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Baby Care Products: Possible Sources of Infant Phthalate Exposure

^a Departments of Occupational and Environmental Health Sciences
^b Pediatrics
^c Biostatistics, University of Washington, Seattle, Washington
^d Centers for Disease Control and Prevention, Atlanta, Georgia
^e Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, New York

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVES. Phthalates are man-made chemicals found in personal care and other products. Recent studies suggest that some phthalates can alter human male reproductive development, but sources of infant exposure have not been well characterized. We investigated the relationship between phthalate metabolite concentrations in infant urine and maternal reported use of dermally applied infant care products.

METHODS. We measured 9 phthalate metabolites in 163 infants who were born in 2000–2005. An infant was considered to have been exposed to any infant care product that the mother reported using on her infant within 24 hours of urine collection. Results of multiple linear regression analyses are reported as the ratio of metabolite concentrations (with 95% confidence intervals) in exposed and unexposed infants. We standardized concentrations by forming z scores and examined combined exposure to multiple metabolites.

RESULTS. In most (81%) infants, 7 phthalate metabolites were above the limit of detection. Exposure to lotion was predictive of monoethyl phthalate and monomethyl phthalate concentrations, powder of monoisobutyl phthalate, and shampoo of monomethyl phthalate. Z scores increased with number of products used. Most associations were stronger in younger infants.

CONCLUSIONS. Phthalate exposure is widespread and variable in infants. Infant exposure to lotion, powder, and shampoo were significantly associated with increased urinary concentrations of monoethyl phthalate, monomethyl phthalate, and monoisobutyl phthalate, and associations increased with the number of products used. This association was strongest in young infants, who may be more vulnerable to developmental and reproductive toxicity of phthalates given their immature metabolic system capability and increased dosage per unit body surface area.

Key Words: phthalate • infant • environmental exposure • baby care product

Abbreviations: DEHP—di-2-ethylhexyl phthalate • DBP—dibutyl phthalate • MEP—monoethyl phthalate • MBP—mono-n-butyl phthalate • MBzP—monobenzyl phthalate • MiBP—monoisobutyl phthalate • DiNP—di-isononyl phthalate • SFFI—Study for Future Families, Phase I • SFFII—Study for Future Families, Phase II • MMP—monomethyl phthalate • MCPP—mono-3-carboxypropyl phthalate • DnOP—di-n-octyl phthalate • MEHP—mono-2-ethylhexyl phthalate • MEHHP—mono-2-ethyl-5-hydroxyhexyl phthalate • MEOHP—mono-2-ethyl-5-oxohexyl phthalate • LOD—limit of detection • LPMC—log phthalate metabolite concentration • CI—confidence interval • NHANES—National Health and Nutrition Examination Survey • DEP—diethyl phthalate • BBzP—butylbenzyl phthalate

Phthalates are synthetic, man-made chemicals of increasing public importance because of potential toxic effects to the developing endocrine and reproductive systems. They are used in the manufacturing of a wide variety of industrial and common household products. These chemicals are found in plastic products such as children's toys, lubricants, infant care products, chemical stabilizers in cosmetics, personal care products, and polyvinyl chloride tubing.^1,2 Phthalates are not chemically bound to these products and are therefore continuously released into the air or through leaching into liquids, leading to exposure through ingestion, dermal transfer, and inhalation.^3–8 Children are uniquely vulnerable to phthalate exposures given their hand-to-mouth behaviors, floor play, and developing nervous and reproductive systems. Although recent data suggest that some phthalates can adversely affect human male reproductive function,^9–12 few studies have characterized phthalate biomarkers or sources of exposure in infants and toddlers.^7,13–15

Phthalates are known developmental and reproductive toxicants in animal models; the immature male reproductive tract is particularly sensitive to di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP). DEHP toxicity leads to an increased incidence of hypospadias and cryptorchidism in rodents,¹⁶ as does DBP.^17,18 Several human studies also support adverse phthalate effects of phthalates on male reproductive function. Urinary concentrations of monoethyl phthalate (MEP), a metabolite of diethyl phthalate, has been associated with sperm DNA damage in male adults and is hypothesized to have widespread effects on endocrine and reproductive systems.^9,19 In male infants, Swan et al¹⁰ observed that prenatal concentrations of MEP, mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP) were associated with decreased anogenital distance, a well-described marker of decreased androgenization in animal studies, in male newborns. Main et al¹² found that phthalate exposure through breast milk was associated with abnormal reproductive hormone levels in 3-month-old infants, suggesting that early human exposures may have an adverse impact on endocrine homeostasis.

