Levels of Seven Urinary Phthalate Metabolites in a Human Reference Population

Abstract

Dialkyl or alkyl aryl esters of 1,2-benzenedicarboxylic acid, commonly called phthalates, are ubiquitous industrial chemicals with a wide range of chemical and toxicologic characteristics. Phthalates are used primarily as plasticizers in flexible polyvinyl chloride (PVC) products such as blood bags and children's toys. Nonpolymeric uses of phthalates as fixatives, detergents, lubricating oils, and solvents lead to their inclusion in numerous and diverse products such as cosmetics and wood finishes. The widespread use of phthalates results in multiple human exposure routes (oral, dermal, inhalation, and intravenous). Phthalates are lipophilic compounds that appear not to bioaccumulate (1). Phthalates are rapidly metabolized to their respective monoesters and further oxidative products, which are glucuronidated and excreted through the urine and feces (1-4).Animal toxicology of several phthalates has been studied. Di-(2-ethylhexyl) phthalate (DEHP) is a rodent liver carcinogen through a mechanism thought to involve peroxisome proliferation (5); however, carcinogenicity by this mechanism is unlikely to be relevant to humans (6,7). Several phthalates, DEHP, dibutyl phthalate (DBP), and benzyl butyl phthalate (BzBP), are teratogenic in animals (8-10). DBP is also toxic to the testes, possibly through its metabolite, monobutyl phthalate (MBP) (11,12); other phthalate metabolites, monobenzyl phthalate (MBzP) and mono-2-ethylhexyl phthalate (MEHP), are Sertoli cell toxicants and teratogens in animals (13,14). Furthermore, administration of DBP and DEHP to pregnant rats interferes with normal fetal development in male offspring (15). Regarding reproductive and developmental effects, phthalates vary in potency, with DEHP being the most potent and DBP and BzBP roughly an order of magnitude less potent (8)(9)(10)(11)(12)(13)(14)(15).Based on the varied toxicities of phthalates, internal dose measurements of specific phthalates and their monoester metabolites (16) are important for exposure assessment, and ultimately for accurate human risk assessment. Previous methods for assessing human exposure to phthalates have been subject to laboratory and sample-collection contamination problems from these environmentally ubiquitous compounds (17)(18)(19)(20). For this reason, previous measurements of internal phthalate dose have focused on highly exposed people (21,22). As the primary urinary metabolite, phthalate monoesters are useful biomarkers of specific phthalate exposure.We report the urinary phthalate monoester levels for a human reference population using a new, highly selective technique (23). This analytical approach allows us to directly measure the individual phthalate metabolites responsible for the reproductive and developmental toxicity of phthalates in animals while avoiding contamination from the ubiquitous parent compound. The metabolites measured are monoethyl phthalate (MEP), MBP, MBzP, mono-n-octyl phthalate, MEHP, and mono-3-methyl-5-dimethylhexyl phthalate (monoisononyl, MINP). Commercially used di-isononyl p...

Airborne Environmental Injuries and Human Health

“…In view of these findings, it is particularly concerning that women of childbearing age had significantly higher urinary concentrations of MBP than women in other age groups (90). However, other studies did not find a significant difference between women of reproduc-tive age (age 20-39 yr) and younger or older females but confirmed that women of all ages had higher urinary concentrations of MBP, MEP, and MBzP compared with men (88,92).…”

“…It has been proposed that the unconjugated monoesters are the mediators of reproductive toxicity in rats (141) because monoesters undergo little glucuronidation in these animals. Conversely, in humans, the majority of phthalate monoesters and even the secondary metabolites are present in urine in the form of glucuronides (89,90). In serum, the metabolites Clinical Reviews in Allergy & Immunology Volume 31, 2006 (at least of MEHP) were reported to be mostly conjugated (89), but this is in marked contrast to the findings from a single human volunteer (142).…”

“…The monoesters of phthalates with higher molecular weights, such as DEHP, di-n-octyl phthalate, and di-isononyl phthalate, undergo rather extensive ω-1 and ω-oxidation of their aliphatic sidechains (88,89). In humans, monoesters and the oxidative metabolites are excreted primarily as glucuronides (89,90). Despite their lipophilic nature, phthalates are metabolized and excreted in feces and urine within 3 d; consequently, bioaccumulation is not believed to be a problem.…”

“…Notably, in the investigation of urinary phthalate monoester metabolites in a subsample of NHANES III, 5% of urine samples from 289 subjects had markedly elevated concentrations (67% above the next lowest level) of unconjugated monoesters (90).…”

Dibutylphthalate and Tween 80 alter ultrastructure inCandida albicans: implications for peroxisome proliferation

“…When urinary MBP was used as biomarker to assess DBP exposure in human volunteers, detection of DBP metabolites provided evidence for environmental exposure and biotransformation in vivo, whereas detection of the parental compound in urine has been considered to be an indication of environmental contamination (Duty et al 2005;Silva et al 2004Silva et al , 2003Blount et al 2000). Bacteria such as Burkholderia cepacia have the ability to grow on phthalates.…”