Target Document® – eTMF and Beyond
Happy President’s Day. We are back to work on Tuesday!
There are no file cabinets at Target Health used for document storage.
Target Document, a 21CFR-compliant document system has been used in Target Health’s clinical research operation since 2004, and is also used in-house for the management of all Target Health’s documents. As a result, at a recent FDA inspection of Target Health, all documents requested by FDA were accessed solely from Target Document. Because documents could be electronically downloaded, there was minimal printing of documents.
1. Separate administration module
2. Role-based access
3. Ability to configure Template Folders for the eTrial Master File
4. Ability to configure Template Folders for any department
5. Document routing for review only
6. Document routing for electronic signoff
7. Document routing maps to route a document to individuals in series or in parallel
8. User management by website administrator or department administrator
9. Secure folder and/or document access
10. Upload and download any document type across the web
11. Document check-in/check-out
12. Document discussion forums
13. Document scheduling with optional expiration date
14. Notifications for document subscribers
15. Locking/unlocking of folders and documents
16. Document history includes all versions of uploaded documents
17. Activity/change history (audit trail) for folders and documents
ON TARGET is the newsletter of Target Health Inc., a NYC – based, full – service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.
For more information about Target Health contact Warren Pearlson (212 – 681 – 2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Flint, Michigan: When Public Health is not a Priority
The brains of adults who were exposed to lead as children show decreased volume, especially in the prefrontal cortex, on MRI. Areas of volume loss are shown in color over a template of a normal brain.
The CDC has set the standard elevated blood lead level for adults to be 10 ug/dl of the whole blood. For children the number is set much lower at 5 ug/dl of blood as of 2012, down from a previous 10 ug/dl. 1) ___ are especially prone to the health effects of lead. As a result, blood lead levels must be set lower and closely monitored if contamination is possible. The major treatments are removal of the source of lead and chelation therapy (administration of agents that bind lead so it can be excreted). However, damage to the nervous system is irreversible, especially in children. Humans have been mining and using this heavy metal for thousands of years, poisoning themselves in the process. Although lead poisoning is one of the oldest known work and environmental hazards, the modern understanding of the small amount of 2) ___ necessary to cause harm did not come about until the latter half of the 20th century.
No safe threshold for lead exposure has been discovered – that is, there is no known sufficiently small amount of lead that will notcause harm to the body.
The city of Flint, Michigan is in the midst of a water crisis several years in the making. The city opted out of Detroit’s water supply and began drawing water from the Flint River in April 2014, part of a, so-called, cost-saving, but apparently untested, move. Eighteen months later, in the fall of 2015, it was discovered that the proportion of children with above-3) ___ lead levels in their blood had doubled. This scandal was allowed to take place, although there are easy to use kits which detect the presence of lead, instantly. The city reconnected to Detroit’s water system in October, but the damage was done. Water from the Flint River was found to be highly corrosive to the lead pipes still used in some parts of the city. Even though Flint River water no longer flows through the city’s pipes, it’s unclear how long those 4) ___ will continue to leach unsafe levels of lead into the tap water supply. Experts currently say the water is safe for bathing, but not drinking. A group of Virginia Tech researchers who sampled the water in 271 Flint homes last summer found some contained lead levels high enough to meet the EPA’s definition of 5) ___ waste. The researchers posted their test results online, which are represented, graphically below with other visuals to help understand just how high above normal, Flint’s lead levels really were.
Lead in water is measured in terms of parts per billion (ppb). If a test comes back with lead levels higher than 15 ppb, the EPA recommends that homeowners and municipalities take steps to 6) ___ that level, like updating pipes and putting anti-corrosive elements in the water when appropriate. But 15 ppb is a regulatory measure, not a public health one. Researchers stress that there is no 100 percent safe level of lead in drinking water, only acceptable levels. Even levels as low as 5 ppb can be a cause for concern, according to the group studying Flint’s water.
Interesting to compare with Flint’s neighboring cities. At the city level, public 7) ___ officials are most concerned with the 90thpercentile level of lead exposure in homes they test — that is, 90% of homes will have a lead level below this threshold, while 10% will register above it. Forty-five minutes away from Flint in Troy, Mich., the 90th percentile level for lead in 2013 was 1.1 parts per billion. Not too shabby at all. In the graphics that follow, each splotch represents 1 part per billion. The splotches aren’t proportionally scaled to the cups — 1 part per billion is way too small to be visualized at this level. But all of the following graphics are scaled proportionally to each other, to give an impression of relative lead levels. Troy, Michigan is the first graphic, showing acceptable levels in that city’s drinking water.
In Detroit, the water supply Flint had previously been connected to, the 90th percentile reading was 2.3 parts per billion — still acceptable. The third graphic above, gives an illustration of water at the 5 parts per billion level. This is below the borderline for EPA acceptability, supported by the team of researchers studying Flint’s water, who say that levels this high can be a cause for concern, particularly for young children.
Now things get interesting and alarming. Below is a glass illustrating the 90th percentile reading among the 271 Flint homes tested by researchers last summer:
At 27 parts per billion, it’s five times as high as the level of concern, and nearly twice as high as the EPA’s already-generous guidelines. According to the researchers who ran these tests, the health effects of lead levels this high can include high 8) ___ pressure and other cardiovascular problems, kidney damage and memory and neurological problems. Recall, though, that 10% of the homes in the sample had lead levels even higher than this. The next graphic shows the highest lead reading in that sample, from a home in the city’s 8th Ward. That’s more than 10 times the 9) ___ limit. It’s 30 times higher than the 5 ppb reading that can indicate unsafe lead amounts. But that 158 ppb reading is far from the worst one that turned up in Flint, unfortunately. In the spring of 2015, city officials tested water in the home of LeeAnne Walters, a stay-at-home mother of four and a Navy wife. They got a reading of 397 ppb, an alarmingly high number. But it was even worse than that. Virginia Tech’s team went to Walters’ house to verify those numbers later in the year. They were concerned that the city tested water in a way that was almost guaranteed to minimize lead readings: They flushed the water for several minutes before taking a sample, which often washes away a percentage of lead contaminants. They also made residents collect water at a very low flow rate, which they knew also tended to be associated with lower readings. So the Virginia Tech researchers took 30 different readings at various flow levels. What they found shocked them: The lowest reading they obtained was around 200 ppb, already terribly high. But more than half of the readings came in at more than 1,000 ppb. Some came in above 5,000 — the level at which EPA considers the water to be toxic waste. The highest reading registered at 13,000 ppb.
