environmental contaminants and reproductive health. . vast majority of chemicals in commerce have...

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Program on Reproductive Health and the Environment

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Tracey J. Woodruff, PhD, MPH

Department of Obstetrics, Gynecology and Reproductive SciencesDirector, Program on Reproductive Health and the Environment

University of California, San Francisco

Environmental Contaminants and Reproductive Health


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Disclosure

No financial conflicts of interest


Chemicals and Reproductive effects

• High exposures and reproductive

health outcomes well known

• What about now?


Case Study: Dibromochloropropane

(DBCP)• DBCP - pesticide widely used in the U.S. to

treat citrus, grapes, peaches, pineapples, soybeans, and tomatoes

• 1961 - testicular atrophy due to DBCP documented in three rodent species

• 1977 - Small group of agricultural workers became aware that none had fathered children

• Investigation of sentinel worker cohort found profound and in many cases 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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Some Reproductive Effects Are Well

KnownExposure Can Increase the Risk of…

Tobacco smoke Miscarriage

Infertility

Preterm delivery

Low semen quality

Low birth weight

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 (e.g., in paint thinner, solvents)

Fetal solvent syndrome

DBCP (pesticide) Low sperm count Other male reproductive effects

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


Since DBCP …

Advances in Reproductive Health Science

• More evidence on link between environmental chemicals at higher levels and adverse reproductive and developmental health outcomes

• Can no longer assume that “low-level” environmental exposures are benign

– For example: neurological, reproductive and developmental health outcomes


Gastroschisis


Our Reproductive Capacity

Is Under Strain

Scientific indicators of declining reproductive function and increasing rates of reproductive illnesses since themid-20th century

� Difficulty conceiving & maintainingpregnancy

� Rates testicular cancer

� Sperm counts

Woodruff TJ, Carlson A, Schwartz JM, et al. Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: Executive summary. Fertil Steril 2008;89:e1-e20; Schettler T, Solomon G, Valenti M, et al. Generations at Risk. Reproductive Health and the Environment. Cambridge, MA: MIT Press 1999; Crain DA, Janssen SJ, Edwards TM, et al. Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril 2008;90:911-40; Colborn T, Dumanoski D, Myers JP. Our Stolen Future: Penguin Books USA, Inc. 1996.

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Swann, Hertz-Picciotto. Family Planning Persp 1999;31:156-157Schettler. Infertiity and related reproductive disorders, 2003 online:http://www.protectingourhealth.org/newscience/infertility/2003-04peerreviewinfertility.htm

The percent of women with impaired fecundity has increased

Age 1982 1988 1995 2002% change

from’82-‘02

15-24 4.3 4.8 6.1 8.3 +90%

25-34 10.0 9.6 11.2

35-44 12.1 10.6 12.8

TOTAL 8.4 8.2 10.2 11.8 +40%


• One out of eight babies

is born prematurely

• Rate has increased 36%

since the early 1980s

Graph from Reproductive Roulette, http://www.americanprogress.org/issues/2009/07/reproductive_roulette.html. Source: Stephanie J. Ventura et al, “Estimated Pregnancy Rates by Outcome for the United States, 1990–2004,” National Center for Health Statistics, National Vital Statistics Reports 56 (15) (April 14, 2008); Stephanie J. Ventura et al., “Trends in Pregnancies and Pregnancy Rates by Outcome: Estimates for the United States, 1976–96,” National Center for Health Statistics, Vital and Health Statistics 21 (56) (January 2000).


• Prevalence of chronic conditions among children and youth

increased from 1988 to 2006

– Obesity, asthma, other physical conditions, and behavior/learning

problems

• 51.5% of 8- through 14-year-olds at one point in the 6-year study period

reported a chronic condition compared with 27.8% in cohort 1

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Health and the Environment

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What’s Changing?

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U.S. Chemical Production

13

0

20

40

60

80

100

120

1945 1955 1965 1975 1985 1995 2005

Year

Pro

duct

ion

(100

=20

02 p

rodu

ctio

n)

Federal Reserve G.17

Chemical production has increased 23.5-fold between 1947 and 2007


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Environmental Contaminants,

What are they?


Toxic Environmental Chemicals Are Found

Everywhere, Everyday … In Virtually Everybody

ozone, particulate matter, lead. Hazardous air pollutants

pesticides, heavy metals (Hg), persistent organic pollutants (DDT, PCBs)

Chlorinated byproducts, pesticides, microorganisms, inorganic & organic chemicals, radionuclides

Bisphenol a

PBDEs, phthalates, formaldehyde

phthalates, formaldehyde, parabens, toluene,1,4 - dioxane

Pesticides


By 2006 …

87,000 chemical substances registered for use in U.S. commerce

3,000 chemicals manufactured or imported in excess of 1 million pounds

700 new industrial chemicals introduced into commerce each year

U.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.

