Health Effects of Workplace Chemicals Toluene, Benzene, Methyl ethyl peroxide, and Epichlorohydrim Includes: Final Report By Tarannum Syed Completed for: Occupational and Environmental Health Coalition Supervising Professor: Dr. David Beresford, Trent University Trent Centre for Community-Based Education Department: Environmental and Resource Studies Course Code: BIOL 3891H Course Name: Community-Based Research Project Term: Fall 2010 Date of Project Submission: December, 2010 Project ID: 4127 Call Number:
Transcript
Health Effects of Workplace Chemicals Toluene, Benzene, Methyl ethyl peroxide, and Epichlorohydrim
Includes: Final Report
By Tarannum Syed
Completed for: Occupational and Environmental Health Coalition Supervising Professor: Dr. David Beresford, Trent University Trent Centre for Community-Based Education Department: Environmental and Resource Studies Course Code: BIOL 3891H Course Name: Community-Based Research Project Term: Fall 2010 Date of Project Submission: December, 2010 Project ID: 4127 Call Number:
Name: Tarannum Syed Professor: Dr. David Beresford Course Code: BIOL 3891H Completion date: December 2010
Health Effects of Workplace Chemicals Toluene, Benzene, Methyl ethyl ketone peroxide, and
Epichlorohydrin
2
Contents
Abstract 2
Keywords 2
Acknowledgements 3
Introduction 5
Part 1 6
Part 2 10
Conclusion 22
Literature Cited 23
Appendix 31
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Abstract
Volatile organic compounds (VOCs) are some of the most hazardous materials workers may
be exposed to. This study reviewed the health effects of toluene, benzene, methyl ethyl ketone
peroxide (MEKP) and epichlorohydrin (ECH). In part 1, the number of studies between the years
2000 to 2010 that have investigated the health effects of each chemical in specific medical categories
and those that have shown a correlation between negative health effects in the categories and the
chemicals are represented in graphical form. In part 2, the most significant results of these studies
are discussed. In reviewing the findings, it is apparent that toluene has significant effects on the
central nervous system (CNS), development, reproductive system, immune system, liver, kidneys,
auditory system and cardiovascular system; that benzene is a potent carcinogen and has pervasive
adverse effects on the blood, CNS, immune system, and respiratory system; that MEKP may cause
cancer and has substantial damaging effects on the skin, gastrointestinal tract and liver; and that
ECH is a potential carcinogen and has negative effects on the cardiovascular system, kidney, liver,
reproductive system and the respiratory system. Overall, the health hazards that this review
highlights will help workplaces identify important health considerations when assessing dangers of
worker exposure to these chemicals.
Keywords
General Keywords Chemical Keywords Health Effects Keywords - Occupational health
and safety - Hazardous
Chemicals - Health - Workplace
- Toluene - Benzene - Methyl ethyl ketone
peroxide - Epichlorohydrin
- Immune system - Cardiovascular system - Respiratory system - Kidneys - Liver - Auditory system - Central nervous system - Blood - Development - Gastrointestinal tract - Skin - Reproductive system
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Acknowledgements
Dr. Beresford’s guidance in what information to include, the most effective way to present
this information, the most efficient way to do literature searches, and the number of chemicals to
research was invaluable to me. He encouraged me to ensure that I am involved in this project in a
way that would be personally and academically satisfying to me. He was always available to answer
my questions and gave me much of his time. I am very appreciative of all of the ways in which Dr.
Beresford supported me during the process of completing this project.
I would also like to thank Paula Goodfellow Meyer, Kathy Dracup-Harris, Heather Brooks-
Hill, John Ball and Dr. Noel Kerin from the “Occupational and Environmental Health Coalition,
Peterborough” for their suggestions, time and dedication to making this project one that I felt
comfortable with and believed would be academically enriching. Also, I appreciate the insights,
experiences and perspectives that John Ball shared with me regarding workplace safety issues at a
manufacturer in Peterborough, ON. I would also like to express my admiration for Mr. Ball’s
perseverance in ensuring that workplace safety health hazards obtain the attention that they deserve
from his community.
In addition, Marjorie MacDonald from the Trent Centre for Community-Based Education
was always available to clarify project procedures and protocols, to connect me with the host
organization, and to provide support during my work on the project. I greatly appreciate her help in
navigating the logical aspects of this project. I would like to thank all parties involved for a very
rewarding experience.
