Phthalate biomarkers and associations with respiratory symptoms and healthcare utilization among low-income urban children with asthma

Highlights

• Phthalates may be associated with increased morbidity risk in children with asthma.

• DEHP and BBzP may increase odds of asthma symptoms and healthcare utilization.

• Exposure to DEHTP, a DEHP replacement, may be linked with asthma symptoms.

• Results warrant replication given ubiquitous phthalate exposures worldwide.

Abstract

Background

Phthalates are synthetic chemicals present in building materials, personal care products and other consumer goods. Limited studies link phthalates to pediatric asthma incidence; however, their effects on respiratory-related outcomes among those with pre-existing asthma remains unclear.

Objective

We examined associations between phthalates and asthma symptoms, healthcare use, lung function, and lung inflammation among children with asthma.

Methods

We collected repeated measures of urinary biomarkers for select phthalates and phthalate replacements (MBzP, MCINP, MCIOP, MCPP, MECPTP, MEHHTP, molar sum of DEHP biomarkers [MECPP, MEHHP, MEHP, MEOHP], MEP, MiBP, MnBP) and asthma symptoms, healthcare utilization, lung function, and inflammation among 148 predominantly low-income Black children (5–17 years) with persistent asthma every 3 months for one year. We used generalized estimating equations to assess associations between biomarker concentrations and asthma-related measures adjusting for age, sex, race/ethnicity, caregiver's education level, presence of smokers in the home, and season. We also considered co-exposures to other contaminants previously associated with asthma morbidity.

Results

We observed consistent positive associations with individual DEHP biomarkers, the molar sum of DEHP, and BBzP with increased odds of asthma symptoms and with healthcare utilization (adjusted Odds Ratio for general asthma symptoms: ΣDEHP:1.49,95% Confidence Interval, CI:1.08–2.07; BBzP:1.34, CI:1.04–1.73). We observed similar associations between the DEHP phthalate replacement biomarker MEHHTP and most asthma symptoms evaluated; and with select low molecular weight phthalates (DiBP, DBP) and healthcare utilization. Results were similar when controlling for other environmental exposures (e.g., PM_2.5, BPA). No associations were observed with lung function or inflammation, and overall, we did not observe consistent evidence of sexually dimorphic effects.

Conclusion

In the present study, we found evidence to suggest that exposure to select phthalates may be associated with asthma symptoms and healthcare utilization. These findings warrant confirmation given the high asthma burden and widespread and disparate phthalate exposures reported among select populations of color.

Introduction

Asthma is a chronic pediatric disease, impacting over 6 million U.S. children (∼7% of U.S. children) and disproportionately affecting Black and Latinx children (Assari and Moghani Lankarani, 2018; Centers for Disease Control and Prevention, 2020; Forno and Celedón, 2009). Emerging evidence suggests that exposure to environmental agents with endocrine disrupting properties like phthalates may increase risk of asthma development and alteration of immune function (Benjamin et al., 2017; Li et al., 2017; North et al., 2014; Robinson and Miller, 2015). Phthalates are synthetic chemicals widely used as plasticizers to impart flexibility and durability and also used as solvents in many consumer products. Phthalates may be grouped into low and high molecular weight. Beyond their chemical properties these two groups generally reflect distinct exposure sources. Low molecular weight phthalates are mostly used in a variety of personal hygiene and cosmetic products, such as fragrances as scent stabilizers; while high molecular weight phthalates are commonly used as plasticizers, including in toys, medical equipment, polyvinyl chloride (PVC) building materials, and as excipients in medications (North et al., 2014; Wang et al., 2019). The primary route of exposure among school-aged children, particularly to high molecular weight phthalates, is believed to be dietary ingestion (foods and drinks packaged in plastic); other exposure routes include inhalation and dermal absorption (Benjamin et al., 2017; Wang et al., 2019).

Although the underlying mechanisms by which phthalates could impact respiratory health have not been clearly elucidated, prior reviews on experimental studies indicate that phthalates can increase allergic immune response, contribute to airway remodeling (Kimber and Dearman, 2010), and possibly induce asthma (Bølling et al., 2020; North et al., 2014; Tsai et al., 2012). Experimental studies also report inconsistent inflammatory pathways based on exposure route and dose, (Kimber and Dearman, 2010), but overall suggest that phthalates may induce oxidative stress, and initiate and augment Th2-dominated airway inflammation potentially leading to adverse respiratory effects (Alfardan et al., 2018; Benjamin et al., 2017; Bølling et al., 2020; Robinson and Miller, 2015). Increasing epidemiologic evidence also continues to support the possible association of phthalates with the development of allergic conditions and asthma (Benjamin et al., 2017; North et al., 2014; Robinson and Miller, 2015; Wang et al., 2019). For example, cross-sectional studies in the U.S. have reported positive associations between phthalate biomarker concentrations and current asthma in children and adults (Hoppin et al., 2013; Odebeatu et al., 2019). Phthalates have also been associated with asthma incidence and allergy symptoms in studies conducted in other countries around the world including Taiwan (Hsu et al., 2012), Sweden (Bornehag et al., 2004), and China (Shi et al., 2018). At present, most studies have focused on asthma incidence in adult populations or in understanding the role of prenatal phthalate exposures on pediatric asthma development; however, studies on the role of phthalates as environmental triggers among those with respiratory conditions remain limited (Benjamin et al., 2017; Li et al., 2017; Wang et al., 2019). For example, the role of phthalate exposure in asthma-related symptoms among those with chronic asthma remains unclear despite ubiquitous and disparate human exposure to phthalates and emerging links with asthma incidence and development (Benjamin et al., 2017; Odebeatu et al., 2019). Furthermore, due to emerging evidence of health concerns linked to phthalates, newer phthalate replacements (such as Di-2-ethylhexyl terephthalate, DEHTP, and di (isononyl)cyclohexane-1,2-dicarboxylate, DINCH) are being widely used even though very limited information about their health impacts exists (Silva et al., 2013, 2019).

In the present study, we sought to examine associations between urinary phthalate biomarker concentrations and concurrent asthma symptoms, healthcare utilization, lung function, and lung inflammation among children with asthma in a low-income urban setting. We also include newer phthalate replacements introduced to the market in recent years given limited exposure and epidemiologic data on these chemical substitutes. We hypothesized that exposure to phthalates and newer replacements would be associated with increased asthma symptoms and healthcare utilization, altered pulmonary function and increased lung inflammation.