environmental no disclosures contaminants & reproductive

10/24/2013

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Program on Reproductive Health and the Environment

Environmental Contaminants & Reproductive Health: What should we tell our patients?

Marya G. Zlatnik, MD, MMS

Maternal Fetal Medicine

UCSF

'What we have to face is not an

occasional dose of poison which

has accidentally got into some

article of food, but a persistent &

continuous poisoning of the whole

human environment‘

- Rachel Carson


No disclosures

• Thanks to Tracey Woodruff, PhD MPH,

UCSF Program on Reproductive Health

& the Environment

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Babies ‘R’ Us & BPA

• 2007: UCSF Program on Reproductive

Health & the Environment formed

• 2008: WalMart and Babies ‘R’ Us stop

selling baby bottles w/ BPA

• 2010: Canada declares BPA to be a

"toxic substance"

• May 2013: RCOG Scientific Paper

• Oct 2013: ACOG/ASRM Opinion

3Program on Reproductive

Health and the Environment

Should we panic? No

• Effects of these chemicals generally subtle

– Chronic exposure often needed to see clinical impact

– Not all routes/types of exposures equally concerning

– Not everyone susceptible

– Often effect only seen clearly on population level

• Analogies:

– Sometimes forgetting sunscreen & risk of skin cancer

– Eating eggs/butter & risk of MI

– NOT: one exposure to HPV & cervical Ca

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Objectives

• Concerning trends

• Concepts of endocrine disruption

• Specific chemicals of concern

– BPA, PDBEs

– Lead, TBT, pesticides in syllabus

• Things our pts can do

– Top Ten Changes to make

• Resources in syllabus

– Epigenetic effects



Mutant Fish

6

http://www.boisestatepublicradio.org/post/two-headed-trout-leads-scrutiny-mine-pollutionLemly, AD 2004. Aquatic selenium pollution is a global environmental safety issue. Ecotoxicology and Environmental Safety, 59, 44- 56. . http://www.srs.fs.usda.gov/pubs/ja/ja_lemly017.pdf

Program on Reproductive Health and the Environment7

Early Puberty


ADHD among 5 – 17 year olds

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Disturbing National Health Trends

Similar trends:PTB, LBW, autism, obesity, GDM, gastroschisis, infertility, hypospadius, childhood cancer

http://www.cdc.gov/media/dpk/2013/dpk-vs-child-obesity.html#graphicshttp://www.cdc.gov/ncbddd/autism/data.htmlhttp://seer.cancer.gov/publications/childhood/ Program on Reproductive


0

10

20

30

40

50

60

70

80

90

100

1945 1955 1965 1975 1985 1995 2005

U.S. Chemical Production 1945 - 2007

Federal reserve data on chemical production is only offered as relative production, which is unit-less. A specific reference year is chosen and values are calculated relative to that years production. In this particular data set 2007 is the reference year and is assigned a value of 100.

Data from: U.S. Federal Reserve Board, Division of Research and Statistics


43Chemicals Detected in

Virtually Every Pregnant Woman in the US

Woodruff T.J., Zota A.R., and Schwartz J.M. Environmental

Health Perspectives 2011Program on Reproductive


True, True, and Unrelated?Do you think these trends are related?

12

Yes,

envi

ronm

e...

No, t

hese p

rob...

No su

re/o

ther

58%

40%

2%

A. Yes, environmental toxins & endocrine

disrupters increase the risk of many

diseases and conditions

B. No, these problems are caused by too

much TV or poor parenting

C. No sure/other

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Endocrine Disrupting Chemicals:Substances that interfere with normal hormonal activity

13Helmestam 2013 Program on Reproductive


Some Reproductive Effects Are Clear

Exposure Can Increase the Risk of…

DES Vaginal cancer,

male subfertility

Uterine malformations,

cervical incompetence

Tobacco smoke Miscarriage

Infertility

Low semen quality

LBW, PTB

Heavy alcohol use Fetal alcohol syndrome

Mental retardation

Behavioral problems

Birth defects

Heavy metals (lead,

mercury)

