Surprise Chemistry: Pharmaceuticals in the Environment

Valerije Vrček

Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia; Faculty of Humanities and Social Sciences, Center of Excellence for Integrative Bioethics, University of Zagreb, Zagreb, Croatia

Corresponding Author: Valerije Vrček, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia; Faculty of Humanities and Social Sciences, Center of Excellence for Integrative Bioethics, University of Zagreb, Zagreb, Croatia, Phone: +385915348345, e-mail: vvrcek@pharma.unizg.hr

Received: 05 June 2024; Accepted: 08 July 2024; Published on: 17 July 2024

ABSTRACT

A number of pharmaceuticals undergo chemical transformation in the environment. These reactions may be induced by (waste) water treatment protocols such as chlorination, ultraviolet (UV) photolysis, or activated sludge processes. In many cases, the reaction pathways are unknown or unexpected, and the resulting byproducts are more toxic than the parent compound. It comes out that human intervention in nature makes the problem worse.

Keywords: Chemistry, Ecology, Environment, Pharmaceuticals, Precaution

SAŽETAK

Mnogi lijekovi podliježu kemijskim transformacijama u okolišu. Te reakcije mogu biti potaknute protokolima obrade (otpadnih) voda, poput kloriranja, UV-zračenja ili procesima u aktivnom mulju. U mnogim su slučajevima reakcijski putovi nepoznati ili neočekivani, a nastali nuzprodukti su toksičniji od početnoga spoja. Proizlazi da ljudska intervencija u prirodu samo pogoršava situaciju.

Ključne riječi: Ekologija, Lijekovi, Kemija, Okoliš, Opreznost

How to cite this article: Vrček V. Surprise Chemistry: Pharmaceuticals in the Environment. Sci Arts Relig 2024;3(3–4):76–79.

Source of support: This research was funded by the Croatian Science Foundation (grant number HRZZ-IP-2022-10-2634).

Conflict of interest: None

INTRODUCTION

It is well known that underground and surface waters, as well as all wastewater, lakes, and oceans, are contaminated by pharmaceuticals and their degradation products. A recent study has published that all rivers around the globe contain measurable traces of antibiotics, analgesics, statins, or chemotherapeutics.¹ In Europe, for example, the only country with no carbamazepine, ibuprofen, or other drugs in rivers is Malta. This is because this island country has no rivers.

The case of pharmaceuticals in water is full of surprises. It is a chemical story that confirms that our understanding of nature is fragile and limited. In this short review, several pharmacy examples have been selected to reveal the message about information gaps. Late lessons from these early warnings illustrate how damaging and costly the neglect of the precautionary principle can be. In each case, the surprise chemistry is the mechanism underlying the ecological fate of pharmaceuticals in water.²

ZOMBIE PHARMACEUTICALS

An unusual behavior of steroid hormones, including trenbolone, a growth-promoting steroid, dienogest, an oral contraceptive, and dienedione, an illicit anabolic steroid, was discovered. During the day, these pharmaceuticals undergo sunlight-mediated degradation, but during the night, they reform back to their original structure. This phenomenon poses a challenge for traditional toxicology—both the dose and the effect exhibit a circadian rhythm. By no surprise, a new name for these compounds has been coined—zombie steroids.³

These compounds are endocrine disruptors, and therefore, their presence in the environment is of high concern. Due to their strange behavior—rising from the dead at night—the environmental risk protocols are compromised, sampling results are uncertain, and the risks of endocrine disruption are unrecognized. According to Edvard Kolodziej, the author of the study, these results cast uncertainty over sampling methods for endocrine disruptors and suggest that a survey of their breakdown compounds in the environment is now urgently needed.

