Summary of pros and cons of selected bioanalytical sample preparation techniques.
\r\n\t
\r\n\tSince they involve very small amounts of energy, high sound pressure levels are increasingly simpler and cheaper to emit. Noise is everywhere - it can be emitted as an energy waste by traffic or factories, but also by teenagers looking for loneliness in an overpopulated world.
\r\n\t
\r\n\tWhen the noise emission ends, it will not be possible to find its footprint in the environment, hence it is necessary to be in the right place at the right time to measure it. Moreover, having adequate instruments, updated protocols and trained personnel are mandatory to achieve that. Even then, decision makers must clearly understand the reported situation to decide the need and importance of taking further actions.
\r\n\t
\r\n\tThis book will address issues of noise in the city, in the neighborhood or at work, aspects about management and consequences of exposure to high sound pressure levels ranging from the auditory, extra-auditory and psychophysics effects to the addiction to noise and the loss of solidarity.
\r\n\t
\r\n\tThe book aims to provide a various points of view and analysis of cases regarding this omnipresent pollutant.
Drug development is an expensive, complicated and time-consuming process. According to current estimates, a new drug approval, on average, takes about 10 years and costs around US$1.0 billion. For all approved drugs, an estimated 30% could make a return on the investment. In addition, large pharmaceutical companies will collectively lose about US$70 billion of revenue over the next five years because of patent expiration (Adams & Vu Brantner, 2010). As a result, there is tremendous sense of urgency for the pharmaceutical industry to develop new tools to accelerate the drug development process and to reduce attrition rate on drug candidates. Microdosing is one of these tools.
\n\t\t\tA “microdose” is defined as a dose less than 1/100 of the test substance calculated to yield a pharmacologic effect, with a maximum dose of 100 μg (Food and Drug Administration, 2006). The concept of microdosing to accelerate drug development was first introduced in 2004 by the Europe Medicines Agency in the position paper on non-clinical safety studies to support clinical trials with a single microdose (Europe Medicines Agency, 2004). The Food and Drug Administration in 2006 issued a guidance document on exploratory Investigative New Drug detailing the regulatory process for microdosing clinical studies (Food and Drug Administration, 2006). In 2008, the Ministry of Health, Labor and Welfare in Japan also issued a guidance on microdose clinical studies as the means to understand the bioavailability and pharmacokinetic profiles of test compounds in human, to evaluate the metabolic profiles of test compounds in human or to obtain the information on the tissue distribution of test compounds in human by using molecular imaging technology (Ministry of Health, Labor and Welfare, 2008). Since the dose is sub-pharmacological, the potential for adverse side effect to a human subject in the clinical study is considered to be minimal. As a result, only an abridged non-clinical package is required to support a microdosing clinical study. This makes the microdosing concept attractive when a speedy decision on drug candidate selection around pharmacokinetics and drug metabolism is critical, particularly when clear decisions cannot be made with in vivo animal and in vitro pre-clinical pharmacokinetic data.
\n\t\tThere are many reasons drugs can fail in clinical trials. Although drug attrition due to unfavorable absorption, distribution, metabolism and excretion properties in humans has dropped from 40% in 1991 to 10% in 2000, while drug attrition for efficacy, toxicity and safety has increased to 20-30% during the same period (Frank & Hargreaves, 2003), one could argue that the reason for the insufficient pharmacological effect in vivo might be related to the low concentrations at the target tissues. In addition, accumulation of the drug or its metabolites in organ tissues might lead to unwanted adverse effects in humans (Sugiyama & Yamashita, 2011). Therefore, issues related to lack of efficacy or safety of drug candidates may be attributed not only to the pharmacodynamics, but also to the pharmacokinetics and metabolism of the compound.
\n\t\t\tTypically, during the pre-clinical stage, a number of in vitro models and in vivo pharmacokinetic and drug metabolism studies are conducted in experimental animals such as rats, dogs and monkeys. The allometric scaling approach, or physiologically based pharmacokinetic models, have often been used to predict human pharmacokinetics. However, large genetic and species differences in drug metabolism, particularly for drugs with high first-pass metabolism, extra-hepatic metabolism, significant polymorphic metabolism, or that are transporter substrates sometimes make prediction of human pharmacokinetics difficult. As a result, unfavorable pharmacokinetic and metabolism properties such as low oral bioavailability, high clearance, short half-life and extensive drug distribution could lead to unexpected adverse effects or lack of efficacy in clinic trials. Therefore, in these circumstances, and where there is conflicting animal data that make predicting human pharmacokinetics and metabolism difficult, microdosing in the clinic could be useful to quickly obtain such information.
\n\t\t\tConceptually, microdosing clinical studies could help (1) choose a drug from a series of candidates with the best human pharmacokinetic and metabolism properties for further development; (2) evaluate if sufficient exposure could be achieved at proposed clinical doses to test pharmacological activity; (3) provide valuable information for formulation optimization; and (4) estimate the amount of active pharmaceutical ingredient to support clinical drug development (Ings, 2009, Garner, 2010). The underlying fundamental assumption, however, for the success of the microdosing concept is that pharmacokinetics are linear from microdose to therapeutic dose in the clinic. In order to accurately characterize microdosing pharmacokinetics and drug metabolism, a highly sensitive and selective bioanalytical method is vital.
\n\t\tMicrodosing studies for pharmacokinetics and drug metabolism investigations rely on analytical techniques with adequate sensitivity. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), accelerator mass spectrometry (AMS) and positron emission tomography (PET) are currently three major analytical tools to study microdosing pharmacokinetics and drug metabolism, and each technique has its advantages and disadvantages.
\n\t\t\tAMS employs an instrument for measuring long-lived radionuclides that occur naturally in our environment. It uses a particle accelerator in conjunction with ion sources, large magnets, and detectors to separate out interferences and count single radionucleotide atoms in the presence of 1x1015 stable atoms. Because of the powerful magnet employed, AMS typically displays excellent sensitivity with the lower limit of quantitation at femtogram or attogram per mL levels (Lappin et al., 2006). Despite its ultra-low sensitivity, AMS has many limitations. It requires the synthesis of 14C-radiolabeled drug, which can be costly and time-consuming (Wilding & Bell, 2005) and necessitates extra precautions during sample handling and preparation to prevent contamination by extraneous sources of 14C. In addition, AMS measures total 14C radioactivity, that is, drug plus metabolites. In order to accurately measure parent drug concentrations, the parent drug in plasma or blood extracts must first be separated by high performance liquid chromatography (HPLC) with fraction-collection followed by subsequent analysis using AMS (Sandhu et al., 2004). At present, unlike LC-MS/MS, there is no direct interface between HPLC and AMS. Furthermore, AMS methodology requires biological samples to be graphitized prior to analysis, which involves a time-consuming process of sample oxidation followed by reduction. These procedures result in low throughput, large instrument space and high operating cost (Lappin & Garner, 2005).
\n\t\t\tPET is a relatively new imaging technique that, due to its high sensitivity, has the potential to support microdosing studies. In pharmacokinetic studies using PET imaging technology, a drug labeled with a positron-emitting radiotracer, such as 11C, is administered. Three dimensional images showing the distribution of the radiolabel with spatial resolution of 2-5 mm are then produced. In dynamic PET, the images can be acquired rapidly and the time-course can be followed with temporal resolution of a few seconds. Typically, the radiotracers employed have very high specific activity, which allows for doses of 10 μg or less, consistent with the microdosing concept (Lappin et.al., 2009). However, the short half-life of positron emitting radionucleotides typically limits the duration of these studies and prevents accurate assessment of pharmacokinetics beyond the initial distribution phase. The main advantage of PET compared with other analytical techniques is the ability to quantitatively image drug distribution in the clinic under a microdosing paradigm, gaining insight into concentrations of drug in specific tissues of interest. Another advantage of PET is that it is non-invasive. Although PET is mainly used to study pharmacokinetics of compounds in the target tissues, it could also be used to analyze blood or plasma samples. In this practice, an HPLC with radiodetection is used to separate parent drug from the metabolites, thereby gaining information on the quantities of both parent drug and metabolites. This procedure, however, could add considerably to the complexity of the experiments and can be challenging due to the short half-life of the radionucleotides. Other disadvantages of PET are that the instrument is expensive and only available at certain locations that have the specialized hot chemistry facilities, an on-site cyclotron and a positron emission tomography camera.
\n\t\t\tLC-MS/MS is widely available in the pharmaceutical industry and academic institutions as a powerful analytical tool to measure drug concentrations. It is easy to use and highly automated. Mass Spectrometry can also be directly linked to a HPLC system to separate parent drug from the metabolites. In addition, LC-MS/MS has the functionality to characterize drug metabolites. LC-MS/MS is relatively inexpensive compared to AMS or PET, and occupies much smaller footprint in the laboratory setting. At present, however, LC-MS/MS can only achieve lower limits of quantitation at picogram or femtogram per mL level, an order of magnitude less sensitive compared to AMS technique. Nevertheless, LC-MS/MS has gained considerable attention in the recent years as an analytical technique to study microdosing pharmacokinetics and drug metabolism.
