Pharmaceuticals, Regulatory Briefing

1

Pharmaceuticals

Pharmaceuticals, Regulatory Briefing

Prepared By:

Nancy L. Pontius

Pontius Water Consultants, Inc.

P.O. Box 150361

Lakewood, CO 80215

303-986-9923

October 16, 2002

National
Rural Water
Association

Pharmaceuticals are primarily prescription and over-the-counter therapeutic drugs. (Illicit drugs are included as well.) They include compounds such as: acetaminophen, benadryl, caffeine, cholesterol, cocaine, ibuprofen, morphine, penicillin, saccharin, testosterone, tetracycline, and warfarin. Pharmaceuticals are biologically and pharmaceutically active; they are purposefully designed to have a biological effect at therapeutic concentrations. (USEPA 2002b)

Pharmaceuticals and personal care products (PPCPs) are a diverse collection of thousands of chemical substances that are consumed by people (or animals) for health or cosmetic reasons including: pharmaceuticals, fragrances, cosmetics, sunscreens, personal hygiene products, and nutritional supplements. (USEPA 2002b) PPCPs are generally synthetic organic compounds.

There is no official list of compounds that are PPCPs, and no official terminology exists. These terms are primarily medical terms, and do not refer to chemical structure, reactivity, or usage. The term “PPCP” is used by the U.S. Environmental Protection Agency (USEPA), and will be used in this briefing. PPCPs in the environment are an area of ongoing research, where data is being gathered, and scientists and others are debating the extent and significance of environmental exposures (USEPA 2002b; USEPA 2002d)

Endocrine disrupters (also called hormonally active agents) are any type of chemical or mixture of chemicals that affect the endocrine system, and cause negative reproductive and developmental health effects for the human or animal and/or its offspring. The endocrine system is a complex network of organs, including the thyroid, pancreas, pituitary, ovaries, testes, and adrenal glands, which secrete hormones into the bloodstream to target cell receptors in other organs or tissues, where the hormone has a specific effect. (Pontius 2001; Symons et al. 2000)

The list of pharmaceuticals and the list of endocrine-disrupting compounds partially overlap. Some (but not all) pharmaceuticals may affect the endocrine system, for example steroids.

PPCPs are used in large amounts throughout the world. However, exact amounts of PPCPs sold and consumed are difficult to verify. Hundreds of tons of certain pharmaceuticals are produced annually, while others are manufactured in only kilograms. Personal care products are made in extremely large quantities -- thousands of tons per year. New pharmaceuticals are also being developed annually. (USEPA 2002b)

Pharmaceuticals are continuously released into the environment in large quantities from the following avenues: manufacturing residues, excretion in urine and feces, disposal of unused pharmaceuticals (including illicit drugs), hospitals, and landfill disposal and subsequent leaching. (USEPA 2002b; Heberer 2002) Another source is animal husbandry, such as confined animal feeding operations (CAFOS), where, for example, antibiotics can enter the environment from run-off and groundwater contamination. (Koschorreck et al. 2002) Also, the large number of pet dogs and cats that receive numerous pharmaceuticals can contribute these compounds to the environment through leaching of urine and feces outdoors.

Pharmaceutical occurrence in the environment is a function of many variables including: quantity manufactured, dosage amount and frequency, how compounds are metabolized, and effectiveness of waste treatment. (Daughton and Ternes 1999)

PPCP residues (and their metabolites) are found in run-off, raw sewage, and treated sewage effluent. The chemicals may or may not have been metabolized by humans or removed by wastewater treatment. Wastewater removal capabilities vary from chemical to chemical and between individual wastewater treatment plants. USEPA has noted that municipal wastewater treatment plants are not engineered for PPCP removal. (USEPA 2002b)

Some PPCPs are easily metabolized or degrade quickly in the environment. However some are poorly metabolized by humans and animals, or are disposed of unused. (USEPA 2002b) Pharmaceuticals may also degrade in soil and aquatic systems, and by exposure to sunlight, and when metabolized by microorganisms. The degradation products of pharmaceuticals are a new area of investigation. (Erickson 2002; Daughton and Ternes 1999)

