No disclosures - ACMT · of poison which has accidentally got into some article of food, but a persistent & continuous poisoning of the whole human environment. Rachel Carson, Silent

Program on Reproductive

Health and the Environment

No disclosures

1



Communicating Risks from Neurological & Metabolic Toxins in Pregnancy

Marya G. Zlatnik, MD, MMSProfessor, Maternal Fetal Medicine & Program in Reproductive Health & the Environment, UCSFAssociate Director, Maternal Fetal Health & the Environment, UCSF-Western States Pediatric Environmental Health Specialty Unit Hanna-Attisha M, AJPH 2016



“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, Silent Spring

“Lead is a potent, known, irreversible neurotoxin.” “in 10, 15, 20 years, we can see the consequences of lead poisoning — …kids in special ed, … problems in our mental health system, we can see the problems in our criminal justice system. “

Mona Hanna-Attisha, NPR interview, 1/23/16



Objectives

• Brief review of pregnancy physiology and fetal development

• Concept of endocrine disruption

• Specific chemicals of concern

– Lead, mercury, BPA, phthalates, PDBEs, pesticides,

• Suggestions for communicating with pregnant women

4



Many Reproductive Aged Women at Risk for Pregnancy

• 6.6 million pregnancies/yr in US

• 51% of US pregnancies unplanned

https://www.guttmacher.org/pubs/FB-Unintended-Pregnancy-US.html#6



Some Women May Be More Vulnerable

• Unplanned pregnancies more common in poor or uneducated women

• If you care for women aged 15-45 years old, or for children who have a mother aged 15-45 years old, or a man partnered with… they may be at risk for unintended pregnancy

https://www.guttmacher.org/pubs/FB-Unintended-Pregnancy-US.html#6



Quick Review of Pregnancy Physiology: Goals of Maternal Adaptation

• Mass effect:

5L abdominal mass

• Hemodynamic:

perfusion of 4kg additional tissue

• Metabolic/Hormonal:

O2 & nutrients for woman & fetus



Quick Review of Pregnancy Physiology: Increased Cardiac Output

• Initial increase in CO associated with increase in stroke volume

– As pregnancy progresses, increased HR

Hunter ‘92

CO

SV

HR



Quick Review of Pregnancy Physiology: Lung Volumes

-2000

-1000

0

1000

2000

3000

4000

Non-Pregnant Pregnant

mL

Inspiratory Reserve

Tidal Volume

Expiratory Reserve

Residual Volume

Tidal Volume ↑ 40%

Respiratory rate No change

Minute ventilation (TV x RR) ↑ 40%



Quick Review of Pregnancy Physiology: Acid-Base Physiology

Parameter Nongravid Gravid

Arterial pH 7.35 – 7.40 7.40 – 7.45

PaCO2 (mmHg) 40 30

PaO2 (mmHg) 85 95-100

HCO3 (mEq/L) 25 20

Typical Changes in Arterial Blood Gases

**Mild respiratory alkalosis,↓ PaCO2 partially compensated by ↑ renal excretion of bicarbonate



Quick Review of Pregnancy Physiology:

Renal Physiology Changes

Renal Plasma Flow ↑ 75%

GFR ↑ 50%

Creatinine clearance ↑

Serum creatinine ↓ 25% (0.5-0.6 mg/dl)

BUN ↓

IMPORTANT: creatinine or BUN @ the upper limit of “normal” worrisome for renal impairment

Serum creatinine should be <0.8 mg/dl, BUN <13 mg/dl



Quick Review of Pregnancy Physiology:

Metabolic Changes

• Bone modeling/resorption

• Goal: maintain normal maternal Ca2+ levels while building fetal bone

•↓ PTH but ↑ absorption of Ca2+ in the gut result of placental production of 1,25-OH vitamin D

•PTH-related peptide (PTHrP) facilitates active placental Ca2+

transfer



Review: Timeline of Fetal Development

Modified from, “Critical or sensitive stages in human prenatal development,” by Image Editor

Weeks after fertilization= GA by LMP-2:1st tri:4-13, 2nd tri:14-26, 3rd tri 27-40wks



The Placenta may not protect the fetus

• Toxins may cross placenta into fetal bloodstream

• Toxins may be metabolized in placenta

• Toxins may alter placental endocrine function



Umbilical Cord Blood Studies



Approximately 1 in 6 US children diagnosed with a developmental disability

Source: Based on data from 2006–2008. Boyle et al. (2010)