\n\t\tSince its widespread introduction more than 20 years ago, LC-MS/MS has made an enormous impact on biomedical research, particularly on the study of drug metabolism and pharmacokinetics (Kamel & Prakash, 2006) in the pharmaceutical industry (Lee, 2005). It has been the preferred technique for bioanalysis of small molecules in biological fluids for more than 10 years (Marzo & Dal Bo, 2007). Although considered as a mature technology, rapid and exciting advances continue to occur that promise even greater performance. The inherent sensitivity, selectivity, robustness and speed of LC-MS/MS make it an attractive technique for supporting microdosing studies even though sensitivity is still somewhat of a challenge at the extremely low doses. Advances in mass spectrometry technology, chromatography and sample preparation have made bioanalytical assays with sensitivities at the low pg/mL range more common, if not yet routine. As the technology continues to advance, improvements in sensitivity are likely to continue.
\n\t\t\tSeveral excellent books are available that cover LC-MS/MS in general (Niessen, 2006) and application to analysis of small molecule pharmaceuticals in biological matrices (Korfermacher, 2004), and numerous review articles (Xu et al., 2007) cover recent developments for the reader interested in a comprehensive review of LC-MS/MS technology. An excellent review on sample preparation, which is a key factor in bioanalysis, is also available (Wells, 2003). The objective of this brief introduction to LC-MS/MS is to provide an understanding of the technology, as well as its promise and limitations, that would assist a researcher interested in microdosing, but not necessarily familiar with analytical chemistry, with emphasis on aspects and recent developments relevant to microdosing studies.
\n\t\t\tLC-MS/MS is a joining of two techniques: HPLC and mass spectrometry (MS). A schematic diagram of a LC-MS/MS system is shown in Figure 1. In an HPLC system, the components of the sample are separated on the basis of physical properties by distributing into two immiscible phases, the stationary phase (contained in a column) and the mobile phase (which flows through the column). The effluent from the HPLC column is directed to the ionization source of the mass spectrometer, where the analyte(s) is converted into gas phase ions. These ions are then introduced in several stages to the high vacuum region of the mass analyzer, where the ions are separated by mass to charge ratio and measured by the detector. In most applications related to bioanalysis, tandem mass spectrometers are utilized.
\n\t\t\tPrior to analysis by LC-MS/MS, complex samples such as plasma are typically pretreated to remove proteins and other potentially interfering materials. Table 1 lists the most common sample preparation techniques along with the key advantages and disadvantages.
\n\t\t\t\tSchematic diagram of a liquid chromatography-mass spectrometry system.
Typical bioanalytical assays involve preparing calibration standard and control samples, then pre-treating the samples prior to injection and analysis by LC-MS/MS. Thus, the technique can be divided into three parts: sample pretreatment, HPLC and MS/MS.
\n\t\t\t\tTechnique | \n\t\t\t\t\t\t\tPro | \n\t\t\t\t\t\t\tCon | \n\t\t\t\t\t\t
Protein precipitation | \n\t\t\t\t\t\t\t• Little or no method development needed • Good recovery of wide variety of analytes (i.e. metabolites) | \n\t\t\t\t\t\t\t• Matrix ion suppression | \n\t\t\t\t\t\t
Liquid-liquid extraction | \n\t\t\t\t\t\t\t• Provides clean extract • Concentrates sample to improve sensitivity | \n\t\t\t\t\t\t\t• Recovery of polar analytes (i.e. metabolites) may be poor • Less amenable to automation and high throughput | \n\t\t\t\t\t\t
Solid phase extraction | \n\t\t\t\t\t\t\t• Provides clean extract • Concentrates sample to improve sensitivity • Amenable to high throughput • Large variety of SPE sorbents | \n\t\t\t\t\t\t\t• Extensive method development may be needed to optimize • Recovery of metabolites may be poor | \n\t\t\t\t\t\t
Online sample preparation (turbulent flow, monolithic) | \n\t\t\t\t\t\t\t• No sample preparation needed • Amenable to automation and high throughput • High sensitivity can be achieved | \n\t\t\t\t\t\t\t• More complex valve switching system is needed • Extensive method development needed to achieve high sensitivity • Higher carry-over | \n\t\t\t\t\t\t
Summary of pros and cons of selected bioanalytical sample preparation techniques.
Solid phase extraction and liquid-liquid extraction are the two most common techniques applied to microdosing studies, since these techniques allow for concentration of the sample to help achieve high sensitivity. Adequate sample clean-up to remove background interferences and to reduce matrix ion suppression is critical for achieving highly sensitive and robust bioanalytical assays. Note that if analysis of metabolites is desired, a less specific sample preparation procedure (i.e. protein precipitation) may be necessary to ensure recovery of the metabolites.
\n\t\t\tSelected techniques and advances in high performance liquid chromatography used in bioanalysis, along with key advantages and limitations, are shown in Table 2.
\n\t\t\t\tTechnique | \n\t\t\t\t\t\t\tPro | \n\t\t\t\t\t\t\tCon | \n\t\t\t\t\t\t
Reverse phase liquid chromatography | \n\t\t\t\t\t\t\t• Most common mode to connect mass spectrometry • Predictable retention of metabolites • Larger variety of stationary phases available | \n\t\t\t\t\t\t\t• Difficult to retain highly polar analytes | \n\t\t\t\t\t\t
Normal phase liquid chromatography | \n\t\t\t\t\t\t\t• Optimal mode for chiral separations | \n\t\t\t\t\t\t\t• Not amenable to electrospray • Unpredictable retention of metabolites | \n\t\t\t\t\t\t
Ion pairing liquid chromatography | \n\t\t\t\t\t\t\t• Provides retention for very polar analytes | \n\t\t\t\t\t\t\t• Ion suppression | \n\t\t\t\t\t\t
Very or ultra high pressure liquid chromatography | \n\t\t\t\t\t\t\t• Higher chromatographic efficiency improves sensitivity and speed | \n\t\t\t\t\t\t\t• Special columns and pumps needed | \n\t\t\t\t\t\t
Fused core particle technology columns | \n\t\t\t\t\t\t\t• Higher chromatographic efficiency improves sensitivity and speed | \n\t\t\t\t\t\t\t• Ultra high pressure liquid chromatography - like performance without special pumps | \n\t\t\t\t\t\t
Hydrophilic interaction liquid chromatography | \n\t\t\t\t\t\t\t• Provides retention and improves sensitivity for very polar analytes | \n\t\t\t\t\t\t\t• Unpredictable retention of metabolites | \n\t\t\t\t\t\t
Two dimensional - high performance liquid chromatography | \n\t\t\t\t\t\t\t• Cleaner background improves sensitivity | \n\t\t\t\t\t\t\t• Special equipment and extensive method development needed | \n\t\t\t\t\t\t
Selected advances and techniques of HPLC along with a summary of the pros and cons of each.
Reverse-phase liquid chromatography, wherethe stationary phase is a non-polar material such as C8 or C18 and the mobile phase is a mixture of polar solvents, is by far the most common configuration. Normal phase, ion pairing (Gao et al., 2005), ion exchange and chiral chromatography (Chen et al., 2005) are less common modes used in bioanalysis. Key technology developments within reverse-phase HPLC that improve sensitivity include ultra-high-pressure liquid chromatography (Guillarme et al., 2010) and fused-core particle columns (Song et al., 2009), which improve the efficiency and speed of liquid chromatographic separations. Improving chromatographic efficiency increases sensitivity in two ways; by producing sharper, more concentrated peaks and by separating matrix components that could cause matrix ion suppression.
\n\t\t\tThe development of atmospheric pressure ionization, in particular electrospray and atmospheric pressure chemical ionization, was the key development that made the union of liquid chromatography and mass spectrometry successful. In electrospray (Figure 2), the mobile phase effluent is nebulized and a charge of 3-5 kV is applied to the spray needle. In the spray zone, small charged droplets are formed and as the solvent evaporates, the excess charge in the droplets becomes more concentrated and, at some point, the Coulomb repulsion overcomes the competing force of surface tension and causes the droplets to disintegrate and gas phase ions of the analyte(s) are produced. The exact mechanisms of how ions are produced from charged droplets are complex and still a matter of intense research and debate, and several reviews summarize practical implications of recent findings (Cech, 2002, Cole, 2000). Electrospray is capable of ionizing almost any polar analyte molecule, and works especially well with weakly basic or acidic compounds. For less polar or non-polar analytes, atmospheric pressure chemical ionization is often used.
\n\t\t\t\t\tElectrospray ionization.
In atmospheric pressure chemical ionization (APCI), the mobile phase effluent is almost completely evaporated in a heated quartz tube and a corona discharge reacts with gas molecules from evaporation of the various mobile phase components, which undergo a series of gas phase ion-molecule reactions, especially proton transfer reactions, that eventually result in the production of gas phase ions of the analyte(s). Unlike electrospray, in atmospheric APCI, ionization occurs in the gas phase, which could explain why atmospheric pressure chemical ionization is less susceptible to matrix ion suppression effects.
