Screening Assessment

Twenty-three Substances on the Domestic Substances List Used Primarily as Pharmaceuticals
Chemical Abstracts Service Registry Numbers

50-06-6 (Phenobarbital), 81-81-2 (Warfarin), 7481-89-2 (Zalcitabine), 50-18-0 (Cyclophosphamide), 126-07-8 (Griseofulvin), 13010-47-4 (Lomustine), 55-86-7 (Mechlorethamine), 148-82-3 (Melphalan), 18883-66-4 (Streptozocin), 55-98-1 (Busulfan), 154-93-8 (Carmustine), 20830-81-3 (Daunorubicin), 56-75-7 (Chloramphenicol), 305-03-3 (Chlorambucil), 29767-20-2 (Teniposide), 57-41-0 (Phenytoin), 443-48-1 (Metronidazole), 30516-87-1 (Zidovudine), 68-22-4 (Norethindrone), 446-86-6 (Azathioprine), 51264-14-3 (Amsacrine), 71-58-9 (Medroxyprogesterone), 604-75-1 (Oxazepam)

Environment Canada
Health Canada
February 2015

(PDF Format - 440 KB)

Table of Contents

• Synopsis
• 1. Introduction
• 2. Summary of Use Information Used as Basis for this Screening Assessment
• 3. Ecological Exposure and Risk Characterization from Industrial Releases and Prescription Use
• 4. Human Health Exposure and Risk Characterization from Indirect Exposure
• 5. Uncertainties
• 6. Proposed Conclusion
• 7. References
• Appendix A: Substance Identity and Human Health and Ecological Classifications for 23 Pharmaceuticals
• Appendix B: Estimated Quantities of 23 Pharmaceuticals Used in Canada for the Years 2007, 2011 and 2012
• Appendix C: Results from Environmental Exposure Modelling for 20 Pharmaceuticals Using Quantity Data from 2012
• Appendix D: Measured Concentrations of 18 Pharmaceuticals in Wastewater Treatment Plant Influent and Effluent, Surface Water, Groundwater and Drinking Water
• Appendix E: Intake Estimates, Lowest Therapeutic Doses and Calculated Margins of Exposure for 18 Pharmaceuticals with Measured Concentrations
• Appendix F: Intake Estimates, Lowest Therapeutic Doses and Calculated Margins of Exposure for Two Substances Based on Modelled Concentrations in Surface Water

Synopsis

Pursuant to section 68 of the Canadian Environmental Protection Act, 1999 (CEPA 1999), the Ministers of the Environment and of Health have conducted a screening assessment of 23 substances on the Domestic Substances List (DSL) that are primarily used as pharmaceuticals. These substances, listed by their Chemical Abstracts Service Registry Numberr^Footnote[1] (CAS RN) in the following table, were grouped together in one screening assessment as they were all identified as priorities for assessment based on classifications by other national or international agencies for carcinogenicity or developmental toxicity. A similar screening assessment approach was therefore applied to all of them.

Drugs containing these substances as ingredients were previously assessed under the Food and Drugs Act (F&DA) with respect to their safety, effectiveness and quality. This assessment focused on uses and exposures that were not covered as part of the F&DA assessment, specifically the risks posed by the residues resulting from manufacture, formulation and disposal after use.

Entry characterization (how the substances are entering the Canadian environment) was conducted by identifying the potential use of these substances outside of their intended pharmaceutical use. With the exception of warfarin, which is also used as a rodenticide, the only other identified use for these substances was as positive controls in research. Quantities in commerce for the consumption of pharmaceutical products that contain these substances have been estimated using information on amounts purchased by hospitals and pharmacies for 2007, 2011 and 2012.

Given that the main releases of these substances to the environment are through either industrial or down-the-drain consumer releases, the principal potential source of exposure is surface water containing these pharmaceuticals.

In order to estimate exposure in the environment, sales volumes were used as an input into modelling for predicted environmental concentrations (PECs). PECs were generated for water as a result of industrial releases and down-the-drain releases from consumer uses. The PECs from both of these scenarios were then compared with the predicted no-effect concentrations (PNECs), which were based on critical toxicity values identified during the DSL categorization process. For all substances, the predicted environmental concentration (PEC) in water was below the PNEC calculated for aquatic species.

Measured concentrations in different media, including drinking water, surface water, groundwater and wastewater treatment plant effluent, were identified in the literature for a subset of these substances, either internationally or in Canada. Where available, the measured concentrations were also compared with the PNEC for each substance; the resulting risk quotients were all less than 1, which supports and generates confidence in the modelling results.

Considering all available lines of evidence presented in this screening assessment, there is low risk of harm to organisms or the broader integrity of the environment from these substances. It is therefore concluded that the 23 substances do not meet the criteria under paragraph 64(a) or 64(b) of CEPA 1999, as they are not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends.

With regard to potential exposure of the general population, upper-bounding estimated intakes from ingestion of drinking water were very low (less than 2.7 ng/kg body weight per day) for all substances. Based on low exposure, risks from exposure to these substances are not expected. To further support this risk characterization, the upper-bounding estimated intakes of the general population were compared with the lowest therapeutic dose identified for each substance. The margins of exposure for these substances were large, ranging from 10 900 to 8 × 1013.

Based on the adequacy of the margins of exposure, it is concluded that the 23 substances do not meet the criteria under paragraph 64(c) of CEPA 1999, as they are not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

Conclusion

It is concluded that these 23 substances do not meet any of the criteria set out in section 64 of CEPA 1999.

1. Introduction

A screening assessment was undertaken on 23 substances on the Domestic Substances List (DSL) that were known or suspected to be used primarily as ingredients in pharmaceuticals and identified during the categorization of substances on the DSL as posing a potential high hazard to human health based on classifications by other national or international agencies for either carcinogenicity or developmental toxicity.

Screening assessments focus on information critical to determining whether a substance meets the criteria as set out in section 64 of the Canadian Environmental Protection Act, 1999 (CEPA 1999) (Canada 1999). Screening assessments examine scientific information and develop conclusions by incorporating a weight of evidence approach and precaution.^Footnote[2]

This screening assessment includes consideration of information on chemical properties, hazards, uses and exposure. Relevant data were identified up to March 2013. Key studies were critically evaluated, along with modelled results, to reach conclusions. When available and relevant, information presented in risk and hazard assessments from other jurisdictions was considered. The screening assessment does not represent an exhaustive or critical review of all available data. Rather, it presents the critical studies and lines of evidence most pertinent to the conclusion.

Drugs containing these substances as ingredients are assessed under the Food and Drugs Act (F&DA) (Canada 1985) with respect to their safety, effectiveness and quality. This assessment focused on uses and exposures that were not covered as part of the F&DA assessment, specifically the risks posed by the residues resulting from manufacture, formulation and disposal after use

The screening assessment was prepared by staff in the Existing Substances Programs at Health Canada and Environment Canada and incorporates input from other programs within these departments. Comments on the approach used to assess the substance with respect to human health were received from Warren Foster, McMaster University, Sam Kacew, McLaughlin Centre for Population Health Risk Assessment, and Beate Escher, University of Queensland. While external comments were taken into consideration, the final content and outcome of the screening assessment remain the responsibility of Health Canada and Environment Canada.

