Lecture 1 - Introduction to EDCs PDF

Lecture-1 An Overview on the Industrial Revolution, Endocrine Disruptors, Irreversible Contamination of Drinking Water and Their Impact on Endocrine Diseases and Disorders. Sakhila K. Banu PhD., Professor (Toxicology/Endo...

Lecture-1 An Overview on the Industrial Revolution, Endocrine Disruptors, Irreversible Contamination of Drinking Water and Their Impact on Endocrine Diseases and Disorders. Sakhila K. Banu PhD., Professor (Toxicology/Endocrinology) Department of Veterinary Integrative Biosciences College of Veterinary Medicine & Biomedical Sciences Texas A&M University, College Station 1 2 https://www.aamc.org/news/why-i-stay- medicine-tony-phan 3  Learning “Look at it as an opportunity to learn, not to get the best grade" N 5  RULE #1 RULE #2 RULE #3 6 Endocrine-Disrupting Chemicals(EDCs) 8 EDCs & it’s disasters: An evidential report from endosulfan tragedy. 9 10 Endosulfan victims from Padre village, Kasargod, Kerala, India In Kerala, the use of Endosulfan caused the death of more than 500 persons and around 5000 victims are living with serious health issues. The epidemiological study (2011) conducted by the Govt. Medical College, Calicut, Kerala has revealed the long term health issues caused due to Endosulfan. 11 https://youtu.be/5jQsaKJf3ic?feature=shared 12 "One glance at a book and you hear the voice of another person, perhaps someone dead for 1,000 years. To read is to voyage through time." – Carl Sagan "Show me a family of readers, and I will show you the people who move the world." – Napoleon Bonaparte EDCs 13  Four Great Ancient Civilizations Ancient INDIA - Ancient Egypt River Sindh River Nile (Hindus civilization) China –Yellow river Babylon- (Huang He Mesopotamia civilization) Euphrates-Tigris HISTORIC BACKGROUND 14  Agricultural Revolution (The 1st wave): The first wave of transformation began when some prescient person about 10,000 years ago, probably a woman, planted a seed and nurtured its growth. The age of agriculture began, and its significance was that people moved away from nomadic wandering and hunting and began to cluster into villages and develop culture. March 1980  The First Wave is the settled agricultural society which prevailed in much of the world after the Neolithic Revolution, which replaced hunter-gatherer cultures.  Day care The Second Wave is Industrial Age society. The Second Wave began in BRITAN with the Industrial Revolution and subsequently spread across the world. Key aspects of Second Wave society are Assisted the nuclear family, a factory-type Living education system and the corporation. "The Second Wave Society is industrial and based on mass production, mass distribution, mass consumption, mass education, mass Old age homes media, mass recreation, mass entertainment, and weapons of mass destruction”. Man made production to machine made production.  Industrial Revolution (The 2nd wave): The second wave was an expression of machine muscle, the Industrial Revolution began in the 18th century. People began to leave the peasant culture of farming to work in city factories. Information Technology (The 3rd wave): It is what we variously call the information or the knowledge age, and while it is powerfully driven by information technology, it has co-drivers as well, among them social demands worldwide for greater freedom and individuation. 19  The Industrial Revolution was the transition to new manufacturing processes that occurred in the period from about 1760 to 1840. This transition included going from hand production methods to machines, new chemical manufacturing and iron production Alvin Toffler processes, improved efficiency of water power, the increasing use of steam power and development of machine tools. “chemical manufacturing” – EDCs – Endocrine Disrupting Chemicals.  The transition also included the change from wood and other bio-fuels to coal. Quiz: The Industrial revolution began in Britain and within a few decades spread to Alvin Toffler Western Europe and the United States. 21  Industrial Revolution – Environmental impact Our ‘Commons’ are in Danger Atmospheric pollution and climate change Water pollution, including ground aquifers Deforestation and loss of oxygenation The oceans, coral reefs and their bounty National parks, wildernesses and wetlands Nonrenewable natural resource depletion – Fossil fuels, mineral ores, topsoil….  