\n\t\t\t\t\tBoth electrospray and atmospheric pressure chemical ionization are “soft” ionization methods, which typically result in protonated molecular ions, [MH]+, in positive mode or deprotonated molecular ions, [M-H]-, in negative mode. In either case, the composition of the mobile phase has a profound influence on ionization (Kostiainen et al., 2009). The choice of composition of the mobile phase is therefore a compromise between its effects on the chromatography and the effects on ionization in the mass spectrometer. The ionization efficiency, and therefore assay sensitivity, is also highly compound dependent.
\n\t\t\t\tThere are many different types of mass spectrometers. In a tandem mass spectrometer, two mass analyzers are used to provide an additional dimension of selectivity, where the first mass analyzer selects ions of only the desired mass to charge ratio, which are fragmented and the resulting fragment ions analyzed by the second mass analyzer. Tandem mass spectrometers improve the selectivity and sensitivity for quantitative assays, and greatly expand the capabilities for gaining qualitative information of unknown metabolites.
\n\t\t\t\t\tLC-MS/MS utilizing a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode is currently the method of choice for quantitative bioanalysis of small molecules. A schematic diagram of a triple quadrupole mass spectrometer is shown in Figure 3.
\n\t\t\t\t\t\tSchematic diagram of a triple quadrupole mass spectrometer.
The first quadrupole acts as a mass filter to select only ions of a specific mass to charge ratio,typically of the [MH]+ or [M-H]- ions of the analyte, to enter into the second quadrupole. The second quadrupole is the collision cell, where collision with a gas (N2 or Ar) causes the ions to fragment through a process known as collision activated dissociation. The resulting fragment ions are transmitted to third quadrupole, where only the fragment ions of the desired mass to charge ratio are allowed to pass and impinge on the detector (electron multiplier). The two levels of selectivity in the multiple reaction monitoring experiment, combined with the chromatographic separation, provided a very high level of selectivity and are critical to achieving high sensitivity.
\n\t\t\t\t\tDespite the current predominance of triple quadrupole mass spectrometers in quantitative bioanalysis, other instrument types show promise and may prove to be powerful tools for use in microdosing studies. Several mass spectrometer configurations are available that, in addition to quantifying parent drug and known metabolites, offer the ability to gain information about metabolite pathways even without a priori knowledge of metabolism. These instruments vary widely in their configurations, principles of operation, but can provide structural information on metabolites. Several examples are briefly discussed below.
\n\t\t\t\t\t\tHigh resolution mass spectrometers, including time-of-flight (Williamson et al., 2007, Williamson et al., 2008), orbitrap instruments (Zhang et al., 2009, Bateman et al., 2009) and linear ion trap-fourier transform ion cyclotron mass spectrometers (Yamane et al., 2009) provide high selectivity and are able to characterize metabolites.
\n\t\t\t\t\t\tIon trap and hybrid triple quadrupole-ion trap mass spectrometers are low resolution instruments that could provide the ability to simultaneously measure and characterize metabolites along with quantitative bioanalysis. The hybrid linear ion trap–triple quadrupole mass spectrometer, or Quadrupole-Trap, by configuring third quadrupole to function either as a quadrupole mass filter or a linear ion trap, combines the features of a triple quadrupole instrument with the features of an ion trap instrument (King & Fernandez-Metzler, 2006). The quadrupole-trap instruments can therefore provide the same sensitivity as a triple quadrupole mass spectrometer and also provide simultaneous qualitative metabolite characterization data, which has allowed these instruments to be used to support microdosing studies.
\n\t\t\t\t\tLC-MS/MS has been successfully used to investigate the pharmacokinetic linearity of drugs in animals as well as in clinical trials. Balani et al. first reported the evaluation of microdosing to assess pharmacokinetic linearity of fluconazole, tolbutamide and an investigational compound MLNX in rats using LC-MS/MS (Balani et al., 2006). In this study, fluconazole was orally administrated at 0.001, 0.005, 0.05 and 5 mg/kg; tolbutamide at 0.001, 0.002, 0.01, 0.1 and 1 mg/kg; and MLNX at 0.01, 0.1, 1, 10 mg/kg to rats. Because of the low plasma clearance, low volume of distribution, and high oral bioavailability for these compounds, the plasma concentrations in rats declined slowly and were easily quantifiable in 24 hour postdose plasma samples. Thus, the LC-MS/MS sensitivity of 0.1 to 1 nM was adequate to support microdosing studies for these compounds in rats. Both fluconazole and tolbutamide showed linear pharmacokinetics throughout the entire dose range and MLNX showed linear pharmacokinetics between 0.1 and 1 mg/kg, but not to 10 mg/kg.
\n\t\t\tA more comprehensive study involving five drugs of antipyrine, metoprolol, carbamazepine, digoxin and atenolol from three different classes of the Biopharmaceutical Classifications Systems and with the diverse chemical structures were used as model compounds to evaluate the feasibility and sensitivity requirements of LC-MS/MS as an analytical tool to support microdosing studies (Ni et al., 2008). These five drugs were individually administered orally to rats at 0.167, 1.67, 16.7, 167 or 1670 µg/kg doses, where 1.67 μg/kg was equivalent to the maximal microdose of 100 μg in 60 kg human. The 10,000 fold dose range from 0.167 μg/kg to 1670 μg/kg was designed to evaluate the linearity of pharmacokinetics. Using 100 µl plasma sample aliquots, the lower limits of quantitation for antipyrine (10 pg/ml), carbamazepine (1 pg/ml), metoprolol (5 pg/ml), atenolol (20 pg/ml) and digoxin (5 pg/ml) were achieved. Proportional pharmacokinetics were obtained from 0.167 to 1670 µg/kg for antipyrine and carbamazepine and from 1.67 to 1670 µg/kg for atenolol and digoxin, while metoprolol, which is known to undergo extensive metabolism in rats, exhibited non-proportional pharmacokinetics.
\n\t\t\tLC-MS/MS technology has also been successfully utilized in support of microdosing clinical studies. A validated assay using LC-MS/MS methodology was developed to support quantitative analysis of fexofenadine in human plasma for microdose and pharmacologic dose clinical trials (Yamane et al., 2007). Calibration standards for microdosing study were prepared in the range from 10 to 1000 pg/ml while calibration standards for pharmacological dosing study were from 1 to 500 ng/ml. The results suggested that it was possible to obtain the plasma drug concentrations at all time points up to 12 hours after microdosing and the linear pharmacokinetic profiles were obtained for fexofenadine between microdose of 100 µg and therapeutic dose of 60 mg (Yamazaki et.al., 2010). Similarly, a sample treatment procedure and LC-MS/MS method for quantitative determination of nicardipine in human plasma were developed for a microdose clinical trial with nicardipine (Yamane et al., 2009). Bioanalytical methods were validated in the calibration ranges from 1 to 500 pg/ml and from 0.2 to 100 ng/ml to support microdosing and pharmacological dosing, respectively. Each method was successfully applied to measure drug concentrations in plasma using LC-MS/MS after administration of 100 µg microdose and 20 mg pharmacological dose to each of six healthy volunteers.
\n\t\t\tIn order to obtain information on absolute oral bioavailability, a technique utilizing simultaneous intravenous microdosing of 14C-labeled drug with oral dosing of non-labeled drug in dogs was exemplified using an investigational compound R-142086 (Miyaji et al., 2009). Plasma concentrations of R-142086 were measured by LC-MS/MS and plasma concentrations of 14C-R-142086 were measured by AMS following R-142086 oral dosing at 1 mg/kg and simultaneous 14C-R-142086 intravenous dosing at 1.5 µg/kg (71.25 nCi/kg). Using this strategy, the oral bioavailability of R-142086 was calculated as 16.1% in dogs. In addition, the correlation between the plasma R-142086 concentration data obtained by AMS and LC-MS/MS was examined at an intravenous dose of 0.3 mg/kg (71.25 nCi/kg). The plasma concentration-time curves for 14C-R-142086 determined by AMS and for R-142086 determined by LC-MS/MS in each dog are compared in Figure 4. Although plasma concentrations of R-142086 determined by LC-MS/MS were approximately 20% higher than those of 14C-R-142086 as determined by AMS, there was excellent correlation (r=0.994) between both concentrations.