The professor who conducted the sampling, Dr. Marc Edwards, was in disbelief. We had never seen such sustained high levels of lead in 25 years of work, he said. According to Edwards, the team retested the water with extra quality controls and assurance checks, and obtained the exact same results. You can check out their description of the testing at the website they set up for their water study. It includes unsettling photos of LeeAnne Walters’ tap water containing rust and metal particles large enough to be seen with the naked eye. The Walters family had stopped drinking the water a long time ago, according to the Virginia Tech team. But still, the lead levels were too high. One of Walters’ 4-year-old sons was diagnosed with lead poisoning.
It appears that the city of Flint and state of Michigan have finally started to take the water problem seriously. Again, they reconnected the city to Detroit’s supply back in October, but the water remains unsafe to drink. In recent days the National Guard was activated to help distribute drinking water to the city’s residents. And in yet another unsettling wrinkle in Flint’s saga, 87 cases of Legionnaire’s Disease, 10 fatal, have been diagnosed in the city since June. It’s not yet clear whether that outbreak is linked to the water. According to news sources, over a year ago, Michigan Gov. Rick Snyder, authorized bottled water be delivered to him and his team at their place of business. Recently, and after not taking any action regarding the data from researchers, (except for ordering bottled water for himself and his political colleagues) Michigan Gov. Rick Snyder asked President Obama to declare both an emergency and an expedited major10) ___ in the county where the city of Flint has been dealing with the fallout from lead-contaminated drinking water.
Testing kits are commercially available for detecting lead. These swabs, when wiped on a surface, turn red in the presence of lead.
Sources: Christopher Ingraham (Brookings Institution & Pew Research Center), The Washington Post; CDC.gov; NIH.gov; Wikipedia
ANSWERS: 1) Children; 2) lead; 3) average; 4) pipes; 5) toxic; 6) reduce; 7) health; 8) blood; 9) EPA; 10) disaster
Herbert R. Needleman MD (1927 to Present)
Herbert L. Needleman MD
Herbert Needleman, M.D., is one of the foremost experts on the effects of lead poisoning on children. Needleman, a pediatrician and child psychiatrist, is known for groundbreaking studies on the developmental implications of lead exposure. In the 1970s, by measuring lead levels in children’s teeth, Needleman provided the first evidence that even low levels of lead lower IQ, shorten attention spans and delay language skills. Needleman conducted follow-up studies on these children and showed that their deficits persisted, resulting in learning disabilities and school failure. Needleman designed the first forward study of lead exposure in the uterus and showed it was associated with cognitive deficits later in life. His recent research shows that boys with high levels of lead in their bones have greater odds of developing aggressive or delinquent behavior, such as bullying, vandalism and shoplifting. Needleman’s research and advocacy was instrumental in federal regulations banning lead from gasoline and paint as well as the removal of lead from government housing. The CDC also issued guidelines for pediatric lead poisoning diagnosis and treatment due, in part, to his research.
Needleman is the founder of the Alliance to End Childhood Lead Poisoning, now called the Alliance for Healthy Homes, a national nonprofit working to prevent and eliminate home hazards such as lead, mold, radon and pesticides. The Dana Foundation and the Heinz Family Fund have honored Needleman for his work. He is an elected member of the Institute of Medicine.
Lead is a normal constituent of the earth’s crust, with trace amounts found naturally in soil, plants, and water. If left undisturbed, lead is practically immobile. However, once mined and transformed into man-made products, lead becomes highly toxic. Solely as a result of man’s actions, lead has become the most widely scattered toxic metal in the world. Unfortunately, lead has a long environmental persistence and never loses its toxic potential, if ingested. The lead dispersed through gasoline exhausts, smelter emissions, and peeling paint, etc. never fully disappears from our environments nor has man evolved a good biological system to offer any protection from it. In the course of evolutionary time, the global contamination of this highly toxic substance into man’s environment has been a very short and recent period.
It is believed that mankind has used lead for over 6000 years. Lead mining probably predated the Bronze or Iron Ages, with the earliest recorded lead mine in Turkey about 6500 BCE. The oldest artifact of smelted lead is a necklace found in the ancient city site in Anatolia. The estimated age of this necklace is 6,000 to 8,000 years ago. Some of the properties which make lead commercially attractive include: easy workability, low melting point, ability to form carbon metal compounds, holds pigments well, very easily recycled, stands up well to the outside weather elements, a high degree of corrosion resistance, inexpensive, etc. There are also several habits and customs of cultures that contributed to human exposure, such as using lead in medicines and cosmetics. Lead’s toxicity was recognized and recorded as early as 2000 BCE and the widespread use of lead has been a cause of endemic chronic plumbism in several societies throughout history. The Greek philosopher Nikander of Colophon in 250 BCE reported on the colic and anemia resulting from lead poisoning. Hippocrates related gout to the food and wine, though the association between gout and lead poisoning was not recognized during this period ( 450-380 BCE). Later during the Roman period, gout was prevalent among the upper classes of Roman society and is believed to be a result of the enormous lead intake.