PPCPs identified in natural waters tend to occur in very low concentrations, ranging from hundreds of micrograms per liter (g/L) to nanograms per liter (ng/L). (USEPA 2002b) New chemical-analysis methods have been necessary to detect these low concentrations, and research is continuing in this area, including new approaches to high-resolution mass spectrometry. (USEPA 2002a; USEPA 2002c; Bruchet et al. 2002; Heberer Th. et al. 2002; Ternes et al. 2002; Kolpin, D. et al. 2002)

Two issues related to PPCPs in the environment that have received the most attention recently are: endocrine disruption by naturally-occurring and synthetic sex steroids, and the increased resistance of microorganisms to antibiotics. (USEPA 2002b; WHO 2000 ; Daughton and Ternes 1999)

Human Health Effects and Exposure

The human risk of long-term exposure to very low concentrations of PPCPs in drinking water is essentially unknown. There is potential concern specifically for infants, fetuses, and people with enzyme deficiencies. (Daughton and Ternes 1999) Research is continuing in this area. (Foster et al. 2002)

Because pharmaceuticals are purposefully designed to have a biological effect at prescribed doses, the potential exists for unexpected impact at low levels. (USEPA 2002b; Daughton and Ternes 1999) Humans are affected by individual pharmaceuticals in different ways, and some compounds have effects at lower concentrations than others. (Erickson 2002)

Some pharmaceuticals are known to affect the function of the endocrine system. Exposure to endocrine disruptors has caused adverse reproductive and developmental affects in humans, wildlife, and laboratory animals. (National Research Council 1999)

Unknown health effects may also occur when individuals are exposed to a mixture of compounds. Although the concentrations of most individual compounds are very low, it is unknown if the presence of numerous pharmaceuticals sharing a specific effect could lead to compounded health effects. (Daughton and Ternes 1999) In streams, as many as 38 different organic wastewater compounds have been found in a single water sample. (Kolpin, D. et al. 2002)

The risk to aquatic life of long-term exposure to very low concentrations of PPCPs is essentially unknown, but research is continuing in this area. (USEPA 2002b; Petrovic, M. et al. 2002) Some scientists speculate the possibility of subtle undetected effects over many generations leading to significant changes to the ecosystem. (USEPA 2002b; Dietrich et al. 2002; Seiler 2002) Exposure to very low levels (<0.001 g/L) of some hormones can have negative effects on aquatic organisms. (Kolpin, D. et al. 2002)

Occurrence

In 1999 to 2000, the U.S. Geological Survey (USGS) studied occurrence of 95 organic wastewater contaminants, including pharmaceuticals, personal care products, and other extensively used chemicals, such as detergent metabolites and insecticides. The study sampled 139 streams suspected to contain chemicals in 30 states. One or more compounds were found in 80 percent of the streams; about one-third of the streams had 10 or more chemicals. Generally, the concentrations were less than 1 g/L. Many different chemicals in low concentrations commonly occurred downstream from areas of high urbanization and animal production in residential, industrial, and agricultural wastewaters. Although individual compounds were generally detected at low levels, total concentration of all organic wastewater contaminants in a single sample often exceeded 1 g/L. (Buxton and Kolpin 2002; Kolpin, D. et al. 2002)

So far, drinking water contamination does not appear to be problematic. Few pharmaceuticals have been found in drinking water, and concentrations are low. In German studies, most drinking water samples did not contain pharmaceuticals, but several were found in concentrations up to 270 ng/L. (Daughton and Ternes 1999)

Recent occurrence studies in 11 countries and the U.S. detected more than 80 pharmaceuticals and metabolites at up to the g/L level in sewage, surface, and ground water. Only a few drinking water samples have contained pharmaceuticals at trace levels. (Heberer 2002)

A large number of pharmaceuticals are found in wastewater, usually at very low concentrations (below 1 g/L). Many of these compounds are not removed by secondary wastewater treatment. This is a particular concern if drinking-water sources include a substantial fraction of treated wastewater effluent. (Daughton and Ternes 1999; Sedlak 1999; Petrovic, M. et al. 2002) Also, PPCP residues may leach into groundwater during recharge and from landfills. (Heberer 2002; Drewes et. al 2002)

