Endocrine-disrupting compounds

Chapter 7 Endocrine-disrupting compounds

and PPCPs

7.1 Introduction and definitions The use of cosmetics and prescribed drugs, including antibiotics and synthetic

hormones, continues to increase each year. Collectively they are known as pharmaceutical and personal care products (PPCPs), and comprise a wide spectrum of compounds. The PPCPs are either ingested or applied externally and used for both human and veterinary purposes. Antibiotics, growth promoters and other pharmaceuticals are also widely used as food additives for a wide range of livestock. These compounds are excreted in urine and faeces either as the active ingredient or an intermediate metabolite with their fate

dependent upon a number of factors (Figure 7.1 ).

While some PPCPs end up in surface waters due to runoff from land, or directly into groundwater from septic tank leachate, the majority of these chemicals end up in sewage that is normally centrally treated at a wastewater treatment plant. Unfortunately PPCPs are only partially removed by conven- tional wastewater treatment processes, with adsorption onto suspended solids the main mechanism. This results in approximately 60% of the PPCPs being incorporated into the sludge, with significant quantities of the active ingredient and any metabolic breakdown products lost in the final effluent, which ends up in either surface or ground waters. There is increasing concern that PPCPs are finding their way into drinking water due to increasing surface and ground water pollution, and the reuse of sewage effluents in areas of water scarcity. Among the more commonly recorded PPCPs are antibiotics, painkillers, beta-blockers, lipid-reducing drugs and sex steroids from birth control and hormone

replacement therapies (Table 7.1 ). While pharmaceutical drugs are designed

to induce specific biological effects in the target organism for a limited time, most of these compounds retain their active ingredient even after wastewater

treatment and subsequent discharge to the environment. Almost nothing is currently known about the risk associated from long-term exposure to these drugs at trace concentrations, or indeed exposure to cocktails of these drugs, on either human or environmental health. It has been suggested that the effects

170 Endocrine-disrupting compounds and PPCPs

Table 7.1 Commonly occurring trace contaminants of a pharmaceutical origin in wastewaters and lowland rivers

Pharmaceutical

Action

Acetylsalicylic acid

Analgesic/anti-inflammatory

Caffeine

Psychomotor stimulants

Carbamazepine

Analgesic/anti-inflammatory

Carboxyibuprofen

Analgesic/anti-inflammatory

Clofibric acid

Lipid-lowering agent

Analgesic/anti-inflammatory

17fi-ethinyl oestradiol

Oestrogen

Hydroxyibuprofen

Analgesic/anti-inflammatory

Ibuprofen

Analgesic/anti-inflammatory

Naproxen

Analgesic/anti-inflammatory

Salicylic acid

Multi-purpose

Sulphadizine

Sulphonamide antibacterial

Sulphomethoxazole

Sulphonamide antibacterial

Sulphonamides

Sulphonamide antibacterial

Trimethoprim

Antibacterial

Veterinary Drugs pathways of PPCPs into

Figure 7.1 Possible

Feed Additives drinking water. STP sewage treatment plant.

Human Drugs

landfill site

(run off) soil

fish-farms

river, creek

groundwater

drug manufacturer Drinking water

7.2 PPCPs

from PPCPs may be so subtle that they are not recognizable in real time, and that it is probable they elicit discernible cumulative effects that appear to have no obvious cause.

To date only two classes of PPCPs have been studied in depth in relation to drinking water, these are antibiotics and sex steroids. The misuse and overuse of antibiotics has led to increased resistance to antibiotics by bacterial pathogens, exacerbated by the exposure of micro-organisms to wastewater antibiotics during sewage treatment and while in water resources. On average 12 500 tonnes of antibiotics have been used annually within Europe over the past decade leading to an acceleration in the evolution of antibiotic-resistant bacterial strains in surface waters that can enter the water supply chain. The release of both natural, endogenous steroids, especially the oestrogens (estrogens), into the environment, as well as their synthetic counterparts, such as those used for reproductive control, has resulted in serious disruption of the endocrine system in aquatic animals in contaminated surface waters. Concerns have been expressed over the level of natural and synthetic sex steroids in surface and ground waters used for supply purposes and the potential physiological effects on consumers.