\n\t\tCorrelation between AMS and LC-MS/MS analyses. Panel A: Comparison of plasma concentrations of R-142086 determined by LC-MS/MS (○) versus those of 14C-R-142086 determined by AMS (●) after intravenous administration of 14C-R-142086 at a higher dose (0.3 mg/kg, 71.25 nCi/kg) in each of three dogs. Panel B: Relationship of concentration of R-142086 in all dogs determined by LC-MS/MS and those of 14C-R-142086 determined by AMS after intravenous dosing of a higher dose (0.3 mg/kg, 71.25 nCi/kg). The coefficient of correlation (r) was 0.994. The regression line was y = 1.14 x -0.191.For AMS analysis, the plasma samples were diluted 5-fold (open square), 20-fold (open circle) or 50-fold (open triangle). (Reprinted with permission from [Miyaji 2009],©2009, The Japanese Society for the Study of Xenobiotics)
LC-MS/MS technology has also been used to characterize and quantify metabolites in microdosing animal and clinical studies. Ni et al. (Ni et al., 2008) reported the characterization of carbamazepine metabolites in both in vitro liver microsomes and in vivo rat at ultra-low concentrations or dose level. Concentrations of 100 nM or 3 nM carbamazepine were incubated in rat liver microsomes, and metabolites were characterized by LC-MS/MS. Incubation concentration at 3 nM was selected because of its close equivalency with plasma Cmax of carbamazepine at the microdose of 1.67 µg/kg in rats. In vitro metabolism data showed the presence of oxidative and conjugated metabolites following incubations at 3 nM and 100 nM. Four metabolites of carbamazepine were detected and characterized in the plasma of rats dosed with 1.67 µg/kg of carbamazepine. The carbamazepine epoxide, among the four metabolites characterized, was the major human circulating metabolite of carbamazepine at the therapeutic doses. Through comparing with carbamazepine metabolism reported in the literature (Lertratanangkoon & Horning, 1982), study results suggested that the metabolic profile in vivo at a microdose is, in general, similar to that at therapeutic doses in rats for carbamazepine.
\n\t\t\tThe metabolites of nicardipine were characterized using linear ion trap-fourier transform ion cyclotron resonance mass spectrometry for in vitro human liver microsomal incubation with 10 µM nicardipine, where the chemical structures and possible fragmentation patterns for nine metabolites were proposed. These nine metabolites were subsequently monitored and detected in human plasma in a microdosing clinical study (Yamane et al., 2009).
\n\t\t\tFurther evaluation took place on the sensitivity requirement for LC-MS/MS as an analytical tool to characterize metabolites in plasma and urine at microdose level in rats. In addition, the investigation of the proportionality of metabolite exposure from microdose of 1.67 µg/kg to a high dose of 5000 µg/kg was conducted for four model compounds of atorvastatin, ofloxacin, omeprazole and tamoxifen (Ni et al., 2010). For all targeted metabolites based upon literature reports, only a few metabolites including the glucuronide metabolite of ofloxacin, the hydroxylation metabolite of omeprazole and hydration metabolite of tamoxifen were detected by LC-MS/MS in rat plasma following microdosing. The exposure of detected metabolites of omeprazole and tamoxifen appeared to increase in a non-proportional manner with increasing doses. For atorvastatin metabolites, the exposure of atorvastatin lactone increased non-proportionally with increasing doses while the exposure of ortho- and para-hydroxyatorvastatin did show proportional increase (Table 3). Following a single oral microdose or high dose to rats, the exposure of area under the curve of detected metabolites of atorvastatin, omeprazole or tamoxifen did not always display a proportional relationship from a microdose of 1.67 µg/kg to high dose of 5000 µg/kg. Therefore, it was concluded that the exposure of metabolites at the microdose level cannot simply be used to predict their exposure at higher doses.
\n\t\tMicrodosing could provide tremendous value to the drug development, particularly for the evaluation of pharmacokinetics and metabolism properties of compounds. In cases where human pharmacokinetic prediction becomes difficult due to conflicting animal
\n\t\t\t\n\t\t\t\t\t\t | Dose | \n\t\t\t\t\t\tCmax (ng/mL) | \n\t\t\t\t\t\tTmax (hour) | \n\t\t\t\t\t\tAUC0-tlast (ng*hours/ml) | \n\t\t\t\t\t|||
μg/kg | \n\t\t\t\t\t\tMean | \n\t\t\t\t\t\tSD | \n\t\t\t\t\t\tMean | \n\t\t\t\t\t\tSD | \n\t\t\t\t\t\tMean | \n\t\t\t\t\t\tSD | \n\t\t\t\t\t|
Atorvastatin | \n\t\t\t\t\t\t1.67 | \n\t\t\t\t\t\t0.158 | \n\t\t\t\t\t\t0.0508 | \n\t\t\t\t\t\t0.556 | \n\t\t\t\t\t\t0.193 | \n\t\t\t\t\t\t0.208 | \n\t\t\t\t\t\t0.0116 | \n\t\t\t\t\t
25 | \n\t\t\t\t\t\t0.508 | \n\t\t\t\t\t\t0.193 | \n\t\t\t\t\t\t0.444 | \n\t\t\t\t\t\t0.193 | \n\t\t\t\t\t\t0.426 | \n\t\t\t\t\t\t0.0474 | \n\t\t\t\t\t|
350 | \n\t\t\t\t\t\t2.68 | \n\t\t\t\t\t\t1.32 | \n\t\t\t\t\t\t0.333 | \n\t\t\t\t\t\t0.00 | \n\t\t\t\t\t\t2.54 | \n\t\t\t\t\t\t0.806 | \n\t\t\t\t\t|
5000 | \n\t\t\t\t\t\t34.8 | \n\t\t\t\t\t\t17.7 | \n\t\t\t\t\t\t0.555 | \n\t\t\t\t\t\t0.385 | \n\t\t\t\t\t\t36.5 | \n\t\t\t\t\t\t21.0 | \n\t\t\t\t\t|
ortho-Hydroxy atorvastatin | \n\t\t\t\t\t\t1.67 | \n\t\t\t\t\t\t0.0985 | \n\t\t\t\t\t\t0.124 | \n\t\t\t\t\t\t0.777 | \n\t\t\t\t\t\t0.507 | \n\t\t\t\t\t\t0.0628 | \n\t\t\t\t\t\t0.0485 | \n\t\t\t\t\t
25 | \n\t\t\t\t\t\t0.463 | \n\t\t\t\t\t\t0.185 | \n\t\t\t\t\t\t0.333 | \n\t\t\t\t\t\t0.00 | \n\t\t\t\t\t\t0.497 | \n\t\t\t\t\t\t0.249 | \n\t\t\t\t\t|
350 | \n\t\t\t\t\t\t5.12 | \n\t\t\t\t\t\t2.76 | \n\t\t\t\t\t\t0.665 | \n\t\t\t\t\t\t0.576 | \n\t\t\t\t\t\t6.63 | \n\t\t\t\t\t\t2.89 | \n\t\t\t\t\t|
5000 | \n\t\t\t\t\t\t50.9 | \n\t\t\t\t\t\t35.5 | \n\t\t\t\t\t\t0.777 | \n\t\t\t\t\t\t0.507 | \n\t\t\t\t\t\t67.4 | \n\t\t\t\t\t\t47.6 | \n\t\t\t\t\t|
para-Hydroxy atorvastatin | \n\t\t\t\t\t\t1.67 | \n\t\t\t\t\t\tNC | \n\t\t\t\t\t\tNC | \n\t\t\t\t\t\tNC | \n\t\t\t\t\t\tNC | \n\t\t\t\t\t\tNC | \n\t\t\t\t\t\tNC | \n\t\t\t\t\t
25 | \n\t\t\t\t\t\t0.0233 | \n\t\t\t\t\t\t0.0133 | \n\t\t\t\t\t\t0.665 | \n\t\t\t\t\t\t0.576 | \n\t\t\t\t\t\t0.0208 | \n\t\t\t\t\t\t0.0111 | \n\t\t\t\t\t|
350 | \n\t\t\t\t\t\t0.241 | \n\t\t\t\t\t\t0.149 | \n\t\t\t\t\t\t0.665 | \n\t\t\t\t\t\t0.576 | \n\t\t\t\t\t\t0.258 | \n\t\t\t\t\t\t0.110 | \n\t\t\t\t\t|
5000 | \n\t\t\t\t\t\t2.13 | \n\t\t\t\t\t\t1.33 | \n\t\t\t\t\t\t0.888 | \n\t\t\t\t\t\t0.508 | \n\t\t\t\t\t\t2.18 | \n\t\t\t\t\t\t1.25 | \n\t\t\t\t\t|
Lactone of atorvastatin | \n\t\t\t\t\t\t1.67 | \n\t\t\t\t\t\t2.33 | \n\t\t\t\t\t\t1.20 | \n\t\t\t\t\t\t0.999 | \n\t\t\t\t\t\t0.332 | \n\t\t\t\t\t\t2.82 | \n\t\t\t\t\t\t1.39 | \n\t\t\t\t\t
25 | \n\t\t\t\t\t\t4.08 | \n\t\t\t\t\t\t0.427 | \n\t\t\t\t\t\t0.444 | \n\t\t\t\t\t\t0.193 | \n\t\t\t\t\t\t5.33 | \n\t\t\t\t\t\t0.648 | \n\t\t\t\t\t|
350 | \n\t\t\t\t\t\t7.58 | \n\t\t\t\t\t\t1.06 | \n\t\t\t\t\t\t0.444 | \n\t\t\t\t\t\t0.193 | \n\t\t\t\t\t\t11.4 | \n\t\t\t\t\t\t0.862 | \n\t\t\t\t\t|
5000 | \n\t\t\t\t\t\t23.8 | \n\t\t\t\t\t\t10.7 | \n\t\t\t\t\t\t0.556 | \n\t\t\t\t\t\t0.193 | \n\t\t\t\t\t\t27.3 | \n\t\t\t\t\t\t8.90 | \n\t\t\t\t\t
The pharmacokinetic parameters of atorvastatin and its metabolites following a single oral dose to male Sprague-Dawley rats.NC: not calculable
pharmacokinetic data, a microdose clinical study could help to determine if a drug has desirable pharmacokinetic properties that warrant further development. Highly sensitive and selective analytical tools such as LC-MS/MS and AMS have made it possible to characterize pharmacokinetics and metabolism of drug candidates at the microdose level. In the past several years, a lot of attention has been focusing on evaluating pharmacokinetic linearity of drug molecules from microdose to therapeutic doses in animals as well as in the clinic. It has been summarized that out of 26 drugs examined so far, 21 compounds, approximately 80%, have demonstrated linear pharmacokinetics between microdose to therapeutic doses (Lappin, 2010). For compounds which have failed to demonstrate pharmacokinetic linearity, there are a number of possible causes. For instance, drug candidates with saturable first-pass metabolism or saturable elimination at therapeutic doses would often result in under-prediction of exposure based upon microdose data. On the other hand, drug candidates with poor solubility would produce over-prediction of exposure based upon microdose data. Therefore, the understanding of physical and chemical properties of compounds and of enzyme kinetics in vitro could be very important prior to the commitment to a microdosing study. In practice, if there is a concern that compound would display nonlinear pharmacokinetics from a microdose to therapeutic doses in the clinic, a pharmacokinetic study could be performed to exam pharmacokinetic linearity in a relevant animal species.
