♂Endocrine Disruptors♀

By Sandy Poulos

Endocrine Disruption

♠ Endocrine System-a complex network of glands that produce and secrete the hormones that regulate all the major body functions.

♠ Endocrine Disruptor-chemical that interferes with the endocrine system to produce an undesired response, which may affect health, growth, and reproduction.

Mechanisms of Action

Mimics Stimulators Blockers Endocrine flushers Enzyme flushers Destructors

EDCs

Estrogens: any family of steroid hormones that regulate and sustain female sexual development and reproductive function

Androgen: a class of male sex hormones related to the steroid androstane and produced in the adrenal cortex and the testes

Substances mimicking feminizing effects are estrogenic and those mimicking masculinizing effects are androgenic

Also anti-estrogenic and anti-androgenic

Classification

Pesticides, herbicides, fungicides Polyaromatic compounds - PAHs Organic oxygen compounds (phthalates,

bisphenol A) Surfactants Drugs Metals Phytoestrogens

Pesticide-DDT

1950’s to 1960’s – DDT Estogenic Affected reproduction system of birds Disrupted the eagle's endocrine system,

interfering with calcium metabolism and produced weak egg shells, feminized frogs

DDT metabolite (DDE) → anti-androgens Atrazine & Endosulfan

DDT

Bisphenol A & Phthalates

Bisphenol A Used in the manufacture of some

clear plastics (e.g. baby feeding bottles), and used in the resin which lines most tin cans

Potency 4 to 6 times less than 17-estradiol

Weakly estrogenic, anti-androgenic Phthalates

Potency 6 to 7 times less than 17-estradiol

Weakly estrogenic

Bisphenol A

Cans – 80 g/kg canned food EU limit 3 mg/kg

Surface water: 0.0005-0.41 g/L Sewage effluent: 0.018-0.702 g/L Sediments: 0.01-0.19 mg/kg Sewage sludge: 0.004-1.363 mg/kg Mean conc. in landfill leachate: 269 g/L

Bisphenol A

Examined for effects on reproductive organs and daily sperm production in male offspring of mice fed BPA during pregnancy

From gestation day 11-17 female mice were fed an average concentration (dissolved in oil) of bisphenol A of 2 ng/g body weight (2 ppb) and 20 ng/g (20 ppb). The 2 ppb dose of bisphenol A is lower than the amount reported to be swallowed during the first hour after application of a plastic dental sealant (up to 931 micrograms; 13.3 ppb in a 70 kg adult). They found that the 2 ng/g dose of bisphenol A permanently increased the size of the preputial glands, but reduced the size of the epididymides. At 20 ng/g, bisphenol A significantly decreased efficiency of sperm production by 20% relative to control males.

Phthalates

Another study in rats 0.75 g/kg (from gestational day 14 to postnatal

day 3) Reduced pregancy weight gain (14-24g) Reduced pup weight (15%) Reduced testis weights (~35%) Males display female-like nipples (up to 87%

compared to 0% in control group)

Phthalates

Exposure of patients to phthalates from polyvinyl chloride PVC tubes and bags during dialysis A group of patients not yet on

dialysis treatment was used as control

The DEHP concentration was 0.8-4.2 g/mL serum in the 17 hemodialysis patients after dialysis

In all of the pre-dialysis patients, DEHP could not be detected (less than 0.1 g/mL).

Phthalates

DEHP Surface water: 0.33-97.8 g/L Sewage effluent: 1.74-182 g/L Sediments: 0.21-8.44 mg/kg Sewage sludge: 27.9-154 mg/kg

Surfactants

APEs: alkylphenol polyethoxylates Used in detergents, cleaning products, paints,

and pesticides Degradation product → 4-octylphenol

Estrogenic Found in surface water Feminized male fish downstream from sewage

treatment plants Impaired testicular development

Surfactants

Surfactants

Fish with both male and female sex tissue have been discovered near Colorado wastewater treatment plants on the South Platte River and Boulder Creek

Newborn male fish become female fish after exposure to hormones

“There are many reports of alkylphenols causing production of a female associated liver protein, vitellogenin, in male fish”

-EPA

Drug Example - DES

DES – Diethylstilbestrol Used from 1938 to 1971

Prescribed to 4.8 million women List - http://www.desaction.org/what.htm Marketed as a miscarriage preventative and a

wonder drug that would make bigger and stronger babies

Drug Example - DES

Actually caused higher miscarriage rate In utero exposure (DES daughters) linked to:

Malformations of reproductive organs Increased infertility 2-3 times risk for miscarriage, premature labor 2.5 times more likely to develop breast cancer

DES mothers : 30-40% increased risk for breast cancer

Sewage Treatment

West Virginia HS student found three antibiotics in the river and tap water

Sewage sludge/biosolids - run-off from agricultural fields Endogenous hormones, synthetic hormonally active

compounds, antibiotics, blood lipid regulators, NSAIDs, beta-blockers, bronchodilators, antidepressants, obsessive-compulsive regulators, antiepileptics, antineoplastics (cancer drugs), impotence drugs, tranquilizers, retinoids, diagnostic contrast media, and numerous personal care products, including fragrances (synthetic musks), preservatives, disinfectants, antiseptics, sunscreen agents, and herbal remedies

