Approaches to the Development of Human Health Toxicity Values for Active Pharmaceutical Ingredients in the Environment

AAPS Journal

Volumn 18, Issue 1, 2016, Pages 92-101

  Sorell, Tamara L ^a  

^a BROWN AND CALDWELL   (United States)

Author keywords

API; human health; PPCPs; toxicity values

Indexed keywords

ACTIVE PHARMACEUTICAL INGREDIENT; CAFFEINE; CHEMICAL COMPOUND; CHLORPROMAZINE; PARACETAMOL; UNCLASSIFIED DRUG; DRUG; DRUG RESIDUE; POLLUTANT;

ARTICLE; CHEMICAL STRUCTURE; ENVIRONMENT; HUMAN; HUMAN HEALTH TOXICITY VALUE; LOWEST ADVERSE EFFECT LEVEL; NO OBSERVED ADVERSE EFFECT LEVEL; NONHUMAN; POINT OF DEPARTURE; REFERENCE VALUE; RISK ASSESSMENT; THRESHOLD OF TOXICOLOGICAL CONCERN; TOXICITY; TOXICOLOGICAL PARAMETERS; UNCERTAINTY; ANIMAL; HEALTH; POLLUTANT; PROCEDURES; STANDARD; TOXICITY TESTING;

ANIMALS; DRUG RESIDUES; ENVIRONMENTAL POLLUTANTS; HEALTH; HUMANS; PHARMACEUTICAL PREPARATIONS; REFERENCE STANDARDS; RISK ASSESSMENT; TOXICITY TESTS;

EID: 84952979566     PISSN: None     EISSN: 15507416     Source Type: Journal    
DOI: 10.1208/s12248-015-9818-5     Document Type: Article

References (77)