\n\t\t\tMicrodosing could also be very valuable to obtain an earlier understanding of metabolism of drug candidates in the clinic. This has become more important with the release of the recent guidance document “safety testing of drug metabolites” by the FDA (Food and Drug Administration, 2008). The guidance document stated that metabolites found only in human plasma or metabolites present at disproportionately higher levels in humans than in any of the animal test species should be considered for safety assessment. In particular, human metabolites that are formed at greater than 10% of parent drug systemic exposure at steady state can raise a safety concern. As a result, it has become very important to obtain human drug metabolism information as early as possible in the drug development stage, and to compare with preclinical metabolism data. Although microdosing studies in the clinic would be ideal to understand the metabolism of drug candidates early on, caution must be exercised to extrapolate the learning from microdose to therapeutic doses. This could be particularly true for compounds where metabolism enzymes have low substrate capacities and can be saturated at low substrate concentrations. For example, the P450 isoform CYP2D6 is a low capacity enzyme and if a novel drug candidate is metabolized primarily through the CYP2D6 pathway, the metabolic pathway of this drug candidate at microdose may be different from that at therapeutic doses. The levels of a particular metabolite relative to parent drug, as the means to identify major metabolites, may be different from microdose to therapeutic doses. In this case, a thorough understanding of metabolic pathways with animals and in vitro would be very useful to assess reliability of drug metabolism prediction from microdose to therapeutic doses. In addition, a microdose clinical study would help to identify if human-specific metabolites are present so that a thorough evaluation of these human unique metabolites could take place in the relevant toxicological species.
\n\t\tThe highly selective and sensitive technology of LC-MS/MS has become a powerful analytical tool that provides the opportunity to understand clinical pharmacokinetics of compounds using the microdosing approach. Furthermore, LC-MS/MS has demonstrated its usefulness for detecting and characterizing metabolites in plasma and urine at microdose level. Although the extrapolation of parent drug exposure from a microdose to a therapeutic dose appears to be promising, such extrapolation for metabolites may be compound and/or metabolite dependent. Extrapolation of metabolite exposure would particularly be difficult if there is involvement of enzyme inhibition, induction or saturation.
\n\t\tHousehold waste is something that is common among most, if not all, living residences. Like any industrial facilities that handle potentially hazardous materials, households too dispose and use hazardous substances. The chemical complexion in the waste substances makes it so if disposed improperly, it could ignite, explode, poison, or corrode. Household hazardous waste (HHW) becomes what it is once thrown away. Methods of the waste being improperly disposed is pouring the substance down the drain, into storm sewers, on the ground, and throwing it in among the trash. It may not be obvious that these substances, once disposed, will be a danger, but particular varieties of HHWs have the prospective to:
cause somatic injury to sanitation workers;
if poured down drains or toilets, adulterate septic tanks or wastewater treatment systems;
pollute—if poured down storm sewers—bodies of water;
become a danger to young or unknowing children and pets if left open in the house;
contaminate ground and/or surface water that is used as a way of obtaining drinking water, if directed to exposed landfills.
A big problem that occurs/can occur through improper disposal of HHW would be the deconstruction that the sewage treatment plants are able to obtain. These plants are not able to deconstruct HHW compounds that people would drain or flush, which will end up traveling into lakes and rivers, unprocessed. As a result, one of the main releasers of dioxins and furans was from sewage systems. The substances proved to threaten human health due to the fact that they were highly carcinogenic. Other than the fact of the carcinogenic dangers, interference with the treatments plants could transpire. The toxins that would be processed could poison the microorganisms in the biological process. That would bring us to the position where our water systems would be more susceptible to harmful contaminants.
\nAs a given, hazardous waste is poisonous to all life forms, exposure of such hazardous substances to any living organism (plants and animals) could devitalize it. As a consequence, to the environment, hazardous waste could diminish natural resources and be contaminating to humans. Giving the young/fetuses, whether human or animal, exposure to these hazards would be substantially dangerous, as they are in a process or rapid growth. Introduction to chemicals for the living body would also interfere with biological structure, causing malfunction of organs and limbs.
\nIn addition to the effects to the human and animal bodies, hazardous waste would hinder plant growth. The impeding of plants that are of much use to the human race through manufacturing and consumption would affect our habitat. If the plants were slowly changing, for the worse, it would affect the animals that are needed for food, farm work, and would cause a whole new era of extinction.
\nIf our plant growth can affect our way of living easily, dumping the HHW into landfills gives us a much bigger problem. Landfills that are improperly maintained are major problem; even if they seem to be isolated from any contact, they can contaminate the environment around them. These landfills produce foul-smelling and toxin gases. Along with the gases and toxins, landfills generate leachate, which can travel to our water sources of lakes, rivers, and oceans. This would dig us into a deeper problem of both environmental and human existences. Thereby, leaving HHW unattended and improperly disposed could potentially destroy the ecosystem.
\nSeparate management of HHW from nonhazardous waste is rare. It is estimated that in countries within the Organization for Economic Cooperation and Development (OECD), household waste contributes to 67% of 540 million tons of municipal solid waste (MSW). The estimated amount of HHW varies considerably due to an unclear definition of what constitutes to household waste as opposed to MSW. In the USA, for the Environmental Protection Agency (USEPA), household products that contain corrosive, toxic, ignitable, or reactive ingredients are considered to be HHW. In general, the HHW is a solid, semisolid, or nonaqueous liquid that can cause or significantly contribute to potential hazard to human health or environment when it is improperly treated, stored, transported, disposed of, or otherwise managed. The portion of HHW in MSW has been estimated to be from less than 0.01–3.4% in several studies. The large variability is due to lack of standard definition as to what constitutes HHW, variability in generation, variability in weighing methods, and limited sample size. Nevertheless, 1% by weight is widely accepted as the fraction of HHW in MSW. Because of this small percentage of HHW produced, households are not practically considered to be hazardous waste producers [1]. While HHW represents a relatively small proportion of current urban solid residues, it is the most toxic part of the waste stream.
\nHHWs in the household waste are often excluded from management as hazardous waste unless collected separately. However, if these waste materials were generated industrially or commercially, they would be subject to strict disposal guidelines. As a result, HHWs are handled the same way as nonhazardous material with no specific regulation or monitoring. Of recent, this mismanagement constitutes a greater problem as the waste stream not only increases in amount but also becomes more diverse with the introduction of more products into the consumer market.
\nAt the source or point of generation, HHW can be placed in the garbage, down the drain, dumped on the ground, or diverted for reuse, energy recovery, or recycle. No matter where HHW is disposed, due to its toxicity as well as municipal treatment facilities that are not equipped to deal with hazardous material, improper management can adversely impact the quality of the environment:
Contaminate ground water bodies.
Contaminate surface water bodies.
Pollute air.
Affect the human health (children and pets if left around the house, cause physical injury to sanitation workers).
On the other hand, in many third world countries, solid waste management facilities are underdeveloped and sometimes nonexistent. The United Nations reported that between 20 and 80% of all household waste that is generated is often dumped in open spaces, water bodies, drains, and burnt or buried. This creates unsanitary environments leading to health hazards. The portion of HHW in household waste generated by developing countries is much less than in developed countries. The small amount of HHW produced as well as unavailability of funds to direct toward implementing sound practices for waste management has led the United Nations Environment Program to suggest HHW with MSW for disposal in landfills [2]. Regardless of the development level of the country, proper management of HHW can be achieved by understanding the environmental and societal impact of poor practices, HHW contaminants, government legislations, and well-developed schemes.