Tin, arsenic, selenium, tellurium, lead, gold, mercury, titanium, platinum, and palladium

Metals

TBT – Tributyl Tin Component of antifouling paint for ships

Leach 200g TBT/day into waters Androgenic properties Masculinization of female mollusks

Arsenic inhibit the function of the receptor when normal

glucocorticoid hormones bind Nat’l Academy of Sciences issued a report in 1999

Exposures at levels below EPA drinking water standard of 50 ppb caused problems with blood sugar regulation

Organotins

Used in plastics industry – found in sponges cellophane wrap, baking parchments transferred to cookies on parchment

EDCs in Cosmetics & Toiletries

Alkylphenol Ethoxylates Benzophenone-3 (Bp-3) Butyl Benzyl Phthalate Butylated Hydroxyanisole

(BHA) Butyl-

methoxydibenzoylmethane (B-MDM)

Dibutyl Phthalate Diethyl Phthalate Homosalate (HMS)

Methyl-benzylidene Camphor (4-MBC)

Nitro Musks Octyl-dimethyl-PABA (OD-

PABA) Octyl-methoxycinnamate

(OMC) Parabens Polycyclic Musks Resorcinol

Parabens?

Methyl, propyl, ethyl, and butylparaben Shampoos, conditioners, hair styling gels, nail

creams, foundations, facial masks, skin creams, deodorants, etc.

Suspected Endocrine Disruptor Parabens have been found to act like the

hormone estrogen in laboratory experiments, although the activity was somewhat weak

UK study has established the presence of intact parabens in human breast tumors

Dioxin

Viktor Yushchenko

Dioxin

Formed as an by-product of many industrial processes involving chlorine such as waste incineration, chemical and pesticide manufacturing and pulp and paper bleaching

Anti-androgenic, anti-estrogenic Birds

heart defects in chicks asymmetric brains in herons hatched from

eggs containing 60 ppt

Dioxin

Rats Female rats

0.1 g/kg/day decrease fertility and litter size 1 g/kg give birth to females with delayed puberty

and abnormal genitals 1 g/kg give birth to males with low sperm count

and testosterone levels, delayed testicular descent, and altered sexual behavior

Male rats - reduces testosterone levels, sperm counts, fertility, appetite, and body weight

Dioxin

Fish LD50 for fertilized lake trout eggs is 65 pg/kg egg

weight LD50 for rainbow trout juveniles is 10 g/kg (ppb)

body weight Monkeys

0, 5, and 25 parts per trillion diet 0 ppt – 8/8 had live births, 17% endometriosis 5 ppt – 6/8 had live births, 71% endometriosis 25 ppt – 1/8 had live births, 86% endometriosis

Dioxin

Diesel oil releases dioxin when burned Rats exposed to diesel exhaust

Lower sperm count, cells linked with an increased risk of testicular cancer

Abnormal ovaries, delayed development of the thymus gland (immunological impairment)

In pregnant rats levels of testosterone were significantly higher than normal

Dioxin

1977 industrial accident released large amounts of dioxin in Seveso, Italy The most heavily exposed mothers gave birth

to almost twice as many girls as boys Love Canal - tooth abnormalities such as

double sets of teeth and teeth at birth Yusho, Japan – contaminated rice oil

high infant mortality almost all affected babies had chloracne

Dioxin

Vietnam – Agent Orange CDC reports a higher incidence of spina bifida,

cleft lip and cleft palate, hydrocephalus, and childhood cancers in children of American Vietnam veterans than in controls

Higher incidence of miscarriages of fetuses fathered by Vietnam veterans

25 pg/g of blood fat compared to 3.9 pg/g

Phytoestrogens

Made by plants Interacts with estrogen

in animals Classified in two main

groups: Isoflavones Lignans

Phytoestrogens

Isoflavones Genistein Daidzein Biochanin A Formononetin

Lignans, Matairesinol Secoisolariciresinol Enterolactone Enterodiol

Coumestans, coumestrol

Isoflavones

Soybeans, legumes Soy milk & babies “A soy-fed baby receives the

equivalent of five birth control pills' worth of estrogen every day. These babies' isoflavone levels were found to be from 13,000 to 22,000 times higher than in non-soy fed infants.”