1. Daughton CG, Ternes TA. Pharmaceuticals and personal care products in the environment: agents of subtle change? Environ Health Perspect. 1999;107(6):907–38.
2. Alder AW, Kimmel TA, Sussman RG. Applying health-based risk assessments to worker and product safety for potent pharmaceuticals in contract manufacturing operations. Pharm Outsourcing. 2009;10:49–53.
3. Barnes KK, Kolpin DW, Meyer MT, Thurman EM, Furlong ET, Zaugg SD, et al. Water-quality data for pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999–2000. Iowa City: U.S. Geological Survey (USGS); 2002. Open-File Report 02–94.
4. Barnes KK, Kolpin DW, Furlong ET, Zaugg SD, Meyer MT, Barber LB. A national reconnaissance of pharmaceuticals and other organic wastewater contaminants in the United States—I groundwater. Sci Total Environ. 2008;402:192–200. doi:10.1016/j.scitotenv.2008.04.028.
5. 2010 Occurrence of pharmaceutical and personal care products (PPCPs) in source water of the New York City water supply, pp. 24. New York (NY): New York City Department of Environmental Protection: 2011.
6. Pharmaceuticals in the Environment. Global occurrence, effects, and options for action. Germany. Umwelt Bundesamt. Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety. Workshop Documentation. Geneva, Switzerland; 2014 April 8-9. 13 p. Available at: http://www.pharmaceuticals-in-the-environment.org/files/en/bereich_2/application/pdf/workshop_documentation_global-relevance-of-pharmaceuticals-in-the-environment.pdf.
7. Ebert I, Silke H, Küster A, Kock-Jugl J, Weber FA, Bergmann A. Environmental relevance of pharmaceuticals: the global perspective. Nashville: Presented at: 34th Annual Meeting SETAC North America; 2013.
8. Daughton CG, Scuderi MST. Pharmaceuticals and personal care products (PPCPs): relevant literature [Internet]. 2008 [updated 2014 Oct 24; cited 2014 Nov 1]. U.S. Environmental Protection Agency, Las Vegas, NV. 2014. Available from: http://www.epa.gov/ppcp/lit.html.
9. U.S. Environmental Protection Agency, U.S. Department of Agriculture, U.S. Department of Health and Human Services, and U.S. Department of Interior. Memorandum of understanding on sustainability of federal collaboration on pharmaceuticals in drinking water; 2012.
10. Daughton, CG. Origins and fate of PPCPs in the environment [image on the Internet]. 2001 [updated 2001 Feb; cited 2014 Nov 1]. U.S. Environmental Protection Agency, Las Vegas (NV). Available from: http://www.epa.gov/ppcp/pdf/drawing.pdf.
11. Anderson PD, D’Aco VJ, Shanahan P, Chapra SC, Buzby ME, Cunningham VL, et al. Screening analysis of human pharmaceutical compounds in U.S. surface waters. Environ Sci Technol. 2004;38:838–49.
12. Jelić A, Gros M, Ginebreda A, Cespedes-Sánchez R, Ventura F, Petrovic M, et al. Occurrence, partition and removal of pharmaceuticals in sewage water and sludge during wastewater treatment. Water Res. 2011;45:1165–76. doi:10.1016/j.watres.2010.11.010.
13. Daughton CG. Cradle-to-cradle stewardship of drugs for minimizing their environmental disposition while promoting human health. I. Rationale for and avenues toward a green pharmacy. Environ Health Perspect. 2003;111:757–74. doi:10.1289/ehp.5947.
14. Daughton CG. Eco-directed sustainable prescribing: feasibility for reducing water contamination by drugs. Sci Total Environ. 2014;493:392–404. doi:10.1016/j.scitotenv.2014.06.013.
15. Lubliner, B, Redding, M, Ragsdale, D. Pharmaceuticals and personal care products in municipal wastewater and their removal by nutrient treatment technologies. Olympia (WA): Washington State Department of Ecology; 2010, 230 p. Publication Number.: 10-03-004. Available from: www.ecy.wa.gov/biblio/1003004.html.
16. Environmental Services. Environmental fact sheet. Available from: http://des.nh.gov/organization/commissioner/pip/factsheets/wwt/documents/web-9.pdf.
17. FAQs about PPCPs: Montana focus [fact sheet]. Montana Department of Environmental Quality; 2008 Aug 8. Available from: http://deq.mt.gov/wqinfo/swp/Guidance/PPCPs_final_Aug’08%20_2_.pdf.
18. Australian guidelines for water recycling: managing health and environmental risks (phase 2). Augmentation of drinking water supplies. Environment Protection and Heritage Council. Health and Medical Research Council. Natural Resource Management Ministerial Council; 2008.
