Endocrine Disrupting Chemicals: Health Effects and Moving ... · 9/9/2019 · a predictor of low...

National Institutes of HealthU.S. Department of Health and Human Services

Endocrine Disrupting Chemicals:

Health Effects and Moving Forward

Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S.Director

National Institute of Environmental Health SciencesNational Toxicology Program

Pesticides & The Chesapeake Bay Watershed Project Conference18 September 2019

Reisterstown, Maryland


• The National Institutes of Health is the primary Federal agency for

conducting and supporting medical research in the U.S.

• More than $39 billion invested annually in medical research

• 50,000 competitive grants awarded to more than 300,000 researchers at

over 2,500 universities, medical schools, and other research institutions

in every state -- and around the world

What is the NIH?

NIH Budget webpage, accessed July 2019


The National Institute of Environmental Health Sciences

Office of the Director

Director: Linda S. Birnbaum, PhD, DABT, ATS

Deputy Director: Rick Woychek, PhD

Office of Management

Executive Officer: Chris Long, MPA

Division of Intramural Research

Scientific Director: Darryl Zeldin, MD

Division of Extramural

Research and Training

Director: Gwen Collman, PhD

Division of the National Toxicology

Program

Scientific Director: Brian Berridge, DVM,

PhD, DACVP

• One of the 27 National Institutes of Health, located in RTP, NC

• Wide variety of programs supporting our mission of environmental health:

‒ Intramural laboratories ‒ Clinical research program

‒ Extramural funding programs ‒ National Toxicology Program

‒ Disease prevention ‒ Public health focus


Our Health

Image adapted from: NHGRI

Genetics


Our Health

Image adapted from: NHGRI

Genetics + Environment

Combustion

by-products

Medicines

Pesticides

Personal care

products

Stress

Chemicals in

electronics

Diet

Microbiome

Synthetic

materials


The Endocrine System

• Extremely complex, many

controls, interacting parts

• Multiple points of regulation for

finely-tuned responses

• Sensitive to perturbations

• Naturally operates at low

doses

• Effects can be activational

and/or organizational


Endocrine Disrupting Chemicals: A Global Health Problem

Hormones

EDCs Nuclear

Receptors• “An exogenous substance or mixture

that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations.”

• Report from The United Nations Environment Programme (UNEP) and the World Health Organization (WHO), “State of the Science of Endocrine Disrupting Chemicals (EDCs)”

– EDCs are becoming a "global threat" that needs to be addressed

WHO. State of the Science of Endocrine Disrupting Chemicals. 2013


Endocrine Disrupting Chemicals (EDCs)

Known EDCs:

• Dioxin and dioxin-like compounds

• Polychlorinated biphenyls (PCBs)

• Some pesticides

• Plasticizers, such as BPA

Health outcomes associated with EDC exposure:

• Developmental

• Reproductive

• Neurological

• Immune

How do EDCs work? EDCs

can mimic the body's natural

hormones or alter the natural

production of hormones

NIEHS, 2019


Lifelong Effects of Early-Life ExposuresDevelopmental Origins of Health and Disease (DOHaD)

Chemical Contaminants in the Chesapeake Bay

Common contaminants:

– Polychlorinated biphenyls (PCBs)

– Pesticides

– Polycyclic aromatic hydrocarbons (PAHs)

– Mercury

– PFAS

Sources of contamination:

– Air pollution

– Agricultural runoff

– Stormwater runoff

– Wastewater discharge

Almost three-quarters of the

Bay’s tidal waters are impaired

by chemical contaminants,

which can harm the health of

both humans and wildlife

Chesapeake Bay Program, 2019


Pesticides, Sources, and Health Effects

NIEHS, 2019. CDC, 2019

• Includes herbicides, fungicides, insecticides, and disinfectants

• Sources include agricultural, residential, and occupational

• Many health effects associatedwith exposure, including:

– Cancer

– Neurological (Parkinson’s disease, autism, IQ)

– Endocrine and metabolic effects (diabetes)

– Respiratory effects


Maternal Pesticide Exposure and Autism in Children

• Finnish Prenatal Studyof Autism

– Mothers with the highest DDE blood levels in early pregnancy were 32% more likely to have a child who developed autism (p=0.03)

• CHARGE Study (CA)

– Mothers living near agricultural pesticide applications had a 60% increased risk for a child developing autism

Brown et al., Am J Psychiatry, 2018. Shelton et al., EHP, 2014.


