Endocrine Disruptive Effects of Phthalates General

There are gender similarities and differences comparing male and female reproductive responses to phthalates. In rats, DEHP works by similar mechanisms and it is a reproductive toxicant in both genders. Conversely, DBP and monobutyl phthalate, its active metabolite, produce developmental effects in males and reproductive tract effects in females. When DBP is administered to pregnant females, it induces a syndrome resembling testicular dysgenesis syndrome in the rat male offspring. This occurs because phthalates can suppress endogenous testosterone production by the fetal testis, thus interfering with sexual differentiation.

The developmental and reproductive effects of DEHP, whose toxicity seems to occur at an older age in females than in males, are especially under scrutiny. DEHP and its metabolite MEHP appear to target analogous sites within the testis and ovary. Hormonal disturbance of the fetal testis development by DEHP has been reported and is dependent on the stage of development at exposure.

Prolonged DEHP exposure increases serum concentrations of both gonadotropin luteinizing hormone and sex hormones (testosterone and 17/3-estradiol (E2)) in rats, which suggests the possibility of multiple cross talks between androgen, estrogen, and *steroid hormone receptors. On the other hand, the presence of estrogen receptors in other tissues, for example, cardiovascular system and bones, implies that the increases in serum E2 levels have implications beyond reproduction, including systemic physiology.

Data available from in vitro experiments

In vitro assays to screen for (anti-)estrogenic/androgenic potency can roughly be classified in one of the following groups:

1. Receptor binding affinity tests. The binding affinity to a receptor is measured with competitive ligand-binding techniques. This assay type does not discern agonists from antagonists.

2. Cellular proliferation assays. These measure proliferation in cell lines that are dependent on hormones.

3. Gene expression tests. Measurement of the gene expression after exposure to contaminants by determining amounts of mRNA, or gene products (e.g., an enzyme), is made. Sometimes, the cell lines have been constructed with the help of recombinant techniques.

In test types 2 and 3, receptor binding of the ligand as well as further events such as interaction with the responsive element on the DNA, DNA transcription, and the resulting production of proteins are measured, whereas in test type 1 only ligand binding is measured. In vitro test systems cannot replace in vivo tests as the sole base for screening chemicals for potential (antiestrogenic/androgenic action. The major objections to using solely in vitro systems are the differences in metabolism, bioavailability, and toxicokinetics between in vitro and in vivo test systems. In addition, intercellular interaction and mechanisms related to endocrine homeostasis are absent in in vitro systems. However, in vitro test systems can give a prediction about the possibility that compounds are able to exert endocrine-disruptive effects. This means that if they are not positive in any of the in vitro tests, it is not likely that the tested substances will be endocrine disruptors in vivo. In vitro tests are therefore used in so-called 'high-throughput screening' of high numbers of chemicals.

For several of the phthalate esters tested, no effects were found at the highest tested concentration in any of the tests. For dibutyl, diethyl, dihexyl, butylbenzyl, di-2-ethylhexyl, diisobutyl, and methyl ethyl phthalate, endocrine-disruptive effects are reported. The relative potency related to the potency of the natural estrogen, 17/3-estradiol, is always low (10" -10" ). This relative potency appears the highest for butyl benzyl phthalate (10"4-10"6); for DEHP, the reported relative potencies are 10"5.

The three major groups in which the in vitro tests are classified do not always show the same picture. For DBP, endocrine-disruptive effects are obtained in all types of in vitro systems, while for DEHP effects are observed in receptor binding assays but not in the proliferation or gene expression assays. Apparently, DEHP is able to bind to the estradiol receptor, but further events such as binding of the ligand-receptor complex to the DNA and resulting transcription and protein production do not take place.

Despite some inconsistencies in the data, the results reported do give rise to the idea that some phthalate compounds are able to act as xeno-estrogens, and thereby are able to act as endocrine disruptors.

Data available from in vivo experiments

Existing mammalian test methods (in general rat and mice) are in general useful for screening of potential (anti-)estrogenic/androgenic action. It is not yet clear however if these methods are predictive for other classes of vertebrate wildlife. The most commonly used in vivo assays in mammals for estrogenic effects are the utero-throphic assay in which the uterine weight is determined, and the vaginal cornification assay. For fish and birds, full and partial life-cycle tests seem suitable assays.

Most in vivo data on endocrine-disruptive effects are available for mouse and rat. Endocrine-disruptive effects are found in in vivo tests for DBP, DEHP, butyl benzyl, diethyl, and dihexyl phthalate, but not for other phtha-lates tested. Especially the two-generation reproduction studies appear sensitive in detecting endocrine disruptive effects. None of the tests with uterine weight showed positive results. The distinction between phthalates which can or cannot act as endocrine disruptors appears to be the same from in vitro and in vivo tests.

Significance for environmental risk assessment

Although in vivo testing is restricted to mammals, it is possible to calculate worst-case concentrations in the environment that are protective against endocrine-disrupting effects. However, several assumptions are needed for this purpose, such as

1. similar sensitivity of mammals tested in vivo and mammalian wildlife,

2. worst-case values of the biomagnification factor (BMF),

3. worst-case values of the biota-to-soil or -to-sediment accumulation factor (BSAF), and

4. complete lack of biotransformation.

From these assumptions, it can be concluded that MPCs as derived from 'regular' toxicity testing (i.e., not focusing on endocrine-disrupting activity) are sufficiently protective against endocrine-disruptive effects. As a matter of course, this conclusion can be invalidated upon generation of new data for mammals or aquatic species not yet tested.

See also-. Biodegradability; Biodegradation; Ecological Risk Assessment; Reproductive Toxicity.

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