Autism

http://www.cdc.gov/NCBDDD/autism/data.html



Brain Drain Chemicals in Pregnant Women

Chemical Found in >80% of Pregnant Women

Decrease in Child IQ

Lead X X

Mercury X X

PCBs X X

Flame Retardants X X

Pesticides X X

Air Pollution X X

Arsenic X* X

* As measured in total US, assumes also represents pregnant women



Lead in Pregnancy

Fetal blood ~ 80% of maternal blood lead

Recommend maternal BLL <5 µg/dL

Cord & prenatal maternal BLL associated w/ adverse neurodevelopmental outcomes (Wright 2008, Ris2004, Gomaa 2002)

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

http://www.cdc.gov/nceh/lead/publications/LeadandPregnancy2010.pdf



Advice for Women: Avoid lead

– Frequent dust-mopping

– Avoid hobbies, lipstick, other sources

– Paint abatement for baby

– For women w/ hx lead exposure, Ca2+ supplements to minimize release of lead from bone stores

– Increase dietary Fe, vit C

20



Lead in unexpected places: ethnic products

• Mexican treatments: Azarcon and greta(also known as liga, Maria Luisa, alarcon, coral, rueda), also candies

• Asian treatments: chuifong, tokuwan, ghasard, bali goli, kandu, bo ying*

• Middle eastern, Ayurvedic treatments or cosmetics: alkohl, saoott, cebagin

• Lipstick: drugstore brands

*



AOEC Guidelines

• Important to reduce fetal exposure to lead on a population basis

– Maternal lead levels less than 5 μg/dL are optimal

• Panel’s recommendation: mother’s BLL should be kept below 5 µg/dL (0.24 µmol/L) from time of conception through pregnancy

– Fetal blood contains ~80% of blood lead concentration of mother

– Risk of spontaneous abortion



Scatterplot and the best-fit line with 95% confidence intervals of the child developmental score up to 36 months old and maternal whole blood lead (BPb) levels in the first trimester (A) and after withdrawal of a few outlier values (>3 standard deviation above the mean) of whole blood lead level (B)





Mercury in Pregnancy: Neurocognitive Outcomes

Minimata, Iraq poisonings

Association with ADHD, etc

Main exposure is methylmercuryin seafood

Less common exposures:

Elemental mercury: broken CFLs, thermometers

Inorganic mercury: face creams, imported medicines, etc.

Sagive 2012; http://www.atsdr.cdc.gov/phs/phs.asp?id=112&tid=24

Maternal hair mercury



Mercury in Pregnancy

Avoid fish with methylmercury

Overall, fish consumption seems protective despite methylmercury

Messaging challenging

Pregnant women consuming less seafood

Not from thimerosal in vaccines!

Fish fatty acids

Hibbeln 2007; http://www.atsdr.cdc.gov/phs/phs.asp?id=112&tid=24



Endocrine Disrupting Chemicals:Substances that interfere with normal hormonal activity

27

Helmestam 2013



Estrogen: the key

BPA: the paperclip pick-lock

Estrogen Receptor:

the key-hole

28

Estrogen, DES and BPA: Endocrine Disruption

Science in Products http://scienceinproducts.blogspot.com

Ruben et al. 2011

http://scienceinproducts.blogspot.com/



BPA has many biological effects

• 1930s: BPA = artificial estrogen, developed by same chemist who developed DES

• 3.6 million tons/year

• Animal/basic science models: estrogen (ant)agonist

• Human epidemiology data: estrogen (ant)agonist

• Found in ~95% of sample of US pregnant women

29

Woodruff, Zota, Schwartz EHP 2011



Gestational urinary BPA & Behaviour

Braun JM 2011

GIRLS BOYS

Fetal BPA exposure associated w/ anxiety, depressive sx, & impaired behavioral regulation at age 3, worse for girls

Beh

avio

ral s

core

s



Prenatal Phthalate Exposure

Some phthalates found in 100% of sample of US pregnant women

Plasticizers in products made with PVC, such as flooring, shower curtains, packaging, & medical equipment

Phthalates also found in personal care products such as perfumes, nail polish, & lotion

31

Woodruff, Zota, Schwartz EHP 2011



Prenatal Phthalate Exposure: Effect on AGI (anogenital distance) in boys

AGI = sensitive index of desmasculization of male reproductive tract

Similar studies with smaller penile sizes

Reproducible in rats

32Swan EHP 2005



Prenatal Phthalate Exposure & reduced masculine play in boys

Change in play if phthalate metabolite concentration in boy’s mother’s prenatal urine was increased from 10th percentile to 90th percentile. p-value of <0.05

33Swan IIA 2010 (online 2009)



