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Tuesday, October 6, 2015

Chemical Threats

From the American Psychological Association Monitor

By Stacy Lu
October, 2015, Vol. 46, No. 9

Researchers are discovering potential links between chemicals in common household items and damage to developing brains.

We know that lead and alcohol can harm children's brains, but a growing amount of research suggests that chemicals known as endocrine disruptors — found in everyday household products including pesticides, plastics and fire repellants — may also contribute to a range of behavioral and learning problems, including autism and attention-deficient hyperactivity disorder (ADHD).

Endocrine disruptors can affect the way estrogen, androgen and thyroid hormones are produced, transmitted and metabolized, affecting developing brains as well as reproductive health. Common in the environment, in wildlife and in almost every human, they can be transmitted to fetuses in utero, and are often present in greater concentrations in infants and young children, just when their developing brains may be most vulnerable.

Hundreds of studies have explored the mechanisms of how these chemicals affect animals' hormones, and more recent human studies suggest effects on children's learning and behavior. They may be slight in an individual, a difference of an IQ point or two or a "quirk that veers children off their normal path of development," says Kimberly Yolton, PhD, a developmental psychologist and researcher at Cincinnati Children's Hospital. "In the environmental toxins I'm studying, the changes are very subtle and difficult to detect, but they're there."

In a 2012 report, the United Nations Environment Programme and World Health Organization (WHO) said endocrine disruptors pose "significant health implications" and called for more research on them. In 2014, an Endocrine Society panel concluded that endocrine disruptors likely contributed to neurobehavioral deficits and disability, including autistic disorders. The panel estimated that the total costs to the EU are some 150 billion euros (U.S. $170 billion) per year in treatment and lost productivity (Journal of Clinical Endocrinology and Metabolism, 2015).

In addition, many researchers suspect that the cumulative effect of endocrine disrupting chemicals is contributing to the rise of neurodevelopmental disorders in children over the past two decades.

"The concentrations of hormones regulating [neurodevelopment] are low in the body, so it doesn't take much to disrupt the endocrine system," says psychologist David Bellinger, PhD, senior researcher at Boston Children's Hospital and a professor of environmental health at the Harvard School of Public Health who has studied the issue. "And that's not going to [affect] just one cognitive outcome, it's going to hit many sex and social behaviors."

Everyday Household Toxins

What worries some scientists is that endocrine disrupting chemicals are virtually inescapable and appear to be harmful even in low quantities. For example, some pesticides with known toxicity have been associated with developmental delays and autism in children exposed to high levels of the chemicals, such as children in agricultural communities, according to a number of studies from researchers at the University of California, Davis (Environmental Health Perspectives, 2014).

Yet even common household chemicals may present a risk. In a national sample of 687 children ages 8 to 15, boys with detectable levels of pyrethroid pesticides — the most commonly used insecticide in homes — in their urine were more than twice as likely to have hyperactive and impulsive symptoms compared with boys who had levels below detection, according to a study by Melissa Wagner-Schuman, M.D., of Cincinnati Children's Hospital, and colleagues, including Yolton (Environmental Health, 2015). The association was not seen in girls.

Because these chemicals appear to have effects on sex hormones in animal models, outcomes that differ by gender are common in endocrine disruption research, Yolton says. As a potential mechanism, the researchers pointed out that mice exposed to pyrethroids show effects on the brain's dopamine transporter levels, especially in male mice. Previous studies have suggested that pyrethroids disrupt dopamine levels in humans, a condition associated with ADHD.

Other endocrine disruptors may be even more prevalent than those in pesticides.

Phthalates, for example, are added to plastics to make them flexible and are known to leach into the environment. In experimental studies, these chemicals have been shown to alter levels of some thyroid hormones, according to a 2014 review in NeuroToxicology by Amir Miodovnik, M.D., a developmental pediatrician and researcher at Boston Children's Hospital, along with Bellinger and other colleagues. Thyroid hormones are important to brain cell growth, neuronal migration and differentiation, as well as in the formation of synapses.

Human studies suggest that early exposure to phthalates may be associated with a variety of childhood outcomes, including disruptive behavior, reduced masculine play in boys, and social and learning problems.

