Endocrine disruptors: Clinical and Public health implications

Nimi Singh, MD, MPH Division of Adolescent Health and Medicine Department of Pediatrics University of Minnesota

Disclosure



I have no relevant financial relationships to disclose



I am not on any Speakers Bureau



I do not intend to discuss unapproved uses of a commercial product

Introduction

Age of onset of puberty in girls has decreased significantly in the last few decades…why? …and what can we do about it?

Overview:



Precocious puberty in girls



Etiology: Endocrine disruptors



Effects on vertebrates



Effects on humans in particular



Clinical implications



Public Health implications

Normal Puberty



Onset of puberty:

–

85%: Breast bud development in girls by age 8 Testicular enlargement by age 9 in boys

–

15%: Adrenarche (axillary / public hair)



Based on Sexual maturity rating by Tanner and Marshall, British orphanages, 1969

Herman-Giddens, et al.

(

Pediatrics

1997;99(4):505-512)    

17,000 girls between ages of 3-12 years Controlled for BMI (fat cells convert estrogens into DHEA, causing axillary hair development and linear growth, or “adrenarche”) Onset of puberty occurring earlier than previously seen:

–

By 8 years of age: 14.7% of Caucasian girls (thelarche: 10%) 50% of African-American girls (thelarche: 38%) Onset of menstruation: NO significant change

– –

Caucasian girls: 12.8 years of age African-American girls: 12.1 years of age

“Normal” Puberty in Girls



Mean age of menarche (U.S.: 12.4 years) has NOT changed significantly in 50 years

–

Slightly higher in Caucasians, slightly lower in African-Americans and Mexican-Americans (Chumlea WC et al, Pediatrics, 2003 Jan; 111 (1): 110-3)



What HAS changed is mean age of isolated

breast bud development

(“thelarche”)

Response of the Biomedical Community



Kaplowitz et al (1999):

–

New definition of “Precocious puberty”: Breast bud or axillary hair development in



Caucasian girls less than

7

years of age



African-American girls less than

6

years of age



Pediatric Endocrine community: “Redefining ‘normal’ doesn’t address why it’s happening”

Colon and Caro et al.

(Environmental Health Perspectives 2000; 108(9) ) 

Puerto Rico: dramatic increase in precocious puberty since 1979: 7 per 1000 (highest known rates in the world)



70% of these were actually premature thelarche, with menstruation occurring at the normal time



Environmental contaminants?

– – –

Hormones in dairy or beef?

Pharmaceutical waste products (Premarin, OCPs)?

Man-made chemicals in the environment?



Synthetic pesticides: bioaccumulation, storage in fat



Plastics used for packaging, storing, preserving foods

Colon and Caro et al., 2000 (cont.):



Looked at girls from ages 6 months to 8 years:

– –

41 girls with premature thelarche 35 age matched “controls” (no signs of puberty)



Measured blood Phthalate esters

–

Results were positive for:



68% of girls with thelarche



17% of girls without thelarche (at much lower levels)

Premature thelarche

(Cromer and Gordon, Pediatrics 2009; 124; 779-801) 

U.S. 2008: EPA and National Institute of Environmental Health expert panel:

–

Secular trend of increased isolated early breast development in girls (U.S., Puerto Rico, China)

–

Adverse health effects:

–   

Early sexual debut Higher risk of sexual abuse/ non-consensual sex Possible increased risk of breast cancer later in life Etiology:

 

Endocrine disruptors Effect persists when studies control for BMI

 Diamanti-Kandarakis E

et al.

2009 Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement.

Endocrine Reviews

30(4):293 342.

Endocrine Disrupting Chemicals



Endocrine Disruptors (“EDs”):

–

Synthetic chemicals that disrupt the body’s normal endocrine functions by mimicking or blocking endogenous hormones



Effects:

–

Reproductive system (breast cancer, prostate cancer, endometriosis, infertility, malformations in developing fetus)

– – –

Thyroid effects Altered insulin and glucose metabolism (Bisphenol A: Alonso Magdalena, Environ. Health Perspect., Sept. 2005) Neurodevelopmental effects (PBDE’s in cord blood and IQ, Environmental Health Perspectives, 2010)

Endocrine Disrupting Chemicals



Examples :

– Medications: – Insecticides: – – – Herbicides: Fungicides:

DES (1938-1974: used to prevent miscarriage) (DDT, DDE) (organophosphates, organochlorates) Atrazine

Industrial organic chemicals:

Bisphenol-A (BPA), Phthalates, Parabens, PBDE’s (flame retardants)

– – – Metals:

Mercury, Arsenic, Tin, Chromium

Dioxin:

by-product of waste-burning incinerators

PCB’s:

coolants and insulating fluids (banned in 1976), also termed “persistent organic pollutants” or “POP’s”

Endocrine Disrupting Chemicals



Routes of exposure:

–

Direct contact (water, air, food)

     

Agricultural and home use: insecticides, herbicides, fumigants, fungicides Industrial work: Detergents, resins, plasticizers, disinfectant bleaches Chemical/ manufacturing processes: by-products Plasticizers: leach out of plastics (food containers, IVF bags and tubing), released into the air when burned Additives in cosmetics, shampoos, lotions, etc..