Prenatal Organophosphate (OP) Exposure and

Decreased Infant Motor Function

• 30 OPs measured in umbilical cord blood

• Motor function assessed at 6-weeks and 9-months in Chinese infants (N=199)

• Prenatal naled and chlorpyrifos were associated with decreased motor function at 9-months

Silver et al., Environ Int, 2017


Pesticides Associated with Neurobehavioral

Effects in Ecuadorian Children

• Conducted behavioral tests between 63 and 100 days after Mother’s Day

• Children tested closer to Mother’s Day had lower neurobehavioral performance

• Periods of peak pesticide use may transiently affect child neurobehavior

Suarez-Lopez et al., NeuroToxicology, 2017

Days after Mother’s Day Harvest

Ne

uro

beh

avio

ral

Sco

re

N = 308 children 4-9 years old


Developmental Pesticide Exposure Induces

Neuroinflammation, Reduces Spatial Learning

• Rats exposed fromGSD 7 to PND 21

• All pesticides induced neuroinflammation, increasing IL-1b in hippocampus

• Effects were pesticide and sex-specific

IL-1b (% control)

Working Memory

Gómez-Giménez et al.,

Food and Chem Toxicol, 2017

Wo

rkin

g e

rro

rs

Pesticide Dose (mg/kg/day)

Cypermethrin 1.5

Endosulfan 0.5

Carbaryl 15

Chlorpyrifos 0.1, 0.3, & 1

Exposure to Agricultural Pesticides and Cancer

Among participants enrolled in the Agricultural Health Study:

• Use of chlorpyrifos and terbufos was associated with increased breast cancer risk among farmer’s wives(Engel et al., Environ Health Perspect, 2017)

• Use of pendimethalin, dieldrin, parathion, and chlorimuron ethyl associated with lung cancer risk in farmers(Bonner et al., Environ Health Perspect, 2017)

• Use of the herbicide alachlor was associated with laryngeal cancer and myeloid leukemia in pesticide applicators(Lerro et al., J Natl Cancer Inst, 2018)


Pesticides and Respiratory Symptoms in Farmers

• Assessed pesticide exposures and wheeze among male participants in the Agricultural Health Study (N=22,134)

• Of 78 pesticides

examined, 21 were

significantly associated

with non-allergic

wheeze, and 19 with

allergic wheeze

• Dose-response

relationships observed

for three commonly used

herbicides: glyphosate,

2,4-D, and atrazine

Hoppin et al., Environ Health Perspect, 2017

DDT and Breast Cancer: The Timing of Exposure

Matters

• Evaluated timing of DDT exposure and breast cancer

• DDT was associated with breast cancer through age 54

• Risk dependedon timing of firstexposure

• DDT may be anendocrine disruptorwith responsivebreast targets fromin utero tomenopause

DDT associated breast cancer by age

at first exposure and age at diagnosisCohn et al., J Natl Cancer Inst, 2019


Pesticides and Endocrine Effects

Organochlorine pesticides: Associated with reduced BMI and height in 8 to 19-year-old boys(Sergeyev et al., Rev Environ Health, 2017)

Organophosphate pesticides: Associated with altered testosterone levels in Thai farmworkers(Panuwet et al., Arch Environ Occup Health, 2018)

Pesticide residue on food: May reduce probability of pregnancy and live birth following assisted reproduction approaches (Chiu et al., JAMA Intern Med, 2018)

Photo by Josh Vogel, Maryland Dept. of Natural Resources

Polychlorinated Biphenyls (PCBs)

• Used in hundreds of industrial and commercial applications

• Banned in U.S. in 1979

• Mobile, persistent, and accumulate in the environment and wildlife

• Associated with a range of health effects:

– Cancer

– Immune

– Reproductive

– Nervous

– Endocrine

EPA, 2018


Early Life PCB Exposure Effects Multiple Systems

• Higher prenatal PCB exposure associated with autism spectrum disorder (Lyall et al., EHP,

2017)

• Prenatal PCB exposure associated with increased levels of sex hormones in 12-year-old boys (Eskenazi et al., Int J Hyg

Environ Health, 2017)

• Boys with the highest levelsof serum PCBs had earlyonset puberty (Burns et al., EHP, 2016)

• Infants with highest PCB exposure had 37% lower response to tuberculosis vaccine compared to lowest exposure group (Jusko et al., EHP, 2016)