Phthalate metabolite concentrations tend to be higher in young children as compared to other age groups.^{7,13–15,20,21} Although studies have demonstrated that children bear a disproportionate burden of these chemicals in their bodies, sources and pathways of childhood phthalate exposure have not been well characterized. Of particular concern for children is sucking and playing with plastic toys and child care products that are used directly on the skin. Although no specific data exist supporting plastic toys as a significant source of childhood exposure, the American Academy of Pediatrics released a statement that endorsed biological plausibility for childhood sucking/chewing on plastic toys and increased phthalate metabolite levels.²² Phthalates have also been found in food products and are thought to be contaminants that enter the food supply during processing and packaging.²³ Ingesting dust that contains phthalates may be another source of exposure for young children who consistently play close to the floor or outside on playgrounds.²⁴

Only one human study has examined sources of exposure in relation to phthalate body burden. Duty et al²⁵ found that use of personal care products predicted MEP urinary concentrations in adult men, but no study has examined sources of exposure in children. We explored the relationship between infant/toddler urine phthalate metabolite concentration and mother's use of dermally applied infant care products. We also examined mother's report of child's use of plastic toys and pacifiers, although we did not measure metabolites of di-isononyl phthalate (DiNP), the primary phthalate associated with such use.

	METHODS

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Study Group
Infants in our study were born to women who were originally recruited in the first phase of the Study for Future Families (SFFI), a multicenter pregnancy cohort study, at prenatal clinics in Los Angeles, California (Harbor-UCLA and Cedars-Sinai), Minneapolis, Minnesota (University of Minnesota Health Center), and Columbia, Missouri (University Physicians), from September 1999 through August 2002. Methods are described in detail elsewhere.^10,26 Briefly, couples whose pregnancy was not medically assisted were eligible unless the woman or her partner was younger than 18 years, either partner did not read and speak Spanish or English, or the father was unavailable or unknown. All participants completed a questionnaire; gave blood samples; and, after urine collection was added midway through the study, also gave a urine sample.

Eighty-five percent of SFFI participants agreed to be recontacted, and we invited these mothers to take part in a follow-up study (SFFII). Women who did not agree to be recontacted differed in distribution by center (more women from IA and CA) and race (fewer white and more Asian women) as compared with participants who agreed to be recontacted. The family was eligible for this follow-up study when the pregnancy ended in a live birth, the infant was 2 to 28 months of age at time of recontact, and the mother lived within 50 miles of the clinic and could attend at least 1 study visit. In total, 347 infants born to mothers in SFFI attended at least 1 study visit after birth. Infants were eligible for this study if data existed on the mother's questionnaire responses, infant urine phthalate measurements, and infant physical examinations. Of these, 163 infants had measured urine phthalate concentrations, a physical examination with weight measurements, and data on infant product use and all covariates examined. This analysis includes these 163 infants from CA, MO, and MN and represents 47% of all 347 infants who attended at least 1 study visit after birth. Our study group tended to be younger, have lower weights, and tended to report ever breast-feeding at a higher rate as compared with the 53% of infants not participating in the study. Human subject committees at all participating institutions approved SFFI and SFFII, and all participants signed informed consents for each study.