Impedes sexual maturation of boys; accelerates sexual

maturation of girls

Food

No. Daidzein, Genistein, Coumestrol,

of foods µg/g µg/g µg/g

analyzed Wet Wt Wet Wt Wet Wt

Tofu 15 76 166 ND

Soy Sauce 3 8 5 ND

Soy Milk 10 18 26 ND

Soy-based specialty formula3 <1 3 ND

Alfalfa sprouts 1 ND ND 47

Mung bean sprouts 1 ND ND ND

Soybean sprouts 3 138 230 7

Soybean, green 1 546 729 NA

Tempeh 3 190 320 NA

Soybean paste 6 159 171 ND

Miso paste 2 266 376 NA

Miso paste (rice

3 79 260 NAor barley)

Soy hot dog,

2 49 139 NAtempeh burger

Lignans

When bacteria in the digestive tract act on plant lignans, these compounds are converted into potent phytoestrogens

Flaxseeds, pumpkin seeds, whole grains, cranberries, and tea

Lignans

Study found that pregnant rats who ate large amounts of flaxseed (5 or 10% of their diet), or a purified lignan present in flaxseed, gave birth to offspring with altered reproductive organs and functions, and that lignans were also transferred to the baby rats during nursing. (25g for humans)

Precocious Puberty

Michigan (1973): Fire retardant containing polybrominated biphenyls (PBBs) was mistakenly added to animal feed, and more than 4,000 people consumed contaminated meat before the problem was detected.

Bovine growth hormone rBGH Soy formula Obesity

Fertility in Danger ?

Declining semen quality? British Medical Journal – analysis of 61 sperm

count studies published between 1940-1990

Decrease in sperm and volume 113 million/mL (1940) to 66 million/mL (1990)

Danish study 1950-1992 Global decline in semen quality of ~2% per year

over the preceding 50 years US 1969-1995 overall decline in male/female

sex ratio from 1.053 to 1.049 Testicular cancer increase 3-4 fold since 1940

Fertility in Danger ?

French study 1977-92 Showed no change in

sperm quality Geographical location:

New York -131.5 Minnesota – 100.8 California – 72.7

Much debate on whether sperm count is actually decreasing!

EDCs & People

Little known about the effects of EDCs in humans Humans are potentially exposed to thousands of

chemicals in the environment, most of which have not been screened for their ability to disrupt the endocrine system

Humans are exposed to mixtures of substances, and the possible cumulative effects of these mixtures have yet to be determined

Human health outcomes may be subtle, unreported, or delayed

References Environmental Estrogens and Related Endocrine Disruptors – Are They Affecting Male Reproductive

Health and Increasing Breast Cancer in Women? Stephan Safe. Center for the Study of American Business, Contemporary Issues Series 98, February 2000.

Endocrine Disruptors in Wastewater and Sewage Treatment Processes. Birkett, Jason and John Lester. Lewis Publishers. 2003 CRC Press. Also online at http://www.environetbase.com/books/1085/L1601_fm.pdf

Definition of endocrine system http://www.whsc.on.ca/Publications/hazardbulletins/winter2002/endocrine.html

List of EDCs in cosmetics http://www.preventcancer.com/consumers/cosmetics/EndoDisrupt.htm Mutated fish in Dever http://www.planetsave.com/ViewStory.asp?ID=5343 and also

http://www.montereyherald.com/mld/montereyherald/news/nation/10684652.htm Info on DES http://www.desaction.org/index.htm and http://www.agi-usa.org/pubs/journals/2908297.html Lignans

http://www.aurorahealthcare.org/yourhealth/healthgate/getcontent.asp?URLhealthgate=%2221801.html%22

Feminized fish in the UK http://www.washingtonfreepress.org/56/EndocrineDisruptors.htm Reasons for difficult in knowing the effects in humans

http://www.childenvironment.org/factsheets/endocrine_disruptors.htm Good articles on diesel exhaust, arsenic, detergents, precocious puberty

http://www.med.harvard.edu/chge/Solomonfull-v3n2.htm Precocious puberty http://www.worldandi.com/public/2001/October/ee.html and flame retardants

http://enhs.umn.edu/5200/estrogen/women.html

References List of various EDC related articles http://www.ourstolenfuture.org/New/recentimportant.htm rBGH http://www.shirleys-wellness-cafe.com/bgh.htm WWF pesticide EDC sheet http://www.mamacoca.org/FSMT_sept_2003/pdf/EDCpesticides.pdf FDA pesticide http://vm.cfsan.fda.gov/~acrobat/pes99rep.pdf EPA wastewater treatment & EDCs http://www.epa.gov/ordntrnt/ORD/NRMRL/Pubs/2001/edc/625r00015.pdf Reproductive and developmental effects of dioxin http://www.safealternatives.org/report.html#Chapter%208 Phthalate effect on rats

http://www.ingentaconnect.com/content/oup/toxsci/2000/00000058/00000002/art00350;jsessionid=e4quk7uwqoph.henrietta

Phthalates in PVC dialysis patients http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3587468&dopt=Citation

Bisphenol A effects on rats http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=9460178&dopt=Citation

Testicular cancer stat, decrease in sperm count http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7902273&dopt=Citation

Isoflavones chart http://extoxnet.orst.edu/faqs/natural/phytamt2.htm

Pharmaceuticals in water http://www.ucowr.siu.edu/updates/pdfn/V120_A1.pdf

List of what’s in sewage sludge http://www.transadvocate.org/id22.html

Free drugs from your faucet http://www.purewatergazette.net/freedrugs.htm and prozac in UK water http://www.nesc.wvu.edu/ndwc/articles/OT/FA04/international.pdf