Toxicological challenges in agriculture Expanded food production led to increased population and consumption It’s one of humanity’s greatest achievements, but at an enormous environmental cost. Globally agricultural land area is approximately five billion hectares, or 38% of the global land surface. About one-third of this is used as cropland, while the remaining two-thirds consist of meadows and pastures for grazing livestock. Chemical fertilizers Pesticides Erosion Changed natural systems Destroy forest 23  We face challenges in climate Scientists have firmly concluded that humans are changing the composition of the atmosphere. The Earth’s surface is warming Melting glaciers Rising sea level Impacted wildlife and crops Increasingly destructive weather  Atmospheric CO2 now hitting 50% higher than pre- industrial levels (March 2021) https://www.weforum.org/agenda/2021/03/met-office-atmospheric-co2- industrial-levels-environment-climate-change/ 25  What is pollution? Pollution is the introduction of harmful substances or products into the environment. Major routes include: – Air Pollution – Land Pollution – Water Pollution 26  Air Pollution Main causes of air pollution: Release of CO2 into the atmosphere, due to Deforestation and fossil fuel burning. Sulfur dioxide release into the atmosphere by burning of sulfur containing compounds of fossil fuels. Sulfur oxides are very dangerous to humans at a high concentration. Sulfur in the atmosphere is responsible for acid rain. Example: According to ATSDR (Agency for Toxic Substances and Disease Registry), 20,000 metric tons of hexavalent chromium, Cr6, is released every year in the U.S. alone, 5000 metric tons as atmospheric emission.  For the first time, scientists have created a global inventory that lists more than 350,000 chemicals and mixtures of chemicals registered for commercial production and use. https://comptox.epa.gov/dashboard/chemical-lists/EPAHPV Description: The US High Production Volume (USHPV) database contains the High Production Volume (HPV) Challenge Program. Chemicals considered to be HPV are those that are manufactured in or imported into the United States in amounts equal to or greater than one million pounds per year. The Environmental Protection Agency (EPA) is challenging the chemical industry to undertake testing on HPV chemicals voluntarily. However, EPA will mandate testing of all HPV chemicals by law under the testing authority of Section 4 of the Toxic Substance Control Act (TSCA). 29  Acid Rain When emissions of sulfur dioxide and nitric oxide from stationary sources are transported long distances by winds, they form secondary pollutants such as nitrogen dioxide, nitric acid vapor, and droplets containing solutions of sulfuric acid, sulfate, and nitrate salts. These chemicals descend to the earth's surface in wet form as rain or snow and in dry form as a gas, fog, dew, or solid particles, it is known as acid rain or acid deposition.  A smoggy city Smog is a mixture of air pollutants and particulates that is sometimes found in the lower levels of the atmosphere. It has a distinctive brownish haze. Smog can reach dangerous levels in built-up areas, causing irritation to the eyes and lungs. A large part of smog is ground-level ozone, a highly toxic gas.  Land Pollution Land and soil can be polluted by two main types of substance: 1. Solid waste – such as plastic, metal, paper and other man- made substances. 2. Chemicals – such as herbicides and pesticides, crude oil and waste from industrial processes.  Land pollution often leads to water pollution, as chemicals are washed into rivers, lakes and aquifers. 34 35  CrVI contamination in the UNITED STATES Sad pages from the real story… http://www.sbsun.com/hinkley From 1952 to 1966, Pacific Gas and Electric Company (PG&E) dumped about 370 million gallons (1,400 million litres) of chromium-contaminated wastewater into unlined wastewater spreading ponds around the town of Hinkley, California, located in the Mojave Desert (about 120 miles northeast of Los Angeles). 