2. Summary of Use Information Used as Basis for this Screening Assessment

Based on the results from categorization of the DSL, the 23 substances listed in this report have all been identified as posing a potential high hazard to human health based on classifications by other national or international agencies for either carcinogenicity or developmental toxicity. The list of substances, along with their hazard classifications and categorization decisions, can be found in Tables A.1, A.2 and A.3 of Appendix A.

For two of these substances, a survey was conducted by issuing a Notice with respect to selected substances identified as priority for action pursuant to paragraphs 71(1)(a) and 71(1)(b) of CEPA 1999. The Notice was published in Part I of the Canada Gazette on March 4, 2006 (Canada 2006). The substances surveyed were medroxyprogesterone and oxazepam.

For five substances, a survey was conducted by issuing a Notice with respect to inanimate substances (chemicals) on the Domestic Substances List pursuant to paragraphs 71(1)(a) and 71(1)(b) of CEPA 1999. The Notice was published in Part I of the Canada Gazette on October 3, 2009 (Canada 2009).The five substances surveyed were zalcitabine, warfarin, chloramphenicol, zidovudine and phenobarbital.

In response to both of these notices, there were no reports of activity (import or manufacture) with respect to these seven substances in Canada above the reporting threshold of 100 kg for the specified reporting years. Additional sources of information were also considered to verify the commercial status of these substances in Canada.

For all 23 substances, entry characterization was conducted by searching for information on sources and releases of the substances in relevant databases, particularly to identify potential for exposure of the general population from sources other than pharmaceutical use (Canada [1978]; HSDB 1983– ; Household Products Database 1993– ; LNHPD 2008; DPD 2010; EAFUS 2011; NHPID 2011). Based on notifications submitted under the Cosmetic Regulations to Health Canada, these substances are not used in cosmetic products in Canada (2012 email from the Consumer Product Safety Directorate, Health Canada, to the Existing Substance Risk Assessment Bureau, Health Canada; unreferenced). Information available for all of these substances indicates that their uses are limited to human or veterinary pharmaceuticals and positive controls in research, with the exception of warfarin, which is also used as a rodenticide. This use of warfarin as a rodenticide is regulated by Health Canada under the Pest Control Products Act (Canada 2002).

Two of these substances, phenobarbital and oxazepam, are considered to be controlled drugs and are listed under Schedule IV of the Controlled Drugs and Substances Act. As controlled substances, these two drugs are subject to the requirements of the Controlled Drugs and Substances Act and the Food and Drug Regulations (Canada [1978]). The remaining 21 substances are regulated as prescription drugs through the Prescription Drugs List and are subject to the requirements of those regulations (Health Canada 2014; Canada [1978]). Twenty of these substances are listed in the Drug Product Database as active ingredients in products available in Canada for the treatment of a variety of medical conditions (DPD 2014). The other three substances, mechlorethamine, griseofulvin and zalcitabine, were at one time used as active ingredients in prescription pharmaceuticals in Canada. Currently, however, no pharmaceutical products containing these substances as active ingredients are being sold in Canada, as they have been discontinued by the company (DPD 2014). As they are no longer being sold, the use and potential for exposure of or risk to humans or the environment are not further considered in certain aspects of the exposure and risk characterization below.

No information was found regarding additional uses or releases of these substances in Canada based on searches conducted up to March 2013.

When a pharmaceutical is prescribed for use, some of the drug may not be absorbed or metabolized, and even drugs that are metabolized may have active metabolites or may revert to the parent form in environmental media. This may lead to excretion of active drug residues into the wastewater system and release of the wastewater effluent containing these residues into surface water (i.e., lakes, rivers), and this surface water has the potential to be used as drinking water. Therefore, the potential for indirect exposure of the general population to these pharmaceuticals was assessed. Given their potential releases, the main source of indirect exposure to these substances is through water. These pharmaceuticals may be present in water as a result of release from manufacturing or formulation sites and/or release of the substances in feces or urine from consumers directly using these substances. An additional source of the pharmaceuticals in water is from the incorrect disposal of unused drugs into household wastewater. No information was available regarding actual releases of these substances from manufacturing or formulation of the pharmaceuticals. Data, however, were available to estimate the amount of each substance sold to hospitals and pharmacies for prescription across Canada for the years 2007 (McLaughlin and Belknap 2008), 2011 and 2012 (MIDAS 2013) (Appendix B).

3. Ecological Exposure and Risk Characterization from Industrial Releases and Prescription Use

A conservative industrial release scenario was used to determine whether there is a potential ecological risk associated with these 20 substances when released to water via industrial releases (as mentioned above, the three substances no longer registered for use as pharmaceuticals in Canada are not being examined further). This is conducted by comparing the conservative predicted environmental concentration (PEC) in the aquatic environment with a predicted no-effect concentration (PNEC). The result is a risk quotient (RQ) based on an industrial non-site-specific scenario. This simple model represents a point source discharge from an industry, its dilution in a small watercourse and calculation of a risk quotient for that scenario.

A conservative PEC was calculated using the following equation:

PEC_aq = (1000 × Q × L) × (1 − R) / (N × F × D)

where:

PEC_aq:

Aquatic concentration resulting from industrial releases (mg/L)

1000:

Conversion factor (g/kg)

Q:

Total substance quantity produced annually at an industrial site (kg/year) (see values for each substance for the most current year, 2012, provided in Appendix B)

L:

Loss to wastewater (fraction) (assumed to be 0.5% of total use for pharmaceuticals)

R:

Wastewater treatment plant removal rate (fraction) (default = 0%)

N:

Number of annual release days (days/year) (assumed to be manufactured in small batches and therefore released 21 days/year)

F:

Wastewater treatment plant effluent flow (m³/day) (default = 3456 m³/day)

D:

Receiving water dilution factor (dimensionless) (default = 10)

This PEC_aq value is then used to calculate a risk quotient, as shown in the following equation:

RQ = PEC_aq / (PNEC)

where:

RQ:

Risk quotient (dimensionless)

PEC_aq:

Aquatic concentration resulting from industrial releases (mg/L)

PNEC:

Predicted no-effect concentration (mg/L). The PNECs selected for this assessment were the values identified during the categorization process and are provided in Appendix C; an assessment factor of 100 was used to account for uncertainties in deriving the PNEC.

For two of the substances, daunorubicin and oxazepam, the industrial scenario was further refined to simulate an industrial production site in a large urban area with a wastewater treatment plant flow rate of 285 120 m³/day and wastewater treatment plant removal rates ranging from 1.9% to 2.5%.

The calculated RQs for all substances were less than 1 (see full results in Appendix C). Given that the industrial scenario provides a conservative estimate of exposure, these results indicate a low potential for ecological harm to the aquatic environment resulting from local exposure from a point source industrial release.