In 2008, Congress banned some phthalates from "accessible parts" in children's toys and child-care products, but phthalates are still used in vinyl, plastic wrap and food containers, and in scented products, such as dryer sheets and air fresheners. They're also elements of fragrances used in scented soaps, lotions and shampoos, one reason that women of reproductive age may have higher levels of the chemical in their bodies than men.

Pam Factor-Litvak, Ph.D., and colleagues from the Columbia University Mailman School of Public Health found that children exposed during pregnancy to elevated phthalate levels had IQ scores more than six points lower, on average, than children exposed at lower levels (PLOS ONE, 2014).

A study by Roni Kobrosly, Ph.D., of Mount Sinai Hospital, and colleagues looked at phthalate levels of 153 pregnant women. The researchers found that higher levels of some phthalates in the pregnant women were associated with conduct and attention problems in their male children (Environmental Health Perspectives, 2014).

Phthalate exposure may also affect social communication, "one of the core symptoms of autism," says Miodovnik. He and colleagues analyzed phthalate concentrations obtained from 404 inner-city pregnant women whose children were later evaluated for social impairments at ages 7 to 9. The children of mothers with higher concentrations of phthalates had poorer scores on measures of social cognition, social communication and social awareness (NeuroToxicology, 2011).

Another ubiquitous chemical is bisphenol A (BPA), which is used to make polycarbonate plastics. It's in some food containers, including the lining of many soda and soup cans, as well as thermal receipt paper commonly used in cash registers. BPA can also migrate into the mouth from compounds used in dental sealants and fillings. It's been found in the urine of more than 90 percent of a nationally representative population. Research shows it might act like estrogen in the body and potentially alter estrogen, androgen and thyroid transmission signals, according to Thaddeus Schug, Ph.D., a researcher at the National Institute of Environmental Health Sciences, and colleagues (Endocrinology, 2015).

Studies in animals and humans suggest it affects reproductive and social behaviors. Neuroscientist Sarah Evans, Ph.D., of Mount Sinai Hospital, and colleagues, conducted a study of 125 women with detectable BPA in their urine at 27 weeks of pregnancy. The researchers found a significant association between levels of BPA and rule-breaking, depression and conduct problems in boys age 6 to 10, but not in girls (NeuroToxicology, 2014).

Critical Windows of Exposure

Timing appears to matter as well as gender; a number of studies show that prenatal exposure to toxins is more likely to be associated with IQ drops and behavior issues in boys than in girls. A team of researchers at Columbia University Mailman School of Public Health measured pre- and post-natal BPA exposure and behavioral measures in children at ages 3 to 5 and again at ages 7 to 9 (Environmental Research, 2015). Boys exposed to higher levels of BPA showed more behavioral problems at both time points, including aggression and rule-breaking, as well as sleep problems, though girls had no similar detectable issues. With exposure in early childhood, though, the chemical appeared to affect girls more than boys.

"Boys and girls develop very differently, and so when there is disruption of the endocrine system, it's going to affect them differently," Yolton says.

Those effects are even more striking when it comes to reproductive health. Evidence in animal studies suggests that very high levels of endocrine disruptors may lead to congenital anomalies in males and early puberty in females, according to a 2012 report by the WHO. Phthalates specifically are associated with uterine abnormalities and with reduced testicle weight and sperm production, and flame retardants with cryptorchidism, or undescended testes.

Humans can excrete BPA, but another class of chemicals used as flame retardants in mattresses, furniture foam and carpet backing tends to linger, particularly in fatty tissue. Manufacturers began to phase out one of these chemical classes, polybrominated diphenyl ethers (PBDEs), in 2004 after scientists found it accumulated in our bodies, in breast milk and in the larger environment. Particles of these chemicals migrate from products and settle into dust, so crawling children who often put fingers and items into their mouths are more likely to come into contact with them, leading to body levels some three to nine times that for adults.

PBDEs are chemically similar to thyroid hormones, which explains why they may tamper with brain development. In a study by epidemiologist Aimin Chen, M.D., of the University of Cincinnati College of Medicine, and colleagues, higher prenatal exposure to PBDEs was correlated with lower IQs of up to five points and higher hyperactivity in 5-year-old children, though researchers saw no effects at earlier ages (Environmental Health Perspectives, 2014).

A 2013 study in the same journal by epidemiologist Brenda Eskenazi, Ph.D., and colleagues from the University of California, Berkeley, found that children whose mothers had the highest urine levels of PBDEs were more likely to have impaired attention at age 5, decreases in verbal and total IQ scores at age 7, and poorer fine motor coordination during both time frames.