37 38 39  There are over 500 abandoned uranium mines on Navajo lands. Navajo Nation was founded in 1868, a Native American reservation in the United States that covers parts of Arizona, New Mexico, and Utah. The Navajo Nation is the largest Native American reservation in the country, covering 27,425 square miles. The reservation stretches from the Grand Canyon in the west to Farmington, New Mexico in the east, and from the red rock buttes of Utah in the north to the empty highways around Holbrook, Arizona in the The uranium mining and milling left a south. legacy of adverse economic, environmental, and human health effects Homes and water sources on the Navajo on the Navajo Nation. Nation have elevated levels of uranium- radiation. Potential health effects include lung cancer, bone cancer, and impaired kidney function. 40 For The Navajo Nation, Uranium Mining’s Deadly Legacy Lingers https://youtu.be/xOUYItCtT1U https://urldefense.com/v3/__https://youtu.be/xOUYItCtT1U__;!!KwNVnqRv!XK6vJ4A7 WvyzidwoPQVGn6OzTVBWajAW4kZ8cNnXWPmsl9XH9UlsKcDLgmV3tln7gQ$ https://youtu.be/xOUYItCtT1U Conference on metal carcinogenesis  https://youtu.be/MMhBoXAay9g Briefly describe uranium contamination of the Navajo nation.  Consequences of Land Pollution Land pollution exterminates wildlife. Acid rain kills trees and other plants The vegetation that provides food and shelter is destroyed. Land pollution can seriously disrupt the balance of nature, cause human fatalities, eg., Chromium pollution in developing countries and in the US. Pesticides can poison birds, bees (pollination!), animals, fish and humans, eg., DDT, endosulfan. Most pesticides kill or damage life forms other than those intended, such as birds and small animals.  Water Pollution - Sources Factors that contribute to water pollution can be categorized into two different groups – Point sources – Non-point sources Point sources are the easiest to identify and control. Nonpoint sources are ambiguously defined and harder to control. Briefly describe point and non-point sources of water pollution.  Point Sources Some point sources of water pollution include – Waste products from factories – Waste from sewage system – Waste from power plants – Waste from underground coal mines – Waste from oil wells They are called point sources because they are direct sources of water pollution and can be reduced and monitored.  Non-point Sources The term non-point source encompasses a large range of sources such as:  when rain or snow moves through the ground and picks up pollutants as it moves towards a major body of water.  the runoff of fertilizers from farm and crop land.  air pollutants getting washed or deposited to earth.  storm water drainage from lawns, parking lots, and streets.  Water Pollution  Inorganic materials - alkalis, acids, inorganic salts, ammonia, phosphates, etc.  Heavy metals - chromium, mercury, nickel, copper, cadmium etc.  Disinfection byproducts - trihalomethanes  Pesticides - organochlorides etc.  Physical factors - turbidity, color, temperature etc.  Groundwater Pollution: Causes Cesspool – an underground reservoir for liquid waste Ocean Pollution https://www.texastribune.org/2024/12/02/texas-farmers-pfas-forever- chemicals-biosolids-fertilizer/ Texas farmers say sewage-based fertilizer tainted with “forever chemicals” poisoned their land and killed their livestock. The fertilizer was promoted as an environmental win-win for years. An untold number of farmers and ranchers across Texas have spread it on their land. December 2024. 51  The Great Lakes Polychlorinated biphenyls (PCBs) Stressors are endocrine disrupting chemicals  LEAD CRISIS IN FLINT, MI  The Flint water crisis is a drinking water contamination issue in Flint Michigan, United States, that started in April 2014.  Flint changed its water source from Lake Huron and Detroit river) to the Flint River.  Officials had failed to apply corrosion inhibitors.  its drinking water had lead contamination, creating a serious public health danger.  The Flint River water that was treated improperly caused lead from aging pipes to leach into the water supply, causing extremely elevated levels of the heavy metal neurotoxin.  In Flint, between 6,000 and 12,000 children have been exposed to drinking water with high levels of lead and they may experience a range of serious health problems.  