\nUnavailable facilities for proper HHW management discourage even their voluntary participation. While the products in the HHW list vary from country to country, below are categories that represent majority if not all products that can be classified as HHW:
Photochemicals
Pesticides
Mercury-containing wastes
CFC-containing equipment
Nonedible oil and fat
Paints, inks, resins, and adhesives
Detergents
Pharmaceuticals
Batteries
Waste electrical and electronic equipment
Wood preservatives
Aerosols
Personal care products
The risks that a hazardous product poses to the environment depend on certain characteristics of the toxic compounds:
Solubility
Mobility
Persistence
Degradability
Toxicity to nonhuman target species
Potential for penetrating landfill liners
Potential to be broken down in wastewater treatment system
HHW is likely to be disposed of improperly because residents do not always understand the level, effect, and potential impact of toxicity in the products that they use. In Figure 1, the disposal trend of households in the UK is presented after a survey with 400 respondents was carried out. One can observe that the predominant method for disposing HHW in households is into the garbage in spite of the toxicity level. A large portion of photochemicals and pharmaceuticals are discarded down the drain with little regard for the compounds that they contain and the consequences for this mode of disposal [4].
\nUsual HHW disposal regime of UK households [3].
Since information about the impact of HHW on the environment is not exhaustive and data relating to disposal are not well known, the potential impact of each of these products in the environment and health is considered as well as the amount that is approximately generated by households where available.
\nOn the other hand, Figure 2 shows a similar study conducted by Statistics Canada in 2009 with over 3800 respondents. While the garbage is still a significant disposal route for HHW, more households reported utilizing drop-off centers and returning products to suppliers and retailers [5].
\nUsual disposal routes in Canadian households (source: Statistics Canada).
These are liquid chemicals used in home developing and printing. Many of the ingredients in these products are toxic solvents and are predominantly disposed of in sewers. The unused portions of these chemicals are hazardous, but also the packaging can be problematic as it can contain some of the chemicals, which end up in the landfill and thus contaminate both soil and groundwater because these chemicals can penetrate the liners transporting to the groundwater and might end up to the surface water through the movement of groundwater. While the amount entering the sewers cannot be estimated, the packaging in the UK is estimated to be about 270 tons/year, most of which will end up in the landfills [6].
\nRapid growth in pesticide use has been observed, and this suggests a proportional increase in the amount that is being disposed of. According to the UK Pesticide Safety Directorate, many of the active compounds have been observed in landfill leachate of which research shows that they pose carcinogenic and endocrine disruptive risks [6]. On the other hand, incineration of pesticides is acceptable, provided that they do not contain mercury or arsenic. In Belgium, around 80% of waste pesticides are collected and incinerated [7].
\nHousehold products that contain mercury include fluorescent bulbs, stockpiled paint, dental amalgam, thermometers, and barometers. Of these, fluorescent bulbs contribute the highest amount of mercury waste. However, as the use of these is reported to have better energy and environmental impacts than regular light bulbs, they are so encouraged [8]. Improper disposal of fluorescent bulbs is where the risks lie. In the UK, it is estimated that 80 million are disposed of each year, of which only a small portion are recycled or processed for mercury extraction. In Brazil, lamps containing mercury contribute 1000 kg of mercury disposed of per year. Mercury exposure poses some health risks such as genetic damage and neurotoxicity damaging the kidney, liver, and central nervous system [6].
\nRefrigeration and air-conditioning appliances/equipment may contain chlorofluorocarbon (CFC) and hydrochlorofluorocarbon (HCFC) refrigerant. CFCs and HCFCs are ozone-depleting substances (ODS). If they released to the environment, they will destroy the protective ozone layer above the earth and potent greenhouse gases, contributing to global climate change. Examples of these types of equipment include motor vehicle and motor vehicle-like air conditioners, central and room air-conditioning units, refrigerators, freezers, chillers, drinking water coolers, dehumidifiers, research equipment, vending machines, etc. Manufacturing of such freezers and refrigerators has been phased out with the CFC component being replaced. However, disposal of these is still ongoing because of their 8- to 12-year life span leaving 4500 tons of CFC in the UK to be safely disposed of. Disposal of equipment that contains ODS is regulated in the EU by the WEEE directive where separate collection is mandatory [6].
\nNonedible oil and fat constitutes to about 15% of HHW in the UK. The waste section comprises mineral oils that often contain additives, which make it hazardous. While they are sometimes collected and rerefined or burned for energy, a significant portion is disposed of by end users down the drain or via oil filters and end up in the landfills. There, the oils can disrupt artificial landfill liners. Preferably, the steel component oil filters can be recycled after the oil is pressed for recovery and processed into fuel by companies [7]. Other examples are maintenance lubricants and greases for vehicles, which contain solvents and hydrocarbons that can be just as harmful.
\nDisposal of paints is the most significant in this category with the solvent-based paints posing the higher risk. In the UK, paints contribute to 17% of the total HHW with large quantities ending up in the sewers or mixed with MSW. However, schemes developed by local charities exist to collect unwanted paint and redistribute them at no charge. This scheme is limited by the quality of paint that can be used and quantity that can be accepted in any given location. Collected paint needs to meet certain criteria to be acceptable for redistribution such as age or packaging. Barely, 1% of the available excess paint is collected due to a small number of collection points [6, 7].
\nThe use of detergents in household is widespread. It has been reported that 5–20% of the phosphate that is found in surface and ground water in northern Europe originates from detergent use. However, not all detergents are classified as hazardous, but those containing acids, bases, and chlorinated solvents are of particular concern [7]. In addition, the biodegradability, the aquatic toxicity, endocrine disruptiveness of the surfactants, and other ingredients in the detergent contribute to its classification as hazardous. When combined, some compounds in detergents can release fumes that affect the eyes and mucous membranes, leading to respiratory failure and death after prolonged exposure [6].
\nIn the US, all over-the-counter (OTC) medicines are regarded as hazardous. However, in the EU, only those that are cytotoxic are classified as hazardous. Consumer disposal is not particularly regulated, as it would be problematic, but also due to the relatively low toxicity. As a result of the inability for wastewater treatment plants to remove pharmaceuticals from the waste stream, in many countries, they are now regarded as water contaminants. This is because they eventually make their way into drinking water supplies. They are transferred to sewage sludge during treatment, which is then applied to agricultural land or sent to a landfill [6].
\nPrimary, lead-acid, and nickel-cadmium batteries are those that fall into this category in HHW making up 6–14% of the HHW in the UK. Mercury in consumer batteries has been banned in Europe and many states in the US. However, many unregulated countries still use batteries containing significant concentrations or mercury, which often ends up in landfills. When buried in landfills, the casing of dry cell batteries can degrade and release heavy metals [9]. Most rechargeable batteries are used in consumer devices and nickel cadmium batteries. In the EU, these types of batteries must be easily removed from electronic devices, and separate collection for recycling is encouraged. However, these end up in MSW where recycling facilities are not well established because it is not mandatory. Cadmium is known to cause health effects like kidney damage. Lead-acid batteries comprise those found in vehicles, or smaller batteries in fire and security alarms. The recycling program for lead-acid batteries in the UK is well established, and 85% collection of the automotive variety has been recorded. However, the batteries from the alarms and from some battery changes carried out at home still end up in MSW. Lead acts as a chronic and acute neurotoxin affecting the kidney [6].
\nFor many years, home electric and electronic equipment has been disposed of in landfills along with their hazardous components. The amount that is being disposed continues to grow as consumer interest in current devices keeps increasing, which leads to discarding of obsolete electronics. WEEEs often have toxic compounds such that special handling is a requirement [8]. Many countries have prohibited the disposal of WEEE in landfills because of the toxicity and the strain of such large quantities of waste on the landfills. In the EU, this group of equipment is regulated under the WEEE directive such that they are collected and treated as hazardous waste. The directive also lists the substances that should be removed and collected from WEEE. Restrictions have also been placed on the use of certain materials in the manufacture of newer equipment [6].
\nThere are three types of treatments that are used to preserve wood, all of which can cause the treated wood to be hazardous, as they have hazardous properties. The types are tar oils, organic solvent-based, and water-based formulations. Creosote, an aquatic contaminant, is often used in tar oils. It is known to be a skin irritant, which causes photosensitivity and skin tumors following long exposure. Tributyltin is an example of organic solvent-based compound that is strictly regulated. A hazardous water-based substance is copper-chrome arsenate (CCA), which contains concentrations of heavy metals that have large health and environmental risks [6]. Arsenate is a priority carcinogenic contaminant of waste, which easily leaches in a landfill and can volatilize during incineration. Landfilling is not acceptable for disposal, and specialized air pollution control equipment is required for incineration [7].
