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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HARMFUL EFFECTS OF THE AGENT

NOTE: Very little information has been obtained from human cases/research!!! Most of the information is data taken from animal (mostly rat/mouse) models research. As you will see below, some of the findings have limited associations exclusively with Phthalates. Many of the symptoms are broad and many of the rodent effects associations with humans are complicated with the differences between the species.

Human Data

  • Symptoms: Irritation of the eyes (lacrimation), skin, nose, throat; headache, dizziness, nausea; possible polyneuropathy, vestibular dysfunction, pain, numbness, weakness, exhaustion, spasms in arms and legs, reproductive effects in animals.XI
  • Research suggests that there is an association between PVC flooring and the development of bronchial obstruction in children. This also suggests that the increasing incidence of asthma could be partially due to the increasing household use of plastics containing phthalates over the last few decades.XIII
    CASE STUDY:
    Researchers have found evidence linking precocious thelarche to common phthalates. Blood samples from two groups of girls in Puerto Rico – 41 baby girls with precocious thelarche and 35 with normal development –were examined for pesticides and phthalates. Pesticides were notfound in either group. Phthalates were present in the blood of 68% of the precocious thelarche group and 14% of the control group. Phthalates tend not to bioaccumulate, so phthalates measured in blood are likely to reflect current exposures, not past exposures.XVIII

Animal Data

  • The different phthalates vary in their ability to produce the following effects in animal studies: testicular injury, liver injury, liver cancer, anti-androgenic activity, teratogenicity and peroxisomal proliferation.
    • Peroxisomal proliferation is highly debated as to whether or not it is relevant in people, because of differing metabolic pathways.
  • In-Vitro experiments: Butlybenzylphthalate (BBP) and Dibutylphthalate (DBP) are oestrogenic to breast cancel cell lines. BBP can also act as an antiandrogen, blocking the action of dihydrotestosterone in a yeast screen containing the androgen receptor.
  • In-Vivo experiments: Research at the Chemical Industry Institute of Toxicology confirmed that DBP does damage the reproductive system of male rats at low exposures, Action disrupts the androgen system, not imitiating the oestrogen. These results demonstrate DBP to be an endocrine disrupter.XIV
  • Animal experiments indicate that MEHP, the metabolite of DEHP can irritate lungs.XIII
  • DEHP is toxic to the developing fetus. The studies documenting these effects range from large studies involving hundreds of animals, to smaller ones with few animals, as well as cell culture studies, and case reports in humans. While most of these effects have been observed in laboratory animals at high doses, in some cases these doses were close to those that might be experienced by individuals undergoing medical treatment. For some adverse effects, such as testicular toxicity, the developing organism appears to be much more sensitive (greater toxicity and irreversibility of effect) than the adult. It is unclear whether a threshold for adverse effects exists.XIX

    Additional factors that may preclude the direct extrapolation or assumption of similar effects in animals and humans include the dose-related, species-specific, and route-specific nature of some of the effects, such as evidence indicating that most of the hepatic changes observed in DEHP-exposed rodents, including liver cancer, result from a mechanism that does not operate in humans.XX


    Figure 1- Shows research derived health effect of DEHPXXI. ATSDR, pg 156.

    Below are health effects seen in the two main Exposure pathways with the most study results:

    Inhalation and Oral Exposures.
    Note: Dermal exposure has very limited known effects data and is thought to be insignificant for adverse health effects. This is due to low absorption rate and low human exposures thru this route. Direct injection exposures are many times thought to have the highest exposure levels, but this is mostly medical procedure related and the benefits of treatment may surpass any acute exposure risks. This population is small percentage of all people.

    Inhalation Exposure
    Death

    • No studies were located regarding lethality in humans after inhalation exposure to DEHP.
    • Studies in animals suggest that DEHP has low toxicity when inhaled.
      • No deaths occurred in rats exposed to 300 mg/m 3 for 6 hours/day for 10 daysXXII or hamsters exposed to 0.015 mg/m3 for their lifetime.XXIII

    Respiratory Effects

    • Unusual lung effects were observed during the fourth week of life in three children who were exposed to DEHP during mechanical ventilation as preterm.XXIV
      • The effects clinically and radiologically resembled hyaline membrane disease, a disorder caused by insufficient surfactant production in the lungs of newborn infants.
      • Interpretation of these findings is complicated by the preexisting compromised health status of the preterm infants.
        • Information indicated the lung disorders were related to DEHP released from the walls of polyvinyl chloride (PVC) respiratory tubes.
    • Increased lung weights accompanied by thickening of the alveolar septa and proliferation of foam cells were observed in male rats that were exposed to 1,000 mg/m 3 of DEHP aerosol for 6 hours/day, 5 days/week for 4 weeks. These effects were reversible within an 8-week post-exposure period.XXV