7.2 Pharmaceutical and personal care products (PPCPs) Clofibric acid, the bioactive metabolite of the lipid-lowering drug clofibrate, was

first recorded in a water supply aquifer that had been recharged with treated sewage effluent in the mid 1970s. This led to the realization that pharmaceutical and other drugs such as caffeine and nicotine were also present in treated effluents and so finding their way into water resources (Kümmerer, 2001 ). It was not until new analytical advances in the 1990s that the extent of the problem was fully realized with treated wastewater effluents found to contain a large range of pharmaceutical drugs and their metabolites, as well as synthetic fragrances (musks) and other components of cosmetics and other personal hygiene products (Daughton and Jones-Lepp, 2001 ).

Most research into PPCPs has focussed on their concentrations in treated sewage effluents and the resulting concentrations in the environment. However,

while there are significant environmental concerns, it is assumed that the concentrations in drinking water recorded at the consumer’s tap are normally

orders of magnitude lower than that currently found in surface waters. Like

12 other micro-pollutants, measuring such low concentrations (10 1 kg 1 ) is technically very difficult so little actual data exist on PPCP concentrations in

drinking water (Kuch et al., 2001 ). However, numerous studies have confirmed the presence of PPCPs in drinking water (Heberer et al., 1998 ; Reddersen et al.,

2002 ; Webb et al., 2003 ) (Table 7.2 ).

After being administered, the unused active ingredient in pharmaceutical products and their metabolites are excreted, along with any unwanted drugs that

Endocrine-disrupting compounds and PPCPs

Table 7.2 Selected pharmaceuticals in drinking water tested in Germany. Reproduced from Ternes ( 2001 ) with permission from the American Chemical Society

Number of Number of samples

samples

90-Percentile Maximum Drugs

LOQ in

with conc.

with conc.

Median in

1 > LOQ

1 1 1 in mg l 1

Antiphlogistics Diclofenac

<LOQ 0.050 Lipid regulators

Clofibric acid 0.001

0.024 0.070 Fenofibric acid 0.005

16 of 30

<LOQ 0.042 Bezafibrate

1 of 30

1 <LOQ

<LOQ 0.027 Contrast media

<LOQ 0.086 Antiepileptics

LOQ: Limit of quantification

may be disposed of down the toilet, and end up in the wastewater. Pharmaceutical and personal care products pass largely unaltered through conventional wastewater treatment (Ternes, 1998 ), and although diluted in surface and ground waters, as they are not removed by conventional water treatment processes then there is a high probability that these compounds could end up in drinking water at concentrations close to that found in the water resource from which the supply is taken. Drugs from a wide spectrum of therapeutic groups, and their metabolites, as well as personal care products such as sunscreens and fragrances have been identified in surface and ground waters at very low but measurable concentrations

1 ) (Daughton and Ternes, 1999 ; Debska et al., 2004 ) (Table 7.3 ). The most common pharmaceuticals sold are those most frequently recorded in water

resources (Table 7.1 ). Full details of the top 300 prescribed drugs dispensed in the USA during 2006 can be accessed at www.rxlist.com/top200.htm/ . In 2005 the top five US drugs dispensed were hydrocodone bitartrate and acetaminophen

for pain relief (101.6 · 10 6 prescriptions dispensed); atorvastatin calcium a lipid- lowering agent (63.2 · 10 6 ); amoxicillin an antibiotic (52.1 · 10 6 ); lisinopril an ACE (angiotensin-converting enzyme) inhibitor used primarily to treat high blood pressure (47.8 · 10 6 ) and hydrochlorothiazide, another drug used for

treating high blood pressure (42.7 · 10 6 ).

7.2 PPCPs

Table 7.3 Concentrations of PPCPs in groundwater located near contaminated surface waters in Berlin. Reproduced from Herberer et al. ( 2001 ) with permission from John Wiley and Sons Ltd

Drug residues

Concentration range in ng l 1

Clofibric acid nd a –7300

Gentisic acid

(Salicylic acid)

nd–1225

Clofibric acid derivative

(nd–2900) b

N-methylphenacetin

(nd–470) b

a nd: not detected; b concentrations were only estimated, because

standards were not commercially available.

