Phthalates

Introduction

Characteristic of the Agent

Fate and Transport

Environmental Impacts

Environmental Monitoring

Exposure Pathway

Routes of Exposure

Methods for Measuring Human Exposure

Strategies for Preventing or Controlling Exposures



Harmful Effects

Dose Response

Absorption, Distribution and Metabolism

Biomarkers

Target Organs and Tissues

Mechanisms of Toxicity

Risk Assessment and Risk Management

References

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ABSORPTION, DISTRIBUTION, and METABOLISM

When DEHP enters the human body, the compound is metabolized into various substances that are more readily excreted. Unfortunately, the most important of these metabolites, mono-ethylhexyl phthalate (MEHP) is thought to be responsible for much of DEHP’s toxicity. The enzymes that break down DEHP into MEHP are found mainly in the intestines but also occur in the liver, kidney, lungs, pancreas, and plasma. Because conversion of DEHP to MEHP occurs primarily in the intestinal tract, exposures to DEHP by ingestion may be more hazardous than by intravenous exposure, which largely bypasses the intestinal tract.

MEHP is not the only metabolite of DEHP and many of the known secondary metabolites have not been studied for their toxicity. The initial metabolism of DEHP is qualitatively similar among mammalian species, so that animal studies are likely to be useful in understanding the consequences of human exposure. The ability to metabolize DEHP is age-related and may also depend on underlying health status in ways that are not well-understood. XXXV

The absorption and disposition of di(2-ethylhexyl) phthalate has been investigated extensively in humans and laboratory animals. In all species studied, the compound underwent rapid metabolism, with the urine and feces being the major routes of excretion. Following oral administration, the bulk of a di(2-ethylhexyl) phthalate dose was absorbed as the monoester, mono(2-ethylhexyl) phthalate. This ester is also formed by esterases in the body following intravenous administration and is subject to extensive oxidative metabolism by the cytochrome P450 system. XXXVI

Absorption

Inhalation Exposure

  • No quantitative data regarding absorption after inhalation exposures of humans or animals to DEHP were located.
    • Absorption can occur through the lungs of humans as evidenced by identification of DEHP in the urine or lung tissue of infants exposed to DEHP during respiration therapy. XXIV
  • In rats, inhalation of an aerosol containing 1,000 mg/m 3 of DEHP resulted in peroxisome proliferation, indicating that absorption had occurred. XXII
    • No quantitative details were provided which could be used to estimate absorption in this study, or rule out inadvertent co-exposure by the oral route.

Oral Exposure

  • Measurement of DEHP excretory metabolites indicate approximately 11–15% of a 30 mg oral dose is excreted in human urine. However, the total absorption is probably higher (perhaps 20–25%), since animal studies indicate that biliary excretion accounts for 15–20% of the absorbed dose. XXXVII
  • Analysis of animal data suggests that rodents absorb DEHP better than other animal species. DEHP is absorbed primarily as MEHP and 2-ethylhexanol, along with small amounts of unhydrolyzed DEHP. XXXVIII
  • At low concentrations, most of DEHP is hydrolyzed in the small intestines and absorbed as the MEHP and 2-ethylhexanol. XXXIX
  • At high concentrations, some unhydrolyzed DEHP is also absorbed. Based on urinary excretion of metabolites, rats can absorb at least 55% of a 2,000 mg/kg oral dose. XXXVIII
  • Actual absorption is probably greater than this since biliary excretion of previously absorbed and metabolized DEHP might account for a considerable portion of the fecal elimination. Larger percentages of smaller doses will be absorbed, since intestinal transport of MEHP and DEHP can be saturated at high doses. XL

Dermal Exposure

  • DEHP does not appear to be readily absorbed through the human skin. Wester et al. (1998) estimated that dermal absorption amounts to approximately 1.8% of a 24-hour applied dose of DEHP solubilized in ethanol. XLI
  • No other reports were located regarding dermal absorption of DEHP in humans.
  • DEHP has been shown to be poorly absorbed through the skin of laboratory animals. Dermal absorption was reported to be approximately 5% in rats exposed for 7 days to an initial dose of 30 mg DEHP/kg (dissolved in ethanol). XLII
  • The mean calculated dermal absorption rate was 0.242 micrograms/cm^2/hour
  • In-vitro studies of DEHP absorption through human, rat and porcine epidermal segments confirm the poor dermal absorption of DEHP. XLI

Distribution

  • Little information is available regarding the distribution of DEHP in humans after exposures.
  • DEHP is lipophilic and tends to accumulate in adipose tissue. DEHP was present in human adipose tissues from accident victims at a concentration of 0.3-1.0 ppm XLIII and in 48% of the adipose tissue specimens from cadavers autopsied in 1982 as part of the Human Adipose Tissue Survey from the National Human Monitoring Program. XLIV
  • DEHP has been isolated in the kidneys of autopsied patients. XLV
    • The presence of DEHP in tissues might be an artifact since DEHP can easily contaminate biological samples during laboratory processing operations making it seem more prevalent than it actually occurs.