19. Moermond CTA. Derivation of WFD water quality standards for carbamazepine, metoprolol, metformin and amidotrizoic acid. The Netherlands: National Institute for Public Health and the Environment; 2014, RIVM Letter Report 270006002, 54 p. Available from: http://www.rivm.nl/en/Documents_and_publications/Scientific/Reports/2014/juli/Environmental_risk_limits_for_pharmaceuticals_Derivation_of_WFD_water_quality_standards_for_carbamazepine_metoprolol_metformin_and_amidotrizoic_acid.
20. Fact sheet: frequently asked questions on pharmaceutical & personal care products (PPCPs). New York City Department of Environmental Protection. New York (NY); [2014; cited 2014 Nov 1]. Available from: http://www.nyc.gov/html/dep/html/drinking_water/ws_ppcp_faq.shtml#Q6.
21. Fact sheet: final third drinking water contaminant candidate list (CCL 3). U.S. Environmental Protection Agency; [2009; cited 2014 Nov 1]. Available from: http://water.epa.gov/scitech/drinkingwater/dws/ccl/upload/fs_cc3_final.pdf (fact sheet).
22. Drinking water contaminant candidate list 3—final. Fed Regist. 2009 Sep 21;74:51850–51862. Available from: https://www.federalregister.gov/articles/2009/10/08/E9-24287/drinking-water-contaminant-candidate-list-3-final.
23. Draft CCL 4 Chemical contaminants. http://www2.epa.gov/ccl/chemical-contaminants-ccl-4.
24. Human health benchmarks for pesticides. U.S. Environmental Protection Agency; accessed 15 Feb 2015. Available from: http://iaspub.epa.gov/apex/pesticides/f?p=HHBP:home.
25. European Parliament. Surface waters: 12 new controlled chemicals, three pharmaceuticals on watch list; 2013. Available from: http://www.europarl.europa.eu/news/en/pressroom/content/20130701IPR14760/.
26. Reference dose (RfD): description and use in health risk assessments. Background Document 1A. U.S. Environmental Protection Agency; 15 Mar 1993. Available from: http://www.epa.gov/iris/rfd.htm.
27. Cunningham VL, Binks SP, Olson MJ. Human health risk assessment from the presence of human pharmaceuticals in the aquatic environment. Regul Toxicol Pharmacol. 2009;53:39–45. doi:10.1016/j.yrtph.2008.10.006.
28. Cunningham VL, Perino C, D’Aco VJ, Hartmann A, Bechter B. Human health risk assessment of carbamazepine in surface waters of North America and Europe. Regul Toxicol Pharmacol. 2010;56:343–51. doi:10.1016/j.yrtph.2009.10.006.
29. Sanderson H. Presence and risk assessment of pharmaceuticals in surface water and drinking water. Water Sci Technol. 2011;63:2143–8. doi:10.2166/wst.2011.341.
30. Schwab BW, Hayes EP, Friori JM, Mastrocco FJ, Roden NM, Cragin D. Human pharmaceuticals in US surface waters: a human health risk assessment. Regul Toxicol Pharmacol. 2005;42:296–312. doi:10.1016/j.yrtph.2005.05.005.
31. Barlow S. Threshold of toxicological concern (TTC). A tool for assessing substances of unknown toxicity present at low levels in the diet. Washington: International Life Sciences Institute; 2005. 37 p.
32. Renwick AG. Structure-based thresholds of toxicological concern—guidance for application to substances present at low levels in the diet. Toxicol Appl Pharmacol. 2005;207:S585–91. doi:10.1016/j.taap.2005.01.034.
33. Mons MN, Heringa MB, van Genderen J, Puijker LM, Brand W, van Leeuwen CJ, et al. Use of the threshold of toxicological concern (TTC) approach for deriving target values for drinking water contaminants. Water Res. 2013;47:1666–78. doi:10.1016/j.watres.2012.12.025.
34. Melching-Kollmuß S, Dekant W, Kalberlah F. Application of the “threshold of toxicological concern” to derive tolerable concentrations of “non-relevant metabolites” formed from plant protection products in ground and drinking water. Regul Toxicol Pharmacol. 2010;56:126–34. doi:10.1016/j.yrtph.2009.09.011.
35. Food additives; threshold of regulation for substances used in food-contact articles. Fed Regist. 1995;60:36582–36596.
36. Cheeseman MA, Machuga EJ, Bailey AB. A tiered approach to threshold of regulation. Food Chem Toxicol. 1999;37:387–412.
37. Cramer GM, Ford RA, Hall RL. Estimation of toxic hazard—a decision tree approach. Food Cosmet Toxicol. 1978;16:255–76.