A down-the-drain release from pharmaceutical use scenario was employed to estimate the potential concentrations in multiple water bodies receiving wastewater treatment plant effluents to which pharmaceutical products containing the substances may have been released based on conservative assumptions regarding the amount of chemical used and released by consumers (Environment Canada 2008b). By default, primary and secondary wastewater treatment plant removal rates are assumed to be 0% for these substances, the fraction released during use is assumed to be 100%, the consumer use of the substance is assumed to occur over 365 days/year and the flow rate used for receiving water bodies at all sites is assumed to be the 10^th percentile value. These estimates are made for approximately 1000 release sites, which account for most of the major wastewater treatment plants across Canada. Although the default values are recognized to be highly conservative, if indication of risk is low based on these assumptions, further refinement of input values is not required at this time.

In light of uncertainty relating to the identity and environmental stability of the metabolites of these substances, a conservative environmental concentration value was obtained by not considering human metabolism in the derivation of the PECs. RQs were calculated using maximum PECs calculated from down-the-drain releases of these substances from pharmaceutical use and PNECs as identified during the categorization process, derived using an application factor of 100 to account for uncertainties associated with the values. The maximum RQ was less than 1 for all of these substances (see full results in Appendix C), indicating a low potential for ecological harm to the aquatic environment resulting from down-the-drain releases from consumer uses.

Measured data for some of these substances were identified for Canada and/or elsewhere in the world and are shown in Appendix D. Concentrations measured in various media, wastewater effluent, surface water, groundwater and drinking water (including bottled water) were examined, and the information available is consistent with the predicted concentrations from the models. The majority of studies did not detect these substances in the media of interest; however, some were measured at concentrations up to 564 ng/L in wastewater effluent. A comparison of the measured values with the PNECs determined for these substances results in RQs that are all less than 1, contributing to the weight of evidence indicating that there is no significant potential for ecological harm to the aquatic environment from these substances.

Given the lack of exposure to these substances, no further collection or analysis of information relevant to the persistence, bioaccumulation and inherent toxicity to non-human organisms of these substances has been conducted beyond what was done for categorization. Therefore, the decisions made on the hazard properties during categorization remain unchanged in this assessment. Accordingly, none of the substances are considered to meet the criteria for persistence or for bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations of CEPA 1999 (Canada 2000).

4. Human Health Exposure and Risk Characterization from Indirect Exposure

Drugs containing these substances as ingredients were previously assessed under the Food and Drugs Act (Canada 1985) with respect to their safety, effectiveness and quality. This assessment focused on uses and exposures that were not covered as part of the F&DA assessment, specifically the risks posed by the residues resulting from manufacture, formulation and disposal after use

Only a portion of pharmaceuticals used would be released into the wastewater system. Drug residues released following prescribed use can be further reduced as a result of wastewater treatment, environmental biodegradation and/or drinking water treatment prior to consumption. The concentration in the water source is also significantly reduced via dilution, as the waste is released into waterways.

Measured data for 18 of these substances were identified for Canada and elsewhere and are shown in Appendix D. Concentrations measured in wastewater effluent, surface water, groundwater and drinking water (including bottled water) were examined. Overall, the studies indicated that the concentration of pharmaceutical measured decreases significantly as the substance moves from the wastewater treatment plant effluent into surface water and then the surface water is treated for drinking water purposes. As there is variability in the use of pharmaceuticals in different countries (due to different population levels, prescription preferences, drug registrations, etc.), the measured concentrations in other countries are not necessarily representative of concentrations in Canadian waters. They can, however, account for releases from all potential sources and for potential reductions in drug concentrations resulting from metabolism, environmental degradation, removal via wastewater treatment, removal via drinking water treatment, etc., depending on the source of the sample. For these reasons, in this case, the measured concentrations are preferable to modelled concentrations, even if measurements were made in other countries. Selection of the most relevant data was based on location of the sampling and the relevance of the media to human exposure. Canadian data were given preference over data from other countries, as they are considered to be most representative of potential exposures of Canadians. Drinking water was considered the most relevant medium, followed by surface water or groundwater, wastewater treatment plant effluent and hospital effluent. If multiple relevant concentrations were available for a particular source (e.g., two measurements in Canadian drinking water), as a conservative approach, the maximum concentration was selected from the measured values identified.

For the two substances for which no measured data were identified, conservative assumptions were used when estimating the potential indirect exposure of the general population. For the purposes of modelling, it was assumed for all substances that 100% of the pharmaceutical purchased by hospitals or pharmacies in the most recent year for which data were available (2012) was dispensed, used as prescribed and eventually released into the wastewater system. It was also assumed that none of the pharmaceutical was removed through wastewater treatment or drinking water treatment processes and that there was no environmental degradation of the substance. It is recognized that these assumptions are highly conservative; however, if indication of risk is low based on these assumptions, further refinement would not be required.

Down-the-drain releases to surface water were modelled using the down-the-drain releases from pharmaceutical use scenario, as described in the ecological exposure section, and maximum PECs can be found in Appendix C. This scenario estimates concentrations in approximately 1000 waterways across Canada. The highest values estimated by this model are typically in small waterways with low dilution capacity, which are unlikely sources of drinking water. As a result, this scenario would be expected to overestimate actual concentrations in drinking water.

The estimated upper-bounding intakes of these pharmaceuticals by the general population were represented by formula-fed infants 0–6 months of age, which is estimated to be the most highly exposed age class, on a body weight basis, of those examined. The equation for deriving the estimated intake is given below:

Intake = (PEC_aq  × IR) / bw

where:

Intake:

Estimated intake of the substance from drinking water (mg/kg bw per day)

PEC_aq:

Predicted environmental concentration in receiving water from modelled or measured data (mg/L)

IR:

Ingestion rate of drinking water for formula-fed infants: 0.8 L/day (Health Canada 1998)

bw:

Default body weight for infants 0–6 months of age: 7.5 kg (Health Canada 1998)

The estimated intakes for 18 substances with measured concentrations are presented in Appendix E, and intakes for 2 substances with only modelled concentrations are presented in Appendix F.

Estimated intakes for all substances were low and range from 1.6 × 10⁻⁷ to 2.7 ng/kg bw per day. Since the majority of the measurements were based on wastewater treatment plant effluent or surface water, it is expected that these estimates provide conservative upper-bounding estimates of possible exposure and that actual exposures would be significantly lower.

Based on low exposure, risks from exposure to these substances are not expected. This determination is further supported by consideration of two additional lines of evidence for evaluation of the potential for harm to human health.

A comparison was made between the range of estimated intake values for this group of 20 substances and the threshold of toxicological concern (TTC) value of 2.5 ng/kg bw per day originally proposed by Kroes et al. (2004). For all 20 substances, estimated intakes are in the range of or below the TTC. Although the TTC may not be applicable to every member of this group, it does provide a reference point against which the range of estimated intakes can be compared. TTC values, which are derived using probabilistic approaches, establish generic human exposure threshold values below which it is expected that the probability of adverse effects is low. A TTC value of 0.15 µg/day (equivalent to 2.5 ng/kg bw per day) has been established for potentially carcinogenic substances with structural alerts for genotoxicity. Additional higher TTC values have been established for substances not containing similar structural alerts (Munro et al. 1996a, b; Kroes et al. 2004; EFSA 2012; Dewhurst and Renwick 2013).

