Yale e360, April 15, 2010

With nearly $800 billion in drugs sold worldwide, pharmaceuticals are increasingly being released into the environment. The “green pharmacy” movement seeks to reduce the ecological impact of these drugs, which have caused mass bird die-offs and spawned antibiotic-resistant pathogens.

The standard that new drugs be safe for human consumption was first enshrined in U.S. regulations in 1938, after an antibacterial drug dissolved in a poisonous solvent killed 100 children. Now, armed with a range of evidence suggesting that wildlife and human health may be threatened by pharmaceutical residues that escape into waterways and elsewhere, a growing band of concerned ecotoxicologists and environmental chemists are calling for yet another standard for new medications: that they be designed to be safe for the environment.

The movement for “green pharmacy,” as it has been dubbed, has grown as new technology has allowed scientists to discern the presence of chemicals in the environment at minute concentrations, revealing the wide dispersal of human and veterinary drugs across the planet. In recent years, scientists have detected trace amounts of more than 150 different human and veterinary medicines in environments as far afield as the Arctic. Eighty percent of the U.S.’s streams and nearly a quarter of the nation’s groundwater sampled by the United States Geological Survey (USGS) has been found to be contaminated with a variety of medications.

This contamination is poised to worsen as the global appetite for medications swells. The drug industry sold $773 billion worth of drugs worldwide in 2008, more than double the amount sold in 2000, and with an aging population and ever-cheaper manufacturing, pharmaceutical production is expected to grow 4 to 7 percent annually until at least 2013. Americans bring home more than 10 prescription drugs per capita per year, consuming an estimated 17 grams of antibiotics alone — more than three times the per capita rate of consumption in European countries such as Germany. U.S. livestock consume even more, with farmers dispensing 11,000 metric tons of antimicrobial medications every year, mainly to promote the growth of animals.

Drugging our bodies inevitably drugs our environment, too, as many medications can pass through our bodies and waste treatment facilities virtually intact. And it is difficult to predict where and how unexpectedly vulnerable creatures may accrue potentially toxic doses. Take, for example, the ongoing mass poisoning of vultures in South Asia by anti-arthritis painkillers.

The popular anti-inflammatory and arthritis drug, diclofenac, is sold worldwide under more than three dozen different brand names, and is used in both human and veterinary medicine. In India, farmers started dosing their cows and oxen with the drug in the early 1990s to relieve inflammation that could impair the animals’ ability to provide milk or pull plows. Soon, about 10 percent of India’s livestock harbored some 300 micrograms of diclofenac in their livers. When they died, their carcasses were sent to special dumps and picked clean by flocks of vultures. It was an efficient system, for unlike feral dogs and plague-infested rats, South Asia’s abundant vulture population — estimated at more than 60 million in the early 1990s — carried no human pathogens and was resistant to livestock diseases such as anthrax.

But vultures who fed on the treated carcasses accrued a dose of diclofenac of around 100 micrograms per kilogram. A person with arthritis would need 10 times that amount to feel an effect, but it was enough to devastate the vultures. Between 2000 and 2007, the South Asian vulture population declined by 40 percent every year; today, 95 percent of India’s Gyps vultures and 90 percent of Pakistan’s are dead, due primarily to the diclofenac that scientists have found lurking in their tissues. South Asian and British scientists who experimentally exposed captive vultures to diclofenac-dosed buffalo found that the birds went into renal failure — scientists still don’t know why — and died within days of exposure. As the vulture population has declined, the feral dog population has boomed, and the Indian government’s attempt to control the rabies they carry has started to flounder.

The governments of India, Pakistan, and Nepal banned veterinary use of diclofenac in 2006, but the drug has still not disappeared from livestock tissues. And last year scientists found that another arthritis drug — ketoprofen — is similarly deadly for the birds.

The poisoning of vultures, while dramatic, is not the only worrisome impact of our medicated environment. Scientists have discovered a range of adverse effects in wildlife exposed to pharmaceutical residues, from impaired reproduction to less-fit offspring.

Ninety-five percent of Gyps vultures in India and 90 percent in Pakistan have died since the early 1990s, due primarily to exposure to diclofenac, an anti-inflammatory and arthritis drug.
For example, freshwater habitats around the world have been found contaminated with the synthetic estrogen used in contraceptive pills, ethynylestradiol. While concentrations are generally found around .5 nanograms per liter, concentrations as high as several hundred nanograms per liter have been reported, as well. A large body of evidence has connected this contamination with excess feminization in fish. In one study, U.S. and Canadian government scientists purposely contaminated an experimental lake in Ontario with around 5 nanograms per liter of ethynyl estradiol, and studied the effects on the lake’s fathead minnow population, a common species that fish like lake trout and northern pike feed on. Minnows normally become sexually mature at two years of age and enjoy a single mating season before perishing. Exposed to ethynyl estradiol, the male minnows’ testicular development was arrested and they started making early-stage eggs instead. That year’s mating season was disastrous. Within two years, the minnow population crashed.

Recent findings in New England of higher concentrations of hermaphroditic frogs around suburban and urban waterways, compared to those in undisturbed and agricultural areas, have led to suspicions that synthetic estrogens may be exerting a similarly disruptive effect on amphibians, according to Yale University ecologist David Skelly, who is currently investigating the possibility.