The chemicals have also been implicated in autism. Led by Janine LaSalle, Ph.D., a biologist at the University of California, Davis, researchers studied female mice with a genetic mutation associated with autism, and exposed some of them to PBDEs. Their female offspring showed impaired learning, memory and social skills (Human Molecular Genetics, 2012).

Safe Until Proven Toxic

Though there are hundreds of animal studies involving endocrine disruptors, studying the potential effects of endocrine disruptors in humans is daunting. First, proving causation is extremely difficult, involving an "incalculable number of parameters," says Susan Koger, Ph.D., professor of psychology at Willamette University and co-author of the forthcoming book "Psychology for Sustainability" (Scott, Amel, Koger, & Manning, 2016).

"Endocrine disruptors are manipulating our biochemical milieu and interacting with our own hormonal system, and it's very difficult to determine their specific impacts because there are so many variables," Koger says.

Because of the different ways they signal cell receptors, some chemicals, including BPA, may have what's called a nonmonotonic dose response curve, with a small exposure sometimes being more harmful than a larger one. Plus, there are many ways humans take them in: via food, including breast milk, through the skin or by breathing them. Exposures, even to the same toxin, may affect one developmental stage but not another, or their effects may vary according to genetic makeup. And finally, effects may not show up until years — or generations — later.

"The dream study involves measuring reliable biomarker levels, including chemical mixtures, in a large cohort of women starting prenatally and covering multiple time points throughout pregnancy and beyond," Miodovnik says. "In addition, health outcomes in the offspring would be assessed using the same, well-validated instruments. Finally, the analysis would control for other confounding risk factors, including the home environment, secondhand tobacco smoke, and family history of psychopathology."

The chemicals may also interact with each other in ways that we don't understand, as Yolton pointed out in a 2014 review in Neurotoxicology and Teratology.

"When we study these combinations by putting multiple exposures into our statistical models, we find different results than when we examine one toxicant at a time," she says. "For example, exposure to lead is clearly harmful, but we're also seeing more dramatic associations when we add flame retardants and other chemicals," adding that research with sufficient sample sizes and lab testing to measure combinations in humans would cost "gobs of money."

Poverty may be another contributing factor, and not only because poor children are more likely to live in areas where they're exposed to pollution or industrial byproducts. Frederica Perera, Ph.D., at Columbia's Mailman School, and colleagues found that even with equal exposure to air pollution, children in families facing greater material hardship had poorer working memory scores (Neurotoxicology and Teratology, 2015). Previous studies showed isolated animals exposed to lead had poorer cognitive function than animals in enriched environments.

"There are lots of data now showing that prenatal stress can change the patterns of DNA methylation, and that appears to be transmissible between generations," says psychologist Bernard Weiss, Ph.D., professor emeritus at the University of Rochester Medical Center, who has researched toxicants for decades. "So here you have an effect of a stressful socioeconomic environment on brain function, plus exposure to toxic substances. That's a lethal combination."

Lifestyle may promote resiliency, too. Yolton studied neonatal exposure to phthalates and behavioral outcomes in 5-week-old babies. The babies born to mothers with higher levels of one kind of phthalate in their urine actually showed developmental benefits; they were more easygoing and had better self-regulation and movement abilities (Neurotoxicology and Teratology, 2011). However, the mothers were generally more affluent and had healthier lifestyles, which Yolton says may have outweighed harmful chemical influences.

In another study in Environmental Health (2013), she found that pregnant women with higher levels of pesticides in their bodies also ate more fruits and vegetables. They also had higher education and income. The babies showed no harmful effects from the pesticides. In fact, they were more active and showed better attention skills than infants of women with lower levels — but that may be because of more beneficial environments and their mothers' healthier diets, Yolton says.

"These things are everywhere, but at some level, maybe some of these chemicals are OK and we can keep using them. But the ones that are unsafe, we need to get off the market," she says. Yet there are relatively few studies showing a lack of effect of endocrine disruptors — a negative outcome "isn't as flashy or exciting," she says — which makes it even harder for officials and the public to assess and prevent truly harmful exposures.

The field also needs more developmental psychologists working with environmental epidemiologists, experts say.