A second comparison was also made to evaluate potential risk. The lowest therapeutic dose (LTD) for each substance was identified, and a margin of exposure (MOE) was calculated to determine the ratio between the upper-bounding estimate of intake by the general population and the dose that would be expected to produce a pharmacological effect. This approach is consistent with methodology described elsewhere (Webb et al. 2003; Schwab et al. 2005; Watts et al. 2007; Bull et al. 2011; WHO 2011). The LTD is the lowest concentration that evokes a desired therapeutic effect among target populations and is equivalent to the lowest dose prescribed or recommended, taking into account the number of doses per day (WHO 2011). These values are derived from an assessment of the balance between safety and efficacy. LTDs were identified for each pharmaceutical by examining the dosage and administration guidelines presented in the product monographs submitted to Health Canada as part of the pre-market drug authorization, which are available from the Health Canada Drug Product Database (DPD 2010).

MOEs were derived using the equation below and are presented in Appendix E or F:

MOE = LTD/Intake

where:

MOE:

Margin of exposure (dimensionless)

LTD:

Lowest therapeutic dose (mg/kg bw per day)

Intake:

Maximum estimated intake for drinking water derived from modelled or measured concentrations (mg/kg bw per day)

MOEs for these substances were large and ranged from 10 900 to 8.0 × 10¹³. Given the very conservative nature of the exposure inputs and the use of human data to derive a point of departure for risk characterization, these MOEs support the determination that risks from indirect exposure to these substances are low.

5. Uncertainties

There is uncertainty regarding the estimation of exposure due to the lack of data on concentrations in Canadian surface water or drinking water for many of these substances. However, confidence is high that actual exposures would be lower than the ones presented from the measured data and models used. The uncertainty in both the environmental and human health risk estimates could be reduced by using measured concentration data from Canadian surface water and/or drinking water for these substances. However, it is unlikely that potential exposures were underestimated.

Potential general population exposures to these substances could occur via other sources, such as ingestion of fish or swimming in waters where the pharmaceuticals are present, but these exposures are expected to be much less than the exposure through drinking water and so are not considered in this assessment.

Some of these substances may have additional off-label or veterinary uses that are not considered in this assessment. The quantities of the substances being used for these purposes are unknown, and so estimation of releases is not possible at this time. For the substances which have measured environmental concentrations these releases may be reflected in those measurements,

It is recognized that the LTD represents an exposure level at which a desired pharmacological response is achieved and further that at this exposure level, adverse effects, in addition to intended effects, may occur in some patients. For certain indications and certain classes of drugs, the nature of these unintended effects may be significant. However, the LTD is developed for patients who require treatment for a particular illness and therefore are likely to be more susceptible to potential effects than a healthy individual. Although the use of the LTD provides a tier 1 type of assessment that does not utilize all the toxicity data that may be available for each substance, the highly conservative exposure defaults that have been used lead to significant MOEs between the LTD and the estimated intakes.

6. Conclusion

Considering all available lines of evidence presented in this screening assessment, there is low risk of harm to organisms and the broader integrity of the environment from these 23 substances. It is concluded that these 23 substances do not meet the criteria under paragraphs 64(a) or (b) of CEPA 1999 as they are not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends.

Based on the information presented in this screening assessment, it is concluded that these 23 substances do not meet the criteria under paragraph 64(c) of CEPA 1999 as they are not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

It is concluded that these 23 substances do not meet any of the criteria set out in section 64 of CEPA 1999.

7. References

Apotex Inc. 2004. Product monograph for Apo-Zidovudine. [revised 2004 Jan 14]. [cited in DPD 2010].

Apotex Inc. 2009. Product monograph for Apo-Azathioprine. [revised 2009 Mar 9]. [cited in DPD 2010].

Baig S, Hansmann G, Paolini B. 2008. Ozone oxidation of oestrogenic active substances in wastewater and drinking water. Water Sci Technol 58(2):451–458.

Baxter Corporation. 2012. Product monograph for Procytox. [revised 2012 Sep 7]. [cited in DPD 2010].

Benotti MJ, Trenholm RA, Vanderford BJ, Holady JC, Stanford BD, Snyder SA. 2009. Pharmaceuticals and endrocrine disrupting compounds in U.S. drinking water. Environ Sci Technol 43:597–603.

Bijlsma L, Emke E, Hernandez F, de Voogt P. 2012. Investigation of drugs of abuse and relevant metabolites in Dutch sewage water by liquid chromatography coupled to high resolution mass spectrometry. Chemosphere 89:1399–1406.

Boleda MR, Galceran MT, Ventura F. 2011. Behavior of pharmaceuticals and drugs of abuse in a drinking water treatment plant (DWTP) using combined conventional and ultrafiltration and reverse osmosis (UF/RO) treatments. Environ Pollut 159(6):1584–1591.

Bristol-Myers Squibb. 2010. Product monograph for CeeNU. [revised 2010 Dec 20]. [cited in DPD 2010].

Bristol-Myers Squibb Canada. 2011a. Product monograph for Coumadin. [revised 2011 Mar 10]. [cited in DPD 2010].

Bristol-Myers Squibb Canada. 2011b. Product monograph for Vumon. [revised 2011 May 27]. [cited in DPD 2010].

Brun GL, Bernier M, Losier R, D_oe K, Jackman P, Lee HB. 2006. Pharmaceutically active compounds in Atlantic Canadian sewage treatment plant effluents and receiving waters, and potential for environmental effects as measured by acute and chronic aquatic toxicity. Environ Toxicol Chem 25(8):2163–2176.

Buerge IJ, Buser HR, Poiger T, Müller MD. 2006. Occurrence and fate of the cytostatic drugs cyclophosphamide and ifosfamide in wastewater and surface waters. Environ Sci Technol 40(23):7242–7250.

Bull RJ, Crook J, Whittaker M, Cotruvo JA. 2011. Therapeutic dose as the point of departure in assessing potential health hazards from drugs in drinking water and recycled municipal wastewater. Regul Toxicol Pharmacol 60:1–19.

Busetti F, Linge KL, Heitz A. 2009. Analysis of pharmaceuticals in indirect potable reuse systems using solid-phase extraction and liquid chromatography–tandem mass spectrometry. J Chromatogr A 1216(31):5807–5818.