Our drugged environment could also affect human health. Background levels of antibiotics in the environment may be hastening the emergence of difficult-to-control antibiotic-resistant pathogens. Bacteria share genes across species, and so any increased drug resistance in one species can cross into other, more pathogenic species. As one might suspect, scientists have found that drug-resistant bacteria populations are much more common in environments where antibiotics are heavily used. For example, in samples from dairy farms where livestock are treated, and from lakes that receive effluent from hospitals, antibiotic-resistant bacteria are up to 70 percent more common than in uncontaminated environments. The facilities that must manage such antibiotic waste, by using the metabolic capacity of bacteria to treat the wastewater, become “selection machines for resistant bacteria,” says University of Gothenburg physiology professor Joakim Larsson.

Experimental evidence suggests that the witch’s brew of drugs, pesticides, and other trace chemicals in the environment could be acting synergistically to ratchet up the adverse effects on wildlife. Scientists have tried to reproduce the effects of these mixtures by studying the impacts of combinations of compounds commonly found together in the environment — analyzing, for example, the effects of trace amounts of the antidepressant, fluoxetine, and the herbicide clofibric acid. They’ve found that low concentrations of fluoxetine have no effect on water fleas. Nor do low concentrations of clofibric acid. But if water fleas are exposed to both compounds in combination, the mixture will kill more than half.

Similarly, water fleas suffer no adverse effect when exposed to low concentrations of the antibiotics erythromycin, triclosan, and trimethoprim. But if exposed to all three simultaneously, scientists have found, water fleas’ sex ratios become skewed.

Such impacts may intensify as the climate changes, especially in poor, arid countries. Countries with few resources and little water are more likely to recycle wastewater into drinking water, particularly as their regions become more arid, increasing the concentrations of pharmaceuticals and other contaminants. “This is becoming a more potent problem,” says University of Freiburg environmental chemist and leading green-pharmacy advocate Klaus Kümmerer. “We may have a closed cycle, and compounds may become enriched.”

Environmental toxicologists agree that while many of the adverse effects they’ve found in wildlife have been subtle, there is nothing preventing a vulture-like die-off from pharma poisoning elsewhere. “The vultures would have been a tough one to predict,” says Mitchell Kostich, who studies the ecological risks of pharmaceuticals at the U.S. Environmental Protection Agency (EPA). “Are we going to be able to predict those kind of cases?”

Given the current state of knowledge and today’s regulatory infrastructure, probably not. Diclofenac was first launched in the mid-1970s, before regulators in the U.S. or Europe required environmental assessments of new drugs. Today, the U.S. Food and Drug Administration (FDA) only requires drug companies to file an environmental assessment if drugmakers plan to manufacture more than 40 tons of a drug. In 2008, just 20 out of more than 10,000 claimants were required to file such an assessment. And the FDA only requires assessments of a single manufacturer’s contribution, not the total volume of the drug that may be produced or leaked into the environment.

Even if a comprehensive environmental assessment had been required, it is unlikely that diclofenac’s effect on vultures would have been detected. Toxicity testing on wildlife is generally conducted on aquatic species, under the assumption that most environmental exposures to pharmaceuticals will occur via wastewater. The most commonly used species for such testing is the crustacean Daphnia, also known as the water flea. “If there is an effect on Daphnia, there may be an effect on other organisms,” says Kümmerer, “But there is no organism that is the most sensitive organism. Test organisms are a compromise between sensitivity and ease of rearing in the lab, and availability.”

And some species, such as Old World vultures, have idiosyncratic reactions. “Chickens could eat diclofenac and have no effect,” notes Brunel University ecotoxicologist John Sumpter. So could New World vultures, who likewise seem mysteriously impervious to the drug. And neither FDA nor European Union rules empower regulators to ban a human medicine based solely on environmental concerns.

While EPA and USGS scientists hope to figure out which pharmaceuticals are most dangerous in the environment and help wastewater treatment facilities learn how to screen for and treat them, green-pharmacy advocates such as Kümmerer are calling for a whole new approach to medicine-making. They argue that rather than aim for the most biologically potent, long-lasting compounds — the miracle cures that have long been the Holy Grail of pharmacology — drug-makers should create drugs that are “benign by design” and should consider environmental impact before new drugs are brought to market. Such an approach could lead to a new category of “green drugs”: compounds that biodegrade quickly and easily in the environments they inevitably end up in.

Drug companies have already made strides in reducing waste in manufacturing because it saves them money and energy, Kümmerer says. But in order to convince companies to consider a drug’s environmental impact, extra incentives will most likely be required. One incentive put forward by the European Environment Agency in January would involve extending patent protection for drugs that are safe, effective, and environmentally friendly.

That alone, by providing a solid boost to profit margins, could prove a powerful incentive for drug companies, and could help unleash a new generation of more easily degradable green drugs. Such drugs will not be as easy to store and distribute as today’s drugs, though. Sensitive to sunlight and heat, they’ll be more likely to be packaged in darkened bottles and require refrigeration. And then it will be up to us, as patients, to choose them anyway — and heal ourselves without sickening our environment.

Courtesy of Yale e360