"Researchers will call me and say, ‘Which instrument should I use to measure this outcome?'" Yolton says. "Having more psychologists in this field is critical because these environmental toxicants are primarily acting on the central nervous system, and who studies the development of the brain over time? We do."

The Regulatory Environment

Current regulations in the United States don't encourage testing of endocrine-disrupting chemicals. Through the Toxic Substances Control Act of 1976, the U.S. Environmental Protection Agency (EPA) may require chemical manufacturers to provide evidence that a new product is safe only if the EPA can prove it poses an "unreasonable" risk to humans that far outweighs cost considerations. However, the EPA has only 90 days to request testing and has only done so for some 200 chemicals. Meanwhile, manufacturers often dispute what findings there are, contributing to delays, researchers say. As a result, of the roughly 83,000 chemicals in use, only five have been broadly regulated with limits on their production and use. Even asbestos use is still legal.

In contrast, under what's called the "precautionary principle," the European Union requires manufacturers to test their own products for safety before they can go to market. The Government Accountability Office deemed the EPA's review and control process for toxic chemicals "high risk" in 2009, due to its failure to limit people's exposure to risky substances.

"It's like Sisyphus — as soon as you roll the boulder up the mountain, it starts to roll down as chemical manufacturers counter your studies with their own data. They may say, ‘Well, you haven't replicated the study results yet,' or, ‘You can't rely on epidemiological studies to show that the chemical causes harm,'" Miodovnik says. "But the truth is, epidemiological studies in humans are not designed to establish the mechanism or the level at which these chemicals cause toxicity."

Yet if scientists do find evidence of harm for one chemical, its replacement may be from the same class, and potentially with the same or worse risks — what scientists call a "regrettable substitution." For example, many manufacturers have replaced BPA with BPS, a similar chemical, and early testing shows that BPS may also have endocrine activity. Companies are replacing PBDEs with chemical compounds in the same class, halogenated flame retardants.

The American Academy of Pediatrics, along with a number of other organizations, petitioned the Consumer Product Safety Commission in March to ban that entire class of chemicals in four types of consumer products, claiming they presented the same range of exposure and health risks.

Many agree the system needs overhauling. At Monitor press time, the Senate was debating a new bill introduced by Sens. Tom Udall (D-N.M.) and David Vitter (R-La.) that would require testing of all chemicals on or coming to market, among other reforms. Many previous bills have failed, however, as environmental groups and Democrats argued they didn't go far enough, and the Udall-Vitter bill may share the same fate.

The EPA, along with the National Institutes of Health (NIH) and the Food and Drug Administration, is developing a strategy it calls Toxicology Testing in the 21st Century, or Tox21, that uses robots, in vitro testing and computational models to assess risk and set review priorities. The system can test thousands of chemicals at once, potentially bypassing lengthy animal studies, says Linda Birnbaum, PhD, director of the NIH's National Toxicology Program and the National Institute of Environmental Health Sciences.

"We're trying to move toxicology into a more predictive science where we take a systems biology approach," she says, adding that of chemicals tested so far, "We're definitely seeing some things giving us signatures of biological activity."

In the meantime, researchers in the field worry about a process that leads to too little prevention, too late.

"It usually does take us a while to sort out these things," Bellinger says. "It took about 20 years before we started to see a strong signal from lead. The animal toxicological evidence is very persuasive [for endocrine disruptors]; it would be nice to go from animal studies to regulation and not wait for human studies. It makes sense to shift the onus to industry to show these products are safe before they're introduced to market so we can stop using our children as guinea pigs."

Further Reading
  • Bellinger, D. C. (2013). Prenatal exposures to environmental chemicals and children's neurodevelopment: An update. Safety and Health at Work, 4(1), 1–11. doi:10.5491/SHAW.2013.4.1.1
  • Grandjean, P., & Landrigan, P. J. (2014). Neurobehavioural effects of developmental toxicity. The Lancet Neurology, 13(3), 330–338. doi:10.1016/S1474-4422(13)70278-3
  • Lanphear, B. (2015). The impact of toxins on the developing brain. Annual Review of Public Health, 36, 211-230. doi: 10.1146/annurev-publhealth-031912-114413
  • United States Environmental Protection Agency. (2013). America's Children and the Environment (3rd. Ed.). (Report No. 1909T/1107T) Retrieved from

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