Avoid food w/ substantial plastic contact: canned foods/sodas, wet foods in plastic pouches/ boxes)

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

#7 (= other): polycarbonate (some water bottles, & 5-gallon jugs) or may be untested

– Choose: #1 PETE, #2 HDPE, #4 LDPE or #5 PP, likely lower health risks. But, if your community does not recycle these, try to avoid them

34



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

35

http://www.healthandenvironment.org/

http://www.healthandenvironment.org/



Pesticides:Organophosphates

• Prenatal exposure to organophosphate pesticides (OP: dialkyl phosphates) is associated w/:

– Shorter length of pregnancy

– Lower IQ in children

– Increased risk of attention problems

CERCGH: the CHAMACOS study: Eskanazi 2011, Bouchard 2011



PBDEs – Ubiquitous Exposure (flame retardants)

© Leona Kanaskie

D SLATER. NYT; September 6, 2012

Upholstered Furniture



PBDE Structures Similar To Thyroid Hormones

PCBs-209 congeners PBDEsThyroid Hormones

BPA

Triclosan



R2=0.15

P-value = 0.03

PBDEs & thyroid disruption in pregnancy

Zota et al., 2011Maternal PDBE level (2nd tri)

Maternal

TSH



Prenatal PBDE Exposures in Rats

•Perinatal Exposure to Low-Dose BDE-47, an Emergent Environmental Contaminant, Causes Hyperactivity in Rat Offspring.

Suvorov et al, Neonatology 2009;95:203-209

Control

BDE-47



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

%

omissionsADHD WISC

verbal



Maternal Prenatal PBDE Concentrations

• Kids w/ higher concentrations of PDBEsscored lower on tests of mental & physical development (incl. IQ)

Herbstman 2010 EHP



-6

-5

-4

-3

-2

-1

0

IQ D

ecr

em

en

ts

Figure 1. Decrements in IQ per interquartile increase in blood PBDE or lead levels, using data from NHANES

Chen 2013Eskanazi 2013Herbstman2001 Schwartz 1994 Lanphear 2005

PBDEs (BDE-47) Lead

PBDEs, Lead & Decreased IQ



Decrease Dust

– Dust/damp mop/vacuum daily, take shoes off outside

– Especially important when dust is particularly likely to have toxins

Get rid of old foam furniture

– Flame retardants worst in foam from prior to 2005 (less likely prior to 1975)

•Risk higher if crumbling

Avoid animal-based, processed foods

44



Perinatal Air Pollutant Exposures & Autism Spectrum Disorder in the Children of Nurses’ Health Study II Participants

45

Association of ASD w/ air pollutant concentration, highest quintile

vs lowest quintile Ors. Roberts 2013



Should we panic? No

• Effects of these chemicals generally subtle

– 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 Chernobyl or HPV & cervical Ca

46



Won’t our patients panic? Maybe

• Many providers worried about “scaring” patients or putting burden of avoiding toxins on already stressed (& caffeine-, wine-, sushi-, turkey-deprived) pregnant women

– Research indicates women want the info

• I argue that the burden of change needs to be on a societal/policy level

• I hope to provide tools & resources for clinicians whose patients are asking questions

47

Morello-Frosch et al., 2009 2014



100% 99%

86%

44%

25%

19%

9%11%

8% 5%

OB providers routinely discuss

Stotland 2014



“If I freak out like, ‘Whoa, look at that kid who’s drinking Coke out of a BPA bottle,’ … which one of those things should I deal with, right?” (Female OB/Gyn)

“Bigger fish to fry”

Stotland 2014

“It’s a little scary barrel to open because I don’t have an answer.” (Female OB/Gyn)

“Pandora’s Box”

OBs views on Counseling Patients:



Does communicating chemical exposures cause undue worry or harm?

Lessons from biomonitoring research:

Studies say pregnant women want info on personal exposures to environmental chemicals

– Believe they have the right-to-know Morello-

Frosch et al., 2009 2014; Nelson et al., 2009a; Sly et al., 2009; Wu et al., 2009

– 97% wanted exposure info even if health implications

are unclear Brody et al., 2007



Small Effects Can Have Large Significance

160140120100806040

IQ

Mean = 100

6.0 million:

“gifted”

130

6.0 million:

“mentally

retarded”

70Adapted from Weiss B. Neurotoxicology. 1997.

more…



Small Effects Can Have Large Significance (continued)

IQAdapted from Weiss B. Neurotoxicology. 1997.