\nAerosols are a large portion of HHW making up 26% of the HHW in the UK. In the past, CFC was widely used in the production of aerosols. However, CFC has been replaced with alternative propellants and solvents, which contribute significantly to the content in HHW. These replacements are often flammable and explosive. Exposure to aerosols can lead to nausea, skin, and throat irritation [6].
\nThe harmful nature of PCP has been supported by the discovery of certain long-term effects on health and the environment. While most PCP will end up in the sewers, unused products are stockpiled and end up in MSW.
\nIt is important to understand the fate of compounds in HHW when mixed with MSW for disposal. This has led to stricter disposal regulations in many developed countries to improve HHW management [6].
\nImproper disposal of HHW eventually leads to the presence of hazardous contaminants in the environment. All the facilities that are used to manage discarded HHW are in direct contact with environment media, air surface water, groundwater, and soil (Figure 3). These media are in constant contact with each other. As a result, when facilities cannot adequately break down hazardous compounds in HHW, the immediate environment is at risk.
\nThe contaminants enter the water cycle via groundwater or lakes, rivers, and streams traveling through the cycle [10] via different paths:
Precipitation from the atmosphere
Percolation through the soil
Direct disposal from a wastewater treatment plant (WWTP) into a surface water body
Residents pouring liquids down the stormwater drain that empties into a lake
In addition, toxic gases from HHW can be emitted into the air from the hazardous compounds that are used in producing them during controlled incineration or sometimes, uncontrolled fires [8].
\nLandfills can be the most economic way for waste management, especially in countries like Canada with large open spaces. However, poorly managed landfills have the potential of causing a number of environmental issues such as contamination of groundwater or aquifers or soil contamination. Modern landfills are not just holes in the ground to be packed with garbage. They can be considered as highly engineered contaminated systems. A modern landfill uses a number of technologies to ensure that the wastes are properly managed to avoid environmental pollution (e.g., ground water contamination, gas emission). Figure 4 shows schematic of a modern landfill process. Advanced protective liners (both natural and manufactured) are typically used to isolate the waste and leachate from leaking into the surrounding ground or ground water. Single, composite, or double liners can be used depending on the nature of the waste materials being deposited (see Figure 5). At minimum, a composite liner should be used for hazardous waste landfill facilities. However, landfills are not usually engineered to handle toxic compounds from HHW [9]. Hazardous liquid waste can be transported from a landfill into the environment if there are no barriers. Leachate that has been contaminated with hazardous material (soluble or insoluble) may destroy synthetic liners and render existing barriers ineffective, and thus, the hazardous waste comes in contact with the soil. Its fate is determined by the characteristics of the soil such as porosity, geological factors, and the contaminant like viscosity. The contaminant may percolate downward and affect the groundwater or spread and contaminate surrounding area [10]. Even if the leachate is collected, the treatment plants are not usually equipped to remove hazardous contaminants and end up releasing them into water bodies [11].
\nImproper disposal path of HHW from household to environment.
Schematic of modern landfill process (source: www.oocities.org).
In addition, the conditions of the landfill such as the air and moisture content can affect the fate of hazardous contaminants such as the rate of degradation or violent reactions [10]. For example, phthalic acid esters (PAEs) are used as plasticizers that are used in furniture, clothes, food packaging, etc., which are items that will invariably end up in the landfill. While readily degradable under aerobic conditions, those that are found in the landfill environment tend to retard biodegradability of PAEs. When the environmental impact of PAE in a landfill in China was studied, it was discovered the more complex congeners were found absorbed in deeper soils and in the groundwater [12].
\nCertain volatile organic compounds can be partially degraded and are readily absorbed by MSW in a landfill rather than volatilize. The moisture in the leachate enhances this process. Leachate-containing toxic compounds can be detoxified faster by recirculation within the landfill, which reduces the potential for leakage from the landfill liner. HHWs contribute volatile organic compounds (VOCs) to landfill gases such as benzene, methylene chloride, trichloroethylene, vinyl chloride, etc. VOCs from landfill gases contaminate off-site groundwater through migration [11].
\nThe quality of air emissions and ash residue is as a result of the fuel being incinerated. Incinerators usually have pollution control devices; however, some of the components that are found in HHW can pose a challenge to be captured. For example, mercury found in dry cell batteries, fluorescent light bulbs, and old paint can be converted to gaseous form and be emitted from the stack. Even the use of air treatment technologies can only remove 75–85%. Once it becomes in the atmosphere, mercury can be solubilized by rain and end up in water bodies. Other contaminants such as hydrogen sulfide and carbon monoxide that enter the atmosphere as gases may react with other compounds to become even more hazardous or remain in the atmosphere if stable, causing damage. Also, toxic metals have been found in the fly ash residue of incinerated MSW containing HHW. Damaging explosions have been reported due to a flammable liquid container being heated, which can lead to a few hours to few years of lost work time [11].
\nHazardous material dumped down the drain will end up in the on-site septic system or wastewater treatment plant depending on which system is employed. HHW can enter into wastewater treatment systems through its intended use or as a disposal method. Local governments usually prohibit disposal of HHW into stormwater drains. Recommended disposal may depend on the product and the industry. Some may be dumped down the drain with lots of running water, while others should be kept for collection [11].
\nConventional wastewater treatment plants combined physical, chemical, and biological treatment methods depending on the nature of the pollutants and desired level of removal. Modern wastewater treatment process consists of four levels, including preliminary, primary, secondary, tertiary, or advanced treatment, in addition to the solid waste management. Preliminary and primary treatments are mainly physical/mechanical (screening and gravity settling), while secondary and tertiary treatments use combination of biological, physical, and chemical treatment process (Figure 6). Preliminary treatment removes larger inorganic materials and floating particles, primary treatment removes a major portion (50–60%) of suspended solids from raw wastewater, and secondary treatment process removes organic matters and suspended solids. Secondary treatment usually consists of biological treatment of wastewater. Most of the WWTPs use aerobic activated sludge process for secondary treatment. The objectives of secondary treatment are to reduce BOD and SS of the effluent to an acceptable level according to the discharge regulation. In some cases, nutrient removal may be also an objective of secondary treatment. Biological treatment processes rely upon the ability of the organisms to utilize the contaminants as substrates and results in the generation of new biomass and biodegradation by-products.
\n(A) Single liner, (B) composite liner, and (C) double liner system.
Typical municipal wastewater treatment process.
Lye and bleach found in cleaning products and other hazardous components can hinder the bacteria that are utilized in the biological treatment processes and will significantly affect the process efficiency. This will cause wastewater to pass through the system without treatment and ultimately will reach the groundwater and/or surface water [10]. This can contaminate aquatic life; nitrates, and phosphates can cause eutrophication (algal bloom), leading to the use of more herbicides for control.
\nExcess loading of nutrients like nitrates and phosphates results in the uncontrolled growth of phytoplanktons and macrophytes. The growth and subsequent death of these organisms form a greenish slime layer at the surface of water bodies. This slime layer reduces the amount of sunlight that can penetrate through and the oxygen that can be replenished into the water. In addition, the excessive growth causes high competition for resources among aquatic organisms and death such that the biodiversity in the water body may be severely affected over time. This is the water pollution phenomenon known as eutrophication. Aside from the negative effects on water esthetics, eutrophication can hamper recreation activities, navigation, and aquatic life [13].
\nOn the other hand, heavy metals are toxic, persistent, and mobile and tend to accumulate. They generally have very low acceptable concentrations in drinking water standard. In WWTP, low-concentration volatile solvents can evaporate from the aeration tank and become air pollutants. However, high concentrations, acids, bases, poisons, and solvents can affect the WWTP workers’ safety and effluent quality and contaminate the sludge. Even if the wastewater flow does not contain HHW, leachate from landfills and combined sewer flow can introduce contaminants from pesticides and motor oil, which originate in the households of which even a small amount of pesticide concentration can cause a WWTP to fail toxicity test [11].
\nMajority of the e-waste collected in the US and other developed countries end up in developing countries in Asia and Africa, which often have less than adequate concern for the environmental impacts of the primitive recycling activities that are conducted. Illegal e-waste recycling activities in Guiyu, China, have led to the release of hazardous chemicals into the environment. Harmful concentrations of heavy metals and compounds such as polybrominated diphenyl ethers (PBDEs) were reported in local children and workers of the recycling facilities likely due to open dumping activities that contaminated the soil and river sediments. Polychlorinated biphenyls (PCBs) released during manual dismantling of electronics and from open combustion of the waste material resulted in the presence of significant concentrations in the local residents as a result of bioaccumulation in fish and inhalation [14, 15].
\nProper disposal of HHW starts with differentiating between hazardous household products and nonhazardous waste products. Mixing of household waste at the source must be addressed and banned. By collecting similar HHWs together, they can be more efficiently managed with regard to environmental safety, human health, and costs. When separated, arsenic-treated wood can be incinerated using proper pollution control technologies reducing any form of carcinogenic environmental impact, which may otherwise be present if it had been landfilled. Even more popular in developed countries is the separation and collection of cleaning products and pesticides. Majority of which can be incinerated according to best practices unless they contain mercury [7].
