Endocrine disrupting effects of widely used

substances Sarah Janssen, M.D., Ph.D., M.P.H.

Science Fellow, Natural Resources Defense Council Assistant Professor, University of California, San Francisco

sjanssen@nrdc.org

•  Examples of chemical exposures with public health implications

•  Describe how science has informed policy initiatives to limit exposure and improve health

•  Describe how physicians can use this information to address patient concerns

Increasing Incidence of Health Conditions

•  Infertility •  Premature births •  Birth defects of genitalia •  Early onset of puberty •  Cancer - testicular •  Neurological conditions – ADHD, autism •  Insulin resistance/Diabetes •  Obesity

Endocrine Disruptor •  “An exogenous agent that interferes with

the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development, and /or behavior.”

U.S. EPA, February 1997

•  Or in simpler terms:

“A substance which interferes with natural hormones.”

Endocrine disruptors and health

•  Abnormal development of reproductive organs or neurological system

•  Reduced fertility – male and female •  Poor birth outcomes – LBW/IUGR, SA •  Development of pre-cancerous/cancerous

lesions •  Lower IQ •  Behavioral abnormalities

Synthetic Estrogens

•  Seven women ages 15-22 presented at the Massachusetts General Hospital with clear cell adenocarcinoma of the vagina, 1966-69

Herbst, AL. et al N Engl J Med 1971, 284:878. The Wood siblings

From: www.desexposure.com

Diethylstilbestrol - DES

Estradiol

DES Health Effects - Female

•  Vaginal cancer (clear-cell adenocarcinoma) •  Gross and cellular structural abnormalities of

reproductive organs: fallopian tubes, uterus, cervix, and vagina

•  Suppression of cell-mediated immunity •  Infertility •  Preterm labor •  Uterine fibroids •  Breast cancer •  Trans-generational effects – DES granddaughters

DES Health Effects - Male

•  Cryptorchidism •  Testicular hypoplasia •  Epididymal cysts •  Semen abnormalities •  Reduced fertility •  Testicular cancer

Lessons from DES

•  The placenta is not a barrier •  Exposure to the mother can have

unexpected, delayed effects in the offspring •  Exposure to a hormonally-active chemical

may result in a variety of adverse health effects

•  Unusual diseases are easier to trace to an environmental cause than are common diseases

Children are More Vulnerable to All Toxins

•  Immature brain, blood/brain barrier; •  Eat, breathe & drink more per kg; •  GI & skin 2x surface area v. adult; •  Outside more & closer to ground; •  Hand/mouth behaviors; •  Mouth breathers; •  Lower enzyme levels.

Wts of after in utero exposure to 1 part per billion DES

Estrogenic agents and obesity

Newbold, et al. 2005. Developmental Exposure to Estrogenic Compounds and Obesity. Birth Defects Research (Part A) 73:478–480.

Common Endocrine Disruptors Banned in US

PCBs Pesticides DDT DBCP Chlordecone (Kepone) Hexachlorobenzene

Not intentionally made

Dioxins Furans PAHs

Still in use Pesticides Atrazine Endosulfan Lindane Flame retardants BFRs/CFRs Plasticizers phthalates bisphenol A Heavy Metals Perchlorate Antimicrobials triclosan/triclocarban

Common Exposures of concern

•  Occupational exposures •  Exposures unique to a community •  Exposures during vulnerable periods

•  Food or drinking water contamination •  Breast feeding •  Toxics in the home

Challenges to HCPs •  Unfamiliarity with the science •  Science pertains to populations and not

individuals •  Translation of scientific studies done

mostly in animals •  Issues of exposure

– Mixtures – Life stage of exposure – Dose

Communication about Health Risk

Informed Consent vs.

–  Risks and benefits

–  Apply to an individual

–  Voluntary procedure or exposure

Environmental Exposure

–  No benefit to exposed

–  Little-no information about the risk

–  Individual risks hard to determine

–  Exposure often unknown

Overall approach •  Take an appropriate Occupational and

environmental history •  Have some knowledge of the contaminant

of concern •  Assess the likelihood of exposure •  Ability to communicate an effective

strategy for reducing exposure •  Redirecting conversation to exposures

which are preventable and controllable

Plastics in Consumer Products

Bisphenol A

•  Over 6 billion pounds produced each year

•  Developed as estrogenic drug 1930s

•  Building block of polycarbonate plastic

•  Food can lining •  Dental sealant •  Cash register receipts

7 PC

Animal studies

•  Cancer promoter –  Prostate hyperplasia/cancer – Mammary cancer

•  Developmental toxin - lower sperm counts - altered onset of puberty - decreased anogenital distance - oocyte anueploidy •  Neurological toxin •  Obesogen/Insulin Resistance

Reproductive Toxicology, Aug 2007

Policy

•  BPA has not been banned in any state or country – although legislation has been introduced

•  FDA has approved BPA as a food additive

April 2008 •  National Toxicology Program draft report •  Health Canada - “dangerous substance”

Public perception •  Market for baby bottles changed – Walmart, Toys ‘R Us

•  "Baby Bargains," a best-selling guide to baby products, have advised parents to stop using bottles made of polycarbonate plastic.

"If you are shopping for bottles, choose an alternative made from BPA-free plastic or glass,"

"If you have polycarbonate bottles, throw them out."

•  Market for beverage containers changed – Nalgene discontinues production of ‘Lexan’ bottles

What are the alternatives?

