Effects of Pharmaceuticals in the Canadian Environment Joanne Parrott, Science and Technology Branch, Environment Canada, 867 Lakeshore Road, Burlington, Ontario L7R 4A6 Why Worry about Pharmaceuticals? Pharmaceuticals are designed to have a therapeutic (=biological) effect Effects on non-target organisms are mostly unknown Aquatic organisms are chronically exposed Potential for multigenerational exposure Little known about environmental persistence, fate 2, Monday 5OCT29, J Parrott, Environment Canada 1
Pharmaceuticals and Personal Care Products (PPCPs) in Municipal Wastewater Effluents - Thames River, ON ng/l 3, 2,5 2, 1,5 1, 5 MAX Mean Painkillers NSAIDS Lishman et al 26 Sci Tot Environ Chol Hormones Naproxen Ibuprofen Dicolfenac Indomethacin Ketoprofen Salicylic Acid Gemfibrozil Estradiol Estrone Triclosan Galaxolide Tonalide Compound Antibacterial Musk fragrances Personal Care Products Pharmaceuticals to Examine Effects in lab organisms at low concentrations (low ug/l or below) compare to levels in municipal wastewater effluents (MWWEs) and Great Lakes rivers and waters anti-inflammatory - Diclofenac antidepressants - Fluoxetine, Fluvoxamine synthetic hormone - Ethinylestradiol complex effluent mixtures - MWWEs 2, Monday 5OCT29, J Parrott, Environment Canada 2
Non-steroidal, Anti-inflammatory drug (NSAID) Diclofenac Expose trout for 28 d to 1 ug/l - examine tissues for changes control Liver - Hepatocytes - solvent control rainbow trout round nuclei (n) regularly arranged ER (er) glycogen storage areas (g) (magnification: 42 ). 1 ug/l diclofenac Liver of a fish exposed to 1 ug/l diclofenac for 28 days. compartmentation changed glycogen areas depleted Triebskorn R, et al. 24. Aquatic Toxicology 68:151 166. 2, Monday 5OCT29, J Parrott, Environment Canada 3
Diclofenac Non-steroidal, Antiinflammatory drug (NSAID) 5 ng/l gill changes, 1 ug/l liver changes, rainbow trout ng/l ug/l 5-15 ng/l, rivers (Metcalfe et al, 23) 215 ng/l, MWWE, summer (Lishman et al, 25) 36 ng/l, max MWWE (Metcalfe et al, 23) 43 ng/l, MWWE, fall (Lishman et al, 25) mean NSAIDs = 1.45 ug/l (Thames R, Lishman et al 26) MAX at one of 12 plants Thames R, 94 ng/l Diclofenac Selective serotonin reuptake inhibitors, SSRIs Fluoxetine (Prozac ) Antidepressant, anti-anxiety drug 2, Monday 5OCT29, J Parrott, Environment Canada 4
Antidepressants in MWWE on Grand R., ON (Metcalfe et al., ET&C in Press 29) Different antidepressants inhibit reuptake of different neurotransmitters: serotonin, dopamine and norepinephrine 1 SN S SDN S S µg/l 1.1.1 Venlafaxine Effexor Citalopram Celexa Bupropion Wellbutrin Fluoxetine Prozac Sertraline Zoloft Antidepressants Sum of all MWWE antidepressants Humans serotonin regulates appetite, sleep, arousal, and mood. Bivalve mollusks - serotonin regulates reproductive processes such as spawning, oocyte maturation and parturition. 2, Monday 5OCT29, J Parrott, Environment Canada 5
% Parturition (release of young) in fingernail clams exposed to fluvoxamine for 4 hours (Fong et al 1998) % Parturition 1 8 6 4 2 control clams * * * * 3 ug/l All significant, p<.1.1.1 1 1 1 1, 1, 1, Fluvoxamine (ug/l) Fluoxetine exposure delayed maturation in female medaka (from Henry et al, 24) Fish with black spot (%) 35 3 25 2 15 1 5 Fluoxetine exposure started 3 4 5 6 7 8 9 Fish age (days) 6 ug/l 6 ug/l 2, Monday 5OCT29, J Parrott, Environment Canada 6
Fluoxetine Antidepressant, anti-anxiety drug 3 ug/l Fluvoxamine, clam spawning 6-6 ug/l, medaka maturation ng/l ug/l 45 ng/l, rivers d/s (Metcalfe et al 3) 1 ng/l, MWWE (Metcalfe et al 3) 3.2 ug/l, sum SSRI antidepressants in MWWE (Metcalfe et al 7) EE2 Ethinylestradiol Synthetic estrogen in birth control pills 2, Monday 5OCT29, J Parrott, Environment Canada 7