Demographic and Exposure Data
We obtained infant demographic and exposure data from the SFFII questionnaire as well as from the study visit at which all infants were weighed, measured, and given a physical examination. Mothers of all infants in this study filled out a questionnaire that included detailed questions regarding infant product use. These were phrased as follows: "We would like to know if you or anyone else has used any of the following products on your infant in the 24 hours before the time we collected his/her urine sample today." Product categories were infant powder/talc/cornstarch, Desitin/diaper creams, infant wipes, infant shampoo, and infant lotion. To estimate plastic toy use, we used the following question: "How many hours per day does your infant usually spend playing with or using the following?" Categories listed were soft plastic toys/teething rings and pacifiers.

Phthalate Metabolite Measurements
Mothers were asked to bring in a wet diaper on the day of infant study visit. Infant urine samples were obtained by squeezing the diaper and collecting urine in containers that were sent to the Centers for Disease Control and Prevention for measurement of phthalate metabolites. Because the analytical method measures metabolites and not parent compounds, there is minimal concern about contamination from the diapers or other sources of parent compound phthalate diesters that may have been introduced during the collection process. Urinary phthalate metabolite measurements were conducted by the Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, which had no access to participant data. The analytical method involved the enzymatic deconjugation of the phthalate metabolites from their glucuronidated form, followed by concentration of the analytes of interest by solid-phase extraction, separation with high-performance liquid chromatography, and detection by isotope-dilution tandem mass spectrometry.^27,28 This approach allows for the simultaneous quantification in human urine of the following phthalate metabolites reported in this work: MEP; MBP; monomethyl phthalate (MMP); mono-3-carboxypropyl phthalate (MCPP); a metabolite of di-n-octyl phthalate (DnOP) and a minor metabolite of DBP, MBzP; MiBP; mono-2-ethylhexyl phthalate (MEHP); and 2 oxidative metabolites of DEHP, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) and mono-2-ethyl-5-oxo-hexyl phthalate (MEOHP). Table 1 lists parent phthalate compounds and associated metabolites measured in this study. Limits of detection (LOD) are in the low nanogram per milliliter range. Isotopically labeled internal standards and conjugated internal standards were used to increase precision and accuracy of the measurements. Quality control and reagent blank samples were analyzed along with unknown samples to monitor performance of the method.

We used linear regression to explore the associations between individual log phthalate metabolite concentrations (LPMC) and mother's report of individual infant products as well as plastic toy use. An infant was considered to have been exposed to an infant care product when the mother reported using that product in the 24 hours before urine collection. Results are reported as the ratio of metabolite concentration in exposed and unexposed infants. We back-transformed (inverse logarithm) all coefficients and confidence intervals (CIs) that were obtained from the regression models.

For each metabolite, we formed a z score (LPMC for individual sample – mean [LPMC of entire distribution])/(SD [LPMC of entire distribution]) to normalize LPMCs so that they would be on a comparable (unitless) scale, and then examined the relationship between the z score and exposure to individual infant products. We also examined joint exposure to multiple phthalates by forming a combined z score that reflected combined exposure to the individual metabolites that were most strongly associated with product use (MEP, MMP, and MiBP).

To dichotomize by age, we selected 8 months as a cutoff, the month closest to the 25th percentile in our age distribution. Children who are older than 8 months have more opportunity for environmental exposures as a result of their age-related behaviors, but most infants who are younger than 8 months are not yet able to cruise or walk, thereby limiting potential exposures.

We examined several potentially confounding factors, including infant age, gender, infant weight, urinary creatinine, geographic location, race/ethnicity, socioeconomic factors, and mother's report of ever breastfeeding. We chose these factors a priori on the basis of past studies looking at human phthalate exposures and urine concentrations (urine creatinine, infant age, gender, weight, race/ethnicity, and socioeconomic factors were found to be significant in the National Health and Nutrition Examination Survey (NHANES) data; child-specific age-related behaviors [breastfeeding status] and study-specific parameters [eg, geographic location] were confounders in past SFF analyses).²⁰ Infant age and urinary creatinine were associated with the exposures of interest and urine phthalate metabolite concentrations. We therefore adjusted for infant age and urine creatinine in all analyses. No other confounding factors changed point estimate values appreciably, and none was used in the final regression analyses. We did examine breastfeeding in terms of whether mothers answered yes/no to breastfeeding in the past week as well as reported number of breastfeedings per day in the past week. Neither of these variables changed point estimates, but significant missing data existed for reported number of breastfeedings per day in the past week. We did not have data on solid foods and therefore could not examine this as a potential confounding factor.

