ToxSquad Outreach Blog
Issues in Environmental Health, Current events, and cutting edge research
Issues in Environmental Health, Current events, and cutting edge research
J Cucchiara and Dani Cucchiara
If the title grabbed your attention, you've most likely seen Game of Thrones. In season 6, episode 2 of Game of Thrones, we hear the character Tyrion Lannister (Peter Dinklage) state, “That’s what I do: I drink and I know things.” This is obviously not the character Jon Snow (Kit Harington) from the show, but there IS a real-life John Snow who deserves that kind of accolade.
In another time and place lived a hero named John Snow. This may sound like an introduction to a Game of Thrones, but it’s actually a chapter taken from our own past – in this case, London, England circa 1854. The story has been told numerous times by women and men of science and medicine.
A series of cholera outbreaks in 1832 and 1849 killed 14,137 people in London. In 1854, the third outbreak, part of a global pandemic reached the Soho district of the city of Westminster in London. This outbreak was responsible for the deaths of 616 people. As a local physician, Snow was concerned that his patients were dying and the ones who weren’t were fleeing the city.
At the time, germ theory, the idea that disease was caused by pathogenic microorganisms, didn’t exist. The best explanation for how people were getting this disease was “bad air,” or the established medical term “miasma.” The only way to change the air was to change where you lived, so people were trying to outrun the disease by moving somewhere else.
Snow didn’t subscribe to the miasma theory. Instead, he thought that cholera was being transmitted via water, but he couldn’t prove it, and the solution needed to be based in fact. Snow knew that he needed numbers, so he drew a map and began to collect data by going door-to-door. Snow interviewed people at each business and residence about those who had contracted and died from cholera.
The darkened lines on the map show the number of people who died at each location. Using this data, Snow was able to show how the number of people dying were distributed throughout Soho. In addition to this information, Snow also plotted the locations of water pumps located throughout the neighborhood. Careful examination of this map shows the Broad Street pump at nearly the exact center of the cholera outbreak. The further away from the pump, the less people dead from cholera.
Despite his diligence, Snow still needed more proof cholera was being spread from the Broad Street water pump. According to the working theory of miasma, bad air may have been centered around that area due to the deaths or the amount of open sewage. The proof Snow needed was also on the same map. Two locations within the Soho neighborhood, a workhouse and brewery, were close to the broad street pump but had significantly lower deaths than the surrounding homes and businesses. Both of these locations had their own water supply. It was enough proof for Snow to convince the local authorities to remove the pump handle from the Broad Street pump. This led to a significant reduction in people dying of cholera.
Later on, Snow found that infected body fluids were being dumped into cesspool located near the well and water pump. The pathogen that causes cholera, Vibrio cholerae, was able to gain access to the well water, infecting people who drank from the water pump. The disease had mostly run its course by the time they removed the pump handle, but what Snow accomplished was the prevention of subsequent outbreaks. By performing a simple statistical analysis of his cholera maps, he became the founding father of epidemiology.
It may be the story that makes John Snow famous today, but the Soho cholera mystery is not the only contribution he made to modern medicine. In fact, John Snow also pioneered the use of ether as an anesthetic. Prior to this there was no reliable anesthetic for people undergoing difficult procedures or surgery. He was able to calculate safe dosages and develop procedures for administering ether in a safe way. Ether allowed physicians to operate on people in an unconscious state so they would remain still and experience no pain until after the procedure was over.
Unlike his Westerosi counterpart, John Snow was a teetotaler. In one address given before he became an MD, he warned people of the evils of alcohol, saying, “I feel it my duty to endeavour to convince you of the physical evils sustained to your health by using intoxicating liquors even in the greatest moderation; and I leave to my colleagues the task of painting drunkenness in all its hideousness, of describing the manifold miseries and crimes it produces, and of proving to you that total abstinence is the only remedy for those evils.”
Apparently, he DIDN’T drink after all. He just knew things. Ironic that a brewery played a part in the events that put him in the history books. Ironic also that in Soho today there is a pub named after him. I wonder how he would have felt about that.
Plastics have been around since the early 20th century, but only recently has the problem of plastic pollution started to attract attention. We’ve all seen the unnerving images of marine animals in distress from plastic exposure (just check out this video of a turtle getting a straw removed from its nostril or this article about a dead whale with a stomach full of plastic bags). National Geographic recognized plastic pollution as one of mankind’s most pressing issues to date, and the U. S. and United Kingdom have recently passed laws banning the use of microplastics in certain commercial products. The ubiquitous nature of plastics in our society begs the question: Just what is all the hype about? And if there really is a problem, can we do anything to fix it?