Miscarriage, Infertility

Menstrual irregularities

Abnormal sperm

Altered pubertal onset

Toluene (solvents) Fetal solvent syndrome

DBCP (pesticide) Low sperm count Testicular atrophy

Sterility

Jones HE, et al. Obstet Gynecol Clin North Am. 1998. EPA. 2008.Woodruff TJ, et al. Fertil Steril. 2008. (Adapted from ARHP Core slides)


Other links are less clear

• Environmental exposures hard to assess

– Who: Exposure to chemicals usually not

documented, different people have different

levels of sensitivity (eg nutritional status,

metabolism, genetics)

– What: Actual chemical may not be known

(“flavors” of BPA)

– When: Timing of exposure unclear & in past

– How much: Amount of exposure unclear



Alcohol in

adolescents

Timing Matters: Development & Periods of Susceptibility

Fertilized Egg

EmbryoFetus

InfantChild

Teenager

Teratogens in

pregnancy

Radiation,

Lead in kids

*Evidence

suggests EDCs also

have different

effects at different

points in time

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Do you worry about BPA?

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No, I

pre

fer t

...

A li

ttle

…I d

id...

Yes.

I drin

k m...

Pre

fer n

ot to ..

.

20%

5%

20%

56%

A. No, I prefer to drink out of a 12-year old

polycarbonate bottle that I use in the

microwave

B. A little…I did buy a stainless steel bottle

C. Yes. I drink my organic local Kombucha

tea out of a glass jar

D. Prefer not to state


BPA clearly has many biological effects

• 1930s: BPA recognized as artificial estrogen by

same chemist who developed DES; BPA’s phenol

groups mimic estrogen

• 3.6 million tons/year

• Animal/basic science models:

– Prenatal BPA exposure � diabetes-changes in adult mice

Liu Plos One 2013

– BPA increases angiogenesis in human endometrial cells

Helmestam Uppsala U. 2013

• Human epidemiology data:

– Prenatal BPA & adult diabetes

http://www.ncbi.nlm.nih.gov/pubmed/2367552318


Complex Science: EDCs = SERMs BPA = mixed agonist/antagonist

• Estrogen: stimulates endometrium,

breast, bone

• Tamoxifen: stimulates

endometrium/bone, down-regulates

breast

• Raloxifene: down-regulates

endometrium & breast, strengthens

bone

• BPA: tissue specific effects, also:

-agonist/antagonist depending on

concentration

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Yin EHP 2012 Program on Reproductive Health and the Environment

Gestational urinary BPA & Executive Function

Braun J M et al. Pediatrics 2011;128:873-882

GIRLS BOYS

Fetal BPA exposure associated w/ anxiety, depressive

sx, & impaired behavioral regulation at age 3, worse

for girls

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BPA: Not just for women & children to worry about…

• Chinese workers in BPA factories, Kaiser DOR

• The BPA-exposed workers (ave urine BPA 58 mcg/gCreat

vs 1.2 mcg/gCr for unexposed) had

– reduced frequency of intercourse (OR = 6.7)

– ejaculation dysfunction (OR = 6.3),

– reduced satisfaction with sex life (OR = 10.0)

– reduced sex drive (OR = 17.7)

– reduced ability to have erection (OR = 15.0)

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Li, et al Human Reprod, 2009Program on Reproductive


PBDEs – Ubiquitous Exposure (flame retardants)

© Leona Kanaskie

D SLATER. NYT; September 6, 2012

Upholstered Furniture


R2=0.15P-value = 0.03

PBDEs & thyroid disruption in pregnancy

Zota et al., 2012Maternal PDBE level (2nd tri)

Maternal TSH


Maternal Prenatal PBDE Concentrations

• Impaired attention age 5

• Poorer fine motor coordination – particularly non-dominant hand

– at age 5 & 7

• Decrements in IQ at age 7

Eskenazi et al. 2012 EHP

• Kids w/ higher concentrations of

PDBEs scored lower on tests of

mental & physical development

(incl. IQ) Herbstman 2010 EHP

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Good News: Maternal PBDE Levels Fall in CA

• 1999: CA bans 2 forms of PDBE

• 2004: US phase-out

• 2013: Levels lower in samples at SFGH, comparing 2011-12 vs2008-9

Zota 2013 EST


Everywhere, Everyday, and Everyone

Outdoor environment

Workplace

Home/Indoor

Food supply

Personal care products


Contemporary Prenatal Exposure to EDCs

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Percentage of U.S. Pregnant Women with Detectable Level of Analyte

Woodruff, Zota, Schwartz EHP 2011 Program on Reproductive Health and the Environment

What can we do???