Rome: The First Mass Distributor of Lead
The Romans conducted lead mining on a massive scale and had several huge lead mine and smelter sites. Lead was in big demand and was a byproduct of refining silver and gold ore. One smelter site located in Spain required tens of thousands of slaves to operate. Another large site was in Greece and the emissions from these two sites would rise high into the atmosphere and get picked up by the world’s air currents. Some lead would fall back to earth in the snow and recently, scientists measured lead particles deposited in Greenland’s ice to determine the history of lead production. The massive mining and smelting of lead went on for hundreds of years and the production of Roman lead was not surpassed till the period of the Industrial Revolution. In ancient Rome, lead poisoning was a disease of the wealthy who used lead extensively: leaden cooking utensils and pots, leaden wine urns, lead plumbing (also to line the aqueducts) (Plumbing is derived from plumbum, Latin for Lead), vessels used to concentrate grape juice, containers used to store wine, and lead-based makeup. In those days there were no substances (like sulfites) to act as preservatives for the wines. Lead is naturally sweet in taste and was found to enhance both the color and bouquet of wine. The Romans shipped wines all over their empire, as far away as northern Germany and a preservative was needed to prevent bacteria from turning the wines into vinegar. The Greeks added pine tree resin to their wines but the Romans preferred sweet Sapa, a boiled down concentrate of grape juice. The problem with Sapa was that the kettle used in boiling unfermented grape juice into a concentrate was made of lead, which leaches into the liquid because of the high acidic content of the grape juice. The final product, Sapa, is a sweet aromatic syrup containing about one gram of lead per liter. Because of its sweet taste, many Romans used it as a sweetening agent in many dishes. When taken together, all the pathways of lead in Roman society, and the intake of lead in Roman times is estimated to have varied from about 35 mg/day to about 250 mg/day, compared to today’s daily intake of 0.3mg in the United states in the 1980’s (National Academy of Sciences 1980). There are many distinguished historians who now believe that this high exposure to lead was a contributing force in the decline of the Roman Empire. With the more recent scientific research proving that lead is a highly neurotoxicant and analyzing the strange behavior of most Roman leaders (Nero, Caligula) and the upper classes, a good case can be made for lead’s role in a declining Roman society. What is ironic is the fact the during Roman times lead poisoning was primarily a disease of the affluent while today it is an affliction of primarily the poorer communities.
The First Law Banning Lead Was for Economic Reasons!
In the German city of Ulm, during the late 1690’s, there was a severe outbreak of colic, an illness characterized by a variety of symptoms, including excruciating abdominal pain. Ulm’s official physician noted that at a local monastery the monks who did not drink wine were healthy while those that did developed colic. Since the monks lived together, ate the same food, and drank the same wine, they provided the astute doctor with an ideal setting for investigating the cause of the disease. Every time he visited the monks he was offered a glass of wine until he too developed colic. Upon a detailed investigation he found the culprit to be the agent used to sweeten the wine, litharge, a white oxide of lead. When this concentrated sweetener was added to sour wine it brought it back to life and made it drinkable. The entire region depended upon the wine export as a major source of revenue. If the word spread that the wine from Ulm caused colic then the city’s economy was threatened. In 1696, Duke Ludwig issued a decree forbidding the use of lead-based additives in any wine product. For anyone who violated this decree, the punishment was death! There were recordings of Roman wine being banned by German tribes because of the sickness which resulted. Surprisingly, many doctors of that period prescribed preparations of mercury or litharge itself to cure colic. On and off over the next centuries liquor would continue to be a source of lead exposure. In 1763, a physician at the court of King George III, discovering that lead fittings used to press cider caused an outbreak of colic. The great gout epidemics of the 18th century in England were traced to the popular port wines from Portugal which were heavily leaded Poorly glazed pottery used to store beers and wines resulted in chronic colic outbreaks in Germany when the lead leached out into the brew. Even today, some wine seals are made of lead and some leaded crystal decanters can leach lead into the liquor. One of America’s first public health laws was to ban the use of leaded coils due to the health problems it caused to people who drank the spirits. In colonial America, the Massachusetts Bay Colony banned lead from being added to wine and cider. But it is not just liquor products where lead can turn up. In Hungary, in 1994, a major health problem occurred when red oxide lead was mixed into paprika to brighten the color of the spice. Research has shown that stone mills, which have lead pieces, can result in putting lead particles into the flour. Lead has shown up in milk where cows have grazed on grasses growing in soil with large lead accumulations from either industrial waste or heavy auto traffic. Weather lead is puffed onto a 18th century nobles’ wig in the form of white lead litharge, innocently drunk with wine made from grapes grown near a busy highway, or added as a filler to ice cream being sold in India, man seems to create unusual pathways for lead to enter the human system.
In the 18th, 19th and 20th centuries, the worst outbreaks of lead poisoning of adults were occupational in origin. It became common knowledge that to work in an industry where you handled lead was certain to make you sick or worse. These workers absorbed lead from inhalation of fine lead dust or fumes, contamination of food eaten at the workplace, or by absorption through the skin. Charles Dickens describes in his essay Star of the East the horrible effects of lead poisoning on women who work in London’s infamous white lead mills, her brain is coming out her ear and it hurts her dreadful. Benjamin Franklin in 1763 wrote about the dry gripes (colic) and dangles (wrist drop) which affected tinkers, painters, and typesetters. Lead’s hazards to the reproductive process have been known for at least a century. British factory inspectors at the turn of the 20th century noted that women who were exposed to lead through working in the cottage ceramic industry tended to be barren and that children who were born to those women were often short-lived. In most western countries during the 1930’s through the 1970’s, awareness among health workers was associated with more lead poisoning cases being reported, and laws protecting workers were being enacted. Today, occupational exposure to lead remains a big problem in developing countries. Occupational lead exposure is likely unregulated in these countries with little monitoring of poisoning being done. What has become a growing concern among health officials is the prevalence of home-based cottage industries in these countries. These cottage industries are located in the where large numbers of people live, especially children. They are of particular concern since these non-regulated businesses deliver the lead right into the homes or yards where children live or play. Children can also be exposed when the working parent brings the lead dust home from work (on cloths, in hair, or on shoes, etc.). With the enactment of worker safety regulations and more accurate monitoring and reporting, the focus of lead research began shifting towards children’s health.