    Hepatic Effects

    • No studies were located regarding hepatic effects in humans after inhalation exposure to DEHP.
    • In male and female rats relative liver weights were increased by exposure to 1,000 mg/m 3 administered as an aerosol 6 hours/day, 5 days/week for a 4-week period.XXIV
      • However, there was no evidence of peroxisome proliferation in thin slices of the livers examined under an electron microscope.
      • Relative liver weights were not increased in animals examined 8 weeks after the last exposure to DEHP

    Developmental Effects

    • No studies in humans
    • Data indicates that there were no developmental effects when DEHP was present in the atmosphere during gestation.

    Reproductive Effects

    • No studies were located regarding reproductive effects in humans after inhalation exposure to DEHP.
    • The fertility and mating performance of male rats was not affected by a 4-week exposure, 6 hours/day, 5 days/week to a DEHP aerosol (10–1,000 mg/m 3).XXIV
      • Mating with unexposed females was carried out at 2 and 6 weeks after the end of DEHP exposure period.
      • At sacrifice, there were no observable effects of DEHP on testicular structure.

    Cancer risk has not been well studied.

    Oral Exposure

    Death

    • Single oral doses of up to 10 g DEHP are not lethal to humans and no cases of death in humans after oral exposure to DEHP were located.XXVI
      • This data indicates DEHP is very unlikely to cause acute mortality in humans.
      • An avg. adult human equivalent dose from studies of rats would equal 4.5 lbs of DEHP for human lethal dose.

    GI Effects

    • Acute exposures to large oral doses of DEHP can cause gastrointestinal distress. When two humans were given a single oral dose of 5 or 10 g DEHP, the individual consuming the larger dose complained of mild abdominal pain and diarrhea.XXVI
    • No other effects of exposure were noted.
    • No adverse gastrointestinal effects were reported in any of the animal studies reviewed with the exception of pseudoductular lesions in the pancreas of rats administered 3,000 mg DEHP/kg/day in the diet for 108 weeks.XXVII

    Hepatic Effects

    • Most animal data exists detailing the effects of DEHP on liver structure and function.
      • Rats and mice are most susceptible to the hepatic effects of DEHP, while dogs and monkeys are less likely to experience changes in the liver after exposure.
    • In general, the data indicate that male rats are more susceptible to the hepatic effects of DEHP than are females.
      • Hepatic hyperplasia appears to be the initial physiological response
    • This study concluded that DEHP is an epigenetic tumor promoting agent in rodents.XXVIII

    Body weight

    • No reports of body weight alterations in humans attributed to oral exposure to DEHP
    • Numerous studies have documented reductions in body weight gain in animals.XXI
    • It is unclear whether reduced food intake is a reflection of poor palatability of the diets containing DEHP, DEHP-induced decrease in appetite, or both.

    Reproductive Effects/Testicular Effects

    • No studies were located regarding reproductive effects in humans after oral exposures to DEHP.
    • Studies in rodents exposed to doses in excess of 100 mg/kg/day DEHP clearly indicate that the testes are a primary target tissue, resulting in decreased testicular weights and tubular atrophy. Weights of the seminal vesicles, epididymis, and prostate gland in rats and mice are also reduced by oral exposure DEHP.XXIX, XXX
    • The age at first exposure to DEHP appears to have a clear influence on the degree and permanence of testicular damage.XXIX
    • Studies suggest that nonhuman primates are less sensitive than rodents to the effects of DEHP using these end points of toxicityXXXI
    • Responsible Metabolite?
      • Evidence suggests that mono(2-ethylhexyl) phthalate (MEHP) might be the toxic metabolite in the testes.
      • In one study, 1,055 mg/kg/day of DEHP administered for 5 days to rats did not affect testicular weight or structure, but an equimolar dose of MEHP had a significant effect.XXXII

    Developmental Effects

    • No studies were located regarding developmental toxicity in humans after oral exposure to DEHP.
    • DEHP has been demonstrated to cause developmental toxicity including teratogenic effects in both rats and mice.
      • Effects observed included decreased fetal/pup body weight, increased rates of abortion and fetal resorptions, or malformations.XXXIII

    Cancer

    • No studies found in humans after oral exposure to DEHP
    • Several chronic feeding studies in rodents indicate DEHP can cause live tumors.
      • Dose of 3,000 mg/kg/day-78 percent of rats developed liver tumors and 29 percent pancreatic islet cell adenoma
      • Findings criticized with the basis that doses given exceeded the maximum tolerated dose and that liver tumors are common in control group of rodents. XXXIII

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