Vast majority of chemicals in commerce have entered the marketplace without comprehensive and standardized information on their reproductive or other chronic toxicities

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“Environmental” Influences

NutritionEnvironmental chemicals

Genetics

Interactions Amongthe Factors

Social and Built Environment


What Is Reproductive Environmental Health?

• Exposure to

environmental

contaminants

(metals and synthetic

chemicals)

• During critical and sensitive windows of

development

• Health effects across

the life course and

generations to come


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Where do we get our information?

Laboratory HumansWildlife

In general, … there is concordance of developmental effects between animals and humans and that humans are as sensitive or more sensitive than the most sensitive animal species. NAS 2000 Scientific Frontiers in Dev Tox and Risk Ass Program on Reproductive


Streams of Evidence for Toxicity Assessment

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Evaluating the evidence base

• Decisions and evidence

– Pharmaceuticals must show efficacy and safety prior to use

• Requires extensive animal and human data

– Manufactured chemicals need to show evidence of harm before removing/regulating

• No specific toxicity testing required

– Except for pesticides

• Human studies are mostly byproduct of already exposed populations

– Ethical issues with intentional dosing studies

Decisions must be made in a timely manner to prevent ongoing harmful exposures


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Limitations of Human Evidence

• Human –

– Measurement of exposure often limited

– Increase “risk” from environmental contaminant

exposure often small

• Many risks in range of 2 fold increase

– Exposure misclassification can hide true associations

• But exposure ubiquitous – so still a public health problem

– Example – particulate matter air pollution

– Increases risk of respiratory and cardiovascular morbidity and

mortality

– RR mortality ~ 1.06 for estimating benefits in the United States

> 184,000 lives “saved” per year


Agents Which Cause Developmental Toxicity

Agent

Earliest Date

Reported

Species Studied in Earliest Report Other Species Studieda Referencesb

alcohol(ism) 1919 Rat Guinea pig, chicken, human, mouse

(Arlitt, 1919)

aminopterin 1950 Mouse & Rat

chicken, human (Thiersch and Phillips, 1950)

cigarette smoking 1941 Rabbit human, rat (Shoeneck, 1941)

diethylstilbestrol 1940 Rat human, mink, mouse (Greene et al., 1940)

heroin/morphine 1969 Hamster rat, human, rabbit Geber and Schramm, 1969)

ionizing radiation 1950 Mouse hamster, human, rat, rabbit (Russell, 1950)

methylmercury 1965 Human cat, rat, mouse (Matsumoto et al., 1965)

polychlorinated biphenyls

1969 Human Rat (Taki et al., 1969)

steroidal hormones 1943 Monkey hamster, human, mouse, rat, rabbit

(van Wagenen and Hamilton, 1943)

thalidomide 1961 Human mouse monkey, rabbit (Lenz, 1961; McBride, 1961)

1984 Kimmel, NCTR Technical Report for Experiment No. 6015

bReferences are given only for the earliest report(s) indicated in parentheses.Program on Reproductive


SCIENCE CHANGERS

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Timing Matters


Child Development and Windows of Susceptibility

Periconception Prenatal Postnatal Childhood →

Blastocyst EmbryoFetus

Infant ChildAdolescent

Environmental Chemical Exposure

Immediate & Long TermConsequences

Proper reproductive development orchestrated by hormones


Developmental Basis of Adult Disease

• Human evidence from study of WW

II Dutch famine

• Prenatal under-nutrition affected

health in adulthood

• Timing of nutritional insult

determined organ system affected

• Exposure in

– Early gestation: three-fold increase in coronary heart disease, more obesity

– Mid-gestation: increase in obstructive airways disease

– Late gestation: impaired glucose tolerance

Painter RC, Roseboom TJ, Bleker OP.Prenatal exposure to the Dutch famine and disease in later

life: an overview. Reprod Toxicol. 2005 Sep-Oct;20(3):345-52. Program on Reproductive Health and the Environment

March 13, 2005

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Preventing genes from functioning normally

Health Impacts of “Everyday” Toxic Environmental

Exposures

Studies show the

levels of chemicals

an average person

is exposed to can

perturb biological

processes:

Sources: National Research Council. Science and Decisions: Advancing Risk Assessment. Washington, DC: The National Academies Press 2008; National Research Council. Phthalates and Cumulative Risk Assessment: The Task Ahead. Washington, D.C.: National Academies Press 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(8): p. 994-1006; Palanza, P., et al., Prenatalexposure to endocrine disrupting chemicals: effects on behavioral development. Neurosci Biobehav Rev, 1999. 23(7): p. 1011

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

Interfere with the hormonal regulation critical to healthy reproduction

Endocrine Disrupting Chemicals: Chemicals which can alter or interfere with natural hormone levels in the body


Cumulative Exposures Matter

• Exposures to multiple chemicals

can have an additive effect

– Risks of chemicals should be

considered together that act on

the same common adverse

outcome

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Lead

Methylmercury

PCBS


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Contaminants in US pregnant women*

Contaminant Percent of US population with

measurable levels*

Some evidence can disrupt endocrine system?

Sources

Phthalates (4 kinds) 80 – 100% Yes Flooring, wall covering, medical devices, food wrap, personal care products, lacquers

Bisphenol A 92% Yes Polycarbonate plastic, food can lining dental

sealent

Polyfluoroalkyl Chemicals (PFOS) (4 kinds)

91-99% Yes Nonstick cookware, stain resistent fabrics, food packaging, dental

products

Parabens (4 kinds) 36-99% Yes Personal care products, food

Benzophenone-3 100% Yes Sunscreen, food packaging

PCBs (many) 100% (with at least one congener)

Yes Banned in 1977 –persistent through food

*Representative US sample from NHANES/CDC generally from 2003/2004Program on Reproductive


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Tracey J. Woodruff, PhD, MPH

Associate Professor and DirectorProgram on Reproductive Health and the Environment

Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of California San Francisco

October 21, 2009

Prenatal Exposures and Adverse Pregnancy Outcomes

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Environmental Tobacco Smoke

• A known risk factor for

– Low birthweight and decreases in birthweight

– Preterm birth

*California Environmental Protection Agency. 2005. Identification of Environmental Tobacco Smoke as a Toxic Air Contaminant;


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Ambient Environment: Air

• Traffic

• Industrial Sources

• Power Plants

• Farming

• Forest Fires

• Second hand

smoke

(Environmental

tobacco smoke)


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LBW & Preterm

• Likely role for air pollution (Slama EHP, 2008)

• Effects are small but exposure ubiquitous and high in certain areas

– For LBW ~ 30 grams reduction in BW for 10 ug/m3 increase in particulate matter air pollution in CA

• ETS (20-30 grams) (Windham et al. 1999)

• Variable critical window


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Personal Environment

• Pesticide use

– In home pesticide use suggested effects on birth

weight (Whyatt et al. 2004 EHP)

• PFOS (Perfluorooctanesulfonic Acid)

• Primarily from animal studies, and small number human

study

• Effects observed on gestational growth

• Persistent compounds

– Organochlorines (DDT/PCBs)

• Some evidence on gestational growth and preterm delivery

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Congenital anomalies and Occupational

Exposures

• Solvents

– Structurally diverse, can dissolve other organic substances

• Glycol ethers, Benzene, toluene, xylene, trichloroethylene, perchloroethylene

• Occupations: Factories, lab techs, printing, painting, chemists, cleaning

– Meta-analysis retrospective studies (5 studies, 7,036 patients) (McMartin Am J Ind Med 1998)

• OR for major malformations 1.64 (CI 1.16–2.30)

– Prospective study (n=125) (Khattak et al. JAMA 1999)

• OR for major malformations 13.0 (1.8-99.5)


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Exposures during prenatal

development and other

effects


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Prenatal exposures and

neurodevelopmental outcomes• Developing brain vulnerable to environmental contaminants

– Cognitive impairments, behavioral deficits

• Environmental contaminants of concern

– Mercury

– PCBs

– Perchlorate

– Pesticides


Percent of U.S. population with detectable

pesticides in their bodies

Source: NHANES 1999–2002 body burden data for organophosphorus pesticides

Organophosphorus (OP) Urinary Metabolites

in U.S. Population (1999-2002)

0

10

20

30

40

50

60

70

80

90

TCPy DETP DEP DMTP MDA DMP DMDTPDEDTP IMPY

OP Metabolite

A meta-analysis of 15 human studies found positive associations … between childhood leukemia and residential pesticide exposu resduring pregnancy and childhood. (30% to 200% increased risk)

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Future reproductive effects


Phthalates found in

Food Wrap

Medical devices

personal care products (perfumes, lotions, cosmetics, hair spray),

Air Fresheners

Toys

flooring, wall coverings, lacquers, varnishes, and wood finishes and coatings

Dibutyl phthalate, Dethylhexyl phthalate, Dimethyl phthalate, Butyl benzyl phthalate


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Lowered fetal testosterone

Cryptorchidism

Hypospadias

Impaired sperm productionin adult life

Testicular Cancer

INFERTILITY

Decreased testosterone

Reduced anogenital distance

• Disrupts male

reproductive

development

– Testicular dysgenesis

syndrome

• Prenatal exposure to

phthalates can

decrease fetal

testosteroneIMPAIREDGERM CELLDIFFEREN-TIATION


Why Do Chemicals in People Matter?