Due to the change in water source, the percentage of Flint children with elevated blood-lead levels may have risen from about 2.5% in 2013 to as much as 5% in 2015. Briefly describe lead crisis in Flint drinking water. According to the World Health Organization, “lead affects children’s brain development resulting in reduced intelligence quotient (IQ), behavioral changes such as shortening of attention span and increased antisocial behavior, and reduced educational attainment. Lead exposure also causes anemia, hypertension, renal impairment, immunotoxicity and toxicity to the reproductive organs. The neurological and behavioral effects of lead are almost irreversible.”  Polluted stream/rivers – developing countries Iraq China Peru India Indonesia Mexico Bangladesh Argentina  Polluted Ocean/stream/rivers Mississippi River Galveston Bay, TX Colorado River, Utah, Oil-polluted river, New Orleans, USA 1989, Exxon Valdez 1969 Santa Barbara Oil Spill Erika oil spill, France, 1999 56 Aug 5, 2015-Animas River The Environmental Protection Agency (EPA) mistakenly released 3 million gallons of toxic orange waste water from an abandoned gold mine into Colorado's Animas River. Lead in Animas - 12,000 times higher than the acceptable level set by the EPA. Mercury - 10 times higher. Beryllium and cadmium - 33 times higher. Arsenic - 800 times higher. http://response.restoration.noaa.gov/oil-and-chemical-spills/oil-spills/largest-oil-spills-affecting-us-waters-1969.html 58 Endocrine System 59  Endocrine disrupting chemicals (EDCs) Endocrine disruptors are man-made synthetic chemicals and natural phytoestrogens (naturally occurring plant- or fungal metabolite-derived estrogen) that act on the endocrine systems of humans and animals by mimicking, blocking and/or interfering in some manner with the natural instructions of hormones to cells. Mandatory exam question The Endocrine System Hypothalamus produces releasing hormones that stimulate pituitary activity; Pituitary produces trophic hormones that stimulate thyroid, adrenal, gonadal and pancreatic activity; Thyroid produces thyroid hormones that regulate metabolism, growth and development, behavior and puberty; 61  Endocrine System Hypothalamo-Pituitary-Adrenal axis Adrenal gland produces corticosteroid hormones and catecholamines to regulate metabolism and behavior;  Pancreas produces insulin and glucagon that regulate blood sugar levels;  Gonads produce sex steroid Hypothalamo-Pituitary-Gonadal axis hormones (androgens and estrogens) that regulate development & growth, reproduction, immunity, onset of puberty and behavior. 62  Parts of the body absorb EDCs at different rates. The head is 4 times more absorbent than the hand and the genital area is 11 times more absorbent. 63 Endocrine disrupting chemicals 64  Endocrine Disrupting Chemicals (EDCs) have many names Environmental Phytoestrogens estrogens Endocrine-disruptors Hormone Endocrine-active mimickers compounds Xenoestrogens Or, generically, Endocrine Disrupting Chemicals (EDCs) Anti-androgens Stressors 65  Commonly used EDCs PESTICIDES Insecticides INDUSTRIAL CHEMICALS Alkylphenol polyethoxylates Fungicides Carbaryl Alkylphenols Chlordane Benomyl Cadmium Dicofol Dioxins Herbicides Hexachlorobenzene Dieldrin Kepone 2,4-D Mancozeb DDT and metabolites Maneb Lead 2,4,5-T Endosulfan Metiram-complex Mercury Alachlor Heptachlor Tributyl tin PBBs Amitrole Heptachlor epoxide Zineb PCBs Atrazine Lindane Ziram Pentachlorophenol Metribuzin Methomyl Penta- to nonylphenols Nitrofen Methoxychlor Phthalates Trifluralin Nematocides Mirex Styrenes Aldicarb Oxychlordane DBCP Parathion Synthetic pyrethroids Tobacco smoke Toxaphene Transnonachlor  Endocrine Disrupting Chemicals (EDCs) Natural - Phytoestrogens (eg. Genistein from soy) - Fungal estrogens (eg. Zearalenone, a nonsteroidal estrogenic mycotoxin produced by numerous Fusarium molds) Synthetic - Hormones - Some pesticides - Industrial by-products ("dioxin-like") - Pharmaceuticals, eg., birth control pills - Some persistent organic pollutants (POPs) EDC - Sources and routes of exposure 68 69 ???? 70  Known sources of EDCs Industrial chemicals such as polychlorinated biphenyls (PCBs), dioxins, and polyaromatic hydrocarbons (PAHs). Pesticides Herbicides Insecticides Fungicides Persistent and non-persistent pesticides - DDT to tributyltin (TBT) 71  Known sources of EDCs Heavy metals – Arsenic – Lead – Cadmium – Mercury 72  Known sources of EDCs Ordinary household products, such as the nonylphenols added to detergents and soaps Commercial cleaners 73  Known sources of EDCs Leaching from most plastic products, especially the phthalates used to make plastics and stabilize them so they do not break down in sunlight. 