Due to the complexity of monitoring these compounds at such low concentrations, analysis has been largely limited to target-based monitoring, thus ignoring all other organic micro-pollutants. In practice monitoring of

pharmaceutical PPCPs is limited to those in Table 7.1 , although some studies

have extended this to in excess of 80 specific compounds of pharmaceutical origin. Thus in practice, our knowledge of what PPCPs are present in our

drinking water is far from complete. Risk and hazard analysis on PPCPs in drinking water has been largely based on high doses required for a measurable therapeutic effect, while the concentrations in drinking water will be several orders lower than this resulting in much more subtle non-therapeutic effects (Webb et al., 2003 ). There are many unanswered questions in relation to risk, which have been discussed by Daughton ( 2004 ). However, the key question must be, what are the potential additive or synergistic effects from the simultaneous consumption of trace concentrations of numerous drugs over a lifetime, and the effect on people already taking low therapeutic index medication?

The key to reducing the concentration of pharmaceutical drugs in drinking water is to reduce their use and subsequent release into waste streams. Recommended therapeutic doses are normally much higher than actually required by individuals, which unnecessarily increases the amount of active ingredients going into the waste stream. The concept of individualizing therapy

Endocrine-disrupting compounds and PPCPs

and more accurately prescribing dose rates would significantly reduce PPCPs reaching the environment and then possibly entering the supply chain. Also

many countries do not have a mechanism for disposing of expired or unwanted drugs; indeed doctors are often faced with significant problems of disposing of

unused samples from suppliers. At worst these should be landfilled, although there is a real risk of the active ingredients being released into the environment

via leachate; ideally they should be collected locally and disposed of safely by incineration. The indirect reuse of treated effluents has been identified as a key

mechanism for meeting the widening deficit between water supply and demand. However, using resources that have already received treated sewage effluent results in PPCP contamination. This was demonstrated by Heberer et al. ( 1998 ) who studied the concentration profiles of clofibric acid and diclofenac in the Teltowkanal in Berlin. They observed significant peaks of the drugs after treated sewage effluent entered the river at three separate locations. This problem has been reviewed by Daughton ( 2004 ).

The use of septic tanks, which are poor at removing PPCPs, and where concentrations can be relatively high due to low dilution, has been highlighted as a major potential source of such chemicals in groundwaters. This is particularly problematic where people discharging to septic tanks are on long- term medication. Many studies have identified septic tanks as a major source of nitrite and pathogen contamination of groundwaters, and so it is inevitable that when these drugs are used in households employing septic tanks, similar contamination will occur.

7.3 Oestrogen and fertility There is a surprisingly large number of natural and synthetic substances that are

now classified as endocrine-disrupting compounds (EDCs). As the name suggests, these substances interfere with the normal functioning of the

endocrine system resulting in a wide range of neurobehavioural, growth, developmental and reproductive problems. Most concern over endocrine disruptors has arisen from their effect on reproductive processes, which have caused a range of worrying effects on wildlife including hermaphrodite fish, reproductive malformation and sex changes in other species. This is most clearly seen in lowland rivers receiving treated and untreated wastewater where the feminization of male fish is now common. There are two key EDCs found in sewage, the natural female steroid hormones oestrogen and 17fl-oestradiol, and the synthetic hormone ethinyl oestradiol from the contraceptive pill, both of which arise from the urine of the female population (Environment Agency, 1998b ). Oestrogen-mimicking compounds such as alkylphenols (APs), alkylphenol ethoxylates (APEs) and Bisphenol A arise from industrial wastewaters, although a much wider group of compounds are also now classed as oestrogen-mimicking or EDCs including pesticides, dioxins and furans, and

7.3 Oestrogen and fertility

Table 7.4 Potential endocrine-disrupting compounds and level of regulatory control in the UK

Substance

Statutory control

Pesticides DDT; ‘Drins; Lindane

A,C,D

Dichlorvos; Endosulphan;

B,C,D

Trifluralin; Demeton-S- Methyl; Dimethoate; Linuron; Permethrin

Herbicides Atrazine; Simazine

B,C,D

PCBs Polychlorinated biphenyls

Dioxins and furans Polychlorinated dibenzofuran;

Dibenzo-p-dioxin congeners Antifoul/wood preservative

Tributyltin

B,C,D

Alkylphenols Nonylphenol

None

Nonylphenol ethoxylate

Octylphenol ethoxylate

None

Steroids Ethinyl osetradiol; 17fl-oestradiol; Oestrone

None

A: EC Dangerous Substances Directive (76/464/EEC) List I substance; B: List II substance; C: Prescribed substance under the Integrated Pollution Prevention and Control Directive (IPPC) (96/61/EEC); D: Statutory environmental quality standards (EQSs) in place in 2000.

organotin compounds such as tributyltin (TBT). A full list of these compounds and their effects has been produced by the Environment Agency ( 1998a ) and the

key EDCs are summarized in Table 7.4 .