	RESULTS

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Demographic Characteristics
Demographic characteristics for 163 infants are shown in Table 2. The study group included slightly fewer boys than girls, with most (50%) infants between ages 9 and 16 months. Approximately 80% of mothers were white, and 10% were Hispanic. Most mothers reported using private health insurance (79%), and 11% used government health insurance. Approximately one half of infants lived in Minnesota (47%), with 26% in California and 26% in Missouri. Mothers reported ever breastfeeding at a rate of 96%.

View larger version (17K): [in this window] [in a new window]   FIGURE 1 Number of phthalate metabolites found in infant urine samples (N = 163).

View larger version (5K): [in this window] [in a new window]   FIGURE 2 Ratio of z score for combined phthalate metabolite concentrations for MEP, MiBP, and MMP in exposed and unexposed infants by number of infant products used (N = 154). All values are adjusted for infant age and square root creatinine. Nine infants had missing creatinine values and were not included in analysis. Trend test P < .05.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Phthalate exposure is widespread and variable in infants. We found that mothers’ reported use of infant lotion, infant powder, and shampoo was significantly associated with MEP, MMP, and MiBP urinary concentrations. This association was strongest in infants who were younger than 8 months. In addition, we found a relationship between phthalate concentrations and the number of products used. At this time, no data exist on phthalate content of specific infant care products, but several studies show that diethyl phthalate (DEP) and DBP are ingredients in many adult personal care products,^30–32 and dermal absorption of phthalates has been shown to occur. Only 1 adult human study examined product use in relation to phthalate concentrations and found that men who used cologne and/or aftershave within the 48-hour period before the collection of the urine sample had higher urinary levels of MEP.^25,30 At this time, it is unknown whether the parent compounds of MiBP and MMP are used in the production of dermally applied infant care products. Our findings suggest that the parent compounds of MiBP and MMP likely exist in these products, specifically lotion, infant shampoo, and infant powder, and additional studies of these products should be initiated to confirm these findings. MEP, whose parent compound, DEP, is commonly found in adult personal care products, was a significant predictor of phthalate metabolite concentration in our data.

In 2004, Silva et al,²⁰ using data from the NHANES, reported widespread human exposure in the United States to several phthalates. In that study, children in the 6- to 11-year age group had higher concentrations of MBP, a DBP metabolite, MBzP, a metabolite of butylbenzyl phthalate (BBzP), and MEHP, a metabolite of DEHP as compared with adult values. In a study of children aged 3 to 14 years in Germany, Becker et al¹⁴ found that concentrations of DEHP metabolites decreased with increasing age. Wormuth et al⁷ estimated potential sources and concentrations of 8 phthalates in different age groups and predicted that infants would experience higher daily exposures to these phthalates as compared with adults. Our data mirrored or were lower than urinary phthalate concentrations found in the childhood NHANES data.