Childhood Lead Poisoning
Modern understanding of lead poisoning in children has evolved through four stages.
First: when childhood lead poisoning was first described in 1892 in Brisbane, Australia, its very existence was disputed by elitist physicians in Sydney. A.J. Turner, a house officer at the Brisbane Children’s Hospital, diagnosed several children with lead intoxication who had been given a previous diagnosis of meningitis. Also at Brisbane, J. Lockart Gibson , an ophthalmologist, recognized lead poisoning in children with retinites and ophthalmoplegia. They investigated and found the source of lead exposure to be paint on rails in the children’s homes. Through their efforts, lead was eventually banned from house paint in Australia in 1914. That same year, childhood lead poisoning was first reported in America.
Second: After its existence was accepted, the prevailing belief among pediatricians was that children who did not die during the acute stage of the disease suffered no lasting ill effects. In 1943, Byers demonstrated the persistence of severe residue in children who had recovered from acute lead poisoning. Dr. Randolph Byers, one of America’s first pediatric neurologists, discovered that several children with learning or behavior disorders had earlier been treated for lead poisoning. Along with Elizabeth Lord, a psychologist at Boston Children’s Hospital, Byer conducted detailed psychometric evaluations of 20 children who had reported previous lead poisoning. They found that 19 of the 20 children were behavior disordered or intellectually impaired. Dr. Byer’s studies in the early 1940’s were the first to prove that children who survived acute intoxication were often left with devastating deficits in intellectual function.
Third: The reality of sequelae was then accepted, but sequelae were thought to afflict only those patients who had had the most severe symptoms. In the late 1970’s, 1980’s, and early 90’s, the publication of papers from around the world showing IQ and behavioral deficits at silent doses of lead, the neuropsychological costs of asymptomatic lead exposure were established to the satisfaction of the scientific community. This controversial issue has now been effectively settled. With the release of extensive research from numerous studies, each confirming the other, almost all workers in the field agree that lead at silent doses produces deficits in psychological function; these include intelligence, perception, attention, language function, and perhaps social adjustment.
Fourth: Regulations began to be shaped to accommodate the realization that lead at silent doses damaged the brains of children. Mass public screening programs were enacted to monitor the lead exposure of young children. For the first time the focus of lead exposure was centered on primary prevention, with many laws being enacted to eliminate lead sources in the environment. Mandatory testing programs were being established in many states to detect early identification of lead problems. In 1991 CDC devised a strategic plan to prevent childhood lead toxicity. This was a historic moment in lead poisoning prevention.
There were two important sources of lead for children in America: paint and leaded gasoline. lead in household paint was recognized as a danger early in the 20th century; it was banned in Australia in 1914 and by international convention in 1925. The United States was not a signatory to that agreement. It was not until 1970 that a statute banning lead in household paint was passed in the United States. Although in the early 1930’s the city of Baltimore recognized the widespread hazards of lead paint to children and took steps to control its use, lead paint was not banned by statute in this country until 1970.
Special Note on the Evolution of the Most Widespread Toxin Ever Made! – Letting the Monster loose: Propaganda, politics, and the old boys club at work
No toxic substance has been more widely distributed throughout man’s environment than the lead additive tetraethyl lead (TEL) in gasoline. For over seven decades, millions of autos of all descriptions have successfully dispersed this toxic substance to all corners of the world. How did such a toxic substance ever gain approval to expose hundreds of millions of people? In 1921, competition in the expanding American automobile market was fierce. Ford’s Model T outsold all other manufacturers, and General Motor’s flagship product, the Cadillac, had a motor knock. The Model T was economical, dependable, and easy to fix. Its performance, however, was unremarkable and it had as much style as an orthopedic shoe. Charles F. Kettering, director of research at General Motors, chafed in second place. He had a plan: he would displace Ford with a high-performance engine in a fashionable GM auto body. The best way to achieve high engine performance is to increase compression in the cylinder. Squeeze the air-fuel mixture in the cylinder into a smaller volume and it will detonate with much more force. But when the gas volume is severely compressed, it acts like diesel fuel and ignites prematurely. This is engine knock, and it causes loss of power and eventual damage to the engine. Kettering set Thomas Midgely, his close associate and principal chemist in GM’s Dayton, Ohio, research laboratory, to find an antiknock agent. In December of that year, after trying and discarding many compounds, Midgely tested an old German patent, tetraethyl lead (TEL), in the laboratory engine, which was knocking on ordinary gasoline. It immediately began to run smoothly and silently. A new product was born, and a new firm, General Motors Chemical Company, Kettering named the new fuel Ethyl Gas. Nowhere was the word lead mentioned on the product label. That Memorial Day the new fuel was used by some of the drivers in the Indianapolis 500. This shrewd marketing step was a spectacular success: the first, second, and third-place winners all ran on ethyl gasoline. Shortly after production began, workers in all three plants began to go crazy and die, often in straightjackets. Somewhere between 13 and 15 known deaths occurred, and over 300 men became psychotic. Workers called the product looney gas and the place where it was fabricated The House of Butterflies. This last sobriquet was earned by the sight of psychotic workers trying to brush phantom insects off of their arms. A moratorium on the use of TEL was called and the Surgeon General convened a meeting of industrialists, public health specialists, and academic physicians to determine if this new product was a serious enough