57%

increase in

“mentally retarded”

population

160140120100806040

Mean = 95

60%

decrease in

“gifted”

population

9.4 million:

“mentally

retarded”

70

2.4 million:

“gifted”

130



Translating Population-Wide Risks into Individual Risks

• Clinicians work with individuals, not populations

• Elevated population-wide risks may be extremely small for an individual



Special situations:

• Patient with occupational or home exposures to lead, mercury, pesticides—or ?s you can’t answer

– Work Matters brochure from UCSF PRHE

– Local Pediatric Environmental Health Unit http://www.pehsu.netUCSF/ Western States PEHSU: 1-866-827-3478

– CDC/ATSDR creating app for OBGYNs

– Occupational Medicine resources, OSHA

54

http://www.pehsu.net/

http://coeh.berkeley.edu/ucpehsu/



Occupation: Guidance for Patients

• Use protective gear with toxic substances or radiation

• With chemicals, wash exposed skin; change work clothes; clean exposed clothes separately

• Understand chemicals used at work

• Take extra care if pregnant (or planning pregnancy)

Resource Tip:

• Learn more from the CDC report, “The Effects of Workplace Hazards on Female Reproductive Health”

Adapted from Schettler T. 2009; Expert Medical Advisory Committee on Environmental Impacts on Reproductive Health. 2009.

http://www.cdc.gov/niosh/99-104.html



Patient level: Actions Matter: Pesticides(see similar results with BPA & fresh food)

56

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



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

57Carwile JAMA 2011 Rudel, EHP 2011



PRHE: All That Matters Publications

• UCSF Reproductive

Environmental Health & Justice

elective for Fellows & Residents



Streams of Evidence for Toxicity Assessment

• Putting burden on consumers is not enough (or fair)

• Need regulatory change to prevent harmful chemicals entering our food, etc.



60

0

2

4

6

8

10

12

14

16

18

20

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

Year

Blo

od

Lead

Levels

(m

g/d

L)

0

50

100

150

200

250

Lead

in

Gaso

lin

e (

KT

on

s)

Lead Gasoline Phase-

out (1973)

Blood Lead

Levels

Lead in

Gasoline

Societal Change is Possible: Lead



Good News: Policy Change Reduces PBDE Levels in CA Pregnant Women

• 2006: CA bans PDBEs

• 2013: Levels lower in 2011-12 samples vs 2008-9 (SFGH)

q Zota 2013 EST



So what can our patients do today?-Top 10

1. Buy organic $$$

– Less pesticide residue

– Wash produce

2. Don’t eat plastic $

– Avoid food in plastic packaging, use glass or stainless to store food or water

– Don’t microwave in plastic

62



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

• Consumer Reports says no tuna!

– Check local advisories if eating local fish

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

63

http://www.montereybayaquarium.org/cr/seafoodwatch.aspx



4a. Wash hands prior to eating $

– Especially important when hands are exposed to toxins

• Agricultural areas

• Pt or spouse works in occupation w/ pesticides, solvents, lead, etc.

4b. Avoid carbonless receipts (phthalates, BPA)

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

– Cashier work: wear gloves, wash hands before eating

64



5. Limit pesticide & solvent use in home $

– Clean with soap, vinegar

– Baking soda for ants, etc.

– Keep counters clean

– Use integrated pest management

6. Bust the Dust! $-$$

– Dust/damp mop/vacuum daily, take shoes off outside

– Especially important when dust is particularly likely to have toxins

65



7. Be thoughtful about body products $-$$

– avoid phthalates, fragrances, triclosan

– risk stratify (“windows of susceptibility,” dosage, water vs. fat soluble chemicals)

– www.ewg.org (Skin Deep)

– https://safecosmetics.cdph.ca.gov/search/(CA Safe Cosmetics Program Database)

8. Get rid of old foam furniture $$

66

https://safecosmetics.cdph.ca.gov/search/



9. Avoid tobacco smoke $

– Quit smoking

– Avoid 2nd hand smoke

– No e-cigarettes

• Nicotine itself not good for reproduction

• Phthalates, etc.

• “E-Cigarettes Expose People to More Than ‘Harmless’ Water Vapor”

10. Avoid lead $-$$$

– Frequent dust-mopping

67

Grana Circulation 2015



Conclusions

• Increasing rates of ADHD and autism 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

– Lead, Mercury, BPA

– Phthalates, PDBEs, pesticides

• Advice for communicating with pregnant women

– Top Ten Changes to make

68

Documents

No disclosures - ACMT · of poison which has accidentally got into some article of food, but a persistent & continuous poisoning of the whole human environment. Rachel Carson, Silent