• Image © 2012 Leo Soderman - Creative Commons Non-

Commercial

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Societal Change is Possible: Recent Past


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0

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1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002

Year

Blo

od

Lea

d L

evel

s ( µµ µµ

g/d

L)

0

50

100

150

200

250

Lea

d i

n G

aso

lin

e (K

To

ns)Lead Gasoline Phase-

out (1973)

Blood Lead Levels

Lead in Gasoline

Actions Matter: Regulatory Change: Lead


Streams of Evidence for Toxicity Assessment

Regulatory Change: Precautionary Approach


Patient level: Actions Matter: Pesticides

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Lu C et al. 2006. Organic diets significantly lower children's dietary exposure to organophosphorus pesticides. Environ Health Perspect. 2006;114:260-3.

Organic diet Organic diet

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Patient level: Actions Matter: BPA

• Harvard cafeteria

• N=75, 5d fresh soup,

5d canned

• Urinary BPA

• 5 bay area families

• 3d catered food: fresh, organic, no BPA or plastics

33Carwile JAMA 2011 Rudel, EHP 2011 Program on Reproductive


Health Care: Program on Reproductive

Health & the EnvironmentMission: To create a healthier

environment for human

reproduction & development

by advancing scientific

inquiry, clinical care, &

health policies that

prevent exposures to

harmful chemicals in

our environment


PRHE: All That Matters Publications

• UCSF Reproductive Environmental Health & Justice elective for Fellows & Residents Program on Reproductive


So what can our patients do today?-Top 10

1. Buy organic $$$

– Organic produce has

less pesticide residue

– Wash produce

– Avoid fast food &

processed food

– Limit foods high in

animal fat

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2. Avoid food w/ substantial plastic contact: canned foods/sodas, wet foods in plastic

pouches/ boxes), plastic containers $$

– Avoid: #3: PVC or vinyl, #6: PS (Styrofoam),

#7 (other): may be polycarbonate (some water

bottles, & 5-gallon water jugs) or may be

something else

– Choose: #1 PETE, #2 HDPE, #4 LDPE or #5 PP,

which have lower potential health risks. But, if

your community does not recycle these, try to

avoid them



2. Avoid plastic: Don’t microwave it! $

– Heating increases leaching of chemicals, especially

w/ fatty foods. Use a paper towel or glass lid to

cover food in the microwave

– BPA is water-soluble (so maybe less of a problem

if not in a “window of susceptibility”??)

38

http://www.healthandenvironment.org/


3. Eat low-mercury fish $-$$$

– Smaller fish generally have lower mercury levels

– Up to 12 oz/wk of shrimp, catfish, pollock,

canned light tuna, salmon

– Check local advisories if eating local fish

– http://www.montereybayaquarium.org/cr

/seafoodwatch.aspx



4. Avoid carbonless receipts $

– Many contain phthalates

– Don’t take receipt if you don’t need it

– If your patient works as a cashier, recommend:

• wear gloves, if possible

• wash hands thoroughly prior to eating

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5. Limit pesticide & solvent use in home $

– Clean with soap, vinegar

– Baking soda for ants, etc.

