Region 9 Journal ClubMarya ZlatnikTimur Durrani

Disclaimers and Acknowledgements

This material was supported by the American College of Medical Toxicology (ACMT) and funded (in part) by the cooperative agreement FAIN: U61TS000238 from the Agency for Toxic Substances and Disease Registry (ATSDR).

The U.S. Environmental Protection Agency (EPA) supports the PEHSU by providing partial funding to ATSDR under Inter-Agency Agreement number DW-75-92301301. Neither EPA nor ATSDR endorse the purchase of any commercial products or services mentioned in PEHSU publications

Understand concept of endocrine disruptionList common sources of exposure to EDCsReview recent literature regarding Endocrine Disrupting Chemicals and reproductive & pediatric exposures● Swan et al., 2014: Phthalates and anogenital distance● Philippat et al., 2015: Phthalates and phenols in adults

and children from personal care products● Kalfa et al., 2015: Prenatal EDC exposure and

hypospadius

Objectives

Substances that interfere with normal hormonal activity

4Helmestam 2013

Endocrine Disrupting Chemicals:

Epidemiological studies report associations between exposure to some phenols & phthalates & several health outcomes including neurodevelopmental disorders, growth, reproductive health & respiratory healthPhenols & phthalates are used in food packaging, manufacture of PVC plastics, paints & varnishes, also as plasticizers & fixatives in fragrances, antibacterial agents & preservatives or sun blockers

Phenols, phthalates and parabens

Estrogen: the key

BPA: the paperclip pick-lock

Estrogen Receptor: the key-hole

6

EDC example: Estrogen, DES & BPA

Science in Products http://scienceinproducts.blogspot.comRuben et al. 2011

Anogenital distance (AGD) is sexually dimorphic• Longer length in males, reflecting prenatal

androgen productionPrenatal phthalate exposure associated with shorter AGD in ratsSome human data suggesting similar associationExposure to phthalates widespread

Study Background

Inclusion: pregnant women in SF, Rochester (NY), Minneapolis, & Seattle Exclusion: <18yo, >13 wks, “medically threatened”Variables Collected: urine sample & questionnaire each trimester, blood in 1st tri• DEHP metabolites, 7 other phthalate metabolites• AGD & penile width measured • Age at exam, GA at birth, length-for-age

Study Methodology and Results

Landmarks for measurements of anogenital distance

S.H. Swan et al. Hum. Reprod. 2015;30:963-972

© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Study Methodology and Results

1st Tri Phthalate Exposure & AGD in Boys

Not stat. sig. for penile width

1st Tri Phthalate Exposure & AGD in Boys

1st Tri phthalate exposure & AGD in Girls

● No association in girls

DEHP metabolites in the 1st trimester associated with shorter AGD in boys but not girlsLargest, most rigorous study to date

Authors Discussion

Phthalates ubiquitous in indoor environmentsDEHP (diethylhexyl phthalate) is a high molecular weight phthalate, used as plasticizer in PVC (flooring, food contact applications, IV tubing)

Authors Discussion

Phthalate levels lower than in previous studies: cannot rule out possible effects in girls or with other phthalates if higher exposures

Article Critique:

Absolute differences in AGD small over range of exposures measuredSmall absolute differences may be associated with significant effects in male fertility over population

Conclusions, implications, & future directions:

Aim:• 1) Study the associations between use of

Personal Care Products (PCPs) & urinary concentrations of biomarkers of select phenols & phthalates among Californian adults & their children

• 2) Compare phenols & phthalate metabolites concentrations measured in adults & children in urine samples collected the same day

Study Background

Flow chart of recruitment and enrollment of northern California families into SUPERB

Hertz-Picciotto I, Cassady D, Lee K, Bennett DH, Ritz B, Vogt R. Study of Use of Products and Exposure-Related Behaviors (SUPERB): study design, methods, and demographic characteristics of cohorts. Environ Health. 2010 Aug 29;9:54.

Subsample of 90 adult–child pairs participating in the Study of Use of Products & Exposure Related Behavior (SUPERB).Each adult & child provided 1-2 urine samples in which metabolites of selected phenols & phthalate were measured. Parents completed a detailed questionnaire for themselves & their child about the use of different PCPs in the 24h preceding the urine collection.

Study Methodology

Characteristics of the study population (SUPERB study, 2007–2009).

