Are phthalates really safe for children? 

Phthalates are important components of many consumer products, including toys, cleaning materials, plastics, and personal care items. Studies to date on phthalates have been inconsistent, with some linking exposure to these chemicals to hormone disruptions, birth defects, asthma, and reproductive problems, while others have found no significant association between exposure and adverse effects. 

A new report by Korean scientists, published by Elsevier in the November 15th issue of Biological Psychiatry, adds to the potentially alarming findings about phthalates. They measured urine phthalate concentrations and evaluated symptoms of attention-deficit/hyperactivity disorder (ADHD) using teacher-reported symptoms and computerized tests that measured attention and impulsivity. 

They found a significant positive association between phthalate exposure and ADHD, meaning that the higher the concentration of phthalate metabolites in the urine, the worse the ADHD symptoms and/or test scores. 

Senior author Yun-Chul Hong, MD, PhD, explained that “these data represent the first documented association between phthalate exposure and ADHD symptoms in school-aged children.” John Krystal, MD, the Editor of Biological Psychiatry, also commented: “This emerging link between phthalates and symptoms of ADHD raises the concern that accidental environmental exposure to phthalates may be contributing to behavioral and cognitive problems in children. This concern calls for more definitive research.” 

The U.S. Centers for Disease Control and Prevention, in the Summary of their 2005 Third National Report on Human Exposure to Environmental Chemicals, state that “very limited scientific information is available on potential human health effects of phthalates at levels” found in the U.S. population. Although this study was performed in a Korean population, their levels of exposure are likely comparable to a U.S. population.

The current findings do not prove that phthalate exposure caused ADHD symptoms. However, these initial findings provide a rationale for further research on this association. 

Reference: Elsevier, Common plastics chemicals linked to ADHD symptoms, November 19, 2009

4-n-Nonylphenol and bisphenol A are endocrine disrupting chemicals that are mainly detoxified through glucuronidation. A factor that may modulate their glucuronidation rates is co-exposure to pharmaceuticals.

This study aimed to identify and characterize the potential metabolic interactions between 14 drugs and these two endocrine disruptors. Nonylphenol and bisphenol A were co-incubated in freshly isolated rat hepatocytes with, drugs at a high concentration.

Statistically significant metabolic inhibition of bisphenol A and nonylphenol biotransformation was observed with nine drugs (>50% inhibition by naproxen, salicylic acid, carbamazepine and mefenamic acid). Inhibition assays of UGT activity in rat liver microsomes revealed: 1) competitive inhibition by naproxen (K(i)(app) = 848.3 muM) and carbamazepine (K(i)(app) = 1023.1 muM), 2) no inhibition by salicylic acid suggesting another mechanism of inhibition.

Detoxification of nonylphenol and bisphenol A was shown to be impaired by excessive concentrations of many drugs and health risk assessment should therefore address this issue.

Reference: Verner MA, Magher T, Haddad S., High concentrations of commonly used drugs can inhibit the in vitro glucuronidation of bisphenol A and nonylphenol in rats, Xenobiotica. 2009 Nov 16.

A study of 145 preschool children reports, for the first time, that when the concentrations of two common phthalates in mothers’ prenatal urine are elevated their sons are less likely to play with male-typical toys and games, such as trucks and play fighting.

The University of Rochester Medical Center-led study is published in the International Journal of Andrology.

Because testosterone produces the masculine brain, researchers are concerned that fetal exposure to anti-androgens such as phthalates “which are pervasive in the environment“ has the potential to alter masculine brain development, said lead author Shanna H. Swan, Ph.D., professor of Obstetrics and Gynecology, director of the URMC Center for Reproductive Epidemiology, and an expert in phthalates.

“Our results need to be confirmed, but are intriguing on several fronts,” Swan said. “Not only are they consistent with our prior findings that link phthalates to altered male genital development, but they also are compatible with current knowledge about how hormones mold sex differences in the brain, and thus behavior. We have more work to do, but the implications are potentially profound.”

Phthalates are chemicals used to soften plastics. Recent studies have shown that the major source of human exposure to the two phthalates of most concern (DEHP and DBP) is through food. These phthalates are used primarily in polyvinyl chloride (PVC), so any steps in the processing, packaging, storage, or heating of food that use PVC-containing products can introduce them into the food chain.

Phthalates are also found in vinyl and plastic tubing, household products, and many personal care products such as soaps and lotions. Phthalates are becoming more controversial as scientific research increasingly associates them with genital defects, metabolic abnormalities, and reduced testosterone in babies and adults. A federal law passed in 2008 banned six phthalates from use in toys such as teethers, play bath items, soft books, dolls and plastic figures.

In Swan’s study, higher concentrations of metabolites of two phthalates, di(2-ethylhexyl) phthalate (DEHP), and dibutyl phthalate (DBP), were associated with less male-typical behavior in boys on a standard play questionnaire. No other phthalate metabolites measured in-utero was linked to the less-masculine behavior. Girls’ play behavior was not associated with phthalate levels in their mothers, the study concluded.

Swan’s interest in phthalates stems from an investigation into the environmental causes of reproductive health problems. Since 1998 she has led the federally funded, multi-center Study for Future Families (SFF), which established a large database from which to explore various scientific questions about toxins.

The current study focused on a small sample of SFF mothers who delivered children between 2000 and 2003. The mothers provided urine samples around the 28th week of pregnancy. The urine was analyzed for phthalate metabolites by the Centers for Disease Control and Prevention (CDC).

Swan hypothesized that phthalates may lower fetal testosterone production during a critical window of development – somewhere within eight to 24 weeks gestation, when the testes begin to function – thereby altering brain sexual differentiation.

