PHTHALATES AND HUMAN HEALTH

he diesters of 1,2-benzenedicarboxylic acid (phthalic acid), commonly known as phthalates, are a group of man-made chemicals with a wide spectrum of industrial applications (fig 1, table 1).High molecular weight phthalates (for example, di(2-ethylhexyl) phthalate [DEHP], di-isononyl phthalate [DiNP], di-n-octyl phthalate [DnOP]), are primarily used as plasticizers in the manufacture of flexible vinyl which, in turn, is used in consumer products, flooring and wall coverings, food contact applications, and medical devices.[1][2][3] Manufacturers use low molecular weight phthalates (for example, diethyl phthalate [DEP] and dibutyl phthalate [DBP]) in personal-care products (for example, perfumes, lotions, cosmetics), as solvents and plasticizers for cellulose acetate, and in making lacquers, varnishes, and coatings, including those used to provide timed releases in some pharmaceuticals.[3][4][5] In this paper, we review the uses and metabolism of phthalates, and the studies on health effects of phthalates in human populations published between 1973 and June 2005.The references included in this review were searched using the Web of Science database which provides interactive citation and literature searching of the Institute for Scientific Information's Science Citation Index Expanded.The database contains data from more than 5000 scientific journals and covers the period from 1980 to present.We also searched the bibliography cited in the selected references for additional relevant citations. ROUTES OF EXPOSURE AND METABOLISM cBecause phthalates are widely used in many personal care and consumer products, the opportunity is high for non-occupational human exposure (table 1).However, to date, the proportional contribution from the various sources and routes of exposure to phthalates is unknown.Traditionally, ingestion has been considered an important route of exposure.Although phthalates have low volatility, they off-gas and are present in residential indoor air.6 7 Dermal contact 1 2 4 5 and parenteral exposure from medical devices containing phthalates may also contribute to exposure. 2 8 On exposure, phthalates are rapidly metabolised and excreted in urine and faeces. 1 2 4 5 During a phase I biotransformation, the relatively polar and low molecular weight phthalates (for example, DEP) primarily metabolise into their hydrolytic monoesters by hydrolysis of one of the ester bonds (fig 1). 4 9 In contrast, the high molecular weight phthalates are first metabolised to their respective hydrolytic monoesters, and then, after enzymatic oxidation of the alkyl chain, to more hydrophilic, oxidative metabolites (fig 2). 1 2 10-14 Monoesters and the oxidative metabolites of phthalates can be excreted in the urine and faeces unchanged or they can undergo phase II biotransformation to produce glucuronide conjugates with increased water solubility and therefore increased urinary excretion.2 4 Glucuronidation not only facilitates urinary excretion of phthalate metabolites, but also may reduce their potential for biological activity if the putative biologically active species is the free metabolite.The percentage of free monoester excretion in humans varies depending on the aqueous solubility of the phthalate metabolites.[15][16][17] Mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), two oxidative metabolites of DEHP, are mostly excreted glucuronidated in humans.16 Most of mono(2-ethylhexyl) phthalate (MEHP), the hydrolytic monoester metabolite of DEHP, is also excreted as a glucuronide, while monoethyl phthalate (MEP), the hydrolytic monoester of DEP, is mostly excreted in its free form.17 For other phthalates, the percentage of free monoester excretion varies between that of MEP and MEHP.15 17 Although the metabolism of the relatively low molecular weight phthalates (for example, DEP) ends with the hydrolytic monoester, 4 5 9 the metabolism of the higher molecular weight phthalates (for example, DEHP, DiNP, di-isodecyl phthalate [DiDP]) continues with transformation of the hydrolytic monoester to oxidative products (fig 2). 1 2 9 11-13 18 Therefore, the use of the hydrolytic monoesters as sole biomarkers for comparing relative exposures to various phthalates in a given study could be misleading.This is especially true when comparing concentrations of the 806 www.occenvmed.