\nSome HHW products can be of value as they can be recycled for a different purpose or may contain material, which can be extracted for use in manufacturing other products, as in the case of antifreeze, which can be repurposed as an engine coolant. Another example is waste motor oil, which can be refined as lubricating oil or processed as low-grade fuel oil. Lead-acid batteries contain lead, which can be extracted to produce new batteries. Dry cell batteries, on the other hand, contain many different heavy metals, which may pose a problem for extraction. By collecting a significant amount separately, they can be disposed of more cautiously as hazardous waste [10]. Many EU states collect and recycle fluorescent tubes; however, in Germany, all the components of fluorescent tubes aside from the fluorescent powder have been reported to be reused [7].
\nRather than discard surplus products in the garbage or down the drain, items such as paint and wood preservatives can be given out to those who require them when in good condition. Charities that facilitate these have been established in certain countries.
\nFor any management system to be successful, efforts from the municipalities, manufacturers, and residents must be combined. Legislation that assigns responsibility for hazardous components and clarifies handling requirements of household hazardous products encourages manufacturers to consider sustainable methods of recycling waste from their products. Collection programs and proper management schemes fostered by municipalities and industries working together can reduce the amount of HHW that is discarded dangerously. At the core of these programs is the voluntary source separation by residents within their households. The participation of municipalities, manufacturers, and retailers is also required for these programs to be successful at HHW management (Figure 7) [1].
\nCollaboration between municipalities, producers, and consumers for proper HHW disposal.
The member states of the European Union (EU) are subject to the Waste Framework Directive (WFD) or the Directive 2008/98/EC of the European Parliament concerning general requirements for waste management. Established in 1975, this directive has been substantially amended with the latest revision provided in 2008. HHW is covered in article 20 of this directive, and as with previous directives, it is excluded from the definition of hazardous waste, while it is mixed with other types of household waste. The exclusion also applies when HHW has been separated from mixed household waste and remains until it has been collected properly. Under this legislation, there is no guidance to the management of HHW or legal obligation to the house owners [1, 16].
\nDirectives exist for specific categories of hazardous waste. These documents provide some direction for member states on collection and disposal of the waste and encourage the education of householders on the importance of separating HHW from mixed municipal waste and of the collection and recycling programs that are available to them. The categories include waste from electrical and electronic equipment (WEEE), batteries and accumulators, and waste oils.
\nWaste oils are covered under the WFD directly in article 21. About 3 million tons of waste oil need to be managed annually in the EU that can severely damage soil and water. The directive prohibits any type of disposal that may adversely affect the environment and human health, discourages mixing of different types of waste oils, and encourages separate collection. The directives for ‘batteries and accumulators’ and WEEE call for accessible and free collection points and requires producers and distributors to take back waste batteries, accumulators and electrical and electronic equipment (EEE). However, while the disposal of industrial and automotive batteries and accumulators in landfills and incinerators are prohibited, no such legislation is put forth for household batteries. On the other hand, disposal of WEEE is prohibited until proper treatment has been carried out [17].
\nHHW in the US is regulated under Subtitle D of the Resource Conservation and Recovery Act as solid waste. It is excluded from hazardous waste, provided that it is material from a permanent or temporary residence [18]. However, since solid waste is regulated by the state and local authorities, some states have more stringent regulations for the management of HHW.
\nAn example is Hawaii. Many of the items that are on the federal list as HHW are the same in Hawaii. However, lamps that contain lead and/or mercury and lead-acid batteries are managed more strictly. In addition, an electronic bill was passed that required computer manufacturers to establish recycling programs. There is also a prohibition on placing motor oil on the ground, in the drainage ways, in sewers, or into water bodies [19].
\nIn Canada, the disposal of solid waste falls under the care of the municipalities with the provinces monitoring operations. While HHW is limited to paint, aerosols, solvents, pesticides, and other products containing hazardous properties, the Waste Diversion Act sets the requirements and guidelines for management of HHW, WEEE, and waste oils in Ontario. Under this act, manufacturers are financially responsible for HHW program, which was developed in 2006 to manage waste from their products. Similarly, WEEE management is mandatorily funded by industry though some retailers charge consumers an environmental fee at the time of purchase of electronic equipment. However, recycling of mercury-containing lamps is voluntary for consumers [20].
\nMunicipalities may establish frequent HHW curb-side pickup as part of the general waste collection program. While convenient for households, this mode can be expensive and time-consuming for waste management authorities [1, 19]. Other options include less frequent collection such as biannually, residents requesting special wastes pick up or personal drop-off at central locations. Such programs for proper disposal and recycling are well established in many countries including the US, Australia, Germany, Denmark, and Sweden [1, 7].
\nThe Extended Producer Responsibility (EPR) is a government policy approach that places the main responsibility of managing a product on the producers or manufacturers. The EU’s WEEE directive and Hawaii’s computer recycling program are primary examples of such a legislative approach. Companies within an industry can collaborate to develop initiatives for handling waste from their products. The Rechargeable Battery Recycling Corporation (RBRC) is a company that was created by the efforts of battery manufacturers in North America. RBRC is responsible for collecting and processing certain types of batteries in order to extract metals that can be used in manufacturing new batteries [11].
\nVery similar to the EPR is the Product Stewardship (PS) approach. The manufacturers, retailers, and consumers share the responsibility for the end of life management of a product. The EU has programs similar to these for the management of pesticides and air fresheners [11]. The US also has a well-established PS system and enforces these programs in some states through laws, subsidies, fees, and mandatory take-backs [1]. The retail take-back system provides a setting for retailers to collect waste materials from consumers whether for exchange or refunds. It is particularly attractive because retailers tend to be within reach and more convenient for consumers. However, there is the potential for such a program to place financial burden on the retailers due to handling and storage requirements. In North America, it has been used successfully for the management of all kinds of waste including automotive batteries, fluorescent lamps, mercury thermostats, etc. Likewise, Japan has a take-back program for home appliances, but it is mandatory and requires consumers to pay the retailer for the waste handling [3].
\nIn this chapter, the adverse impacts of improper disposal of HHW on the environment were discussed. Improper disposal of HHW introduces harmful compounds, which cannot be removed by treatment facilities into the environment, and these chemicals end up in human, animal, and plant tissues. What constitutes to inadequate disposal varies from pouring down the sink or drainage, dumping in the garbage or even out on the ground outdoors. Even when proper disposal routes are provided by municipalities such as drop-off centers are available, many classes of HHW are still disposed in the garbage. Public education, source separation, and recycling are key strategies to reducing the quantity of HHW stream into municipal facilities and by extension of the environment. The success of these strategies for HHW disposal requires voluntary action from residents, legislation from governments mandating manufacturers to take better responsibility, and schemes that make proper disposal more accessible to residents.
\nAs this section deals with legal issues pertaining to the rights of individual Authors and IntechOpen, for the avoidance of doubt, each category of publication is dealt with separately. Consequently, much of the information, for example definition of terms used, is repeated to ensure that there can be no misunderstanding of the policies that apply to each category.
",metaTitle:"Copyright Policy",metaDescription:"Copyright is the term used to describe the rights related to the publication and distribution of original works. Most importantly from a publisher's perspective, copyright governs how authors, publishers and the general public can use, publish and distribute publications.",metaKeywords:null,canonicalURL:"/page/copyright-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\\n\\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\\n\\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
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\\n\\nWork - a Chapter, including Conference Papers, and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
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The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
\\n\\nContent reuse:
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\\n\\nContent reuse:
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\\n\\nPolicy last updated: 2016-06-08
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\n\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\n\nAgreement samples are listed here for the convenience of prospective Authors:
\n\n\n\nDEFINITIONS
\n\nThe following definitions apply in this Copyright Policy:
\n\nAuthor - in order to be identified as an Author, three criteria must be met: (i) Substantial contribution to the conception or design of the Work, or the acquisition, analysis, or interpretation of data for the Work; (ii) Participation in drafting or revising the Work; (iii) Approval of the final version of the Work to be published.
\n\nWork - a Chapter, including Conference Papers, and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
\n\nMonograph/Compacts - a full manuscript usually written by a single Author, including any and all text, graphics, images and/or other materials.
\n\nCompilation - a collection of Works distributed in a Book that IntechOpen has selected, and for which the coordination of the preparation, arrangement and publication has been the responsibility of IntechOpen. Any Work included is accepted in its entirety in unmodified form and is published with one or more other contributions, each constituting a separate and independent Work, but which together are assembled into a collective whole.
\n\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
\n\nIntechOpen platform - IntechOpen website www.intechopen.com whose main purpose is to host Monographs in the format of Book Chapters, Long Form Monographs, Compacts, Conference Proceedings and Videos.
\n\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
\n\nTERMS
\n\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported License, a license which allows for the broadest possible reuse of published material.
\n\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
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Creative Commons Attribution 3.0 Unported (CC BY 3.0) | \n\t\t\t\n\t\t\t 5 October 2011 (2011-10-05) \n\t\t\t | \n\t\t\tCurrently | \n\t\t
The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
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\n\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
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