threat to be banned or whether it could be sold to the general public. At the Surgeon General’s meeting, a young assistant professor of pathology at the University of Cincinnati, Robert Kehoe, emerged as the principal industrial expert and spokesman. When workers died in the Dayton plant in 1923, General Motors asked Kehoe to consult and make preventive recommendations. He made some measurements of lead levels in the plant and in workers directly exposed to TEL. His control group was workers in the plant who had no direct contact with the compound. This assignment marked the beginning of a major career shift for Kehoe. C. F. Kettering would, with support from the Ethyl Corp., DuPont, and others, open the Kettering Laboratory on the University of Cincinnati Medical campus and name Kehoe as its director. Kehoe would also become Medical Director of the Ethyl Corp. and a corporate officer at GM. In the Surgeon General’s meeting and others that followed his words were put forward as the final opinion on lead by the industry representatives, and he was treated with considerable deference. Kehoe was not burdened with a hypertrophied sense of modesty. He spoke with great confidence that his data was the best, if not the only, guide to the truth. Kehoe’s sway in lead toxicology held until the late 1960’s. The durability of the extraordinary scientific solecism that lead in the body was natural is a testament to the shielding power of reputation. It pays to advertise. There were no scientific challengers to Kehoe until Clair Patterson. His methods and conclusions could not have been more different. Patterson aimed his attack at Kehoe’s assertion that lead was a normal component of the human body, insisting that what he called normal was in fact typical. This was more than a semantic quarrel. Patterson fundamentally altered the vocabulary with which the debate over the health effects of lead was conducted. Most people, following Kehoe’s arguments, referred to normal levels of lead in blood, soil, and air, meaning values near the average. They assumed that because these levels were common, they were harmless. Normal also carries some of the meaning natural. Patterson argued that normal should be replaced by typical. Simply because a certain level of lead was commonplace did not mean it was without harm. Natural, he insisted, was limited to concentrations of lead that existed in the body or environment before contamination by man. Kehoe and other workers in lead completely missed this distinction because their reagents, instruments, and the very air in their laboratories were freighted with lead. As a result the baseline measurements of all their samples were raised and their results blurred. In addition, the control subjects in Kehoe’s studies, the workers in the Dayton plant who did not directly handle TEL, were nevertheless exposed to it. His second unexposed group, the Mexican farmers, ate food that had been cooked in and served from lead-containing ceramic pots and plates.
Patterson was able to demonstrate and correct this fundamental error because of the extraordinary measures he took to avoid contamination of his specimens. Because his lab was cleaner than others, his measurements of isotopic ratios were free of the contamination that confounded the findings of Kehoe and others. Where Kehoe measured lead in unexposed workers in a TEL plant and Mexican farmers, Patterson studied pre-iron age mummies and tuna raised from pelagic waters. Patterson stumbled on the problem of global lead contamination while measuring the concentration of mineral isotopes in his study of the age of the earth. He noticed that the lead levels in his reagents and in soil and ice were much higher than predicted by theory. It would have been understandable if he treated the contamination of his reagents as a severe annoyance to be overcome and then forgotten, but that was not his style. To him it was not a nuisance but a clear signal of the contamination by lead of the biosphere. This was an unrecognized danger, he believed, to everyone. In this regard, he provided facts to flesh out the warnings 40 years earlier of Yandell Henderson, David Edsall, and Alice Hamilton. Alice Hamilton of Harvard Medical School, a pioneer in the study of occupational diseases and a recognized expert in lead poisoning, spoke briefly at the hearings to review TEL: I would like to emphasize one or two points that have been brought out. One is the fact that lead is a slow and cumulative poison and that it does not usually produce striking symptoms that are easily recognized. The other is that if this (as does seem to have been shown) is a probable danger, shall we not say that it is going to be an extremely widespread one? She said that while it might be possible to educate a workforce on avoiding lead poisoning, it would be impossible to control the behavior of a whole country, and that TEL should be replaced with a less poisonous antiknock agent. These health scientists predicted at the Surgeon General’s 1925 meeting that tetraethyl lead would lead to widespread increases in human lead burden. Patterson began to divert a considerable proportion of his extraordinary mind and energy away from pure geochemistry to the study of lead contamination. By conducting his experiments in his ultra-clean chamber in which the air was filtered, the experimenters gowned and masked, and the reagents and water supply purified of any trace of lead, he was able to avoid contamination and establish the true concentrations of lead in his samples. He showed that technological activity had raised modern human body lead burdens 100 times that of our pretechnologic ancients. In addition to tuna caught in the deep strata of the Pacific Ocean and brought to the surface with great care to avoid contamination on the way up and pre-iron age mummies buried in sandy soil, he sampled cores of the Greenland ice pack. By slicing the ice cores he was able to precisely date the specimen and show the time course of lead in the atmosphere.
The removal of lead from gasoline in 1990, regarded by many as one of the major public health triumphs of the 20th century, had an immediate impact. Between 1976 and 1994, the mean blood lead concentration in children dropped from 13.7 mcg/dL to 3.2 mcg/dL, in direct proportion to the amount of tetraethyl lead produced. One could want no clearer testimony to the efficacy of a well-conceived and consistently applied public health policy. In 1993, the National Academy of Sciences verified that lead at extremely low doses caused neurobehavioural deficits.