To explore the question, researchers reconnected with mothers from the SFF sample and asked them to complete a standard research questionnaire, called the Preschool Activities Inventory (PSAI), for their children ages 3 1/2 to 6 1/2 years.

The PSAI is designed to discriminate play behavior within and between the sexes, and in the past has been shown to reflect the endocrine-disrupting properties of other toxins, such as PCBs and dioxins. The PSAI addressed three aspects of play: types of toys children choose (trucks versus dolls), activities (rough-and-tumble play, for example), and child characteristics.

However, researchers were concerned about how the choice of toys available in any given household might skew results, so in addition they asked about parental views toward atypical play. For example, the survey asked, “What would you do if you had a boy who preferred toys that girls usually play with?” The possible answers included “strongly encourage” (him to play this way) to “strongly discourage.”

The final survey scores are designed to reflect sex-typical play. Higher scores meant more male-typical play and lower scores meant more female-typical play.

Researchers then examined boys play-behavior scores in relation to the concentration of phthalate metabolites in their mothers’ prenatal urine samples, finding that higher concentrations of DEHP and DBP metabolites were associated with less masculine play behavior scores.

Earlier studies by Swan and others have shown that phthalate exposure during pregnancy might affect the development of genitals of both male rodents and baby boys. Scientists refer to this cluster of genital alterations as the “phthalate syndrome,” and research suggests that in rodent pups, the syndrome can have adverse consequences for later sexual development.

If endocrine disrupters such as phthalates can impair genital development and hormone levels in the body, the play-behavior study noted, then a deeper examination of how these chemicals impact the brain is warranted.

Reference: University of Rochester Medical Center, Pilot study relates phthalate exposure to less-masculine play by boys, Nov. 16, 2009

Autism affects an estimated 1 in 150 children today, making it more common than childhood cancer, juvenile diabetes and pediatric AIDS combined. Despite its widespread effect, autism is not well understood and there are no objective medical tests to diagnose it. Recently, University of Missouri researchers have developed a pupil response test that is 92.5 percent accurate in separating children with autism from those with typical development. In the study, MU scientists found that children with autism have slower pupil responses to light change. 

“No comprehensive study has been conducted previously to evaluate the pupils’ responses to light change, or PLR, in children with autism,” said Gang Yao, associate professor of biological engineering in the MU College of Agriculture, Food and Natural Resources and the College of Engineering. “In this study, we used a short light stimulus to induce pupil light reflexes in children under both dark and bright conditions. We found that children with autism showed significant differences in several PLR parameters compared to those with typical development.” 

In the study, scientists used a computerized binocular infrared device, which eye doctors normally use for vision tests, to measure how pupils react to a 100-millisecond flash light. A pupil reaction test reveals potential neurological disorders in areas of the brain that autism might affect. The results showed that pupils of children diagnosed with autism were significantly slower to respond than those of a control group. 

“There are several potential mechanisms currently under study,” Yao said. “If these results are successfully validated in a larger population, PLR response might be developed into a biomarker that could have clinical implications in early screening for risks of autism. Studies have shown that early intervention will improve these children’s developmental outcome.” 

Yao’s study, completed with Xiaofei Fan, post-doctoral fellow at MU, Judith Miles, professor and William S. Thompson Endowed Chair in Child Health, and Nicole Takahashi, senior research specialist at MU’s Thompson Center for Autism and Neurological Disorders, has been published in the Journal of Autism and Developmental Disorders. In October, the scientists received a grant from the National Institutes of Health for the next phase. For this study, the researchers hope to amplify the earlier study’s measurements and investigate any correlation between PLR and several other medical conditions that could be associated with autism. 

Reference:

Xiaofei Fan, Judith H. Miles, Nicole Takahashi and Gang Yao. Abnormal Transient Pupillary Light Reflex in Individuals with Autism Spectrum Disorders. Journal of Autism and Developmental Disorders, 2009; 39 (11): 1499 DOI: 10.1007/s10803-009-0767-7 

Adapted from materials provided by University of Missouri-Columbia, via EurekAlert! Nov. 11, 2009

Picture: University of Missouri

Little attention has been paid to possible cardiovascular involvement in patients with chronic fatigue syndrome (CFS), although many of their symptoms and signs suggest cardiovascular dysfunction. Possible cardiovascular symptoms and cardiac function were investigated in CFS patients. 

Cardiovascular symptoms were intensively investigated and cardiac function was evaluated echocardiographically. Fifty-three patients (23 men and 30 women, mean age: 31+/-7 years) with CFS under 50 years were studied. 

Slender build (body mass index <20 kg/m(2)) was common (47%). Possible cardiovascular symptoms including shortness of breath (32%), dyspnea on effort (28%), rapid heartbeat (38%), chest pain (43%), fainting (43%), orthostatic dizziness (45%) and coldness of feet (42%), were all frequent complaints. Hypotension (28%) was occasionally noted. Electrocardiograms frequently revealed right axis deviation (21%) and severe sinus arrhythmia (34%) suggesting accentuated parasympathetic nervous activity. Small heart shadow (cardiothoracic ratio <or=42%) was noted on the chest roentgenogram in 32 patients (60%). Echocardiographic examination demonstrated low cardiac indexes (<2 L/min/m(2)) with low stroke volume indexes (<30 mL/m(2)) due to a small left ventricular chamber in 19 (36%, p<0.05 vs. 8% in 36 controls). None had reduced left ventricular ejection fraction. 

Cardiovascular symptoms are common in CFS patients. Cardiac dysfunction with low cardiac output due to small left ventricular chamber may contribute to the development of chronic fatigue as a constitutional factor in a considerable number of CFS patients. 

Reference: Miwa K, Fujita M., Cardiovascular dysfunction with low cardiac output due to a small heart in patients with chronic fatigue syndrome, Intern Med. 2009;48(21):1849-54.