Other: Teflon, flame-retardant cloth, cloth dyes (denim), computer casings, cars

Endocrine Disrupting Chemicals



Biochemical features:

–

Poorly degraded: persist in the environment for decades or longer (DDT →DDE)

–

Fat-soluble: accumulate in fat (higher levels in children and women, in obese individuals), harder for body to detoxify

– –

Crosses the placenta: exposure to fetus in utero Bio-accumulate up the food chain ( greatest exposure: fatty foods, fish from contaminated water)

–

Ubiquitous, widespread in the environment

 

CDC (2005): Average American tests positive for 148 of 200 chemicals tested In cord blood and meconium of newborns (vertical transmission) and in concentrations of ng/dL

Endocrine Disrupting Chemicals



Toxic effects:

–

Often have ‘estrogen-like’ effects (termed “xeno estrogens”) disrupting normal endocrine functioning

–

Plants and animal species have been showing toxic effects for over 60 years

–

Humans now showing significant effects

Toxic effects of EDs



Animals:

–

1960’s: Rachel Carson “Silent Spring” (birds and pesticides), eventually led to ban of DDT in U.S.

–

1976: Congress passes “Toxic Substances Control Act” (but no other substances have been regulated)

–

Lake Apopka, Florida

   

1980: Accidental release of difocol (DDT-like pesticide) Massive efforts made to clean up lake 1990’s: Alligators in Lake Apopka, Florida

–

Low hatch rate (20%)

–

High death rate of babies

–

Feminization of males (malformed penises, ambiguous genitalia) 2000: Toft et al.: persistent effects in male fish (low sperm counts)

Toxic effects of EDs



Humans:

–

Last 50 years: EDs widely dispersed

–

Epidemiologic evidence of “synthetic estrogen” effect:



Premature thelarche (Puerto rico, U.S., China)



Sperm count down by 40% in US and Europe, more pronounced in agricultural areas (Carlsen et al., 1992; Andersen et al., 2000; Swan et al, 2003)



Denmark: mothers working as gardeners had male infants with higher rates of cryptorchidism as compared to infants of non-exposed mothers (Weidner et al., 1998)

Toxic effects in Humans (cont.)



Evidence of “synthetic estrogen” effect:

–

1970 1990’s: rate of hypospadias in U.S. has doubled from 20 to 40 males per 10,000 (Paulozzi et al., 1996)

–

Increasing rates of gynecomastia in otherwise normal adolescent males

 

1990: 49% (Biro, et al.,) Phthalates and “pubertal gynecomastia”: Durmaz et al., Jan 2010: significant correlation (p<0.01, n=40, controls=21)

–

Other: Endometriosis, Uterine fibroids, Breast cancer, Benign Prostatic Hypertrophy

ED’s in the food system

(Institute for Agriculture and Trade Policy, Aug 2009) 

Intentional:

–

Steroid growth promoters (beef cattle, 8X more anabolic than testosterone)

– –

Arsenic growth promoters (chicken feed, promotes angiogenesis)

–

rbGH (increases milk production, increases mastitis/ use of antibiotics in cows, which has increases antibiotic resistance in bacteria) Synthetic pesticides (27 are defined as ED’s by European Union, another 73 are being studied by EPA)



Unintentional:

–

Food packaging (polyvinyl chloride (PVCs), Bisphenol A, Polyethylene tetrachloride (PET) )

–

Refeeding of contaminated animal fat to other animals and fish

Mechanism of action of ED’s (challenges to demonstrating causality) 

NOT a simple dose-response relationship



Age at exposure

– – – Effects of exposure in adulthood different than exposure in childhood Fetal and post-natal exposure linked to adult disease Prenatal exposure in utero linked to abnormalities at birth/ in childhood 

Recognition of multiple exposures

– – – Contamination of environment by multiple compounds Multiple exposures: synergistic effect “One-cause-one effect” not reflective of true environmental exposure

Mechanism of action of ED’s



Non-traditional dose-response dynamics:

– Very low levels of exposure during critical developmental window (when organism is extremely sensitive/ vulnerable to chemical exposure, such as in utero) – Low doses exert more powerful physiological effects than higher doses in some instances 

Trans-generational (epigenetic) effects:

– Effect is not on DNA directly, but to regulation of DNA via DNA methylation and histone acetylation – Changes in DNA regulation get passed on to future generations (propensity towards insulin resistance and obesity)

Public Health

U.S. Regulation of manufactured chemicals:

– – –

80,000 chemicals in use today 7,000 are produced or imported a year (25,000 lbs/ yr) NOT considered a food or a drug, therefore do not come under the jurisdiction of the FDA

–

NO TESTS DONE TO DETERMINE TOXICITY

–

Chemicals only pulled from market after years of research documenting ill effects PLUS strong advocacy efforts (DDT, BPA)

Public Health Interventions

  

EDUCATION

– –

Of the public Of the Health Care community RESEARCH and ADVOCACY

– –

Increased research on ED’s Burden of proof needs to be on safety, NOT harm (“precautionary principle”)