* Howdeshell et al. 2007 ToxSci, Swan et al. 2005 EHP

50-97% of people have Phthalates in their bodies

Flooring, wall covering, medical devices, food wrap, personal care products, lacquers

Animal studies show increases deformities in penis and testicles and lower testosterone from prenatal exposures

Phthalates in pregnant women associated with decrease in anogenital distance – a marker for feminization

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QuickTime™ and a decompressor

are needed to see this picture.

Strength of the Evidence

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.


“So What Do I Do?”

– Science for environmental exposures

and reproductive health is:

• Primarily based on animal studies

• Warrants guidance to limit/avoid exposure

– Approach patients on case-by-case

basis

– Exposure is unavoidable, but specific

changes can make a difference

Expert Medical Advisory Committee on Environmental Impacts on Reproductive Health. 2009.


Patient Counseling: Focus on Windows of

Susceptibility

– For male and female adolescents

– For male and female patients who

experience unintended pregnancy

– For women and men during pregnancy

planning

– For pregnant women

– For male and female patients with

newborns

and childrenExpert Medical Advisory Committee on Environmental Impacts on Reproductive Health. 2009.


The Environmental Health History

Identify and reduce or eliminate

potentially harmful exposures





Environmental Health History Should Be

Routine

HO

W?

WH

Y?

WHEN?

Vulnerable Stages:� Early childhood� Puberty� Adolescence� Preconception planning

(men & women)� Pregnancy

Expert Medical Advisory Committee on Environmental Impacts on Reproductive Health. 2009.

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Actions can reduce exposure

• 23 children monitored for metabolites before/after organic diet

• Levels of urinary metabolites for chlorpyrifos and malathion reduced to non-detectable

• Again elevated on re-introduction of conventional diet

Source: Lu C et al. 2006. Organic diets significantly lower children's dietary exposure to organophosphorus pesticides. Environ Health Perspect. 2006 Feb;114(2):260-3.

Organic diet Organic diet

Program on Reproductive Health and the Environment50

FASTEP - Reproductive

Environmental Health

Toolkit

• Clinical guidance based on AAP-Endorsed PSR Pediatric Environmental Toolkitand other authoritative sources

• Co-branded by FASTEP Alliance partners

• Disseminating with PSR Pediatric Environmental Toolkit, Centers for Excellence in Women’s Health, Magee Women’s Hospital, and other partners

• Concrete advice on how women can avoid harmful chemicals

www.prhe.ucsf/prhe


5 Areas of Focus

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• Prevent Exposure At Home

– Example – don’t smoke, eat organic when possible

• Prevent Exposure At Work

– Example – know what is in your workplace and talk with your

healthcare provider

• Prevent Exposure In Your Community

– Example - drive less, do not burn trash

• Become A Smart Consumer

– Example – consumer guides can help you buy less toxic

products

• Make The Government Work For You

– Example – the government should know you care


We Can’t Shop Our Way out

the Problem

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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 L

ead

Leve

ls (

µµ µµg/

dL)

0

50

100

150

200

250

Lead

in G

asol

ine

(KT

ons)Lead Gasoline Phase-

out (1973)

Blood Lead Levels

Lead in Gasoline

Actions can reduce exposures


We expect to know about drugs before they go to market, why not

chemicals?

www.fda.gov/cder/about/history/ and Pomper, G.M., Ordinary Heroes and American Democracy* Except for pesticide active ingredients

– Pharmaceuticals must have data to show efficacy and safety prior to use

– Do manufactured chemicals have to have data on safetybefore use?

NO


Program on Reproductive Health and the

Environment

Mission

• To create a healthier environment for

human reproduction and development by

advancing scientific inquiry, clinical care,

and health policies that prevent exposures

to harmful chemicals in our environment

– Targeted research

– Expanding clinical practice

– Advancing science-based policy

solutions

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environmental contaminants and reproductive health. . vast majority of chemicals in commerce have...

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