Context: Phthalates are a commonly used class of compounds present in many commercial products. Some phthalates (generally those of greater molecular size) make plastics soft and flexible. These plasticizers are found in medical devices, home products and infant and children’s toys. Other kinds of phthalates (the smaller molecules) in perfumes, cosmetics, varnishes, pesticides, and other products enhance odor, stickiness and strength.
Because of their widespread use, virtually every American has measurable, although usually very small, amounts of the breakdown products – called metabolites - of several phthalates in their bodies. . Phthalates do not build up in the body like some other environmental contaminants. The synthetic chemicals are broken down fairly quickly – usually within hours to days. The compounds are found in everyone because of nonstop exposure.
To determine phthalate exposure, researchers measure phthalate metabolites, usually in people’s urine, rather than the original "parent" compound. Parent chemicals like DEHP are found in plastic syringes and other medical devices used in human research studies and can easily leach and contaminate blood samples. But by measuring the metabolites – the chemicals that result when the body breaks down phthalate molecules -- the contamination problem is essentially eliminated. For instance, the human digestive tracks first converts DEHP into MEHP, the parent phthalate’s first breakdown product. Researchers then measure MEHP to gauge exposure to the commonly used plasticizer DEHP.
Prior laboratory studies find the product additives can affect animal health. Some phthalates at high doses cause problems with testicular development and function in lab animals, particularly rats and mice. A few studies show phthalates can change thyroid gland function. For instance, DEHP (a plasticizer phthalate) and DBP (one of the lighter weight phthalates) lower thyroid hormone levels in rodents. Until now, no one has looked for possible effects of phthalate exposure on human thyroid function and hormone levels.
Thyroid function is assessed by measuring hormones made by the thyroid gland and the hormone, produced by the brain, that stimulates the gland to make thyroid hormones. When the thyroid is not functioning correctly, it may be due to a problem with the thyroid gland itself, or instead, a problem in how the brain is stimulating the gland.
Serious health problems arise from too little or too much thyroid hormones. Not enough causes hypothyroidism, a condition characterized by a slow metabolism, affects women more often than men with symptoms such as dry skin, weakness, cold intolerance, and memory loss. Thyroid hormone overload causes hyperthyroidism and symptoms such as nervousness, fatigue, heart palpitations, heat intolerance and insomnia. Graves Disease is a common form of hyperthyroidism. Abnormal thyroid hormone levels can also affect fertility, brain development and heart function.
The thyroid gland, located in the neck, releases the two major thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Enzymes in cells convert T4, the principal hormone secreted by the thyroid, to T3, the more active of the two hormones.. The hormones travel to cells throughout the body in the bloodstream, either by themselves (free) or attached to special proteins.
Researchers generally use the free thyroid hormone levels in the blood, rather than total hormone levels (amount of free and protein-bound hormone), to indicate thyroid hormone activity. The total is less helpful because it can increase with either more free hormone or more protein carriers that do not actually change the amount of free hormone.
The level of "thyroid stimulating hormone" (TSH) produced by the brain is another good measure of thyroid function. If the brain does not detect enough thyroid hormone in the blood, it produces more TSH, which under normal conditions stimulates the thyroid gland to make more T3 and T4. |
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What did they find? The researchers found that as MEHP concentrations in the urine increased, blood levels of free T4 and total T3 dropped. The relationship, though, was not linear and resembled non-monotonic responses reported for other hormone-like compounds.
The strongest effects occurred in the fourth quintile exposure group where levels and T3 and T4 hit their lowest levels. Free T4 dropped by about 9% and total T3 by about 5%, as compared with the lowest exposure first quintile exposure group. However, the trend reversed in the highest exposure 5th quintile group where T4 and T3 increased. Note how the figure shows this U-shaped relationship between MEHP and free T4.
Other phthalate metabolites had no effect on thyroid hormone levels. Also, no link was found between MEHP levels and TSH.
The researchers also looked at the ratio of three metabolites of DEHP, the commonly used plasticizer, and found that men with a higher percentage of MEHP (the first breakdown product of DEHP) in their urine had lower free T4 levels.
What does it mean? Meeker et al. found statistically significant results linking MEHP levels in men’s urine, a marker of DEHP exposure, and changes in thyroid hormones. Thyroid hormones have many important effects on brain development in children, on energy metabolism and other body functions in people of all ages. The results suggest phthalates or their breakdown products may affect thyroid levels possibly leading to altered thyroid hormone function. The important preliminary findings suggest this topic deserves further study. According to the authors, "Urinary MEHP concentrations may be associated with altered free T4 and/or total T3 levels in adult men but additional study is needed to confirm the observed findings."
Cross-sectional studies like this one can yield preliminary results usually because the study measures the chemical exposure (phthalates) and the possible effects (thyroid hormones) at the same time. Cross-sectional studies are relatively quick and inexpensive. They generate clues that guide researchers to the most promising associations to follow during the more expensive, and more definitive, multi-year studies. Sometimes, cross-sectional studies show false associations between exposures and effects because they are linked by some unidentified confounding variable. Results can suggest there is a relationship, or effect, that is not found when more elaborate studies are done. In this case, Meeker et al. caution that, for instance, decreased thyroid hormone function might, in some as yet unknown manner, change the way phthalates are metabolized, thus creating a false link between phthalate levels and thyroid hormone levels.
The results could also be artificially small, since the researchers statistically adjusted their results for the BMI (a measure of obesity) of the men in the study. If phthalate exposure causes decreased thyroid function, and since people who are hypothyroid typically gain weight, adjusting the researchers' results for BMI might have made the results less impressive. There are other reasons to adjust for BMI, though it would be intriguing to see what their results look like without the BMI adjustment.
Differences in how individuals metabolize phthalates may influence the phthalate-thyroid relationship. In this study, higher ratio of MEHP to the other DEHP metabolites was associated with lower free T4. . This ratio might indicate how fast the subjects metabolize DEHP, since MEHP is an earlier breakdown product of DEHP than other metabolites. Hence, the more MEHP you find, the slower the metabolism – assuming continuous exposure to DEHP. Perhaps, slow-metabolizers are more susceptible to phthalate effects than fast-metabolizers. Another explanation is also possible: the enzymes that metabolizes DEHP may also be responsible for metabolizing other pollutants. It could be that a higher ratio of MEHP really indicates that the other pollutants are breaking down more slowly too, and perhaps those pollutants are causing the problems.
Finally, the researchers found that the relationship between MEHP (in urine) and the two thyroid hormones (in blood) was not a simple straight line, where more MEHP was always linked to less thyroid hormone. The relationship was a U-shaped curve. If this preliminary study has discovered a real effect of phthalates on thyroid function in people, future studies will need to take into account the non-linear shape of the phthalate dose-response curve or risk missing real effects. |