eggs survival, % hatch fry Fathead minnow lifecycle exposure sampling times and endpoints survival, length, weight 3 and 6 days post-hatch juveniles survival, length, weight, abnormalities adult fathead minnows 16 days-post-hatch 2 o sex characteristics length, weight, liver weight, gonad weight egg prod, fertilization, % hatch % male adults 7 6 5 4 3 2 1 Percent male fathead minnows at maturity Fewer male fish * * Male Female No male fish water eth.32 1. 3.5 9.6 23 Controls EE2 (ng/l) 2, Monday 5OCT29, J Parrott, Environment Canada 8
Reduced egg fertilization success Eggs Fertilized (%) 1 8 6 4 2 p=.25 * p<.1 * water eth.32 1. Controls EE2 (ng/l) no eggs, no males Ethinylestradiol Synthetic estrogen in birth control pills EE2 effects on egg fertilization at.32 to 1 ng/l (Parrott & Blunt, 25) EE2 effects on fish populations 5-6 ng/l (Kidd et al 7) ng/l ug/l < 1 ng/l (Lee et al 4) 4 of 7 US streams, > 5 ng/l (Kolpin et al 2) avg 9 ng/l (Ternes et al 99) EE2 12 Kg/yr Canada = MWWE ~.2 ng/l 2, Monday 5OCT29, J Parrott, Environment Canada 9
What s in a Municipal Wastewater Effluent (MWWE)? Nutrients (N, P), metals, oils, Trace levels of SOME. Natural/synthetic hormones, household chemicals, pharmaceutical drugs, personal care products Western tip of Lake Ontario City of Hamilton (.5 million people) Lake Ontario 2 km Municipal Wastewater Effluent (MWWE) 2, Monday 5OCT29, J Parrott, Environment Canada 1
Egg Production in Fathead Minnows Exposed to MWWE for a Lifecycle Egg Production 16, 14, Lab control water 12, 1% H MWWE 1, 1% H MWWE 8, 6, 4, 2, Per 12-13 females 9 1 11 12 13 14 15 16 Days post-hatch White sucker collected downstream of MWWE, Boulder, Colorado MWWE is 1 % to 75 % of stream flow High EE2, natural estrogens, bisphenol A, nonylphenols Fewer males downstream of MWWE Vajda et al 28, ES&T Intersex Males downstream of MWWE 2, Monday 5OCT29, J Parrott, Environment Canada 11
Conclusions Some PPCPs appear to cause effects in lab organisms at concns of low ng/l to low ug/l. Some MWWEs in Great Lakes discharge PPCP concentrations in these ranges. Thresholds for effects of synthetic estrogens very low (ng/l). Other PPCPs higher thresholds (ug/l and above). Some evidence of effects with lab fish and wild fish exposure to MWWE. What we don t know Which compounds should we monitor in MWWEs and rivers? Are there widespread effects in wild fish, frogs, turtles, etc. in Canadian Rivers? Are we looking at the right biological endpoints? 2, Monday 5OCT29, J Parrott, Environment Canada 12
Ethinylestradiol Synthetic estrogen in birth control pills Ministry of the Environment, British Columbia, Canada Proposed draft water quality guideline.5 ng/l Ambient Water Quality Guidelines for the Protection of Pharmaceutically- Active Compounds (PhACs) 17α-Ethinlyestradiol For the protection of freshwater aquatic life, it is recommended that the 3-day average concentration of 17α-ethinylestradiol (EE2) in water, based on 5 weekly samples, should not exceed.5 ng L-1 with no single value to exceed.75 ng L-1 (no more than 5% above the guideline value). Most PPCPs not enough data to set limits or do environmental risk assessment Environmental Assessment Work Group (EAWG) Health Canada, Environment Canada, industry stakeholders, non-government organizations Propose new Environmental Risk Assessment Regulations under Food & Drug Act PPCPs and other compounds Exposure Assessment based on DOSES of pharmaceutical (not AMOUNT produced/imported) Effects Assessment based on longer tests relevant to exposure route and mechanism of action (not short standard tests of fish survival etc.) 2, Monday 5OCT29, J Parrott, Environment Canada 13
Thank You!! 2, Monday 5OCT29, J Parrott, Environment Canada 14