Some pharmaceuticals persist in the environment and may also be mobile. However, even if the compounds break down, they are continually introduced into the environment, and the effect is as if they are persistent. (USEPA 2002b) A recent study of selected pharmaceuticals found that biodegradation appears to be low, and that the compounds were relatively persistent. (Ternes et al. 2002) Pharmaceuticals are considered to be resistant to biodegradation. (Dietrich et al. 2002) Pharmaceutical metabolites have been found in water, and further study is needed. (Kolpin, D. et al. 2002)

Research is continuing on PPCP occurrence. (Bruchet et al. 2002; Heberer Th. et al. 2002; Drewes J. E. et al. 2002; Erickson 2002) Data on new USGS studies of occurrence in groundwater and in sources of drinking water should be available in early 2003. (Kolpin 2002)

Treatment

Treatment information is limited in the public literature. Treatment is specific to the compound being removed. Most pharmaceuticals are very water soluble. (Daughton and Ternes 1999) For the many pharmaceuticals that are synthetic organic compounds (SOCs), granular activated carbon (GAC), powdered activated carbon (PAC), reverse osmosis, and nanofiltration are likely to be effective.

In 2002, a German study of drinking-water treatment processes that effectively remove low levels of selected pharmaceuticals found that flocculation with iron (III) chloride and slow-sand filtration were ineffective. In some cases, ozonation and filtration with GAC were very effective. Advanced oxidation processes and reverse osmosis have been shown to be effective for certain compounds. (Ternes et al. 2002) In other studies, ozonation and membrane filtration were found to be effective. (Heberer 2002)

Advanced treatment technologies, such as reverse osmosis, may be required to completely remove pharmaceuticals from wastewater. Research is continuing on effective wastewater treatment. (Drewes J. E. et al. 2002)

Regulation

USEPA has not set a national primary drinking water regulation (NPDWR) for PPCPs. USEPA believes there is not sufficient information to warrant regulation of PPCPs at this time. (USEPA 2002b) Other countries are considering how pharmaceuticals might be regulated. (Lange and Dietrich 2002)

Under the National Environmental Policy Act of 1969, the U.S. Food and Drug Administration (FDA) requires Environmental Assessments on the impact of individual pharmaceuticals on the environment. (Daughton and Ternes 1999)

USEPA does not require routine monitoring for PPCPs at this time. USEPA has not included contaminants on the Drinking Water Contaminant Candidate List (DWCCL) solely on the possibility of their endocrine disruption potential. But, USEPA may add certain representative PPCPs to the DWCCL and Unregulated Contaminants Monitoring Rule (UCMR) in the future. (USEPA 2002b)

There is no single analytical method to detect all pharmaceuticals. In order to detect most pharmaceuticals at very low concentrations, sophisticated analytical research methods with very low detection limits are necessary. The special analytical equipment needed for testing water samples for pharmaceuticals is only found in certain analytical research laboratories, or certain commercial laboratories that also specialize in methods research.

Some commercial laboratories can analyze for a limited number of pharmaceuticals. Currently, the test method used is specific to the compound that is being looked for (analyte). Certain PPCPs can be detected with USEPA methods; for example, a screen for 30 to 40 semi-volatile synthetic organic compounds, including caffeine, can be detected with USEPA method 525.2. This screen costs approximately $300 per sample at a certified laboratory. (MWH Laboratories 2002)

References

Bruchet, A., C. Prompsy, G. Filippi, and A. Souali. 2002. A Broad Spectrum Analytical Scheme for the Screening of Endocrine Disruptors, Pharmaceuticals, and Personal Care Products in Wastewaters and Natural Waters. Water Science and Technology. 46:3:97-104.

Buxton, H. T. and D. W. Kolpin. 2002. Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. Streams. Fact Sheet FS-027-02. USGS.

Daughton, C. G. and T. A. Ternes. 1999. Pharmaceuticals and Personal Care Products in the Environment: Agents of Subtle Change? Environmental Health Perspectives. 107:6:907-938.