38. Stevens JP. Drinking water contaminants of emerging concern program, Special project: evaluating, testing, and reporting of alternative risk assessment methods. Selection, evaluation and recommendations of viable alternative risk assessment methods for the development of drinking water guidance values. St. Paul: Minnesota Department of Health. Contaminants of Emerging Concern (CEC) Program. Environmental Health Division; 2012.
39. Greenlaw, E. OTC pain relief: understanding acetaminophen [internet]. 2010 [cited 2014 Nov 01]. Available from: http://www.webmd.com/drug-medication/otc-pain-relief-10/pain-relievers-acetaminophen.
40. American Medical Association. Module 6 pain management. Pediatric pain management. Continuing medical education [Internet]. June 2013 [cited 2014 Nov 1]. Available from: http://ama-cmeonline.com/pain_mgmt/module06_2012/.
41. James L, Sullivan JE, Roberts D. The proper use of acetaminophen. Paediatr Child Health. 2011;16:544-547. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223888/.
42. Adams, CE, Awad, GA, Rathbone, J, Thornley, B, Soares-Weiser, K. Chlorpromazine versus placebo for schizophrenia (review). In: The Cochrane Library, Issue 1.John Wiley & Sons, Ltd; 2014.
43. Glaser EM, Newling PSB. Side effects of chlorpromazine hydrochloride. Br J Pharmacol. 1955;10:429–33.
44. Keast RSJ, Riddell LJ, Hall RL. Caffeine as a flavor additive in soft-drinks. Appetite. 2007;49:255–9. doi:10.1016/j.appet.2006.11.003.
45. Acetaminophen [professional product information]. McNeil Consumer Healthcare; 2010.
46. Kolpin DW, Furlong ET, Meyer MT, Thurman EM, Zaugg SD, Barber LB, et al. Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999–2000: a national reconnaissance. Environ Sci Technol. 2002;36:1202–11. doi:10.1021/es011055j.
47. Lin AY, Tsai Y. Occurrence of pharmaceuticals in Taiwan’s surface waters: impact of waste streams from hospitals and pharmaceutical production facilities. 2009; 407:3793–3802. doi: 10.1016/j.scitotenv.2009.03.009.
48. Toxicological summary for: acetaminophen. Minnesota Department of Health. St. Paul; 2014 Aug. 16 p. Available from: www.health.state.mn.us/divs/eh/risk/guidance/dwec/sumacetamin.pdf.
49. Kroes R, Kleiner J, Renwick A. The threshold of toxicological concern concept in risk assessment. Toxicol Sci. 2005;86:226–30. doi:10.1093/toxsci/kfi169.
50. Ebert I, Hein A. Pharmaceuticals in the environment—a first compilation of German monitoring data, 8 p. Federal Environment Agency; 2013.
51. Nawrot P, Jordan S, Eastwood J, Rotstein J, Hugenholtz A, Feeley M. Effects of caffeine on human health. Food Addit Contam. 2003;20:1–30. doi:10.1080/0265203021000007840.
52. Gardinali PR, Zhao X. Trace determination of caffeine in surface water samples by liquid chromatography–atmospheric pressure chemical ionization–mass spectrometry (LC–APCI–MS). Environ Int. 2002;28:521–8.
53. Pettenuzzo LF, Noschang C, Toigo EV, Fachin A, Vendite E, Dalmaz C. Effects of chronic administration of caffeine and stress on feeding behavior of rats. Physiol Behav. 2008;95:295–301. doi:10.1016/j.physbeh.2008.06.003.
54. Regional screening levels. US Environmental Protection Agency, Office of Research and Development [Internet]. [updated 2014 May; cited 2014 Oct 31]. Available from: http://www.epa.gov/reg3hwmd/risk/human/rb-concentration_table/Generic_Tables/index.htm.
55. The European Agency for the evaluation of medicinal products. Paracetamol. Summary Report;. Committee for Veterinary Medicinal Products; 1999 Feb. EMEA MRL/551/99-FINAL.
56. Kochanowski B. Acetaminophen OTC dosing for children. Consumer Health Products Association [slides]. 2011.
57. Lapenna S, Worth A. Analysis of the Cramer classification scheme for oral systemic toxicity—implications for its implementation in Toxtree. European Union. European Commission Joint Research Centre Institute for Health and Consumer Protection. 2011 EUR 24898 EN – 2011. Available from: http://www.jrc.ec.europa.eu/ laboratories-research/predictive_toxicology/doc/EUR_24898_EN.pdf. 39 p.
58. Chlorpromazine (PIM 125). [Internet]. International Programme on Chemical Safety. Cited 2014 Oct 12. Available from: http://www.inchem.org/documents/pims/pharm/chlorpro.htm#SectionTitle:2.1 Main risks and target organs.