•  Non-polycarbonate plastic or glass baby bottle

•  Born-Free (polyamide) others •  Polypropylene

•  Unlined stainless steel bottle •  Eat fresh food when possible, - frozen over canned •  Buy processed food in cardboard or brick

containers

Phthalates in consumer products

Phthalates: Anti-Androgens

“Phthalate Syndrome” – Absent testes, prostate

gland, seminal vesicles – Testicular atrophy – Decreased sperm count – Decreased fertility – Cryptorchidism – Hypospadias –

decreased AGD

Fisher J. Reproduction.127:305-15, 2004

Phthalates and PVC •  Make PVC flexible and soft •  Not tightly bound, migrates with use •  Ubiquitous exposure •  General Uses

-  Building materials - Toys - Clothing - Childcare Products - Packaging - Cosmetics and -  Medical Devices personal care products -  Air fresheners

Most Sensitive System: Immature Male Reproductive

Tract •  “Phthalate syndrome” •  Mechanism of Action

–  testosterone synthesis; interference with Leydig cell differentiation with fetal exposures

•  Target Tissues – Sertoli cells, Leydig cells – Seminiferous tubules, sperm, epididymis, penis,

prostate

NTP-CERHR-DEHP-00, Oct 2000 Moore, 2001 EHP 109:229; Gray LE, Toxicol Sci. 2000 Dec;58(2):339-49.

Human exposures •  Routes of exposure: inhalation, dermal,

oral, intravenous •  Phthalates found in blood, urine, amniotic

fluid, breast milk and cord blood. •  NHANES 2000, >97% DEHP, DBP or

BBzP – Children > adults – NHB > Caucasians

•  Increased levels associated with use of application of lotions, PCCPs

DEHP in Medical Devices •  Used to make PVC plastic flexible

•  20 - 40 % by weight; up to 80% in tubing.

•  Not bound to the vinyl; readily leaches.

•  Leaching increased by lipid-like content of fluids, temperature, agitation, storage time.

Sources of Medical Exposure to DEHP

•  Intravenous fluids, medications •  Exchange Transfusions •  Replacement Transfusions •  Extra Corporeal Membrane Oxygenation •  Dialysis •  Surgery (e.g. large exposures during cardiopulmonary bypass)

•  Hyper-alimentation •  Gastric Feeding, NG Tubing •  Artificial Ventilation

Testicular Dysgenesis Syndrome

•  Hypospadias •  Cryptorchidism •  Leydig cell

hyperplasia (micronodules)

•  Sperm density •  Testicular cancer

Skakkebaek NE. Human Reproduction 16:972, 2001 Moller H. APMIS 106:232-239.

Epidemiology

•  Prenatal exposures –  Shortened AGD (Swan, 2005)

•  Neonatal exposures – Hormonal alterations (Main, 2006)

•  Adult men – Poor semen quality (Hauser, 2006 and 2007)

– Occupational exposures associated with lower fT (Pan, 2006)

Air freshener testing

•  14 air freshener products tested – 8 aerosol sprays; – 5 continuously-emitting liquids; – 1 solid

•  12 found to contain phthalates – None were labeled –  “unscented” and “all natural” products

Conclusions of study

•  Preliminary findings – More comprehensive, in-depth testing needed

•  Not clear what exposure to individual would be

•  Consumers are not aware of potential danger – No labeling – Not regulated by CPSC

Phthalates in consumer products

Recommendations to patients phthalates and “plastics”

•  Avoid using PVC plastics (#3) •  Avoid use of soft toys that can be heavily

mouthed. •  Use unscented products •  Check on-line guides for cosmetics http://www.ewg.org/reports/skindeep/

Policy Initiatives around phthalates

•  EU, Argentina, Japan and Mexico – banned 6 different types of phthalates from children’s toys and products

•  EU also banned phthalates from cosmetics

•  California “toxic toy” ban – September 2007

•  San Francisco “toxic toy” ban – May 2006

Bush expected to sign bill toughening standards on toy safety Jane Kay, Chronicle Environment Writer Thursday, July 31, 2008

(07-31) 19:05 PDT -- The U.S. Senate passed legislation today strengthening enforcement provisions of the nation's consumer products safety agency and banning lead and other harmful chemicals in children's toys.

White House spokeswoman Dana Perino said President Bush is expected to sign the bill, which passed the Senate 89-3 and the House of Representatives 424-1 on Wednesday. The amendment prohibits the manufacture, sale or importation of toys and other products that contain certain phthalates, with different protections for children ranging up to the age of 12.

"This is the first legislation of its kind," Feinstein said in an interview. "For the first time, we are essentially able to establish precautionary standards. "It puts the responsibility on the companies to know that what they're pushing is benign and does not impact human health," she said. "Once it's in the product, and in the marketplace, we had to wait for people to get sick from it."

What are the alternatives?

•  Toys •  Cosmetics •  Air fresheners •  Medical devices

Take home messages •  Hormonally-active agents exist in drugs,

cosmetics, dietary supplements, pesticides, consumer products, and industrial chemicals.

•  Laboratory animal experiments suggest that exposures to these agents could be impacting reproductive health.

•  The developing fetus, infants and children are most vulnerable because their organs are still developing

Take home messages, cont’d

•  Consequences of early life exposures are sometimes manifest until adulthood and can be permanent and irreversible

•  Chemicals can have multiple sites of action with multiple effects.

•  The impacts of exposures to mixtures of chemicals is not understood

Resources

Natural Resources Defense Council www.nrdc.org

Simple Steps www.simplesteps.org