulation of anti-DNA antibody responses due to phthalate-isomers. J Autoimmun 25: 33-45.
- Larsen ST, Hansen JS, Hansen EW, Clausen PA, Nielsen GD (2007) Airway inflammation and adjuvant effect after repeated airborne exposures to di-(2-ethylhexyl)phthalate and ovalbumin in BALB/c mice. Toxicology 235: 119-129.
- Larsen ST, Nielsen GD (2007) The adjuvant effect of di-(2-ethylhexyl) phthalate is mediated through a PPARalpha-independent mechanism. Toxicol Lett 170: 223-228.
- Tanaka M, Inoue K, Momoi T, Takano H (2013) In vivo immunoamplifying effects of di-(2-ethylhexyl) phthalate on cytokine response. Immunopharmacol Immunotoxicol 35: 147-150.