– Keep counters clean

– Use integrated pest

management

strategies

in the garden



6. Be thoughtful about body products $-$$

– avoid phlalates, fragrances, triclosan

– risk stratify (“windows of susceptibility,” dosage,

water vs. fat soluble chemicals)

– www.ewg.org (Skin Deep)

42

http://www.ewg.org/skindeep/app/


7. Dust/damp mop/vacuum daily, take shoes off outside

– Especially important when dust is particularly

likely to have toxins

• Agricultural areas

• Urban neighborhoods

• Pt or spouse works in occupation w/

pesticides, solvents, lead, etc

– Commercial grade door mat “Twister”: 75% as

effective as shoe removal (Roberts 1991)



8. Get rid of old foam furniture $$

– Flame retardants most likely in foam from

prior to 2005 (less likely prior to 1975)

– Dust mopping, vacuuming with HEPA filter

– Also, avoid fatty animal foods

•Flame retardants are fat soluble

•Half-life 1-3 years in human fat

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9. Avoid tobacco smoke $

– Quit smoking

– Avoid 2nd hand smoke



10. Avoid lead $-$$$

– dust-mopping

– avoid hobbies, lipstick, other sources

– paint abatement

– increase dietary Fe, vit C

– For women w/ hx lead exposure, Ca2+

supplements to minimize release of lead

from bone stores

46


Special situations:

• Patient with occupational or home exposures to lead, mercury, substantial pesticide exposures

– Work Matters brochure

– Occupational Medicine resources

– Local Pediatric Environmental Health Unit, OHSA



Conclusions

• Concerning health trends may or may not be related

to environmental toxins, but the basic science &

epidemiology is concerning enough that the

precautionary principle makes sense

• Specific chemicals of concern

– BPA, PDBEs

– Lead, TBT, pesticides in syllabus

• Things we can do

– Top Ten Changes to make

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Thank you!



Extra slides/references

50


Professional Societies Taking Action

http://prhe.ucsf.edu/prhe/pdfs/Professional%20Statements%20Database.pdf

Kaiser

Catholic Healthcare West

California Medical Association


Other Resources

• ACOG/ASRM statement http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Health_Care_for_Underserved_Women/Exposure_to_Toxic_Environmental_Agents

• Environmental Working Group (& Skin Deep website) http://www.ewg.org/http://www.ewg.org/skindeep/

• EPA/state Pediatric Environmental Health Specialty Units

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Other Resources

• Collaborative on Health and the Environment (Toxicant & Disease database) http://www.healthandenvironment.org/

• NIH NLM http://householdproducts.nlm.nih.gov/products.htm

• TEDX (includes List of Possible Endocrine Disruptors & Critical Windows of Development) http://www.endocrinedisruption.com/home.php

• CDC (esp re: lead) http://www.cdc.gov/nceh/lead/publications/LeadandPregnancy2010.pdf

• Preconception Health Council of California http://www.everywomancalifornia.org



Strength of the Evidence

QuickTime™ and a decompressor

are needed to see this picture.

Diamanti-Kandarakis E et al. 2009Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement. Endo Rev 30(4):293-342

Evidence for adverse reproductive outcomes (infertility, cancers, malformations) from exposure to endocrine disrupting chemicals is strong, and there is mounting evidence for effects on … thyroid, neuroendocrine, obesity and metabolism, and insulin and glucose homeostasis.


Estrogen: the key

BPA: the paperclip pick-lock

Estrogen Receptor: the key-hole

56

Estrogen, DES and BPA: Endocrine Disruption

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

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PBDE Structures Similar To Thyroid Hormones

PCBsPCBsPCBsPCBs----209 congeners209 congeners209 congeners209 congeners PBDEsPBDEsPBDEsPBDEsThyroid HormonesThyroid HormonesThyroid HormonesThyroid Hormones

BPABPABPABPA

TriclosanTriclosanTriclosanTriclosan


Lead in Pregnancy

• Fetal blood ~ 80% of maternal blood lead

• Risk of SAb, recommend maternal BLL <5 µg/dL (0.24 µmol/L) from the time of conception through pregnancy

• Cord & prenatal maternal BLL associated w/ adverse neurodevelopmental outcomes (Wright 2008, Ris 2004, Gomaa 2002)

CDC Lead in Pregnancy 2010http://www.cdc.gov/nceh/lead/publications/LeadandPregnancy2010.pdf