Reactions and comments from other experts ranged from curiosity to caution. ”This is a very comprehensive and impressive study, and its implications for aquatic ecosystems are sobering,” said Karen Kidd of the University of New Brunswick in Canada.⁴ “It’s a potential game-changer for ecological risk assessment. My eyebrows went up,” added Deborah Liebl Swackhamer, environmental chemist at the University of Minnesota. The mechanism underlying the unexpected zombie-drug transformations is sunlight-driven chemical reactions, forming photoproducts. The latter are unstable during the night and revert to the starting compound. Douglas Latch, a photochemist from Seattle University in Washington, has a different view—”it makes total sense when you look at it. It’s unexpected in the sense that no one had designed experiments to find that.” In any case, these findings must be incorporated into risk assessment. According to Kathrin Fenner of the Swiss Federal Institute of Aquatic Science and Technology in Dübendorf—“these results just cannot be ignored.”

The confusion among scientists is evident, as standard protocols for monitoring, sampling, and environmental assays have been challenged and compromised. It becomes obvious that the element of surprise should be considered when investigating the chemical fate of pharmaceuticals.

CHEMICAL FATE IN TREATMENT PLANTS

Another surprise chemistry is at play when pharmaceuticals are exposed to chlorine, ozone, or ultraviolet (UV) light. These chemicals (and photons) are regular ”ingredients” used in wastewater treatment plants. During chlorination, ozonation, or UV irradiation, some pharmaceuticals may be transformed into byproducts that are more toxic. This means that disinfection protocols, intended to make water cleaner and/or drinkable, lead to the formation of chemicals with unknown or unexpected toxic profiles. Several studies describe the accidental conversion of pharmaceuticals to harmful substances. Instead of being resolved, the environmental risk has grown larger.

The first case is acetaminophen, a very popular painkiller and the active ingredient in drugs like ”paracetamol,” ”panadol,” or ”tylenol.” It has been reported that acetaminophen may react with hypochlorous acid to form a number of oxidized products, two of which were identified as harmful compounds—para-quinone and N-acetyl-p-benzoquinone imine (NAPQI).⁵ The former is an oxidized form of benzene and has genotoxic and mutagenic properties. NAPQI is a toxic byproduct of the reaction between chlorine and acetaminophen, which may induce severe damage to the liver (hepatotoxicity in humans). In terms of experimental (eco)toxicity, both products were approximately 60 and 30 times more harmful than the parent structure, respectively.

This troublesome discovery has triggered scientists’ interest in the fate of pharmaceuticals during the chemical treatment of wastewater. ”This is one of the first papers that details the products of chlorine reaction of a pharmaceutical. When looking at pharmaceuticals in the environment, we may simply not be looking at the right compounds,” says David Sedlak, professor of environmental chemistry at the University of California, Berkeley. He emphasizes the importance of investigating the chemical fate of drugs more closely, as the reaction products may be more harmful or, typically, more persistent compared to the starting compounds.

Triclosan, a common disinfectant and antibacterial agent, is another notable example of damaging transformations of pharmaceuticals in the environment. It has been shown that sunlight can convert triclosan into a form of dioxin.⁶ The latter is a notorious carcinogenic substance that accumulates in the environment as a persistent organic pollutant. This simple light-driven reaction occurs not only in the laboratory but also in surface water. Researchers at the University of Minnesota investigated this photochemical reaction in Mississippi River water exposed to air and daylight. William Arnold, a professor of civil engineering who wrote the paper, said, ”this study shows that the disappearance of a pollutant such as triclosan doesn’t necessarily mean an environmental threat has been removed. It may just have been converted into another threat.”

The use of triclosan has significantly increased during the coronavirus pandemic. A tenfold increase in the use of disinfectants for personal and environmental decontamination has been observed.⁷ It is therefore expected that wastewaters and surface water have been loaded with an additional amount of triclosan. Any exposure to UV light or sunlight converts it to dioxin. Unlike the zombie chemicals, triclosan is converted to dioxin and becomes harmful during the day. Unfortunately, these toxic photoproducts do not revert to triclosan in the dark.

The levels of toxic polychlorinated aromatic byproducts resulting from intramolecular ring closure in triclosan induced by sunlight increase over time. This is a warning that the contribution of triclosan-derived structures to overall dioxin risks requires additional analysis. It is yet another cautionary note about the unusual reaction mechanisms underlying the chemical fate of pharmaceuticals in the water environment.

In addition to acetaminophen and triclosan, a number of other pharmaceuticals undergo unexpected chemical transformations resulting in more toxic byproducts.⁸ In all cases, the message is similar—water treatment makes the problem worse.