Dietrich, D., S. Webb, and T. Petry. 2002. Hot Spot Pollutants: Pharmaceuticals in the Environment. Elsevier Toxicology Letters. 131:1-3.

Drewes, J.E., T. Heberer, and K. Reddersen. 2002. Fate of Pharmaceuticals During Indirect Potable Reuse. Water Science and Technology. 46:3:73-80.

Erickson, B. E. 2002. Analyzing the Ignored Environmental Contaminants. Environmental Science and Technology. April 1, 2002. pg. 140A-145A.

Foster, W., C. Hughes, S. Chan, and L. Platt. 2002. Human Developmental Exposure To Endocrine Active Compounds. Elsevier Environmental Toxicology and Pharmacology. 12:75-81.

Heberer, T. 2002. Occurrence, Fate, and Removal of Pharmaceutical Residues in the Aquatic Environment: A Review of Recent Research Data. Elsevier Toxicology Letters. 131:5-17.

Heberer, Th., K. Reddersen, and A. Mechlinski. 2002. From Municipal Sewage to Drinking Water: Fate and Removal of Pharmaceutical Residues in the Aquatic Environment in Urban Areas. Water Science and Technology. 46:3:81-88.

Kolpin, D. et al. 2002. Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. Streams, 1999-2000: A National Reconnaissance. Environmental Science & Technology. 36:6:1202-1211.

Kolpin, D. (USGS project coordinator for the national effort on emerging contaminants). 2002. Telephone interview. Iowa City, Iowa.

Koschorreck, J., C. Koch, and I. Ronnefahrt. 2002. Environmental Risk Assessment of Veterinary Medicinal Products in the EU--A Regulatory Perspective. Elsevier Toxicology Letters. 131:117-124.

Lange, R. and D. Dietrich. 2002. Environmental Risk Assessment of Pharmaceutical Drug Substances--Conceptual Considerations. Elsevier Toxicology Letters. 131:97-104.

Montgomery Watson Harza Laboratories. 2002. Telephone interview. Pasadena, California.

Petrovic, M., M. Sole, M. Lopez de Alda, and D. Barcelo. 2002. Endocrine Disruptors in Sewage Treatment Plants, Receiving River Waters, and Sediments: Integration of Chemical Analysis and Biological Effects on Feral Carp. Environmental Toxicology and Chemistry. 21:10:2146-2156.

Pontius, F. 2001. A Balanced Approach to Regulating Endocrine Disrupting Chemicals in Drinking Water. Inside EPARisk Policy Report. October 15. pg. 32-35.

Sedlak, David L. 1999. Pharmaceutically Active Compounds in the Aquatic Environment and Their Relationship to Water Reuse. Presented at the 9th Biennial Symposium on the Artificial Recharge of Groundwater, Tempe: Arizona. June 10-12.

Seiler, J. 2002. Pharmacodynamic Activity of Drugs and Ecotoxicology—Can the Two be Connected? Elsevier Toxicology Letters. 131:105-115.

Symons, J. et al. 2000. The Drinking Water Dictionary. Denver: AWWA.

Ternes T. A. et al. 2002. Removal of Pharmaceuticals During Drinking Water Treatment. Environmental Science & Technology. 36:17:3855-3863.

USEPA. 2002. Analytical Environmental Chemistry: Identification of Pollutant Unknowns by High Resolution Mass Spectrometry. USEPA National Exposure Research Laboratory Environmental Sciences. /

USEPA. 2002. Frequently Asked Questions: PPCPs as Environmental Pollutants. USEPA web site /

USEPA. 2002. Ion Composition Elucidation (ICE)- A New Approach to High-Resolution Mass Spectrometry for Pollutant Identification. USEPA National Exposure Research Laboratory Environmental Sciences. /

USEPA. 2002. PPCPs and One Approach of EPA/ORD’s to “Emerging” Sciences Issues. USEPA National Exposure Research Laboratory Environmental Sciences. /

WHO. 2002. Drug Resistance Threatens to Reverse Medical Progress. Press release at WHO web site /

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