Our study findings also suggest that dermal exposure may be an important route of exposure for some phthalates, particularly for young infants, for whom associations were stronger than for older infants. Several studies have demonstrated that phthalate exposures may come from multiple sources, including plastics, personal care products, and household products, and that multiple exposure routes may be involved. Oral ingestion is the most studied and widely accepted as a major route of exposure; ingestion of phthalates may occur through food, medicines, and indirect dust ingestion.^8,22 In addition, recent studies showed that some phthalates can be airborne and inhaled as well as absorbed through the dermal route.⁵ Children have unique development and behavior that may predispose them to higher exposure susceptibility. When children are born, they immediately develop hand-to-mouth behaviors.³³ They cannot move on their own and are therefore exposed predominantly to ambient air exposures, oral ingestion of breast milk/formula, and dermal exposure to specific infant care products. As infants develop, they begin to move around, crawl, and have increased hand-to-mouth behaviors with the potential for increased exposure to phthalate sources in the environment.³³ We believe that the stronger association that was observed in the youngest age group between baby lotion, baby powder, and baby shampoo and MEP, MMP, and MiBP concentrations may reflect limited routes of exposure therefore a higher contribution of exposure from dermal routes. Few studies of the dermal absorption of phthalates in humans exist, and dermal absorption of phthalates has not been studied in infants and children. It is likely that infants and children in this study are being exposed to phthalates through multiple sources and routes of exposure. Although the total body contribution and dermal absorption of phthalates has not been studied in infants and children, it is plausible that dermal transfer may be a principal route of exposure for infants along with oral ingestion. Janjua et al,³⁴ examined dermal absorbtion in 26 healthy young men who were administered an inert basis cream with phthalate parent compounds spread over the entire body daily, and serum samples were taken every hour over 4 hours to study phthalate metabolites in blood. These authors found a significant increase in MEP and MBP metabolites several hours after application and concluded that systemic uptake through the skin is likely to be an important route of exposure for humans.³⁴ We found a strong association between several phthalates and infant care products that are applied dermally and therefore conclude that this is a major source and route of exposure for infant phthalate exposure, but phthalates from these products may also be ingested orally and inhaled. Several factors affect dermal absorption rates, including specific body part exposed, chemical concentration, quantity of skin surface area exposed, duration of exposure, absorption of chemical through the skin, and internal dosage. Children have a larger body surface area to volume compared with adults and are therefore exposed to a higher internal dosage of chemicals, but specific data on skin permeability do not exist, except for preterm infants, for whom data exist to support increased skin permeability to chemicals. Additional research should be done to elucidate sources and routes of phthalate exposure in infants.

DiNP and DEHP are the primary phthalates in plastic toys and pacifiers (CPSC and California Environmental California Research and Policy Fund) and are thought to leach into children's saliva from oral sucking/mouthing behaviors.³⁵ Simulation studies show that phthalates leach from toys and plastic products, and 1 adult study measured phthalate leaching rates from phthalate-containing products into saliva.³⁶ We did not find an association between phthalate metabolite concentration and mother's report of plastic toy/pacifier use. There are likely several reasons for this finding. First, DINP metabolites were not measured in our population, so the association for these with plastic toy/pacifier use could not be assessed. Second, the questionnaire asked about plastic toy/pacifier use in the past 24 hours but did not ask specifically about mouthing/sucking versus handling of toys. It is likely that oral behaviors would be a better predictor of increased phthalate metabolite concentration in relation to plastic toy/pacifier use. Finally, the question did not ask about which kind of plastic toys were used; usually only, soft vinyl toys contain phthalate compounds.

We did not find a relationship between infant wipe use and phthalate metabolite concentration, although this may reflect the high prevalence use of this product (94% of mothers reported using infant wipes). Desitin and diaper creams were also not associated with phthalate metabolite concentrations. It may be that these products do not contain phthalates or that we did not measure the metabolite(s) of the phthalate that is contained in the product.

We examined time of product use in relation to urine phthalate metabolite concentration but did not see an association between these. Because urine samples were collected at home in diapers and brought to the study site, we did not know the time of urine collection. In the future, it would be of interest to ask mothers for time of diaper change as an estimate of time of urination.

A limitation of this study is that phthalate content of specific products is not known, unfortunately, in part because manufacturers do not list phthalate contents in the ingredients list; it is assumed on the basis of data of phthalate content in adult personal care products. Both the Environmental Working Group and Health Care Without Harm have tested adult beauty care products for phthalates and found a majority of them to contain several different types of phthalate compounds.^30,37 In addition, the US Food and Drug Administration tested 48 consumer cosmetic products and found that diethyl phthalate was detected most frequently at high concentrations.³² Additional limitations of this study include small sample size and lack of specificity of questionnaire data. In addition, we did not ask mothers to quantify the amount of product used and therefore could not examine dosage-response relationships.