DE NOVO SYNTHESIS OF DRUGS

Surprise chemistry of pharmaceuticals in the environment may be induced by chlorine and sunlight (see above), but reactions of wonder may also occur in activated sludge. Activated sludge is the conventional wastewater treatment process designed to remove harmful substances, including pharmaceuticals, from aqueous environments. As expected, most pharmaceuticals are successfully eliminated during the activated sludge wastewater treatment process. However, doses of some drugs actually increase after treatment. Blair et al. from the University of Wisconsin found that some compounds came out at higher doses than they went in.⁹ It seems that facilities for the biological treatment of wastewater may act as pharmaceutical manufacturing sites, effectively synthesizing substances like the antiepileptic carbamazepine or the antibiotic ofloxacin.

Instead of decreasing, the concentration of carbamazepine and ofloxacin increases over time. The observed increase is by 80 and 129%, respectively. The mechanism underlying de novo synthesis is not clear, but the authors suggest that microbes living in the sludge are responsible for regenerating pharmaceuticals. These microbes have the ability to piece together bioactive structures back into pharmaceuticals. ”It’s a fascinating idea. Microbes seem to be making pharmaceuticals out of what used to be pharmaceuticals,” said Blair.

His publication is the leading study in which negative mass balances of pharmaceuticals have been reported. The amount of soluble and sorbed concentrations of pharmaceuticals in an aerobic batch reactor increased over time. These results go against chemical intuition and violate the concept of wastewater treatment plants. The discovery of bacteria-making medications in wastewater outflows demonstrates yet another failure in technology designed to address the challenge of water remediation. It remains unclear why certain drugs increase while others decrease after treatment.

In any case, this is an early warning that the chemical fate of pharmaceuticals is not easily predictable. One more lesson from the surprise chemistry.

ECOSOCIAL IMPACT OF PHARMACEUTICALS

The occurrence of pharmaceuticals in the environment may have ecological, toxicological, and social impacts. The case of diclofenac is unique, as it led to a cascade of effects resulting in the population collapse of vultures in India and Pakistan. The cause of death of white-backed vultures was unknown until 2004, when it was identified as poisoning from consuming carcasses containing traces of the painkiller “Voltaren.”¹⁰

Along with the ecological disaster, the entry of the veterinary drug diclofenac into nature has induced a series of additional disorders. For example, after the extinction of vultures, the population of feral dogs has exploded.¹¹ Instead of bird scavengers, the livestock carcasses were eaten by wild dogs. However, these dogs are known as a reservoir of rabies. India has a high rate of rabies, and dog bites are the primary cause. As expected, parallel with the vulture decline, the frequency of these bites and rabies cases has increased.

Interestingly, not only has the wild dog population increased, but the leopard population has also increased, as the former has become easy prey for big cats. As a result, leopards have been entering villages, and the number of incidents of contact between animals and humans has increased. Around 100 accidents have been recorded in the aftermath of the vultures’ decline.

In addition, the deficit of vultures has been followed by an increase in the rodent population, specifically rats. Instead of vultures, rats have appeared as crucial scavengers at cadaver dumps. This describes a typical perturbation of equilibrium in an ecosystem. It is likely that the increased number of rats contributes to a higher incidence of leptospirosis, as well as plague, in the human population.

Finally, some religious and ethnic groups have also been affected by the loss of vultures. A group of Zoroastrians, called Parsis, is a small community living in the cities of Mumbai, New Delhi, and Hyderabad, and they do not practice the incineration or burial of human corpses. They place dead bodies in a raised structure called a ”Tower of Silence,” where vultures may consume the remains. With the demise of the vultures, this religious practice has been hindered. After the century-old ritual was interrupted, the Parsis started to search for other solutions, but with limited success.

To conclude this part, the introduction of diclofenac into veterinary practice in the Indian subcontinent has generated a sequence of harmful outcomes, none of which were predictable earlier. What was once just an analgesic pill has emerged as a pill of surprises, creating a chain of adverse events—ecological, toxicological, medical, financial, and social.

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