Per- and Polyfluoroalkyl Substances (PFAS)

• Group of nearly 5,000 chemicals

• Mobile, persistent, and accumulate in the environment

• Resistant to grease,water, and oil

• Emergence of alternatives which are less well studied

PFMOAA

PFOA

PFOS

GenX


PFAS Exposure Pathways

Sunderland et al., J Expos Sci & Epidemiol, 2019

PFAS Health Effects

PFAS exposure has been associated with:

• Altered immune function

• Cancer

• Decreased birthweight

• Liver effects

• Metabolic outcomes

• Neurodevelopmental outcomes

• Thyroid disruption

Savitz et al., Environ Health Perspect, 2012;

Sunderland et al., J Expos Sci & Epidemiol, 2019PFOS (ng/mL)

OR

(9

5%

CI)

of

T2

DPositive relationship between PFOS and

risk of type 2 diabetes. Sun et al., Environ Health Perspect, 2018

Higher PFNA was

associated with

poorer executive

functioning. Vuong et

al., Environ Int, 2018

Measure of executive function


PFAS Levels Associated with Altered Kidney and

Thyroid Function

• Repeated measures ofserum PFOS associatedwith increased thyroidstimulating hormone

• Repeated measures ofserum PFNA, PFHxS,and PFDeA associatedwith decreased kidneyfunction

• PFHxS retained high stability between serum measurements over a period greater than 10 years

Blake et al., Environ Pollut, 2018

Phthalates

• Large group of chemicals used to make plastics more soft and flexible

• Found in food contact materials and food processing equipment

• Diet is a significant source of exposure for certain phthalates, especially DEHP

• Phthalates enter our food through packaging, processing, and handling

Varshavsky et al., Environ Int, 2018

DEHP

DiNP DiDP

Phthalate Health Effects• Endocrine outcomes

• Reproductive outcomes

• Fetal development

• Obesity

• Neurodevelopment

• Cancer

• Diabetes and insulin resistance

• Immune systemand allergic disease

Benjamin et al., J Haz Materials, 2017

Q1 Q2 Q3 Q4 Q5

ΣDEHP

Od

ds

Ra

tio

(95

% C

I)

10

1

ADHD increases with

prenatal DEHP exposureModified from: Engel et al., EHP, 2018

Monobenzyl phthalate correlated

with decreased sperm motility

Thurston et al., Andrology, 2016

Od

ds R

ati

o

Prenatal exposure to

some phthalates associated with

increased child BMI

Modified from: Harley et al., Pediatr Res, 2017

MEP MBP MiBP MBzP ΣDEHP

Phthalates, Anogenital Distance and Sperm Count

• Male Anogenital Distance (AGD) strongly correlates with all semen parameters and is a predictor of low sperm concentration.

• In animals, male AGD at birth reflects androgen levels during masculinization programming window and predicts adult AGD and reproductive function.

• Androgenic environment during early fetal life exerts fundamental influence on both AGD and adult sperm counts in humans.

• Data support the hypothesis that prenatal phthalate exposureat environmental levels adverselyaffects male reproductive development.

Mendiola et al, 2011. EHP;119:958–963


Prenatal Phthalate Exposure Associated with Birth

Defects in Mice

• Pregnant mice were exposed to 0, 5, 250, or 500 mg/kg DEHP

• DEHP had major effects on fetalsurvival and development:

Ungewitter et al., Toxicol Sci, 2017

– Reduced rate of fetal survival

– Increased incidence of limbmalformations and neural tube defects

– Altered expression of genesimportant in male reproductivedevelopment Prenatal DEHP exposure led to a birth

defect of additional digits in this mouse

hind limb (black arrows).


Phthalate Exposure Before Birth May Hinder Brain

Development

• Female rats were exposed to phthalate mixture throughout pregnancy and for 10 days during lactation

• Adult offspring of exposed rats had a smaller medial prefrontal cortex with fewer neurons and synapses

• Rats with fewer overall synapses were less cognitively flexible than those with more synapses

Kougias et al., J Neurosci, 2018


Bisphenol-A (BPA)

• Used to produce polycarbonate plastics and epoxy resins

• >8 billion pounds produced annually

• Found in:

– Food packaging, consumer and medical products

– Thermal receipt paper

– Industrial emissions

– Metal and plastic equipment and appliances


BPA Health Effects

BPA exposure has been associated with:

• Increased risk of obesityand type 2 diabetes

• Poor reproductive outcomes (e.g., ovary and uterine function and sperm quality)

• Higher levels of anxiety,depression, aggression,and hyperactivity in children

Legeay et al., Fundam Clin Pharmacol, 2017;

Hwang et al., BMC Endcrine Disorders, 2018;

Ejaredar et al., J Expos Sci Environ Epidemiol, 2017

Log BPA (ng/mL)

Me

as

ure

of

ins

uli

n

resis

tan

ce

Direct association between urinary BPA levels

and insulin resistance in obese children(Adapted from: Menale et al., Pediatr Obes, 2017)


Moving Forward: Research Needs and Reducing

Exposures

• Assess health and environmental effects of alternative chemicals

• Consider health effects of complex chemical mixtures

• Develop and promote strategies individuals and communities can use to reduce exposures


Real-World Exposures Occur As Mixtures

• We are all exposed to a mixture of chemical and non-chemical stressors

• Mixtures can produce health effects greater than each exposure alone

• Studying mixtures requires evaluation of:

– Individual chemicals withinthe mixture

– Interactions between those chemicals

– Combined effect of mixtureon health

EDC Mixtures and Gestational Diabetes

• Examined associations between EDCs– individually and in combination – on gestational diabetes risk during pregnancy

– Looking at parabens individually yielded no significant results

– Looking at parabens as a chemical mixture showed a positive association

Bellavia et al., Environ Res, 2019

Differences in glucose in mg/dL as a

function of 1st trimester paraben

concentrations. Point estimates for

exposure changes between the 10th

and 90th percentile of their distribution.


Technology & Application Contaminant PI, Org, Grant

Biochar to sequester contaminants in

aquifersDioxins

S. Boyd,

Michigan State University

Magnetic nanocomposites for water

remediationPCBs

Z. Hilt,

University of Kentucky

Functionalized membrane filters for

groundwater remediationPCBs

D.B. Bhattacharyya,

University of Kentucky

Activated carbon to immobilize

contaminants in aquatic ecosystems PCBs, Mercury

U. Ghosh

U Maryland, Baltimore

Poplar trees to remove chemicals

from soil and waterPCBs

J. Schnoor,

University of Iowa

Controlled release polymers for

contaminated aquifersPAHs

A. Carpenter,

AxNano

Combined in situ/ex situ expedited

aquifer remediationPFAS

R. Ball,

EnChem Engineering

NIEHS grantees develop new technologies and

approaches to clean up contaminants in water, sediment, and soil

Cleaning up Contaminants in the Environment


Activated Carbon Reduces Bioaccumulation

of EDCs

• Activated carbon is a porous, manufactured material created from coal or wood

• Tested ability of granular activated carbon (GAC) and pelletized fine activated carbon (PfAC) to limit bioaccumulation in contaminated sediments

• Measured organochlorines in the blackworm (Lumbriculus variegatus)

• PfAC significantly limited bioavailability and reduced worm body burdens

Dang et al., Chemosphere, 2018

Wo

rm b

od

y b

urd

en

(n

g/g

ww

)

no AC with GAC with PAC

Triclosan

Wo

rm b

od

y b

urd

en

(n

g/g

ww

)

no AC with GAC with PAC

Triclocarban


Green Infrastructure to Reduce Stormwater Runoff

• Researchers modeled benefits of installing green infrastructure on vacant lots in three flood-prone Houston neighborhoods

• Analysis showed that the designs would capture 7-40 million gallons of stormwater per year

• Additional benefits: More tree coverage,walkable space, and green space Newman et al., Landsc Archit Front, 2019

Stormwater runoff is the fastest growing source of pollution in

the Chesapeake Bay(Chesapeake Bay Program, 2019)


Reducing Pesticide Exposure

• Break the take-home pathway: Farmworkers can reduce pesticide exposure to their families by wearing gloves, washing hands,and removing work clothes before returning home

• Use an IPM Approach:An integrated pest management (IPM) approach can be used in agricultural and non-agricultural settings to reduce direct exposures and pesticide runoff

NIEHS/EPA Children’s Centers Impact Report, 2017

Thank You!

Any Questions?

Date post:	17-Aug-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

Endocrine Disrupting Chemicals: Health Effects and Moving ... · 9/9/2019 · a predictor of low...

Documents