74  Known sources of EDCs Drugs such as birth control pills, DES, Cimetidine. DES, diethylibestrol, given to mothers to prevent morning sickness, caused genital cancers in their children after 4 genera ions. Tagamet HB, Acid Reducer (cimetidine), Heartburn Relief (cimetidine) Comp Biochem Physiol C Toxicol Pharmacol. 2016 Nov;189:44-53. doi: 10.1016/j.cbpc.2016.07.004. Epub 2016 Jul 27. Cimetidine disrupts the renewal of testicular cells and the steroidogenesis in a hermaphrodite fish. María García-García et al.,  Persistence Some chemicals are more stable than others, persisting for longer in the environment. DDT (dichlorodiphenyltrichloroethane) and PCBs are persistent. Temperature, moisture, exposure to sunlight, etc., affect rate of degradation. Most toxicants degrade into simpler breakdown products. Some of these are also toxic. (DDT breaks down to DDE, also toxic.) 76  Poisons accumulate in tissues The body may excrete, degrade, or store toxicants. Fat-soluble ones are stored. DDT is persistent and fat soluble, builds up in tissues: bioaccumulation. Bioaccumulated chemicals may be passed on to animals that eat the organism—up the food chain… 75.5/0.00005 = 15,100,00  What is the concern about? WHO/ UNEP report 2012 – Many EDC-related diseases are on the rise – Human and wildlife populations are exposed to EDCs – Numerous laboratory studies support the idea that chemical exposures contribute to endocrine disorders. – Internationally agreed and validated test methods capture only a limited range of the known spectrum of EDC effects The 2012 report raises a global concern on EDCs Jerry Heindel, Ph.D. Health Scientist Administrator NIEHS http://www.unep.org/pdf/WHO_HSE_PHE_IHE _2013.1_eng.pdf EnDocrine disruption is associated with: female reproductive health male reproductive health sex ratio in humans thyroid related disorders and diseases neurodevelopment in children and wildlife hormone related cancers adrenal disorders in humans and wildlife immune function, immune diseases and disorders metabolic disorders wildlife population & sustainability loss 80  EDCs- Effects 1960’s Eagles – Eggshell thinning and have average of 10ppm DDT – DDT affected reproduction 81  EDCs- Effects 1970’s Fish-eating birds – Gulf Coast, Great Lakes – Abnormalities of reproductive system structures/functions – Malformed offspring  EDCs- Effects 1980’s Decline in alligator population by 90% after difocol, DDT, DDE chemical spill Smaller penis size Abnormal gonad morphology Altered sex steroid concentrations  EDCs- Effects Human sperm count depleted. – 50% drop 1938-1990. Increased human prostate, testicular cancers reported Increased female reproductive dysfunctions Increased human breast, ovarian cancer rates Increased PolyCystic Ovarian Disease Related to neonatal androgenization (rodents) early onset estrus cyclicity https://america.cgtn.com/2021/03/22/declinin g-sperm-counts-around-the-world-could- reach-zero-in-just-24-years 85  Health Effects of Endocrine Disruptors Alterations in sexual and functional development; neurologic disorders, diabetes mellitus, immunologic disorders, early puberty in young girls. Cancers: breast, colon, vaginal, endometrium, cervix, testicular. Sexual differentiation: of the brain and other estrogen target tissues, structural abnormalities of the oviduct, uterus, cervix and vagina, a contributing factor to subfertility. Developmental defects and organ growth: genital birth defects, cryptorchidism, reduced sperm counts, and enlargement / reduction of prostate, hypospadias (abnormal urethral opening in males). 86  Health Effects of Endocrine Disruptors Neurologic effects: Developmental, behavioral and mental disorders, anger, inattention, decreased mental capacity, learning disabilities, dyslexia, attention deficit / hyperactivity disorder (ADHD), autism, propensity to violence, reduced motor skills, and gross and fine eye- hand coordination. Childhood cancer: The incidence of all cancers among infants less than one year old, both sexes, has risen 36% when comparing the years 1976-1994.  