As it turns out, plastic pollution does pose a real threat to humans and the environment, but the problem is much more complex than a whale with a stomach full of plastic bags.
What is all the hype about?
Gut obstruction and animal confinement. The most well-known problem associated with plastic pollution is gut obstruction in marine animals and birds and the incidental confinement of marine animals by plastic debris. Both can result in death or injury for the animal
Sorption of secondary contaminants. Although plastics are biologically inert, they can grab onto secondary contaminants like a toxic ocean flypaper. These contaminants usually include organic pollutants like pesticides and industrial chemicals. Such organic pollutants are often resistant to environmental degradation, tend to hang out in fatty tissues, and love to accumulate on the surface of plastics. In fact, the concentrations of contaminants stuck on a plastic surface can greatly exceed ambient concentrations in the surrounding waters.
Now the real question is.....What can we do about this?
Reduce. Reuse. Recycle. The most effective way to address plastic pollution on a personal level is to replace single-use plastic items with reusable items. Grocery shop with a reusable bag. Avoid using plastic straws at restaurants. Carry a reusable water bottle instead of a crinkly plastic one. These small lifestyle changes will help us turn the tides on the plastic pollution problem, and you might even find that the reusable items work better than the single-use plastic items! When you must use plastic materials, make sure to choose plastic materials that can be recycled - and actually recycle them!
Make your voice heard. The use of plastic microbeads in personal care products was banned in the United States in 2015, but the use of microplastics in other products (cosmetics, sunscreen, glitter, toothpaste, nail polish, abrasives in dish detergent pods) has not been addressed. And although some companies are taking action to reduce single-use plastics in their business design, the problem of single-use plastics has not been formally addressed by state or federal regulations. Be vocal and let your legislature know how you feel about these problems!
There is often a historical truth behind fictional characters, no matter how absurd it may seem. I was 22 years old, in my first class as a PhD student, when I learned that there was something more to an iconic character from my childhood than I realized. Alice in Wonderland’s Mad Hatter may not have been just this fun, crazy, unpredictable character - he was possibly inspired by real-life hat makers suffering from chronic mercury poisoning.
Often cited as a classic example in occupational toxicology, Mad Hatter Disease (also known as Erethism) is a neurological condition resulting from daily exposure to mercury fumes. Mercury was used to help hatters manipulate felt into hats. However prolonged (chronic) inhalation exposure to mercury often led to hatters experiencing tremors and various psychological symptoms, including depression, irritability, and even hallucinations. Various reports of this disease and its relationship to hat-making emerged as early as the 1800s; in fact, a cohort of New Jersey hat makers were experiencing these symptoms in 1860, just 5 years prior to the publication of Alice in Wonderland by Lewis Carroll.
Long after the hazards of occupational mercury exposure were first observed, the United States outlawed the use of mercury in the felt industry in 1941. This was not the only time the United States government has acted to protect workers from occupational hazards; for instance, in 1989 the Environmental Protection Agency banned the use of asbestos in building materials after evidence emerged that asbestos exposure results in chronic respiratory problems. As technology continues to advance, we must work to proactively protect workers before they become ill. While the Mad Hatter is an iconic and beloved character, the reality behind his origin is heartbreaking, and is a powerful reminder of the importance of occupational safety procedures and regulations.
Rachel Louise Carson was born on May 27, 1907 (she would celebrate her 101st birthday today!) in Springdale, Pennsylvania, a small town along the Allegheny River just east of Pittsburgh. She grew up in a poor family, but was awarded a scholarship to attend the Pennsylvania College of Women - today known as Chatham University in Pittsburgh. She originally planned to study English and writing, but realized that years exploring the wilderness around her childhood home had fostered a love for biology and the environment. After receiving a bachelor’s degree in biology, she continued her studies at the oceanographic institute at Woods Hole, Massachusetts and at Johns Hopkins University, where she earned a master’s degree in zoology. Carson then went on to work for the U.S. Bureau of Fisheries where she wrote radio segments about marine life. In her spare time, she wrote freelance pieces for newspapers and magazines on the topics of conservation and nature. She was eventually promoted to Editor-in-Chief of all Fish and Wildlife Service publications. During this time, she also published three acclaimed books about aquatic life, Under the Sea-Wind (1941), The Sea Around Us (1951), and The Edge of the Sea (1955).
