Amir Miodovnik

Prenatal Phthalate Exposure Is Associated with Childhood Behavior and Executive Functioning

Background Experimental and observational studies have reported biological consequences of phthalate exposure relevant to neurodevelopment. Objective Our goal was to examine the association of prenatal phthalate exposure with behavior and executive functioning at 4–9 years of age. Methods The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urines were collected and analyzed for phthalate metabolites. Children (n = 188, n = 365 visits) were assessed for cognitive and behavioral development between the ages of 4 and 9 years. Results In multivariate adjusted models, increased loge concentrations of low molecular weight (LMW) phthalate metabolites were associated with poorer scores on the aggression [β = 1.24; 95% confidence interval (CI), 0.15– 2.34], conduct problems (β = 2.40; 95% CI, 1.34–3.46), attention problems (β = 1.29; 95% CI, 0.16– 2.41), and depression (β = 1.18; 95% CI, 0.11–2.24) clinical scales; and externalizing problems (β = 1.75; 95% CI, 0.61–2.88) and behavioral symptom index (β = 1.55; 95% CI, 0.39–2.71) composite scales. Increased loge concentrations of LMW phthalates were also associated with poorer scores on the global executive composite index (β = 1.23; 95% CI, 0.09–2.36) and the emotional control scale (β = 1.33; 95% CI, 0.18– 2.49). Conclusion Behavioral domains adversely associated with prenatal exposure to LMW phthalates in our study are commonly found to be affected in children clinically diagnosed with conduct or attention deficit hyperactivity disorders.

Endocrine disruptors and childhood social impairment.

Prenatal exposure to endocrine disruptors has the potential to impact early brain development. Neurodevelopmental toxicity in utero may manifest as psychosocial deficits later in childhood. This study investigates prenatal exposure to two ubiquitous endocrine disruptors, the phthalate esters and bisphenol A (BPA), and social behavior in a sample of adolescent inner-city children. Third trimester urines of women enrolled in the Mount Sinai Childrens Environmental Health Study between 1998 and 2002 (n=404) were analyzed for phthalate metabolites and BPA. Mother-child pairs were asked to return for a follow-up assessment when the child was between the ages of 7 and 9 years. At this visit, mothers completed the Social Responsiveness Scale (SRS) (n=137), a quantitative scale for measuring the severity of social impairment related to Autistic Spectrum Disorders (ASD) in the general population. In adjusted general linear models increasing log-transformed low molecular weight (LMW) phthalate metabolite concentrations were associated with greater social deficits (β=1.53, 95% CI 0.25-2.8). Among the subscales, LMWP were also associated with poorer Social Cognition (β=1.40, 95% CI 0.1-2.7); Social Communication (β=1.86, 95% CI 0.5-3.2); and Social Awareness (β=1.25, 95% CI 0.1-2.4), but not for Autistic Mannerisms or Social Motivation. No significant association with BPA was found (β=1.18, 95% CI -0.75, 3.11). Prenatal phthalate exposure was associated with childhood social impairment in a multiethnic urban population. Even mild degrees of impaired social functioning in otherwise healthy individuals can have very important adverse effects over a childs lifetime. These results extend our previous finding of atypical neonatal and early childhood behaviors in relation to prenatal phthalate exposure.

Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6-10 years of age.

Background: There is concern over potential neurobehavioral effects of prenatal phthalate exposures, but available data are inconsistent. Objectives: We examined associations between prenatal urinary concentrations of phthalate metabolites and neurobehavioral scores among children. Methods: We measured phthalate metabolite concentrations in urine samples from 153 pregnant participants in the Study for Future Families, a multicenter cohort study. Mothers completed the Child Behavior Checklist when the children were 6–10 years of age. We estimated overall and sex-specific associations between phthalate concentrations and behavior using adjusted multiple regression interaction models. Results: In boys, concentrations of monoisobutyl phthalate were associated with higher scores for inattention (β = 0.27; 95% CI: 0.04, 0.50), rule-breaking behavior (β = 0.20; 95% CI: 0.01, 0.38), aggression (β = 0.34; 95% CI: 0.09, 0.59), and conduct problems (β = 0.39; 95% CI: 0.20, 0.58), whereas the molar sum of di(2-ethylhexyl) phthalate metabolites was associated with higher scores for somatic problems (β = 0.15; 95% CI: 0.03, 0.28). Higher monobenzyl phthalate concentrations were associated with higher scores for oppositional behavior (β = 0.16; 95% CI: 0.01, 0.32) and conduct problems (β = 0.21; 95% CI: 0.06, 0.37) in boys, but with reduced anxiety scores in girls (β = –0.20; 95% CI: –0.39, –0.01). In general, the associations reported above were close to the null among girls. Model coefficients represent the difference in the square root–transformed outcome score associated with a 1-unit increase in log-transformed metabolites. Conclusions: Our results suggest associations between exposure to certain phthalates in late pregnancy and behavioral problems in boys. Given the few studies on this topic and methodological and population differences among studies, additional research is warranted. Citation: Kobrosly RW, Evans S, Miodovnik A, Barrett ES, Thurston SW, Calafat AM, Swan SH. 2014. Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6–10 years of age. Environ Health Perspect 122:521–528; http://dx.doi.org/10.1289/ehp.1307063