There is a lack of knowledge of the metabolism and toxicokinetic parameters for phthalates in infants. A few studies in adults have examined phthalate metabolism, but pathways vary by individual phthalate as well as by the individual receiving dosing. In humans, phthalates are converted to monoesters and, depending on the phthalate, then oxidized and/or conjugated before excretion. Urinary biomarkers of phthalate metabolites are assumed to be indicative of exposure to parent compounds. We do not know whether early childhood phthalate exposure leads to adverse developmental effects in the future. Developmental effects of prenatal exposures to phthalates observed in animal studies are similar to observations in human studies, suggesting similarities across species. Additional research must be done in this area to understand the toxicities associated with early childhood phthalate exposures. There is a large animal database to support developmental toxicity.

Several factors affect generalizability of these data. First, this study group was primarily white with private health insurance and therefore may not be representative of the US population. Silva et al²⁰ found that non-Hispanic black children aged 6 to 12 had higher concentrations of urinary MEP and hypothesized that this was attributable to increased beauty and hair care product use specifically marketed to this population. The findings of Silva et al may or may not apply to infants or young children. Additional research much be done in this area to determine how phthalate exposure and metabolism vary by race and socioeconomic status.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
We observed that reported use of infant lotion, infant powder, and infant shampoo were associated with increased infant urine concentrations of MEP, MMP, and MiBP, and this association is strongest in younger infants. These findings suggest that dermal exposures may contribute significantly to phthalate body burden in this population. Young infants are more vulnerable to the potential adverse effects of phthalates given their increased dosage per unit body surface area, metabolic capabilities, and developing endocrine and reproductive systems. In 2006, the European Union banned the use of 6 phthalate softeners in polyvinyl chloride toys designed to be placed in the mouth by children who are younger than 3. The ban covers 6 phthalates: DiNP, DEHP, DBP, di-isodecyl phthalate, DnOP, and BBzP.³⁸

In the United States, there is no requirement that products be labeled as to their phthalate content. Parents may not be able to make informed choices until manufacturers are required to list phthalate contents of products. Until additional information is available on infant care product phthalate content, providers may want to educate and counsel families regarding phthalate exposures via infant care products and potential ways to reduce exposure to these chemicals. Several companies have started to decrease use of phthalates in the production process and label products as phthalate-free, but safety of these alternatives has yet to be established. If parents want to decrease exposures, then we recommend limiting amount of infant care products used and not to apply lotions or powders unless indicated for a medical reason.

Phthalate toxicity is of increasing importance in the scientific and public community. Additional research should be conducted to determine specific sources of phthalate exposure for infants and specific phthalate concentrations in commonly used infant products. In the future, these findings should be used to assess potential health impacts to the infant's developing endocrine and reproductive systems.

	ACKNOWLEDGMENTS

 
This study was supported by grants from the US Environmental Protection Agency; National Institutes of Health grants R01-ES09916 to the University of Missouri, MO1-RR00400 to the University of Minnesota, and MO1-RR0425 to Harbor-UCLA Medical Center; grant 18018278 from the State of Iowa to the University of Iowa; National Institute of Environmental Health Sciences grant 5 T32 ES 007262–15; and Environmental and Molecular Epidemiology Training Grant to the University of Washington (Seattle, WA).

We gratefully acknowledge the technical assistance of Manori Silva, Jack Reidy, Ella Samandar, and Jim Preau (Centers for Disease Control and Prevention, Atlanta, GA) in measuring the urinary concentrations of phthalate metabolites. We also thank the health care providers and study participants at University Physicians Clinic (Columbia, MO), Fairview Riverside Women's Clinic (Minneapolis, MN), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Cedars-Sinai Medical Center, and University of Iowa Hospitals and Clinics and several helpful reviewers.

	FOOTNOTES

 
Accepted Jul 16, 2007.

Address correspondence to Sheela Sathyanarayana, MD, Department of Occupational and Environmental Health Sciences, Division of General Pediatrics, Child Health Institute, University of Washington, Building 296200, NE 74th St, Seattle, WA 98115-8160. E-mail: sathyana{at}u.washington.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the CDC.

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