Role of Lead and Behavioral Toxicology
Behavioral toxicology, the study of chemical toxicants and their influence on brain function, is a young field. The notion that a chemical can affect the brain and that the earliest expression of toxicity could be found in altered behavior, thinking, or mood is not new; it was voiced at least 2000 years ago by the Greek Dioscerides when he wrote, Lead makes the mind give way. Despite this early warning, the scientific community has until recently paid little systematic attention to the impact of neurotoxicants on behavior. The first textbook on this subject was published in 1975. Behavioral teratology, the study of the effect on behavior of chemical exposure of the fetus in utero, is an even newer discipline. Until recently, the uterus had been visualized as a time capsule with a 9-month lease, sheltering the developing fetus from most adverse influences such as drugs, toxicants, or nutritional deprivation. The thalidomide and Minamata disasters quickly disabused scientists and laymen alike of this false comfort. It is now clear that many chemicals cross the placenta and impinge on the developing brain. Behavioral deficits have been shown for some agents at doses well below those that cause anatomical alterations. Three important classes of neurotoxicants are metals, solvents, and pesticides. The clearest data on the deleterious effects of prenatal exposure to toxicants come from the study of two metals, lead and mercury, and from epidemiologic investigations of the effects of alcohol taken during pregnancy. Less complete data are available for two other groups of agents, solvents and pesticides. What we do know about their effects on the fetal brain is convincing enough to demand caution in their distribution. In the late 1970s, attention began to shift to the question of intrauterine exposure to lead. Scanlon measured umbilical-cord blood lead concentrations in newborns and showed that infants born to inner city mothers tended to have higher blood lead levels than those born to suburban mothers. The observation that lead crossed the placenta sparked studies of prenatal exposure on infant development. The first study examined a large cohort of births at the Boston Hospital for Women. Umbilical-cord bloods were obtained from almost 12,000 births over a 2-year period. Lead was found to be related to minor birth defects in a subsample of 5000 of these infants. A subsample of these subjects that was evenly divided among low exposure (<3 ug/dl), medium exposure (6-7 ug/dl), and high exposure (>10 ug/dl) was followed. Subjects were seen at 6, 12, 24, 57, and 120 months of age. Significant deficits in infant IQ scores were found in children in the high cord blood lead group as late as 24 months of age. At 57 and 120 months of age, the effect of umbilical-cord blood was no longer significant, but the effect of the 24-month blood lead level was statistically significant . Similar data have subsequently been reported from studies in Cincinnati and Australia. It is clear that lead exposure during pregnancy is a behavioral teratogen. The Center for Disease Control classified the causes of disease and death as follows:
50% due to unhealthy life styles
25% due to the environment
25% due to innate biology and
25% due to inadequate health care.
Lead poisoning is an environmental disease, but it is also a disease of life style. Lead is one of the best-studied toxic substances, and as a result we know more about the adverse health effects of lead than virtually any other chemical. The health problems caused by lead have been well documented over a wide range of exposures on every continent. The advancements in technology have made it possible to research lead exposure down to very low levels approaching the limits of detection. We clearly know how it gets into the body and the harm it causes once it is ingested, and most importantly, how to prevent it! Using advanced technology, we can trace the evolution of lead into our environment and discover the health damage resulting from its exposure. Winston Churchill said: Make no small plans. By this he meant that most enterprises are not completely successful. To diminish one’s goals at the beginning is to guarantee that success will be limited. Those who wish to end childhood lead toxicity should aim high: make a large plan. They should also be patient, and expect to spend a considerable amount of time in the struggle to succeed. Source: Herbert R. Needleman MD
Editor’s note: This NIH link will give you a further in-depth account of Dr. Needleman’s life and how he battled the lead industry. He is a real hero!
Genomic Signature Shared by Five Types of Cancer
The following is a quote from the NIH press release: No one in my group slept the night after that discovery, Dr. Elnitski said. We were so excited when we found this candidate biomarker. It’s the first of its kind to apply to so many types of cancer.
Dr. Elnitski is head of the Genomic Functional Analysis Section and senior investigator in the Translational and Functional Genomics Branch at NHGRI. In 2013, her research group discovered a methylation mark (or signature) around ZNF154 in 15 tumor types in 13 different organs and deemed it a possible universal cancer biomarker.
Current blood tests are specific to a known tumor type. In other words, clinicians must first find the tumor, remove a sample of it and determine its genome sequence. Once the tumor-specific mutations are known, they can be tracked for appearance in the blood. The potential of the new approach reported below, is that no prior knowledge of cancer is required, it would be less intrusive than other screening approaches like colonoscopies and mammograms and it could be used to follow individuals at high risk for cancer or to monitor the activity of a tumor during treatment. Once the blood test is developed, the scientific community must conduct studies to ensure that it does not indicate the presence of cancer when it is not there or miss cancer when it is there.
According to a study published in The Journal of Molecular Diagnostics (5 February 2016) a striking signature has been identified in tumor DNA that occurs in five different types of cancer. The study also found evidence that this methylation signature may be present in many more types of cancer. The specific observed signature results from a chemical modification of DNA called methylation, which can control the expression of genes like a dimmer on a light switch. Higher amounts of DNA methylation (hypermethylation), like that found in some tumor DNA, decreases a gene’s activity. Based on this advance, the authors hope to spur development of a blood test that can be used to diagnose a variety of cancers at early stages, when treatments can be most effective.
For the study, the authors developed a series of steps that uncovered telltale methylation marks in colon, lung, breast, stomach and endometrial cancers. They showed that all the tumor types and subtypes consistently produced the same methylation mark around ZNF154. The NIH Intramural Sequencing Center sequenced the tumor DNA that had been amplified using a technique called polymerase chain reaction (PCR). Results showed elevated levels of methylation at ZNF154 across the different tumor types.