Computed correlation coefficients to compare concentrations measured in adults’ &children’s urine samples collected the same day. Restricted Analysis to:

• Metabolites of phenols: benzo-phenone-3 and triclosan• Metabolites of phthalates: diethyl phthalate (DEP),

monoethyl phthalate (MEP), di-n-butyl phthalate, di-isobutyl phthalate

• Parabens: methylparabens, propylparabens, butylparabens

Study Methodology

Adults most frequently used PCPs: • toothpaste (100%) • liquid soap (88%) • deodorant (74%) Children most frequently used PCPS:• toothpaste (98%) • liquid soap (86%)• shampoo (34%)40% of the adults & 30% of the children reported using toothpaste which may have contained Triclosan (Colgate brand)

Results

Urinary concentrations of phenols & phthalate metabolites corrected for creatinine among adults & their children

Benzophenone-3 & parabensconcentrations were higher in adults

Children had higher mono-n-butyl phthalate &mono-isobutyl phthalate concentrations

Adjusted associations between the use of PCPs & phenol & phthalate metabolite urinary concentrations in adults

Adults reporting use of 7–15 PCPs in the past 24 h had higher urinary concentrations of methyl, propyl & butyl paraben than adults using < 7 PCPs.

Lower concentrations of methyl, propyl &butyl parabens were found in users of bar soap in both adults & children

Concentrations of benzophenone-3 was 9X higher than the general population, likely reflecting higher sunscreen use.

Observed higher variability in children compared to their parents. This might be explained by changes in both behaviors related to phenol & phthalate exposures (e.g., diet, type of PCPs used) & physiology/metabolism.

These results strengthen the body of evidence suggesting that use of PCPs are an important source of exposure to parabens & diethyl phthalate in adults & provide data on exposure to selected phenols & phthalates through use of PCPs in children.

Authors Discussion

Did not collect information on the amount of PCPs usedClassified PCPs by category of products, not brand (except for Colgate toothpaste)Did not measure the phthalate & phenol content of the specific PCPs usedCollected only one urine sample at the end of the day & may have missed the rise in urinary concentrations following PCP usePopulation is not representative of the US general population

Article Critique:

Use of PCPs represents a non-negligible part of the total exposure to certain phenols, parabens & some phthalates in both adults & children.The total number of scented PCPs used is positively associated with parabensconcentrationColgate Total toothpaste is the only FDA-approved toothpaste containing triclosan

Conclusions, implications, & future directions:

Hypospadius common malformation of male genitalia

Study Background

Minority of cases attributable to genetic causeMost multifactorial, with environmental causes playing a roleIncreased incidence noted in some areasConcern raised that EDCs may play a role

Study Background

Case control; matched for ethnic originInclusion: • 408 boys with isolated hypospadius• Controls: 302 “normal” boys hospitalized for

appy, trauma, intussusception, pyloric stenosisExclusion: • Non-isolated defect (micropenis, cryptorchidism)• Familial forms or mutations excluded (108 pts)

Study Methodology and Results

Variables Collected:• Severity of phenotype• Pregnancy data: GA, BW, twinsQuestionnaire data (collected by MD):• Maternal occupational exposures• Maternal & paternal professionsEnvironmental exposures based on geo-coding at time of pregnancy

Study Methodology and Results

Table/Figure Review

Parental professions: Maternal (A) Paternal (B) Hypospadius (L) Control (R)

Residential proximity to exposures & hypospadius

Association of EDC exposure & hypospadius:Multivariate analysis

Confirmation that EDCs cause hypospadiusdifficult given ubiquitous exposure & complex to studyPresent study more definitive:• Isolated hypospadius cases only• Prospective enrollement• Genetic/familial cases excluded• Controls examined & had normal genitalia• Matching for ethnic background & geographic

area

Authors Discussion

Fetal exposure to EDCs was a risk factor for hypospadius (OR 3.8? vs 3.1)Detergents, pesticides, & cosmetics accounted for 75% of casesMaternal & paternal exposures both important (paternal effect weaker) Exposures appeared cumulative (environmental, occupational multiplicative)“Cocktail effect” of multiple EDCs not unexpected, & should be studied

Authors Discussion

Methodology not fully fleshed outNot clear how well controls were matched for other risk factors including SES, maternal diabetes or medication use (cases enrolled up until age 12)Some of the stats unclear (to me)

Article Critique:

Exposure to EDCs (occupationally or via residential proximity to industry) is associated with a higher risk of hypospadiusA causal relationship is not confirmed by this study, but the strength of the association warrants further study & a precautionary approach

Conclusions, implications, & future directions:

Articles open for discussion

• Swan et al., 2014: Phthalates and anogenitaldistance

• Philippat et al., 2015: Phthalates and phenols in adults and children from personal care products

• Kalfa et al., 2015: Prenatal EDC exposure and hypospadius