The evidence that the presence of these compounds is having a similar effect on humans as seen with fish is not well developed and current theories of a link

is based on the work of a Danish paediatric endocrinologist Neils Skakkebaekit.

Endocrine-disrupting compounds and PPCPs

In the early 1990s he observed that 84% of men tested had sperm quality below the World Health Organization standard although they appeared healthy in every other respect. He found that on average sperm counts had almost halved during the period 1940 to 1990. This has now been confirmed both in the USA and in other European countries with a study in Edinburgh showing males born in the 1940s to have an average sperm count of 128 million compared to only 75 million in males born in the late 1960s. Skakkebaekit has suggested that the steady reduction in sperm counts over the past 50 years, and a similar increase in prostate and testicular cancers, is due to overexposure of the male fetus during gestation to oestrogen-like substances that the mother has obtained from the environment. The exposure of the fetus to excessive oestrogen-like substances results in a delay in the formation of the sex hormone-producing cells in the testicles, which in adulthood results in reduced sperm production. It is also suspected that exposure to excessive oestrogen-like substances during pregnancy can effect the formation of the male fetuses’ sex organs. The theory is supported by studies into the use of diethylstilbestrol, an orally active synthetic non-steroidal oestrogen, widely prescribed to prevent miscarriage in the USA during the 1950s and 1960s. These studies showed that high levels of oestrogen and oestrogen-like substances were not beneficial but caused testicular abnormalities and reduced sperm counts in males and anatomic abnormalities in females leading to infertility and in some cases a rare cancer of the vagina. Like many other pharmaceuticals, diethylstilbestrol is now classified as a teratogen. This is seen by many scientists as confirmation that abnormal exposure to oestrogen or oestrogen-like substances during pregnancy could damage the unborn fetus, and that these effects might not

be seen for many years. What is clear is that the human body perceives oestrogen- like substances as natural oestrogens, and that even small concentrations of oestrogen can have a physiological effect on human development. Other chemicals can also affect the natural hormonal balance in the body by blocking either oestrogen receptors or the androgen receptors or both, which may make them even more potent than many EDCs. The link, although widely accepted, remains unproven and as such EDCs are not included generically in drinking water standards, although some individual pesticides and industrial organic solvents which are known EDCs are included but due to their carcinogenic or toxic properties. For example atrazine,

1 , is a classified EDC that is known to promote the conversion of testosterone to oestrogen. It is one of the

most abundant and ubiquitous herbicides found in drinking water, and has even been recorded at concentrations

1 in precipitation. Yet atrazine can induce hermaphroditism in frogs at concentrations of just

with tadpoles developing extra testes and even ovaries (Hayes et al., 2002 ). Atrazine is now accepted to be a potent endocrine disrupter, with the induction of aromatase, the enzyme that converts androgens to oestrogens, the mechanism that causes feminization in amphibians; a mechanism that also occurs in all mammals including humans (Hayes, 2005 ).

7.4 Conclusions

The number of organic compounds that are known to be endocrine disrupting is growing each year, and with the widespread use of these chemicals it is inevitable that the majority of these will find their way into water resources and probably to consumers’ taps. Many of these chemicals are persistent, fat-soluble and bioaccumulate in the food chain, resulting in exposure not only from drinking water but also from food. Our chance of avoiding these chemicals in food is slim, although with proper treatment they can be excluded from drinking water. In an experiment that examined the degree of human exposure to various pharmaceutical compounds in drinking water, Webb et al. ( 2003 ) found the average daily intake of oestrogen from drinking water to be negligible. They concluded that as humans naturally produce and intake various forms of oestrogen at levels up to two orders of magnitude greater than that found in drinking water, that current increased levels of oestrogen in the environment should not cause harmful effects to humans. However, oestrogens represent only

a small fraction of the total EDCs found in drinking water.