To verify the connection between increased methylation and cancer, the authors developed a computer program that looked at the methylation marks in the DNA of people with and without cancer. By feeding this information into the program, the authors were able to predict a threshold for detecting tumor DNA. Even when the amount of methylated molecules was reduced by 99%, the computer could still detect the cancer-related methylation marks in the mixture. Knowing that tumors often shed DNA into the bloodstream, the authors also calculated the proportions of circulating tumor DNA that could be found in the blood.
The authors will next begin screening blood samples from patients with bladder, breast, colon, pancreatic and prostate cancers to determine the accuracy of detection at low levels of circulating DNA. Tumor DNA in a person with cancer typically comprises between 1-10% of all DNA circulating in the bloodstream. The group noted that when 10 percent of the circulating DNA contains the tumor signature, their detection rate is quite good. Because the methylation could be detected at such low levels, it should be adequate to detect advanced cancer as well as some intermediate and early tumors, depending on the type.
Uncorrected Farsightedness Linked To Literacy Deficits In Preschoolers
In most children with hyperopia, the condition is mild and has little impact on vision. A small number of preschool children have high hyperopia (more than 6 diopters) that is corrected with eyeglasses. It’s estimated that 4-14 percent have moderate hyperopia, which often goes undiagnosed and untreated.
According to an article published in the journal Ophthalmology (26 January 2016), a study has shown that uncorrected farsightedness (hyperopia) in preschool children is associated with significantly worse performance on a test of early literacy. The results of the Vision in Preschoolers-Hyperopia in Preschoolers (VIP-HIP) study, which compared 4- and 5-year-old children with uncorrected hyperopia to children with normal vision, found that children with moderate hyperopia (3 to 6 diopters) did significantly worse on the Test of Preschool Early Literacy (TOPEL) than their normal-vision peers. A diopter is the lens power needed to correct vision to normal. The higher the diopter, the worse the hyperopia.
The VIP-HIP study is a follow-up to the NEI-funded multi-center initiative called the Vision in Preschoolers (VIP) study, which established the most effective tests for preschool vision screening and showed that well-trained non-professionals were able to effectively screen children. In the current analysis, researchers examined 492 children, aged 4-5 years old, and divided them into two equal-size groups: those with moderate hyperopia and those with normal vision. Participation in the study included an eye examination to determine eligibility. An educational assessor unaware of the child’s visual status administered the TOPEL. The results revealed significantly worse performance on the TOPEL among children with uncorrected moderate hyperopia, especially those who also had reduced near visual function (including clarity of binocular vision and depth perception). Performance was most affected in the print knowledge domain of the test, which assesses the ability to identify letters and written words.
The study concluded that these differences are meaningful because formal learning for many children begins in the preschool years, and other research exploring the long-term effect of early deficits in literacy has shown them to be associated with future problems in learning to read and write. According to the authors, preschool children with moderate hyperopia and decreased near vision may benefit from referral for assessment of early literacy skills and that educational interventions for children with early deficits can lead to greater educational achievement in later years. The authors added that further research is needed to determine whether correction of moderate hyperopia with glasses can prevent the development of deficits in early literacy skills.
FDA Seeks $5.1 Billion Total for FY 2017
The FDA is requesting a total budget of $5.1 billion to protect and promote the public health as part of the President’s fiscal year (FY) 2017 budget – an 8% increase over the enacted budget for FY 2016. The overall request includes a net increase of $14.6 million in budget authority and $268.7 million in user fees for initiatives tied to several key areas, including the implementation of the FDA Food Safety Modernization Act (FMSA) and efforts to improve medical product safety and quality. The agency is also seeking $75 million in new mandatory funding to support the National Cancer Moonshot initiative being led by the Vice President.
The FY 2017 request covers the period from Oct. 1, 2016, through Sept. 30, 2017. Highlights of the FDA FY 2017 budget include (net increases of):
Continued Implementation of a New Food Safety System (+$18.4 million in budget authority; +$193.2 million in user fees): The FDA has finalized major rules that implement the core of FSMA, the most sweeping overhaul of the country’s food safety system since the first federal food safety law was passed in 1906. The FY 2017 budget builds on this work by supporting federal and state efforts to establish enforceable safety standards for produce farms. Funding also will enable the FDA to continue progress to hold importers accountable for verifying that imported food meets U.S. safety standards, as well as conduct food safety audits of foreign food facilities.
Improving the Safety and Quality of Medical Products (+$3.2 million in budget authority; +$38 million in user fees): The FDA’s FY 2017 budget request seeks to improve safety and quality and support innovation across a wide range of regulated medical products that are crucial to the health of Americans and impact nearly every aspect of medical care in the United States. With this request, the FDA will improve medical product safety and availability by: evaluating precision medicine tools to personalize the diagnosis and treatment of disease; improving the safety of compounded drugs through sustained or increased inspection and enforcement activities, and policy development; addressing public health safety concerns associated with antimicrobial drug use in animals to better protect antibiotic effectiveness for both human and animal populations; and supporting animal drug and medical device review. These efforts are in concert with other top priorities such as identifying solutions to prevent prescription opioid abuse, speeding the access to safe and effective generic drugs and reducing the number of drug shortages.
Supporting the National Cancer Moonshot Initiative (+$75 million in mandatory funding): In order to support the dramatic increase in the number, complexity, and effectiveness of cancer diagnostics and therapeutics, the FDA will develop a virtual Oncology Center of Excellence to leverage the combined skills of regulatory scientists and reviewers with expertise in drugs, biologics, and devices. This center will expedite the development of novel combination products and support an integrated approach in: evaluating products for the prevention, screening, diagnosis, and treatment of cancer; supporting the continued development of companion diagnostic tests, and the use of combinations of drugs, biologics and devices to treat cancer; and developing and promoting the use of methods created through the science of precision medicine.