–

Support efforts to get strong governmental regulation LOBBYING

–

Need “champions” to take up cause (premature sexual development: not a priority health issue of the Puerto Rican health authorities, therefore not much has been done)

Clinical interventions: Prevention and Education



Pediatric Environmental Health Toolkit

(http://www.psr.org/resources/pediatric-toolkit.html) – Endorsed by the AAP  Anticipatory guidance (prenatal to teen visits)  Environmental health desk reference card – Toxin/ topic (lead, mercury, indoor air pollutants, PCB’s…) – Health effects summary – Sources and Routes of exposure – Prevention strategy  Free downloadable materials  Free on-line PEHT training

Individual-level Interventions



1. REDUCE EXPOSURE:

–

Educate self and family members

–

Dietary recommendations:

–    

Peel fruits and vegetables or wash with diluted vinegar Buy organic foods when possible Cut down on/avoid fatty foods ( cheeses, fatty meats, fatty fish) Avoid heating foods in plastic containers (use glass, ceramic) Avoid using herbicides and pesticides (use baits/traps instead)

– – –

Eliminate pesticide use in schools Avoid giving children plastic teething toys (use cloth) Avoid cosmetics, soaps, shampoos containing Parabens and other known endocrine disruptors

Individual-level Interventions



2. INCREASE ELIMINATION:

– – – – –

Exercise (lymphatics, lungs) Keep well-hydrated (first phase of liver detoxification, kidneys) Reduce fat stores Regulate bowel function (eat veggies, fiber, take probiotics especially after antibiotic use) Only put on your skin what you’d be willing to eat (safecosmetics.com, natural food-based alternatives)



3. REDUCE EFFECTS BY OPTIMIZING HOMEOSTASIS:

– – –

Get enough sleep Reduce stress Eat a well-balanced diet high in anti-oxidants and phyto-nutrients

Research and Advocacy:



European Union:

June 2005: Over 100 research scientists convened to review the data on endocrine disruptors  Prague Declaration, a joint signed statement (15 countries):

“In view of the magnitude of the potential risks associated with endocrine disruptors, we strongly believe that scientific uncertainty should not delay precautionary action on reducing the exposures to and the risks from endocrine disruptors”

 2007: Manufacturers are required to provide basic data on the properties of thousands of chemical substances. The European Chemicals Agency will then review the chemicals, and require substitutions of the most dangerous ones (“precautionary principle”)

Research and Advocacy

 U.S., 2009: – MINNESOTA:  First state in the nation to ban Bisphenol A in manufacturing of baby bottles, sippy cups and food containers intended for children under 3 years of age (January 2010)  700 studies total, 12 in humans   Driving force: not science alone, but also consumer advocacy groups Note: Canada declared BPA a “toxin” earlier in the same year – Toys Я Us, Nalgene, Gerber and Playtex to eliminate use of BPA in all products (consumer preferences drives industry!!)

Research and Advocacy

 U.S.: – Sept ‘09: Environmental Protection Agency:  To regulate six high-profile chemicals: BPA, phthalates, brominated flame retardants, perfluorinated compounds (non-stick coatings and food packaging), some parafins, benzidine dyes.

 To revise 1976 Toxic Substances Law (required the EPA to prove a toxic substance “presents and unreasonable risk of injury to health or the environment” and to “consider the cost of restricting its use” to industry, and choose the “least burdensome” approach in regulating industry)

Some “champions” in the U.S…



Charlotte Brody, RN

– Founder of “Health care without harm”, Executive Director of “Commonweal” in Bolinas, CA 

David Wallinga, MD, MPH

– Director, Food and Health Program, Institute for Agriculture and Trade Policy, Minneapolis, MN 

Environmental Working Group



Physicians for Social Responsibility

Industry and Govt. Research

(Environmental Working Group) 

The story of Bisphenol A (BPA):

– – – 1930’s: BPA A found to have synthetic estrogen properties 1940’s: BPA used to make “polycarbonate” plastics 1982: National Toxicology Program: Lowest Adverse Effect Level: 50 mg/kg/d – – 1997: First study showing toxic effects in humans at much lower doses 2003: NIH nominates BPA for evaluation, and hires Scientific International, an independent research contractor to evaluate effects of BPA – – SI hand-pick 15 scientists for expert panel, but exclude scientists with most research experience with BPA to minimize “bias” 2006: SI, and therefore FDA conclude that “BPA is safe” at current exposure levels

Industry and Govt. Research

(Environmental Working Group) 

The story of Bisphenol A (BPA):

– February 2007: SI found to have corporate clients such as DOW and BASF – April 2007: Chapel Hill Panel: “BPA toxic at low levels” – – – 2008: Health Canada deems BPA “toxic” based on scientific review  Over 100 studies demonstrate toxic effects at low dose (breast and prostate damage, early puberty, behavioral problems) 2008: Nestle, Abbott and Mead Johnson announce intent to eliminate BPA 2009:   Harvard study: students who drink from plastic bottles have 70% higher concentrations of BPA than those who drink from stainless steel Several states ban use of BPA in manufacturing