Lead in unexpected places: ethnic products

• Mexican treatments: Azarcon and greta

(also known as liga, Maria Luisa, alarcon,

coral, rueda)

• Asian treatments: chuifong, tokuwan,

ghasard, bali goli, kandu

• Middle eastern treatments or cosmetics:

alkohl, saoott, cebagin

• Lipstick


Lesson From the Past: Dibromochloropropane (DBCP)

• DBCP - pesticide widely used in the U.S. (fruit and soybeans)

• 1961 - testicular atrophy documented in three rodent species

• 1977 - Agricultural workers became aware that none had fathered children

• Investigation of sentinel worker cohort found profound and permanent effects on spermatogenesis due to exposure to DBCP

• 1985 DBCP was banned from all food crops in the U.S., its export was not

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Preventing genes from functioning normally

Multi-generational Impacts of Environmental Exposures

National Research Council. Science and Decisions: Advancing Risk Assessment. Washington, DC: The National Academies Press 2008; National Research Council. Phthalates and Cumulative Risk Assessment: 2008; Welshons, W.V., et al., Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. Environ Health Perspect, 2003. 111; Palanza, P., et al., Prenatal exposure to endocrine disrupting chemicals: effects on behavioral development. Neurosci Biobehav Rev, 1999. 23

Photo credits: www.jeffwarren.org/radio/epigenetics www.encognitive.com/node/1129

Interfere w/ hormonal regulation critical to healthy reproduction


Lesson From the Past: DES

• Rx’d 1940-70s for threatened Ab

– ~ 2-8 million births affected

• Adverse effects in children

– Vaginal CA in female offspring (<0.1%) &

breast CA

– Reproductive tract dysfunction in male

& female offspring (>90%)

• Adverse effects in grandchildren

– Menstrual irregularities, ovarian CA

– Hypospadius

62From Newbold 2007 UCSF/CHE Summit


Epigenetic Effects

• F0 animals exposed to substance prior to conception and

during pregnancy

• F1 animals were exposed directly during in utero

• F2 animals were potentially exposed as germ cells of the F1.

Effects noted in F1 and F2 generations are termed

“multigenerational” (Skinner 2008).

• F3 animals are the first generation that received no exposure

to TBT at any time, and phenotypes observed in F3 animals

are considered to be transgenerational and permanent

(Anway and Skinner 2006; Jirtle and Skinner 2007).


“Warnings from a Flabby Mouse”Nicholas Kristof, NY Times 1/19/13

• Tributyltin: fungicide, banned by Intl.

Maritime Org., but persistent in

environment, measurable levels in

humans

• Prenatal TBT exposure increased fat

• TBT reprogrammed MSCs toward fat

cells in all 3 generations

• Prenatal TBT exposure led to fatty

liver & changed liver fat metabolism

in 3 subsequent generations

64

Chamorro-García Environmental Health perspectives 2013

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• Prenatal TBT exposure

led to hepatic lipid

accumulation & up-

regulated hepatic

expression of genes

involved in lipid

storage/transport,

lipogenesis, & lipolysis in

all 3 subsequent

generations

65

Chamorro-García Environmental Health perspectives 2013


Post pubertal exposure: No increased risk of breast cancer

Prepubertalexposure: 5 fold increased risk of breast cancer

* From Cohn et al. EHP 2007

Lesson From the Past - DDT


Air Pollution and Autism



~ 87,000 chemicals listed for use or import into U.S.

~ 3,000 chemicals manufactured or imported > 1 million pounds

~ 700 new added chemicals each yearU.S. EPA. What is the TSCA Chemical Substance Inventory. US Environmental Protection Agency 2006; National Research Council. Toxicity Testing for Assessment of Environmental Agents. The National Academies Press. Washington, D.C. 2006; Wilson MP, Chia DA, Ehlers BC. Green Chemistry in California: A Framework for Leadership in Chemicals Policy and Innovation. California Policy Research Center, University of California. 2006. http://www.ucop.edu/cprc/documents/greenchemistryrpt.pdf.

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March 13, 2005

environmental no disclosures contaminants & reproductive

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