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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MECHANISM OF TOXICITY

In mature animals, each phthalate has a different toxicity profile. The liver, kidneys, thyroid, and testes are common targets for general toxicity from oral exposures. Our discussion will be focused on the following toxicities.

Hepatocarcinogenicity

  • The involved proper mechanism is believed to be attributable to the modulation of peroxisomal beta-oxidation, the Peroxisome Proliferator-Activated Receptor (PPAR) alpha-receptor, gap junctional intercellular communication, and replicative DNA synthesis. Two major mechanisms have been proposed to account for peroxisome proliferator-induced hepatocarcinogenicity in rodents: Induction of sustained oxidative stress and Enhanced cell proliferation and promotion.XXI

Reproductive toxicity

  • One possible mechanism of DEHP-induced testicular atrophy in rats is associated with depletion of zinc in the testis. ZnT-1 is a zinc transporter that is highly expressed in the testis. DEPH might exert its toxic effects on the testis by altering expression of ZnT-1.
  • Another possible mechanism of DEHP-induced testicular atrophy in rats, mice and guinea pigs is related to reduction of the biosynthesis of testosterone in Leydig cells along with inhibition of Follicle Stimulating Hormone (FSH) stimulated cAMP accumulation in Sertoli cells. This has been shown in recent in-vitro studies using cultured Sertoli cells. The proposed mechanisms is as follows: First, mono(2-ethylhexyl) phthalate (MEHP) affects Sertoli cells and separates germ cells from Sertoli cells. Secondly, solubilized Fas Ligand (sFasL) is produced from Sertoli cells and Fas is expressed on surface of the separated germ cells. Finally, the binding of sFasL and Fas induces apoptosis of the germ cells. In the ovary Pre-ovulatory follicle granulosa cells has been speculated to be target sites of phthalate esters. With the use of in-vitro studies of cultured granulosa cells, MEHP inhibited Follicle stimulating hormone (FSH) stimulated c-AMP accumulation, and reduced 17 beta-estradiol production and aromatase m-RNA expression. This might be the major cause of infertility in females in reproductive toxicity studies.LIV

Developmental toxicities

  • Adverse effects include embryolethality and teratogenic pregnancy such as cleft palates, malformation of cervical and thoracic vertebrae, ribs, and dilatation of renal pelvis, but no changes in reproductive organs.
  • The involved mechanism is not considered to be via androgen receptor because of lack of interaction with androgen receptor, but considered as endocrine disruptors in rodents because of anti-androgenic effect in male rats and decrease of 17 beta_-estradiol level in blood in female rats. In-vivo study of neonatal males orally administrating DEHP and DBP reduced Sertoli cell numbers and MEHP induced separation of gonadocytes from Sertoli cells in co-culture system prepared from neonatal males. However, the mechanism of MEHP action in neonatal males may be different from that in adults because FSH stimulated cAMP accumulation in Sertoli cells was not affected by MEHP.
  • The findings suggest that long-term alterations in the male reproductive system might be a consequence of perinatal exposure to DEHP. Available evidence also indicates that DEHP is not an androgen receptor antagonist, but acts as an antiandrogen during a critical stage of reproductive tract differentiation by reducing testosterone to female levels in the fetal male rat.
  • The phthalates reported to have the strongest oestrogenic potencies are butyl benzyl phthalate (BBP) and di-n-butyl phthalate (DBP). LIV
  • Peroxisome Proliferation is in question as to its occurrence in humans. Peroxisomes are normal components of cells, including liver cells, which break down fatty acids and help synthesize cholesterol. When exposed to substances like DEHP, they multiply abnormally and are thought to become promoters of liver cancer. This effect is seen clearly in rodents, but its relevance to humans is in dispute. There is no evidence that DEHP is an endocrine disruptor in humans at the levels found in the environment. Information from animals administered DEHP for periods ranging from a few days to lifetime studies indicate that DEHP is a developmental and reproductive toxicant by mechanisms not yet completely understood. The mechanisms do not appear to involve binding of DEHP to the estrogen or androgen receptors.
  • There is still considerable uncertainty as to the exact mechanisms by which DEHP may cause various different adverse effects in diverse organs of laboratory animals.
  • Mechanisms of toxicity are likely to be multiple and variable, depending on the health endpoint, the organ, and species studied.
  • Mice exposed to DEHP show fetal toxicity, teratogenicity, testicular lesions, and kidney cysts, though not liver lesions, in laboratory animals bred without the receptor necessary for mediating the enzymatic activity of peroxisomes (PPAR alpha, a receptor also present in humans). These mice have been bred to lack one of the receptors necessary for the peroxisome development, in response to exposure to a peroxisome proliferator, still exhibit toxic effects of DEHP. These studies strongly support the conclusion that much of the non-hepatic toxicity of DEHP is at least partly independent of peroxisome proliferation. XIX