Canada. [1978]. Food and Drug Regulations, C.R.C., c. 870. Available from: www.canlii.org/en/ca/laws/regu/crc-c-870/latest/crc-c-870.html

Canada. 1985. Food and Drugs Act, R.S.C. 1985, c. F-27. Available from: www.canlii.org/ca/sta/f-27/whole.html

Canada. 1999. Canadian Environmental Protection Act, 1999. S.C., 1999, c. 33. Canada Gazette, Part III, vol. 22, no. 3. Available from: publications.gc.ca/gazette/archives/p3/1999/g3-02203.pdf

Canada. 2000. Canadian Environmental Protection Act, 1999: Persistence and Bioaccumulation Regulations, P.C. 2000-348, 29 March 2000, SOR/2000-107. Available from: http://gazette.gc.ca/archives/p2/2000/index-eng.html

Canada. 2002. Pest Control Products Act, 2002. S.C., 2002, c. 28. Canada Gazette, Part III, vol. 25, no. 3. Available from: www.gazette.gc.ca/archives/p3/2002/index-eng.html

Canada, Dept. of the Environment. 2006. Canadian Environmental Protection Act, 1999: Notice with respect to selected substances identified as priority for action. Canada Gazette, Part I, vol. 140, no. 9, p. 435–459. Available from: publications.gc.ca/site/archivee-archived.html?url=http://publications.gc.ca/gazette/archives/p1/2006/2006-03-04/pdf/g1-14009.pdf

Canada, Dept. of the Environment. 2009. Canadian Environmental Protection Act, 1999: Notice with respect to inanimate substances (chemicals) on the Domestic Substances List. Canada Gazette, Part I, vol. 143, no. 40, p. 2945–2969. Available from: www.gazette.gc.ca/rp-pr/p1/2009/2009-10-03/html/notice-avis-eng.html#d101

Castiglioni S, Bagnati R, Calamari D, Fanelli R, Zuccato E. 2005. A multiresidue analytical method using solid-phase extraction and high-pressure liquid chromatography tandem mass spectrometry to measure pharmaceuticals of different therapeutic classes in urban wastewaters. J Chromatogr A 1092(2):206–215.

Castiglioni S, Bagnati R, Fanelli R, Pomati F, Calamari D, Zuccato E. 2006. Removal of pharmaceuticals in sewage treatment plants in Italy. Environ Sci Technol 40(1):357–363.

Catastini C, Mullot JU, Sahidou B, Mazellier P, Levi Y, Cervantes P, Ormsby JN. 2008. Assessment of antineoplastic drugs in effluents of two hospitals. Eur J Water Qual 39:171–180.

Chan L, Receveur O, Sharp D, Schwartz H, Ing A, Tikhonov C. 2011. First Nations Food, Nutrition and Environment Study (FNFNES): results from British Columbia (2008/2009). Prince George (BC): University of Northern British Columbia.

Chan L, Receveur O, Batal M, David W, Schwartz H, Ing A, Fediuk K, Black A, Tikhonov C. 2014. First Nations Food, Nutrition and Environment Study (FNFNES): Results from Ontario (2011/2012). Ottawa: University of Ottawa, 2014. Print.

Chang H, Wu S, Hu J, Asami M, Kunikane S. 2008. Trace analysis of androgens and progestogens in environmental waters by ultra-performance liquid chromatography–electrospray tandem mass spectrometry. J Chromatogr A 1195(1–2):44–51.

Chang H, Wan Y, Hu J. 2009. Determination and source apportionment of five classes of steroid hormones in urban rivers. Environ Sci Technol 43(20):7691–7698.

Chang H, Wan Y, Wu S, Fan Z, Hu J. 2011. Occurrence of androgens and progestogens in wastewater treatment plants and receiving river waters: comparison to estrogens. Water Res 45(2):732–740.

Choi K, Kim Y, Jung J, Kim MH, Kim CS, Kim NH, Park J. 2008. Occurrences and ecological risks of roxithromycin, trimethoprim, and chloramphenicol in the Han River, Korea. Environ Toxicol Chem 27(3):711–719.

Dévier MH, Le Menach K, Viglino L, Di Gioia L, Lachassagne P, Budzinski H. 2013. Ultra-trace analysis of hormones, pharmaceutical substances, alkylphenols and phthalates in two French natural mineral waters. Sci Total Environ 443:621–632.

Dewhurst I, Renwick AG. 2013. Evaluation of the threshold of toxicological concern (TTC)--Challenges and approaches. Regul Toxicol Pharmacol 65(1):168–177.

[DPD] Drug Product Database [database on the Internet]. 2010. Ottawa (ON): Health Canada. [cited 2013 Mar]. Available from: www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php

[EAFUS] Everything Added to Food in the United States [database on the Internet]. 2011. Silver Spring (MD): US Food and Drug Administration. [cited 2013 Mar]. Available from: www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm115326.htm

[EFSA] European Food Safety Agency. 2012. Scientific opinion on exploring options for providing advice about possible human health risks based on the concept of threshold of toxicological concern (TTC) [Internet]. EFSA J 10(7):2750. Available from: www.efsa.europa.eu/en/search/doc/2750.pdf

Eisai Limited. 2012. Product monograph for Gliadel Wafer. [revised 2012 Aug 17]. [cited in DPD 2010].

Environment Canada. 2006. CEPA DSL categorization overview and results [CD-ROM]. Gatineau (QC): Environment Canada, Existing Substances Division. Available on request.

Environment Canada. 2008a. Guidance for conducting ecological assessments under CEPA, 1999--Science Resource Technical Series. Technical guidance module: the Industrial Generic Exposure Tool – Aquatic (IGETA). Working document. Gatineau (QC): Environment Canada, Existing Substances Division.

Environment Canada. 2008b. Guidance for conducting ecological assessments under CEPA, 1999--Science Resource Technical Series. Technical guidance module: Mega Flush consumer release scenario. Preliminary draft working document. Gatineau (QC): Environment Canada, Existing Substances Division.

Erfa Canada Inc. 2002. Product monograph for Cerubidine. [prepared 2002 Dec 6]. [cited in DPD 2010].

Erfa Canada Inc. 2005a. Prescribing information/product monograph for AMSA PD Inj 50mg/ml. [prepared 2005 Aug 16]. [cited in DPD 2010].

Erfa Canada Inc. 2005b. Prescribing information/product monograph for Chloromycetin Succinate Injection. [prepared 2005 Aug 16]. [cited in DPD 2010].

Erfa Canada Inc. 2011. Product monograph for Cerebyx. [revised 2011 Oct 28]. [cited in DPD 2010].

[ESIS] European Chemical Substances Information System [database on the Internet]. ©1995–2012. Joint Research Centre (JRC). [cited 2012 Jan]. Available from: esis.jrc.ec.europa.eu/

Fernandez MP, Ikonomou MG, Buchanan I. 2007. An assessment of estrogenic organic contaminants in Canadian wastewaters. Sci Total Environ 373(1):250–269.

Fernandez MP, Noguerol TN, Lacorte S, Buchanan I, Pina B. 2009. Toxicity identification fractionation of environmental estrogens in waste water and sludge using gas and liquid chromatography coupled to mass spectrometry and recombinant yeast assay. Anal Bioanal Chem 393:957–968.

Garcia-Ac A, Segura PA, Gagnon C, Sauve S. 2009a. Determination of bezafibrate, methotrexate, cyclophosphamide, orlistat and enalapril in waste and surface waters using on-line solid-phase extraction liquid chromatography coupled to polarity-switching electrospray tandem mass spectrometry. J Environ Monit 11(4):830–838.

Garcia-Ac A, Segura PA, Viglino L, Fürtös A, Gagnon C, Prévost M, Sauvé S. 2009b. On-line solid-phase extraction of large-volume injections coupled to liquid chromatography–tandem mass spectrometry for the quantitation and confirmation of 14 selected trace organic contaminants in drinking and surface water. J Chromatogr A 1216(48):8518–8527.