Inhalation Exposure

  • No studies were located regarding the distribution of DEHP in the tissues of humans or animals after inhalation exposure to DEHP.

Oral Exposure

  • No studies were located regarding the distribution of DEHP in humans after oral exposure to DEHP.
  • Since environmental exposures DEHP occur primarily through foods, the data concerning the presence of DEHP in human adipose deposits is a reflection of distribution following oral exposures, assuming that contamination was avoided.
  • The liver, kidney, testes, and blood were identified as sites of DEHP metabolism or utilization after 14-day oral exposure of rats to a 2,000 mg/kg/day dose containing 12C-DEHP labeled in the phenyl ring.
  • Concentrations were 10-15% of the amounts in the rat, reflecting the lower coefficient of absorption for the DEHP in the monkey and possible differences in other aspects of pharmacokinetics. XXXVIII
  • Studies show a possible increased permeability of the blood-brain barrier to DEHP in neonates or developing organisms. XLVI

Dermal Exposure

  • No studies were located regarding the distribution of DEHP in human tissues after dermal exposures to DEHP.
  • In rats exposed to 30 mg/kg DEHP applied to the skin for 7 days, the liver contained 0.063% of the applied dose, the kidney 0.012%, the muscles 1.162%, and the fat 0.066% The small intestines were found to contain 0.161% of the dose, giving evidence for either intestinal uptake of DEHP from non-oral routes of exposure or the excretion of metabolites in the bile. XLII

Metabolism

  • Based on data from human and animal studies, metabolism of DEHP involves a complex series of reactions that produce 30 or more metabolites. XXXIX
  • Some impact of DEHP on carbohydrate metabolism in the liver of rats has been observed
  • The Mixed Function Oxidase (MFO) system is a second hepatic enzyme system that appears to be affected by DEHP in rodents, but not in monkeys. The MFO system consists of cytochrome P-450, a series of hydratases and hydroxylases. Peroxisome proliferators particularly induce P-450 isoenzymes of the CYP4A subfamily. The effect of the changes in the MFO enzymes on the liver is difficult to evaluate.
    • Is there an oxidized intermediary metabolite produced by the initial MFO reaction more toxic than are the parent compounds?
  • Membrane Structure: The effect of DEHP on liver metabolism might be modulated through a change in the structure of the cell membranes. Both membrane proteins and lipids are altered with DEHP exposure.
  • The first step in metabolism is the hydrolytic cleavage of DEHP resulting in the formation of MEHP and 2-ethylhexanol.
    • Occurs rapidly in the intestine and the formation of approximately equal proportions of MEHP and 2-ethylhexanol. XLVII
    • The formation of MEHP from the parent ester is achieved by lipases that have been identified in the pancreas and intestinal mucosa, as well as the liver, kidneys, lungs, skin and plasma.
      • The pancreatic tissue is the richest source of these esterases. XXXIX
  • The Omega-oxidation step of MEHP can be followed by Alpha or Beta-oxidation reducing the number of carbons in the 2-ethylhexyl side chain.
  • After the primary metabolic conversions described above, the oxidized derivatives of MEHP can be conjugated with glucuronic acid for excretion.
  • 2-Ethylhexanol is also metabolized through oxidative pathways. XXXIX
  • The primary urinary products from 2-ethylhexanol are 2-ethylhexanoic acid and several keto acid derivatives which appear to be products of Beta-oxidation. XLVIII
  • Metabolism following inhalation or dermal routes of exposure is expected to be similar to that after inhalation exposures, since there are lipases present in the alveolar cells of the lungs and the epidermis.
  • There have been studies of the metabolism of DEHP in humans after oral exposures as reflected by its urinary excretory products.
    • MEHP accounted for 6–12% of the measured metabolites.
    • Approximately 65% of DEHP metabolites are excreted as glucuronide conjugates in humans.
  • Each of these major metabolites is the product of oxidation of a different carbon in the 2-ethylhexyl substituent. (See Figure 8)
  • The same DEHP metabolites are found in the urine and feces of monkeys, rats, mice, guinea pigs, and hamsters, although there are some differences in the proportion of the metabolites excreted as conjugates of glucuronic acid.
    • Monkeys are similar to humans and excrete 60% of metabolites as conjugates. XLIX

Figure 8: DEHP Metabolites XXI. ATSDR.