However, it is her fourth book, called Silent Spring, which makes her a renowned figure in the fields of ecology, toxicology, and environmental health. Published in 1962, Silent Spring outlines the negative impact of pesticide use on the environment, ecosystems, and human health. She wrote specifically about the insecticide DDT (dichlorodiphenyltrichloroethane), which at that time was sprayed aerially throughout the United States to control insect populations. DDT had been linked to the thinning of eagle eggshells, causing them to crack during incubation and ultimately leading to a decline in the eagle population. The book was a bestseller, and launched the environmental justice movement in the United States. Silent Spring and Carson faced substantial backlash from chemical companies, but also made Americans more aware of the fragility of our environment and the need to protect it from irresponsible chemical use. Her book and subsequent appearance before the Senate subcommittee in 1963 would plant the seeds for the founding of the Environmental Protection Agency in 1970, the passage of the Clean Air and Water Acts, the establishment of Earth Day, and the eventual banning of DDT in the United States in 1972. Unfortunately, Carson did not live to see the full impacts of her work, and lost her battle to breast cancer on April 14, 1964. Posthumously awarded the Presidential Medal of Freedom, she left behind a legacy of appreciating and protecting the environment, best illustrated by her quote:
“The more clearly we can focus our attention on the wonders and realities of the universe about us, the less taste we shall have for destruction.”
This month, the University of Toronto’s Green Chemistry Initiative and the Gainesville ToxSquad teamed up to co-author a post about the Indian Vulture Crisis…
Shira Joudan (Green Chemistry Initiative) and Alexis Wormington (ToxSquad)
Pharmaceuticals have drastically changed our society, quality of life, and life expectancy. Advances in chemistry are the driving forces behind the optimization of pharmaceuticals and other synthetic chemicals which have shaped the way we live our lives. Sometimes, a chemical used has undesired side effects, such as non-target toxicity to animals in the environment. A historic example of the consequences of chemical use is the toxicity of the pesticide dichlorodiphenyltrichloroethane (DDT) to eagles, which was profiled in Rachel Carson’s famous book Silent Spring. Although current regulations require extensive toxicity testing for new chemicals, those with a high production volume can still elicit unforeseen environmental effects on the environment.
More recently, there have been unforeseen environmental implications of chemical use in another essential bird population in India, a phenomenon now known as the Indian Vulture Crisis. Between 1993 and 2000, Indian vultures (Gyps bengalensis, Figure 1) began to mysteriously disappear, with the population declining by over 97% in less than 10 years (Figure 2). Researchers worked frantically to identify the cause, and came up with several theories ranging from infectious disease to food shortage to chemical exposure. Scientists began noticing visceral gout on a majority of the dead vultures, which is a sign of kidney failure in birds, and from there it didn’t take long to determine the culprit was a chemical contaminant. In 2004, a paper reported startling amounts of diclofenac (Figure 3) in the tissues of the dead vultures, providing compelling evidence that the non-steroidal anti-inflammatory drug (NSAID) was the cause of the population collapse.3 To figure out how to restore the vulture population, or at least slow down its decline, researchers needed to figure out how the vultures were being exposed to diclofenac, why it was killing them, and if there was a chemical alternative to the deadly pharmaceutical.
So, What Happened?
The problem began when diclofenac was approved for veterinary use in India in the early 1990s, where it was widely utilized to treat inflammation in cattle due to its efficacy and affordable cost. As a result, many livestock carcasses in India were contaminated with diclofenac, which brought catastrophic consequences to any vulture that consumed the carcasses. Vultures within the Gyps genus cannot metabolize diclofenac, and are extremely sensitive to the drug, with toxic doses ranging from just 0.1-0.8 mg/kg depending on the species.1 A vulture would receive a lethal dose of diclofenac after consuming a small amount of contaminated tissue, and die of renal failure within 48 hours. Just one contaminated carcass affected several vultures at once due to their group feeding behaviour, and because of this, diclofenac contamination in as little as 1 of every 200 carcasses would have been enough to cause the decline in the vulture population.
Although diclofenac is either banned or not used for veterinary purposes in most countries, it is still legally utilized throughout Europe, which has drawn controversy in those countries where it is approved for use in food animals.