EDCs exploit innocent children: who are at greater risk for EDCs??? Children are at greater risk because they play close to the ground, regularly have their hands in their mouths, eyes or noses, and have unique diets. They absorb more pesticides from their environment than adults. Reduced ability to detoxify and excrete pesticides. All children, without exception, are exposed to toxic synthetic chemicals before birth and continuing through the rest of their lives. The mechanisms of EDCs…. The mechanisms by which these compounds have their impact vary, but they share the general properties of: Mimicking the effects of natural hormones by recognizing their binding sites (receptors). Antagonizing the effect of these hormones by blocking their interaction with their physiological binding sites. Reacting directly and indirectly with the hormone in question. Altering the natural pattern of synthesis of hormones. Altering hormone receptor levels. 89  EDCs and endocrine disease: a SERIOUS concern Globally, 24% of human diseases and disorders are attributable to EDCs. EDCs play a role in 80% of the most deadly diseases, including cancer and respiratory and cardiovascular diseases. The incidence of endocrine-associated pediatric disorders, including male reproductive problems (cryptorchidism, hypospadias, testicular cancer), early female puberty, leukemia, brain cancer, and neurobehavioral disorders, have all risen rapidly over the past decades.  EDCs and endocrine disease The recent update on developmental disabilities from the National Health Interview Survey (NHIS) report “Prevalence and Trends of Developmental Disabilities among Children in the United States: 2009–2017” reveals a 9.5% increase in prevalence over 9 years. In 2020, preterm birth affected 1 of every 10 infants born in the United States. Preterm birth is associated with increased rates of neurological disorders, respiratory conditions and childhood mortality, as well as obesity, type 2 diabetes, and cardiovascular disease in adulthood.  Key Concerns Three strands of evidence fuel concerns over endocrine disruptors: 1. the high incidence and the increasing trends of many endocrine-related disorders in humans; 2. observations of endocrine-related effects in wildlife populations; 3. the identification of chemicals with endocrine disrupting properties linked to disease outcomes in laboratory studies. Disease risk due to EDCs may be significantly underestimated.  The patterns of effects of EDCs: Complexity! Vary among species and among compounds. The EDCs may have entirely different effects on the embryo, fetus, or perinatal organism than on the adult. The effects are most often manifested in offspring, not in the exposed parent. The timing of exposure in the developing organism is crucial in determining its character and future potential. Although critical exposure occurs during embryonic development, obvious manifestations may not occur until maturity. EDCs in the environment: Are we really protected?  Doses as low as one part per trillion, applied at specific times in development, can cause permanent physical and mental abnormalities that may not be recognized until after puberty.  “Fetal onset of adult diseases…”  High production volume chemicals (HPV chemicals) are produced or imported into the United States in quantities of 1 million pounds or 500 tons per year.  The USHPV database contains information about chemicals that are included in the HPV  https://comptox.epa.gov/dashboard/chemical-lists/EPAHPV  Less than half of the HPV chemicals have been tested for toxicity.  Very few of the 87,000 chemicals in commercial use have been tested at all.  And almost none of the more than 3 million registered chemicals have been tested. 94  Our Stolen Future - take home message Some of the developmental impairments reported in humans today are seen in adult offspring of parents exposed to synthetic hormone disruptors (agonists and antagonists) released in the environment. The concentrations of a number of synthetic sex hormone agonits and antagonists measured in the US human population today are well within the range and dosages at which effects are seen in wildlife populations. In fact, experimental results are being seen at the low end of current environmental concentrations. Unless the environmental load of synthetic hormone disruptors is controlled, large scale dysfunction at the population level is possible. The scope and potential hazard to wildlife and humans are great because of the probability of repeated and/or constant exposure to numerous synthetic chemicals, EDCs.