Environmental Neurotoxicants and Developing Brain

The brain of infants and children is uniquely sensitive to environmental neurotoxicants at levels far below those that are known to harm adults. There are multiple windows of vulnerability during which environmental exposures can interfere with normal development. The timing and duration of neurotoxicant exposures during development can give rise to a broad spectrum of structural and functional deficits. Only about 200 chemicals out of more than 80,000 registered with the United States Environmental Protection Agency have undergone extensive neurotoxicity testing, and many chemicals found in consumer goods are not required to undergo any neurodevelopmental testing. The cumulative effects of co-contaminants and the difficulties in analyzing biomarkers of exposure in human tissues have complicated comprehensive risk assessment. Furthermore, population-based studies that measure subtle effects on neurobehavioral outcomes are challenging to interpret and costly to conduct. Despite the fact that developmental neurotoxicity may be more severe and irreversible compared with adult toxicity, there is a relative paucity of toxicological data on developing systems for many high-production chemicals. This article provides an overview of the adverse neurological, cognitive, and behavioral outcomes associated with environmental exposures, with an emphasis on human studies.

Children's health and the environment: an overview.

Environmental pediatrics, the branch of pediatric medicine that studies the influence of the environment on childrens health, has in the past decade grown exponentially. Rising rates of pediatric chronic disease and growing recognition of childrens extensive exposures and great vulnerabilities to toxic hazards in the environment have catalyzed this expansion. New scientific initiatives have resulted. They include 14 Centers for Childrens Environmental Health and Disease Prevention Research supported by the US National Institutes of Health and the US Environmental Protection Agency; a global network of Pediatric Environmental Health Specialty Units supported by the US Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry; new postdoctoral training programs in pediatric environmental medicine; and the National Childrens Study, the largest prospective epidemiological study of childrens health ever undertaken in the United States, which launched in 2009 and will follow 100,000 children from conception to age 21 to assess environmental influences on health and development. These research initiatives have delineated the exquisite vulnerability of fetuses, infants, and children to toxic hazards in the environment. They have led to discovery of new environmental causes of disease and disability in children. This issue of The Mount Sinai Journal of Medicine focuses on childrens health and the environment. We have brought together thought leaders in childrens environmental health to critically examine new research findings, to explore new opportunities for translating research to treatment and prevention, and to offer a vision for the future of this rapidly expanding field.

Polymorphisms in the maternal sex steroid pathway are associated with behavior problems in male offspring.

Objective Slight perturbations in maternal sex steroid production and metabolism may interfere with normal fetal neurodevelopment. The balance of maternal estrogens and androgens may have direct fetal effects, may influence the fetal hypothalamic–pituitary–gonadal axis, or may alter local hormonal activity within the fetal brain. We investigated maternal functional polymorphisms of CYP17, CYP19, and CYP1B1, which control three major enzymatic steps in sex steroid biosynthesis and metabolism, in relation to childhood behaviors. Methods The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic urban pregnancy cohort from 1998 to 2002 (n=404). DNA was obtained from maternal blood (n=149) and from neonatal cord blood (n=53). At each visit, mothers completed the Behavior Assessment System for Children, a parent-reported questionnaire used to evaluate children for behavior problems. We focused on problem behaviors more commonly associated with attention deficit-hyperactivity disorder (Hyperactivity, Attention Problems, Externalizing Behaviors, Conduct Disorder, Poor Adaptability) to determine whether maternal genetic variants in sex steroid production and metabolism influence sexually dimorphic behaviors in offspring. Results The more active gene variants were significantly associated with Attention Problems and poorer Adaptive Skills in male compared with female offspring. The CYP19 variant allele was also significantly associated with worse scores for boys on the Hyperactivity, Externalizing Problems Composite, and Adaptive Skills Composite scales (P<0.05). Conclusion We observed maladaptive behaviors in the male offspring of mothers who carried functional polymorphisms in the sex steroid pathway. The strongest associations were in domains commonly affected in attention deficit-hyperactivity disorder.

The U.S. Food and Drug Administration risk assessment on lead in women's and children's vitamins is based on outdated assumptions.

Background Following a recent report of lead in certain commercial vitamin products, the U.S. Food and Drug Administration (FDA) conducted a nationwide survey to determine the Pb content in 324 multivitamin/mineral products labeled for use by women and children. The FDA compared estimated Pb exposures from each product with safe/tolerable exposure levels, termed provisional total tolerable intake (PTTI) levels, previously developed for at-risk population groups in 1992. Objective We investigated the FDA’s conclusions that Pb concentrations in all vitamin products examined do not pose a hazard to health because they are below the PTTI levels for all groups considered. Discussion For their initial estimations of PTTI levels, the FDA used a blood lead level (BLL) of 10 μg/dL as the threshold for adverse effects in children and in pregnant or lactating women. Studies have repeatedly linked chronic exposure to BLLs < 10 μg/dL with impairments in cognitive function and behavior in young children despite the absence of overt signs of toxicity. The FDA analysis also omitted any consideration of nonfood sources of Pb exposure, which is inconsistent with our current understanding of how most children develop elevated BLLs. Conclusion We feel that based on these oversights, the FDA’s conclusions are unduly reassuring and that reconsideration of their current recommendations appears warranted.