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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BIOMARKERS

Background

  • A biomarker is broadly defined as any measurement reflecting an interaction between a biological system and an environmental agent. The agent may be chemical, physical, or biological. There are three classes of biomarkers:
    1. Biomarker of exposure; an exogenous substance or its metabolite or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a compartment within an organism.
    2. Biomarker of effect; a measurable biochemical, physiological, behavioral, or other alteration within an organism that, depending upon the magnitude, can be recognized as associated with an established or possible health impairment or disease.
    3. Biomarker of susceptibility; an indicator of an inherent or acquired ability of an organism to respond to the challenge of exposure to a specific xenobiotic substance.
  • Goal of use for biomarkers is to use them in the risk assessment process, but they must be validated through establishment of the relationship between the biomarker, the exposure and the health outcome. The selection, validation, and application of any biomarker is a complicated process.
  • Biomarkers need to be identified and validated for each organ system that the parameters are used to indicate dysfunction within and need to have their specificity, sensitivity, and method of measurement established.
  • May be used to confirm the diagnosis of acute or chronic poisoning, assess the effectiveness of a treatment, and evaluate the prognosis of individual cases.
  • The preferred biomarker of exposure is generally the substance itself or substance-specific metabolites in readily obtainable body fluid or excreta.
  • The use of biomarkers is not a straight forward process. The following are factors that confound the use and interpretation of biomarkers of exposure:
    • The presence of a substance may be the result of exposures from more than one source.
    • The substance measured may be a metabolite of another xenobiotic substance (ie. High urinary levels of phenol can result from several different aromatic compounds).
    • The substance and all of the metabolites may have left the body when sampling actually takes place. This is especially true with a rapidly metabolized and excreted agent such as DEHP.
    • Identification of individuals who have been exposed to toxins is difficult for substances that are commonly found in body tissues and fluids (eg. Essential mineral nutrients such as copper, zinc, and selenium).

Biomarkers used to identify or quantify exposure to DEHP

  • DEHP and its hydrolyzed derivatives, MEHP and 2-ethylhexanol are absorbed from the intestinal tract, skin, and lungs into the blood. XXI
  • MEHP and several oxidized MEHP metabolites may be measured in blood and urine, and are biomarkers of exposure.
  • Once absorbed they are widely distributed in the body with the liver being the major repository organ.
  • The half-life in humans is approximately12 hours. LII
  • They are rapidly metabolized to a variety of oxidized derivatives that are excreted in the urine and bile. Some phthalic acid is also produced.
  • DEHP and metabolites may be measured in the blood and urine to confirm recent exposure.
    • Urine and blood are equally reliable measures for metabolites, therefore the least invasive method of sampling, urine, is preferred for monitoring.
    • MEHP, 2-ethyl-5-carboxypentyl phthalic acid, 2-ethyl-5-oxyhexyl phthalic acid, or 2-ethyl-5-hydroxyhexyl phthalic acid are the major urinary metabolites in humans. Monoester metabolites allow for biomonitoring through direct measurement of monoester metabolites without directly measuring DEHP.
    • Urine analysis for DEHP is fraught with false positives and laboratory contamination. Little DEHP is excreted in the urine, so due to these considerations, urine analysis is not suggested.

RESEARCH- There has been some limited research investigating the use of biomarkers for phthalates. The following is a study conducted in the United States. Further research needs to be conducted before we can know how effectively these biomarkers gauge exposure levels.

  • Third National Health and Nutrition Examination Survey. XXI
    • Studied the feasibility of using monoester metabolites as specific biomarkers of exposure to DEHP and six other commonly used phthalates.
    • Analysis of urine samples from 289 adult subjects (1988-1994).
    • Monoesters with highest urinary levels were MEHP (DEHP exposure), monobutyl phthalate (dibutyl phthalate exposure), and monobenzyl phthalate (benzyl butyl phthalate exposure).
    • Established a basis for exposure biomonitoring.
    • Calculations needed to relate dose.
    • Suggests that average total daily ambient exposure in the US is likely <3.6µg/kg/day.
    • Did not establish demographic variations in exposure and metabolism.

The benefit of delineating biomarkers for DEHP has been questioned. It has not been determined whether this ubiquitous agent is harmful to human health. More research is needed.