59. Blanchet PJ, Parent MT, Rompré PH, Lévesque D. Relevance of animal models to human tardive dyskinesia. Behav Brain Funct. 2012;8:12. doi:10.1186/1744-9081-8-12.
60. Chlorpromazine. Summary report. Committee for Veterinary Medicinal Products. The European Agency for the Evaluation of Medicinal Products. 1996; EMEA MRL/111/96-FINAL.
61. Thorazine (chlorpromazine) drug information: warnings and precautions—prescribing information at RxList. [homepage on the Internet]. [updated 2014; cited 2014 Oct 12]. Available from: http://www.rxlist.com/thorazine-drug/warnings-precautions.html.
62. Migraines & Headaches Health Center. [Internet] [updated 2014; cited 2014 Oct 31] Available from: http://www.webmd.com/migraines-headaches/guide/triggers-caffeine.
63. Somogyi LP. Caffeine intake by the U.S. population. Prepared for The Food and Drug Administration and Oakridge National Laboratory, 90 p. 2010.
64. Furlong ET, Noriega M, Kanagy L, Coffey LJ, Burkhardt MR. Determination of human-use pharmaceuticals in filtered water by direct aqueous injection-high-performance liquid chromatography/tandem mass spectrometry: U.S. Geological Survey techniques and methods, book 5, chap. B10, 49 p. 2014. doi.org/10.3133/tm5B10.
65. Jacobs EJ, Newton CC, Stevens VL, Gapstur SM. A large cohort study of long-term acetaminophen use and prostate cancer incidence. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res. 2011;7:1322–8. doi:10.1158/1055-9965.EPI-11-0210.
66. Vila-Luna S, Cabrera-Isidoro S, Vila-Luna L, Juárez-Díaz I, Bata-García JL, Alvarez-Cervera FJ, et al. Chronic caffeine consumption prevents cognitive decline from young to middle age in rats, and is associated with increased length, branching, and spine density of basal dendrites in ca1 hippocampal neurons. Neuroscience. 2012;202:384–95. doi:10.1016/j.neuroscience.2011.11.053.
67. Verherk RHJ. The paradox of overlapping micronutrient risks and benefits obligates risk/benefit analysis. Toxicology. 2010;278:27–38. doi:10.1016/j.tox.2010.02.011.
68. Fourth national report on human exposure to environmental chemicals. Atlanta: Centers for Disease Control and Prevention; 2009.
69. Boxall ABA, Rudd MA, Brooks BW, Caldwell DJ, Choi K, Hickmann S, et al. Pharmaceuticals and personal care products in the environment: what are the big questions? Environ Health Perspect. 2012. doi:10.1289/ehp.1104477.
70. Sandman PM. Responding to community outrage: strategies for effective risk communication. American Industrial Hygiene Association; 2012. Available from: http://psandman.com/media/RespondingtoCommunityOutrage.pdf.
71. Jones-Lepp TL, Stevens R. Pharmaceuticals and personal care products in biosolids/sewage sludge—the interface between analytical chemistry and regulation. Las Vegas, NV: US Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Washington, DC: Office of Water, Office of Science and Technology, 2006. doi 10.1007/s00216-006-0942-z.
72. −6 as a definition of acceptable risk. Vancouver: Proceedings of the 84th Annual Meeting Air & Waste Management Association; 1991.
73. Superfund public health evaluation manual. Washington, DC: US Environmental Protection Agency, Office of Emergency and Remedial Response; 1984. EPA 540/1-86/060. OSWER Directive 9285–4.1.
74. Risk assessment guidance for superfund. Human Health Evaluation Manual 1989 et seq., Volume I. Washington, DC: US Environmental Protection Agency, Office of Emergency and Remedial Response; 1984. EPA 540/1-89/002.
75. Wambaugh JF, Setzer RW, Reif DM, Gangwal S, Mitchell-Blackwood J, Arnot JA, et al. High-throughput models for exposure-based chemical prioritization in the ExpoCast project. Environ Sci Technol. 2013;47:8479–88. doi:10.1021/es400482g.
76. Dorne JLCM, Walton K, Renwick AG. Human variability in xenobiotic metabolism and pathway-related uncertainly factors for chemical risk assessment and review. Food Chem Toxicol. 2005;43:203–16. doi:10.1016/j.fct.2004.05.011.
77. Khan, Nicell. Human health relevance of pharmaceutically active compounds in drinking water. In: PhACs in the environment: sources, risks, trade-offs and sewer epidemiology. 2014. Submitted for publication.