Godfrey E, Woessner WW, Benotti MJ. 2007. Pharmaceuticals in on-site sewage effluent and ground water, western Montana. Ground Water 45(3):263–271.

Gonzalez Alonso S, Catala M, Maroto RR, Gil JLR, de Miguel AG, Valcarcel Y. 2010. Pollution by psychoactive pharmaceuticals in the rivers of Madrid metropolitan area (Spain). Environ Int 36:195–201.

Gonzalez Alonso S, Valcarcel Y, Montero JC, Catala M. 2012. Nicotine occurrence in bottled water: analysis of 10 brands of water in Spain. Sci Total Environ 416:527–531.

Gros M, Petrovic M, Barceló D. 2009. Tracing pharmaceutical residues of different therapeutic classes in environmental waters by using liquid chromatography/quadrupole-linear ion trap mass spectrometry and automated library searching. Anal Chem 81(3):898–912.

Health Canada. 1995. Investigating human exposure to contaminants in the environment: a handbook for exposure calculations. Ottawa (ON): Health Canada, Health Protection Branch, Great Lakes Health Effects Program.

Health Canada. 1998. Exposure factors for assessing total daily intake of priority substances by the general population of Canada. Unpublished report. Ottawa (ON): Health Canada, Environmental Health Directorate.

Health Canada. 2014. Health Canada Prescription Drug List. Available at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/pdl-ord/index-eng.php

Herberer T. 2002. Tracking persistent pharmaceutical residues from municipal wastewater to drinking water. J Hydrol 266:175–189.

Household Products Database [database on the Internet]. 1993– . Bethesda (MD): National Library of Medicine (US). [updated 2013 Jan; cited 2013 Jan]. Available from: www.householdproducts.nlm.nih.gov/

[HSDB] Hazardous Substances Data Bank [database on the Internet]. 1983– . Bethesda (MD): National Library of Medicine (US). [revised 2006 Dec 30; cited 2013 Jan]. Available from: www.toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Hua WY, Bennett ER, Maio XS, Metcalfe CD, Letcher RJ. 2006. Seasonality effects on pharmaceuticals and s-triazine herbicides in wastewater effluent and surface water from the Canadian side of the upper Detroit River. Environ Toxicol Chem 25(9):2356–2365.

Huerta-Fontela M, Galceran MT, Ventura F. 2010. Fast liquid chromatography–quadrupole-linear ion trap mass spectrometry for the analysis of pharmaceuticals and hormones in water resources. J Chromatogr A 1217(25):4212–4222.

Huerta-Fontela M, Galceran MT, Ventura F. 2011. Occurrence and removal of pharmaceuticals and hormones through drinking water treatment. Water Res 45(3):1432–1442.

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1976. Some naturally occurring substances. IARC Monogr Eval Carcinog Risks Hum 10. Available from: monographs.iarc.fr/ENG/Monographs/vol10/volume10.pdf

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1977. Some miscellaneous pharmaceutical substances. IARC Monogr Eval Carcinog Risks Hum 13. Available from: monographs.iarc.fr/ENG/Monographs/vol13/volume13.pdf

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1978. Some N-nitroso compounds. IARC Monogr Eval Carcinog Risks Hum 17. Available from: monographs.iarc.fr/ENG/Monographs/vol17/volume17.pdf

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1987. Overall evaluations of carcinogenicity: an updating of IARC monographs volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum Suppl 7. Available from: monographs.iarc.fr/ENG/Monographs/suppl7/index.php

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1990. Pharmaceutical drugs. IARC Monogr Eval Carcinog Risks Hum 50. Available from: monographs.iarc.fr/ENG/Monographs/vol50/index.php

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1996. Some pharmaceutical drugs. IARC Monogr Eval Carcinog Risks Hum 66. Available from: monographs.iarc.fr/ENG/Monographs/vol66/index.php

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 2000. Some antiviral and antineoplastic drugs, and other pharmaceutical agents. IARC Monogr Eval Carcinog Risks Hum 76. Available from: monographs.iarc.fr/ENG/Monographs/vol76/index.php

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 2001. Some thyrotropic agents. IARC Monogr Eval Carcinog Risks Hum 79. Available from: monographs.iarc.fr/ENG/Monographs/vol79/index.php

[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 2012. A review of human carcinogens: pharmaceuticals. IARC Monogr Eval Carcinog Risks Hum 100A. Available from: monographs.iarc.fr/ENG/Monographs/vol100A/index.php

[IMS] Intercontinental Marketing Services. 2013. Health Canada Sales Database 2011 & 2012 [MIDAS database on CD]. IMS Brogan,Toronto (ON), IMS Brogan

Janssen-Ortho Inc. 2012. Product monograph for Micronor. [revised 2012 Dec 19]. [cited in DPD 2010].

Kasprzyk-Hordern B, Dinsdale RM, Guwy AJ. 2007. Multi-residue method for the determination of basic/neutral pharmaceuticals and illicit drugs in surface water by solid-phase extraction and ultra performance liquid chromatography–positive electrospray ionisation tandem mass spectrometry. J Chromatogr A 1161(1–2):132–145.

Kleywegt S, Pileggi V, Yang P, Hao C, Zhao X, Rocks C, Thach S, Cheung P, Whitehead B. 2011. Pharmaceuticals, hormones and bisphenol A in untreated source and finished drinking water in Ontario, Canada--Occurrence and treatment efficacy. Sci Total Environ 409:1481–1488.

Kosjek T, Perko S, Zupanc M, Zanoški Hren M, Landreka Dragicevic T, Zigon D, Kompare B, Heath E. 2012. Environmental occurrence, fate and transformation of benzodiazepines in water treatment. Water Res 46:355–368.

Kroes R, Renwick AG, Cheeseman M, Kleiner J, Mangelsdorf I, Piersma A, Schilter B, Schlatter J, van Schothorst F, Vos JG, Würtzen G. 2004. Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem Toxicol 42:65–83.

Kümmerer K, Al-Ahmad A. 2010. Estimation of the cancer risk to humans resulting from the presence of cyclophosphamide and ifosfamide in surface water. Environ Sci Pollut Res 17(2):486–496.

Labadie P, Budzinski H. 2005a. Development of an analytical procedure for determination of selected estrogens and progestagens in water samples. Anal Bioanal Chem 381(6):1199–1205.

Labadie P, Budzinski H. 2005b. Determination of steroidal hormone profiles along the Jalle d’Eysines River (near Bordeaux, France). Environ Sci Technol 39(14):5113–5120.

Laboratoire Riva Inc. 2006. Product monograph for Riva-Oxazepam. [prepared 2006 Mar 2]. [cited in DPD 2010].

Lee HB, Peart TE. 2007. Occurrence of anticonvulsant and anti-anxiolytic drugs in municipal wastewaters. Unpublished internal report submitted to Health Canada. Burlington (ON): Environment Canada, Aquatic Ecosystem Protection Research Division.

Lindberg RH, Wennberg P, Johansson MI, Tysklind M, Andersson BAV. 2005. Screening of human antibiotic substances and determination of weekly mass flows in five sewage treatment plants in Sweden. Environ Sci Technol 39(10):3421–3429.

