Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP.

Albro, Phillip W.; Corbett, Jean T.; Schroeder, Joanna L.; Jordan, Sandra J.; Matthews, H. B.

doi:10.1289/ehp.824519

Cited by 200 publications

(72 citation statements)

References 11 publications

(5 reference statements)

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“…The bulk of a single oral dose of DEHP in rats (> 97%) is excreted within 7 days, with the half-life in various tissues ranging from 1 to 5 days (36), whereas on prolonged exposure, metabolic disposition quickly reaches a steady state of body burden (within 4 days) independent of the administered dose (37). In the present investigation, therefore, increased body burden with the continued exposure or selective retention in specific tissues would not be expected to influence DEHP-induced gonadotoxicity and reproductive dysfunction, nor would it have affected the recovery from these effects.…”

Section: Discussionmentioning

confidence: 99%

Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Agarwal¹,

Eustis²,

Lamb³

et al. 1986

Environ Health Perspect

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Dietary exposure of adult male F344 rats to 0, 320, 1250, 5000, or 20,000 ppm DEHP for 60 consecutive days resulted in a dose-dependent reduction in total body, testis, epididymis, and prostate weights at 5000 and 20,000 ppm. Degenerative changes were observed in testis, along with decreased testicular zinc content, reduced epididymal sperm density and motility, and increased occurrence of abnormal sperm at 20,000 ppm. There was a trend towards reduced testosterone and increased luteinizing hormone and follicle stimulating hormone in serum at 5000 and 20,000 ppm. The mean percentage of fertile animals was unchanged and reduction in fertility parameters, although not marked in severity, were correlated with gonadal effects. Average litter size was reduced at 20,000 ppm, but initial pup weights and growth were unaffected. There were no grossly observed abnormalities in the offspring and the rate of neonatal deaths was similar in control and DEHP treated groups. Characteristic toxicity manifestations of DEHP included dose-dependent enlargement of liver and reduced sperm triglycerides and cholesterol. Additionally, serum albumin and total proteins were dose dependently increased upon treatment with DEHP. Cessation of exposure to DEHP initiated partial to complete recovery from toxicity in most cases. The magnitude of recovery were variable with that ofthe gonads being slower than other systems. These data suggest a lack of reproductive dysfunction in F344 male rats at DEHP doses below 20,000 ppm which produced measurable testicular degeneration and afflicted epididymal sperm morphology under the present experimental conditions.

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Section: Discussionmentioning

confidence: 99%

Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Agarwal¹,

Eustis²,

Lamb³

et al. 1986

Environ Health Perspect

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“…For example, the guinea pig only produces small quantities of oxidized DEHP metabolites (42). For this reason we have attempted to exclude such metabolic factors by studying the effects of DEHP metabolites on peroxisomal enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

“…For example, guinea pigs produce only small quantities of oxidized DEHP metabolites (42), while the marmoset appears to absorb only a small proportion of an orallyadministered dose of DEHP (43).…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Elcombe¹,

Mitchell²

1986

Environ Health Perspect

163

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The exposure of cultured rat hepatocytes to mono(2-ethylhexyl)phthalate (MEHP) for 72 hr resulted in marked induction of peroxisomal enzyme activity (13-oxidation; cyanide-insensitive palmitoyl CoA oxidase) and concomitant increases in the number of peroxisomes. Similar treatment of cultured guinea pig, marmoset, or human hepatocytes revealed little or no effect of MEHP. In order to eliminate possible confounding influences of biotransformation, the proximate peroxisome proliferator(s) derived from MEHP have been identified. Using cultured hepatocytes these agents were found to be metabolite VI [mono(2-ethyl-5-oxohexyl) phthalate] and metabolite IX [mono(2-ethyl-5-hydroxyhexyl) phthalate]. The addition of these "active" metabolites to cultured guinea pig, marmoset, or human hepatocytes again revealed little effect upon peroxisomes or related enzyme activities (peroxisomal 1-oxidation or microsomal lauric acid hydroxylation). These studies demonstrate a marked species difference in the response of hepatocytes to MEHP-elicited peroxisome proliferation. Preliminary studies have also suggested that peroxisome proliferation due to MEHP may be due to an initial biochemical lesion of fatty acid metabolism.

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“…Escherichia coli β-glucuronidase (K12; Roche Biomedical, Indianapolis, IN) has excellent glucuronidase activity and no measurable lipase activity on phthalate diesters. Although this enzyme lacks sulfatase activity, no phthalate conjugates other than glucuronides have been detected in human urine (27). For previously published phthalate monoester measurements, H. pomatia β-glucuronidase/sulfatase was used; therefore artifactually high results may be present (3,22).…”

Section: Methodsmentioning

confidence: 99%

Levels of Seven Urinary Phthalate Metabolites in a Human Reference Population

Blount¹,

Silva²,

Caudill³

et al. 2000

Environmental Health Perspectives

116

147

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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...

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Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP.

Cited by 200 publications

References 11 publications

Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Levels of Seven Urinary Phthalate Metabolites in a Human Reference Population

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