Human Health Impact of the Vulture Crisis
India is a developing country and relies more on natural processes for the removal of dead animals, where scavengers like vultures play a huge role. With the loss of the vultures, less efficient scavengers such as rats and dogs have moved in to replace them, leading to major problems with disease in the affected areas. Unlike vultures, which are terminal hosts for pathogens due to their strong stomach acid, dogs and rats are reservoirs for diseases – and now these animals are the primary scavengers in India. A rise in feral dogs has caused an increase in the number of rabies cases in humans, which has cost India approximately 998-1095 billion Rupees in healthcare costs between 1992 and 2006 (15-16.5 billion USD).
In addition to the economic and health costs associated with a rise in infectious diseases, the disappearance of the vultures has also lead to issues with the prolonged decomposition of carcasses. Vultures play a major role in the decomposition process – a group of them can skeletonize a body within a few hours. But in their absence, bodies take days or months to decompose, which can lead to issues with water or food contamination. This ‘carcass crisis’ has had cultural implications as well, threatening the ancient Parsi burial tradition where bodies are not buried, but disposed of through natural means (i.e. vultures). Without the vultures, the Parsis struggle to continue the two-thousand-year-long practice and are forced to seek alternative methods of body disposal, causing a deep divide within the community.
Diclofenac and Green Chemistry: Could This Have Been Prevented?
The short answer: probably not. For a drug to be approved for human or animal use, toxicity research must be conducted (although these requirements vary by country, read more about how drugs are approved in Canada10 and how drugs are approved in the USA11). Unfortunately, potential ecosystem toxicity (ecotoxicity) is not often at the forefront of the drug-approval process. Even if ecotoxicity studies were performed with diclofenac, it is unlikely that the toxicity to vultures would have been discovered before drug approval, as vultures are not a common test animal used in these types of studies. Only a full chemical assessment with ecosystem modelling and subsequent toxicity tests could have predicted the toxicity to the vultures; but these tests are expensive, time consuming, and not the norm during the current drug-approval process.
In India, farmers cannot afford to lose animals, and rely on affordable NSAIDs such as diclofenac to improve the health and quality of life of their livestock. Since NSAID use cannot be prevented, it is up to green chemists to find a suitable replacement for diclofenac that is efficient, affordable, and less toxic to vultures.
To predict the potential toxicity of a pharmaceutical or chemical to humans and the environment, it is important to consider all interactions that occur once the compound enters the body. Every pharmaceutical has a “therapeutic index” (the difference between an effective and toxic dose), which can vary between different species or susceptible populations (e.g. infants, elderly). If the concentration of a drug exceeds the toxic level, toxic endpoints such as renal failure or death could be observed. The toxic level of a drug depends on two major processes: drug excretion and metabolism. The sum of these two processes determines how quickly a pharmaceutical is broken down and eliminated from the body. In the case of diclofenac, vultures could not metabolize or eliminate the drug, so it was free to wreak havoc on susceptible organ systems. For an NSAID to be a suitable replacement for diclofenac, vultures should be able to break it down and excrete it safely.
Currently, meloxicam has replaced diclofenac as an NSAID for livestock in India. Both drugs have a similar mechanism of action in the treatment of inflammation; however, unlike diclofenac, meloxicam is rapidly metabolized and excreted by vultures. In a study where different vulture species were administered meloxicam, researchers observed the production of three metabolites identical to those observed in humans during clinical trials. Vultures have the enzymes required for the metabolism of meloxicam (specifically cytochrome P450s and glucuronide transferase). The formation of metabolites alters the biological activity of meloxicam, increasing its water solubility and allowing for faster renal excretion.
Understanding the biological interactions of a drug can also help us eliminate potential replacements for diclofenac. An example of a poor replacement for diclofenac in cattle would be aceclofenac, because it is metabolized to form diclofenac via hydrolysis. This particular pharmaceutical would not do anything to improve the vulture population, and should not be selected as a replacement for diclofenac.
Current Status and Remaining Challenges
In 2016, the Indian minister of the environment launched the Gyps Vulture Reintroduction Programme with the hope of restoring the vulture population to 40 million individuals within the next decade through breeding programs. Although this effort to restore the Indian vultures is a step in the right direction, there are still many challenges in way of their recovery. Despite the fact that meloxicam is a safer NSAID for use in livestock, diclofenac is still obtained and used illegally among farmers in India due to its affordability. Since the ban of diclofenac for veterinary use in 2006, the decline rate of Gyps has decreased, but vultures are still likely to decline by 18% per year despite the ban. Until the drug is completely removed from the equation, the reintroduction and recovery of the vultures remains a challenge.