[LNHPD] Licensed Natural Health Products Database [database on the Internet]. 2008. Version 1.0. Ottawa (ON): Health Canada. [cited 2013 Mar]. Available from: webprod3.hc-sc.gc.ca/lnhpd-bdpsnh/index-eng.jsp

Lundström E, Adolfsson-Erici M, Alsberg T, Bjorlenius B, Eklund B, Laven M, Breitholtz M. 2010. Characterization of additional sewage treatment technologies: ecotoxicological effects and levels of selected pharmaceuticals, hormones and endocrine disruptors. Ecotoxicol Environ Saf 73(7):1612–1619.

McLaughlin A, Belknap A. 2008. Annual kg quantity of medicinal ingredients distributed and dispensed in Canada: analysis of intercontinental medical statistics (IMS) data for 2007. [Excel format data summary]. Ottawa (ON): Health Canada, Health Products and Food Branch, Environmental Impact Initiative.

Metcalfe CD, K_oenig BG, Bennie DT, Servos M, Ternes TA, Hirsch R. 2003. Occurrence of neutral and acidic drugs in the effluents of Canadian sewage treatment plants. Environ Toxicol Chem 22(12):2872–2880.

Mompelat S, Thomas O, Le Bot B. 2011. Contamination levels of human pharmaceutical compounds in French surface and drinking waters. J Environ Monit 13:2929–2939.

Morteani G, Möller P, Fuganti A, Paces T. 2006. Input and fate of anthropogenic estrogens and gadolinium in surface water and sewage plants in the hydrological basin of Prague (Czech Republic). Environ Geochem Health 28(3):257–264.

Munro IC, Ford RA, Kennepohl E, Sprenger JG. 1996a. Correlation of a structural class with no-observed-effect-levels: a proposal for establishing a threshold of concern. Food Chem Toxicol 34:829–867.

Munro IC, Ford RA, Kennepohl E, Sprenger JG. 1996b. Thresholds of toxicological concern based on structure–activity relationships. Drug Metab Rev 28 (1–2):209–217.

Mylan Pharmaceuticals ULC. 2009. Product monograph for Mylan-Azathioprine. [revised 2009 Dec 18]. [cited in DPD 2010].

Mylan Pharmaceuticals ULC. 2011. Product monograph for Mylan-Warfarin. [revised 2011 Sep 22]. [cited in DPD 2010].

[NHPID] Natural Health Products Ingredients Database [database on the Internet]. 2011. Version 2.1. Ottawa (ON): Health Canada. [cited 2013 Mar]. Available from: webprod.hc-sc.gc.ca/nhpid-bdipsn/search-rechercheReq.do

Novopharm Limited. 2004. Product monograph for Novo-AZT. [revised 2004 Mar 13]. [cited in DPD 2010].

Novopharm Limited. 2005. Product monograph for Novo-Warfarin. [prepared 2005 Feb 18]. [cited in DPD 2010].

[NTP] National Toxicology Program (US). 2011. Report on carcinogens. 12^th ed. Research Triangle Park (NC): US Department of Health and Human Services, National Toxicology Program. Available from: ntp.niehs.nih.gov/go/roc12
PendoPharm. 2013. Prescribing information for Phenobarb and Phenobarb Elixir. [revised 2013 Jan 23]. [cited in DPD 2010].

Peng X, Wang Z, Kuang W, Tan J, Li K. 2006. A preliminary study on the occurrence and behavior of sulfonamides, ofloxacin and chloramphenicol antimicrobials in wastewaters of two sewage treatment plants in Guangzhou, China. Sci Total Environ 371(1–3):314–322.

Peng X, Tan J, Tang C, Yu Y, Wang Z. 2008. Multiresidue determination of fluoroquinolone, sulfonamide, trimethoprim, and chloramphenicol antibiotics in urban waters in China. Environ Toxicol Chem 27(1):73–79.

Peschka M, Eubeler JP, Knepper TP. 2006. Occurrence and fate of barbiturates in the aquatic environment. Environ Sci Technol 40(23):7200–7206.

Pfizer Canada Inc. 2009. Product monograph for Zanosar Sterile Powder. [revised 2009 Mar 30]. [cited in DPD 2010].

Pfizer Canada Inc. 2010. Product monograph for Premplus and Premplus Cycle. [revised 2010 Dec 8]. [cited in DPD 2010].

Prasse C, Schlusener MP, Schulz R, Ternes, T. 2010. Antiviral drugs in wastewater and surface waters: a new pharmaceutical class of environmental relevance? Environ Sci Technol 44(5):1728–1735.

Rodriguez C, Cook A, Van Buynder P, Devine B, Weinstein P. 2007. Screening health risk assessment of micropollutants for indirect potable reuse schemes: a three-tiered approach. Water Sci Technol 56(11):35–42.

Rosal R, Rodríguez A, Perdigón-Melón JA, Petre A, García-Calvo E, Gómez MJ, Agüera A, Fernández-Alba AR. 2010. Occurrence of emerging pollutants in urban wastewater and their removal through biological treatment followed by ozonation. Water Res 44(2):578–588.

Sanis Health Inc. 2010. Product monograph for Azathioprine. [prepared 2010 Feb 3]. [cited in DPD 2010].

Sanofi-aventis Canada Inc. 2011. Product monograph for Flagyl. [revised 2011 May 19]. [cited in DPD 2010].

Schulman LJ, Sargent EV, Naumann BD, Faria EC, Dolan DG, Wargo JP. 2002. A human health risk assessment of pharmaceuticals in the aquatic environment. Hum Ecol Risk Assess 8(4):657–680.

Schwab BW, Hayes EP, Fiori JM, Mastrocco FJ, Roden NM, Cragin D, Meyerhoff RD, D’Aco VJ, Anderson PD. 2005. Human pharmaceuticals in US surface waters: a human health risk assessment. Regul Toxicol Pharmacol 42:296–312.Smyth SA, Teslic S. 2013. Occurrence and fate of pharmaceuticals and personal care products in municipal wastewater treatment systems. Unpublished year-end report, March 22, 2013. Ottawa (ON): Health Canada, New Substances Assessment and Control Bureau; 14 p.

Snyder SA, Wert EC, Rexing DJ, Zegers RE, Drury DD. 2006. Ozone oxidation of endocrine disruptors and pharmaceuticals in surface water and wastewater. Ozone Sci Eng 28(6):445–460.

Solé M, De Alda MJL, Castillo M, Porte C, Ladegaard-Pedersen K, Barceló D. 2000. Estrogenicity determination in sewage treatment plants and surface waters from the Catalonian area (NE Spain). Environ Sci Technol 34(24):5076–5083.

Sosiak A, Hebben T. 2005. A preliminary survey of pharmaceuticals and endocrine disrupting compounds in treated municipal wastewaters and receiving rivers of Alberta. September 2005. Edmonton (AB): Alberta Environment, Environmental Monitoring and Evaluation Branch. Available from: environment.gov.ab.ca/info/library/7604.pdf

Sui Q, Huang J, Deng SB, Yu G. 2009. Rapid determination of pharmaceuticals from multiple therapeutic classes in wastewater by solid-phase extraction and ultra-performance liquid chromatography tandem mass spectrometry. Chin Sci Bull 54(24):4633–4643.