Investing in the FDA’s Infrastructure (+$3 million in building and facilities funding; +$600,000 in other infrastructure-related funding): The FDA’s responsibilities continue to escalate as the agency works to fulfill the mandates of groundbreaking legislation passed in recent years. This expansion of authorities urgently requires that the FDA’s critical infrastructure at its owned locations is properly functioning to enable the agency to carry out its mission and respond to food safety and medical product emergencies.
Lamb Meatballs with Mint & Feta
On a dreary cold February Valentine’s Day, treat yourself and significant other with a favorite red wine, warm crusty bread, and these delicious lamb meatballs over capellini and homemade marinara sauce. The topping is a simple mixture of chopped mint leaves and crumbled feta cheese. ©Joyce Hays, Target Health Inc.
Aromatic warm and juicy. Each bite, a delicious savory morsel. ©Joyce Hays, Target Health Inc.
For the Meatballs
1 medium onion, peeled and finely diced
2 garlic cloves, minced not squeezed
1/4 cup heavy cream
2 egg yolks, extra-large
1/2 teaspoon ground cinnamon
1 teaspoon ground cumin
Pinch chili flakes
1 Tablespoon fresh cilantro, well chopped
1 Tablespoons fresh mint, well chopped
2 pounds ground lamb
1 pinch each Kosher salt and freshly ground black pepper
1 cup Panko
1/4 cup chopped parsley
For the Sauce
One 28-ounce can whole tomatoes
3 Tablespoons extra-virgin olive oil
1 small sprig rosemary
1 pinch chili flakes
1 medium onion, peeled and diced
2 garlic cloves, sliced not squeezed
1/2 teaspoon fresh thyme leaves
1/2 teaspoon ground cumin
Pinch ground cinnamon
1 bay leaf
1/2 teaspoon white sugar
1/4 cup orange juice
One 3-inch strip of orange peel, pith removed
Pinch Kosher salt and pinch black pepper
4 ounces feta cheese, crumbled
2 Tablespoons fresh mint leaves, thinly sliced
These are the ingredients that make this recipe so yummy. Feel free to substitute the cream with chicken stock or chicken broth. ©Joyce Hays, Target Health Inc.
Preheat broiler. In a large bowl, mix together the onion, garlic, cream, egg yolks, cinnamon, cumin, red pepper and 1 pinch of the chili flakes. Put the lamb in the bowl, and season it with salt and pepper. Add the Panko and parsley, and combine the mixture well. Shape the meat into balls that are a little larger than golf balls.
Mixing all the ingredients for the lamb meatballs. Might as well mix with your hands, since you’ll be making the meatballs by hand. ©Joyce Hays, Target Health Inc.
Forming the meatballs by hand. ©Joyce Hays, Target Health Inc.
Brown the meatballs quickly: Grease a frying pan with olive oil, and put the meatballs onto it, spaced evenly. Cook over a high flame, turning once or twice, until the meatballs are well browned, approximately 5 to 7 minutes, then set meatballs aside.
Cooking the lamb meatballs. ©Joyce Hays, Target Health Inc.
Turn them and cook the other side. ©Joyce Hays, Target Health Inc.
Preheat oven to 400.
Meanwhile, make the sauce. Quickly puree the tomatoes in a food processor. Heat a saucepan over medium-high heat for a minute, then add olive oil, rosemary and shake the pan, to combine. Cook for another minute, then add onion, garlic, thyme, cumin, cinnamon, 1 pinch chili flakes and bay leaf and saut? until the onions are translucent, approximately 5 to 7 minutes. Add tomatoes, sugar, orange juice and peel, along with salt and pepper.
Hand-squeezed fresh orange juice for the sauce. This is a Middle Eastern sort of thing to add to a tomato sauce, that gives it a je ne sais quoi flavor, that I will continue to use in this and other recipes. ©Joyce Hays, Target Health Inc.
Making the sauce in food processor. ©Joyce Hays, Target Health Inc. ©Joyce Hays, Target Health Inc.
Cook for 8 to 10 minutes over medium-low heat, until reduced by a third.
Cooking the sauce. ©Joyce Hays, Target Health Inc.
Pour the tomato sauce into a large baking dish that you can also put on the table, later. Transfer the meatballs to the sauce, putting them about 1/2 inch from each other. Bake for 15 or 20 minutes, in the 400 degree oven, until the sauce is bubbling and the meatballs are cooked through.
Out of the oven. ©Joyce Hays, Target Health Inc.
Top with crumbled feta and scattered chopped mint leaves. Serve with your favorite pasta or warm rice, pita bread or any crusty bread and an Ugli Salad.
Topping: simply mix together the chopped mint leaves and crumbled feta cheese ©Joyce Hays, Target Health Inc.
Sprinkle the topping over the lamb meatballs in the serving dish or over each individual serving. ©Joyce Hays, Target Health Inc.
After reading a long interesting piece in the New York Times a few weeks ago, recounting the story of a young Italian traveling to Argentina in search of the right combo of soil, rain fall and sunlight, for the perfect vineyard, our curiosity was raised enough to locate a few bottles of the Pinot Noir, that you see above, from the Bodega Chacra Estate in Patagonia’s Negro Valley. We were not disappointed, first with a deep inhalation, then a lightness on the palate, followed by a long strong finish, that truly warmed the throat. ©Joyce Hays, Target Health Inc.
A fun mini-adventure, finding this Barda Pinot Noir from Argentina ©Joyce Hays, Target Health Inc.
We had a wonderful Valentine’s Day together and hope you did too. Here’s a toast to love wherever you find it! There’s a short supply, in the world today. May your life be warm and cozy with the glow of love.
From Our Table to Yours !