By Amanda Buerger, Sara Humes, and Alexis Wormington
One aspect of environmental health revolves around understanding how changes in the environment, whether human or naturally-caused, may impact the health of global populations and ecosystems. Model organisms are non-human species used to understand biological processes in a laboratory setting. Model species should be affordable, easy to keep in a laboratory setting, and an appropriate species to study in the context of the scientific question being asked. In this post we’ll go over three model species that are commonly used in the field of environmental health, why we use them, and their advantages and disadvantages as models.
Daphnia, commonly known as the “water flea”, are a genus of aquatic crustaceans used very commonly in basic toxicological studies. Daphnia species are favored because they are very inexpensive, low maintenance animals with a short life cycle. Since they are invertebrates, the ethical and legal requirements for their use are minimal compared to more complex models, such as non-human primates and rodents. Daphnia are unique because they typically reproduce asexually, meaning all of their offspring are genetically identical to the mother. They can produce over 100 eggs at a time, and reproduce approximately every two days! Because of their rapid and unique life cycle, these organisms are valuable to use in both reproductive studies and toxicity tests. Daphnia studies often provide the foundation for the basic toxicity of chemicals.
Like with any model, using Daphnia comes with its disadvantages. Since Daphnia are invertebrates, their application to human health is very limited, as mammals and invertebrates have vastly different molecular, chemical, and physical processes involved in biological function. Additionally, their brief life cycle makes them impossible to use in long-term studies, which restricts the kinds of questions we can ask and answer using Daphnia as models.
Alternatives to invertebrate and mammalian models are fish, which are generally smaller, cheaper, and easier to care for than rodents, non-human primates, and other higher level models. There are several species of model fish, from tiny minnows, to predatory trout and bass, to one of the most common fish models - zebrafish. While not as closely related to humans as mammals, fish share several characteristics with humans, including conserved biochemical processes in the brain, gastrointestinal system, and cardiovascular system. In the case of the zebrafish, the gut is similar to that of humans, and therefore these fish are used to study diseases related to the intestinal tract, such as obesity and inflammatory diseases. Due to increased funding of studies using zebrafish, this inexpensive model organism is becoming more commonly used in scientific research. Because of their prolific use, the genome of the zebrafish has been sequenced, and scientists are able to utilize this knowledge to create zebrafish that are useful for their studies. Finally, the development of zebrafish is easy to monitor, as the embryos and larvae are transparent.
As with any model, there are limitations to its use. Most fish species experienced a duplication of genes millions of years ago, and therefore generally have two functioning genes for each one human gene. Additionally, there are some other differences between fish and humans, such as the respiratory tract and the presence of two pairs of kidneys in some fish, each with distinct function. Fish are also housed together in tanks, and there is uncertainty as to whether the whole tank should count as one sample or if each fish in a tank should be considered individually. As we understand more about zebrafish, we will be able to evaluate the use of this organism as a model for different human diseases.
The most commonly used and well-established mammalian models in scientific research are the mouse and rat. Compared to other mammalian models, such as non-human primates, livestock, and cats, mouse and rat models are less expensive and easier to house. Some advantages of using mice and rats for toxicological research include their short lifespan, small size (for easier care and housing), short gestation times for large litters, and genetic and biological similarity to humans. Approximately 95% of some 30,000 genes are shared between mice, rats, and humans, resulting in a lot of biological resemblance. This similarity makes rats and mice a good stepping stone between lower models and humans. Additionally, we have fully sequenced the genome of the mouse and rat, making it easier to focus on a particular gene of interest for a research project. Knowing the full genome allows researchers to create genetically engineered rodents that are missing or have an excess of certain genes or proteins to shed light on their function and role in response to toxicological stressors. Research rodents are also bred so that two animals of the same strain are nearly genetically identical, eliminating much of the variability between individual animals.
Despite these advantages, there are some disadvantages to using rodent models. Rodents and humans still have some fundamental differences in physiology, limiting their application to humans in certain cases. For example, rodents cannot cough, so study outcomes related to the respiratory system may be different than those observed in humans. Since rodents are mammals, there are also many more regulations, training, financial resources, and ethical considerations required to work with them compared to non-mammalian models. Regardless, rodents are a well-respected, frequently used model in all areas of scientific research, and their use has led to many scientific advancements.