Sun L, Yong W, Chu X, Lin JM. 2009. Simultaneous determination of 15 steroidal oral contraceptives in water using solid-phase disk extraction followed by high performance liquid chromatography–tandem mass spectrometry. J Chromatogr A 1216(28):5416–5423.

Ternes T. 1998. Occurrence of drugs in German sewage treatment plants and rivers. Water
Res 32:3245–3260. [cited in Schulman et al. 2002].

Teva Canada Limited. 2010. Product monograph for Teva-Azathioprine. [prepared 2010 April 21]. [cited in DPD 2010].

Trenholm RA, Vanderford BJ, Holady JC, Rexing DJ, Snyder SA. 2006. Broad range analysis of endocrine disruptors and pharmaceuticals using gas chromatography and liquid chromatography tandem mass spectrometry. Chemosphere 65(11):1990–1998.

Triton Pharma Inc. 2010a. Product monograph for Alkeran. [prepared 2010 Nov 29]. [cited in DPD 2010].

Triton Pharma Inc. 2010b. Product monograph for Imuran. [prepared 2010 Oct 29]. [cited in DPD 2010].

Triton Pharma Inc. 2010c. Product monograph for Leukeran. [prepared 2010 Nov 29]. [cited in DPD 2010].

Triton Pharma Inc. 2010d. Prescribing information for Myleran. [prepared 2010 Nov 29]. [cited in DPD 2010].

Valcarcel Y, Gonzalez Alonso S, Rodriguez-Gil JL, Gil A, Catala M. 2011. Detection of pharmaceutically active compounds in the rivers and tap water of the Madrid region (Spain) and potential ecotoxicological risk. Chemosphere 84:1336–1348.

Valcarcel Y, Gonzalez Alonso S, Rodriguez-Gil JL, Castano A, Montero JC, Criado-Alvarez JJ, Miron IJ, Catala M. 2013. Seasonal variation of pharmaceutically active compounds in surface (Tagus River) and tap water (central Spain). Environ Sci Pollut Res 20:1396–1412.Valeant Canada Limited. 2005. Product monograph for Oxpam tablets. [prepared 2005 Jul 11]. [cited in DPD 2010].

Vanderford BJ, Snyder SA. 2006. Analysis of pharmaceuticals in water by isotope dilution liquid chromatography/tandem mass spectrometry. Environ Sci Technol 40(23):7312–7320.

Verlicchi P, Al Aukidy M, Galletti A, Petrovic M, Bercelo D. 2012. Hospital effluent: investigation of the concentrations and distribution of pharmaceuticals and environmental risk assessment. Sci Total Environ 430:109–118.

ViiV Healthcare Shire Canada. 2012. Product monograph for Combivir. [prepared 2012 Oct 4]. [cited in DPD 2010].

Vulliet E, Wiest L, Baudot R, Grenier-Loustalot MF. 2008. Multi-residue analysis of steroids at sub-ng/L levels in surface and ground-waters using liquid chromatography coupled to tandem mass spectrometry. J Chromatogr A 1210(1):84–91.

Vulliet E, Cren-Olivé C, Grenier-Loustalot MF. 2011. Occurrence of pharmaceuticals and hormones in drinking water treated from surface waters. Environ Chem Lett 9:103–114.
Watts C, Maycock D, Crane M, Fawell J, Goslan E. 2007. Desk based review of current knowledge on pharmaceuticals in drinking water and estimation of potential levels. Final report prepared by Watts and Crane Associates for Drinking Water Inspectorate, Department for Food, Environment and Rural Affairs (Defra Project Code: CSA 7184/WT02046/DWI70/2/213). Available from: dwi.defra.gov.uk/research/completed-research/reports/dwi70-2-213.pdf

Webb S, Ternes T, Gibert M, Olejniczak K. 2003. Indirect human exposure to pharmaceuticals via drinking water. Toxicol Lett 142:157–167.

Wennmalm Å, Gunnarsson B. 2005. Public health care management of water pollution with pharmaceuticals: environmental classification and analysis of pharmaceutical residues in sewage water. Drug Inf J 39(3):291–297.

Wert EC, Rosario-Ortiz F, Snyder SA. 2009. Using ultraviolet absorbance and color to assess pharmaceutical oxidation during ozonation of wastewater. Environ Sci Technol 43(13):4858–4863.

[WHO] World Health Organization. 2011. Pharmaceuticals in drinking-water. Geneva (CH): World Health Organization, Public Health and Environment, Water, Sanitation, Hygiene and Health. Report No.: WHO/HSE/WSH/11.05.

Xu WH, Zhang G, Zou SC, Li XD, Liu YC. 2007a. Determination of selected antibiotics in the Victoria Harbour and the Pearl River, South China using high-performance liquid chromatography–electrospray ionization tandem mass spectrometry. Environ Pollut 145(3):672–679.

Xu W, Zhang G, Li X, Zou S, Li P, Hu Z, Li J. 2007b. Occurrence and elimination of antibiotics at four sewage treatment plants in the Pearl River Delta (PRD), South China. Water Res 41(19):4526–4534.

Yoon Y, Ryu J, Oh J, Choi BG, Snyder SA. 2010. Occurrence of endocrine disrupting compounds, pharmaceuticals, and personal care products in the Han River (Seoul, South Korea). Sci Total Environ 408(3):636–643.

Yu JT, Bouwer EJ, Coelhan M. 2006. Occurrence and biodegradability studies of selected pharmaceuticals and personal care products in sewage effluent. Agric Water Manage 86(1–2):72–80.

Yu JT, Bisceglia KJ, Bouwer EJ, Roberts AL, Coelhan M. 2012. Determination of pharmaceuticals and antiseptics in water by solid-phase extraction and gas chromatography/mass spectrometry: analysis via pentafluorobenzylation and stable isotope dilution. Anal Bioanal Chem 403:583–591.

Zuccato E, Calamari D, Natangelo M, Fanelli R. 2000. Presence of therapeutic drugs in the environment. Lancet 355(9217):1789–1790.

Appendix A: Substance Identity and Human Health and Ecological Classifications for 23 Pharmaceuticals

Appendix B: Estimated Quantities of 23 Pharmaceuticals Used in Canada for the Years 2007, 2011 and 2012

Appendix C: Results from Environmental Exposure Modelling for 20 Pharmaceuticals Using Quantity Data from 2012

Appendix D: Measured Concentrations of 18 Pharmaceuticals in Wastewater Treatment Plant Influent and Effluent, Surface Water, Groundwater and Drinking Water

Appendix E: Intake Estimates, Lowest Therapeutic Doses and Calculated Margins of Exposure for 18 Pharmaceuticals with Measured Concentrations

Appendix F: Intake Estimates, Lowest Therapeutic Doses and Calculated Margins of Exposure for Two Substances Based on Modelled Concentrations in Surface Water

Date modified:

2015-02-20