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Introduction
The study of Occupational Health and Safety is concerned with worker exposure to
hazardous chemicals within the workplace (Papadopoulos et al. 2010). Hazardous chemicals are
elements, synthetic substances, or mixture of elements and synthetic substances that are considered
harmful to employees (Papadopoulos et al. 2010). One group of hazardous chemicals is volatile
organic compounds (VOCs) (Papadopoulos et al. 2010). VOCs evaporate more readily than water
and have high vapour pressures (Boyes et al. 2007). They present unique challenges for workers
because their vapours often have the ability to result in potent health effects, and individuals who are
not directly exposed to these chemicals but share the same workplace air are susceptible to the risks
of them; as such, compounds that are classified as VOCs are considered to be some of the most
hazardous chemicals in workplaces (Papadopoulos et al. 2010). Some VOCs are toluene, benzene,
methyl ethyl ketone peroxide (MEKP) and epichlorohydrin (ECH) (Papadopoulos et al. 2010; Boyes
et al. 2007; Zhang et al. 2010; Shin et al. 2010; Hanausek et al. 2004).
Although there are ongoing concerns regarding the adverse health effects of toluene,
benzene, MEKP and ECH, they continue to be used in many workplaces, with several million
workers within Canada exposed daily (Papadopoulos et al. 2010). The primary purpose of this study
is to review significant findings on the health effects of toluene, benzene, MEKP and ECH that have
been published between 2000 to 2010. It is essential to conduct such a study in order to address
information that needs to be communicated to workplaces and workers that use these chemicals.
Toluene, benzene, MEKP and ECH have many widespread health effects that remain after exposure
occurs, and thus can significantly reduce the quality of life of many workers, emphasizing the need
for workplaces to be pro-active (Shin et al. 2010). This study is also important because it will
highlight gaps in the literature on these chemicals that could affect the current understanding of the
health risks they pose.
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Part 1: Quantitative Presentation of Literature on Health Effects of Toluene, Benzene, Methyl Ethyl Ketone Peroxide and Epichlorohydrin
Methods
The Trent University Scholars Portal Database was used to research studies investigating the
toxicity of the following chemicals: toluene, benzene, MEKP and ECH. In the initial search, the full
name of each chemical was entered as a keyword. The titles/abstracts were reviewed to determine
the medical categories that were relevant to the health effects of each chemical. During the next
search, the chemical was entered as a keyword, and each medical category was entered in the
abstract field. In the search results for each medical category, abstracts were reviewed to determine
whether a relationship had been found between the chemical and the category. The search was
limited to studies published within the years 2000 to 2010. The total number of studies that
investigated the relationship between each chemical and each medical category was recorded. In
addition, for each chemical, the number of studies showing toxicity effects within each category was
recorded. A bar graph was generated for each chemical.
To illustrate how these methods were applied to each chemical in this study, methyl ethyl
ketone peroxide can be used as an example. “Methyl ethyl ketone peroxide” was entered in the
search field and “keyword” was selected. In the refine by date field, the years 2000 to present were
selected. The titles and/or abstracts of the results retrieved in the search were reviewed to determine
what medical categories were relevant to methyl ethyl ketone peroxide toxicity. The skin,
gastrointestinal tract and carcinogenesis were identified as prominent categories that had been
investigated in studies that focused on the health effects of methyl ethyl ketone peroxide. In the next
search, methyl ethyl ketone peroxide was entered in the search field and “keyword” was selected.
Also, “skin” was entered in the search field and “abstract” was selected. In the results that were
obtained, the abstracts were read to determine whether the studies had found that methyl ethyl
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ketone peroxide produced toxic effects on the skin. The total number of results from this search was
recorded, and the number of results that showed a correlation between toxic skin effects and methyl
ethyl ketone peroxide was also recorded. This data was used to generate a bar graph. These steps
were repeated with two other searches: one using “gastrointestinal tract” in the abstract search field
and the other using “carcinogenesis” in the abstract search field. In both of these searches, “methyl
ethyl ketone peroxide” remained in the keyword search field.
Results
As can be seen in figure 1, for toluene, the CNS had the most support and the liver had the
least support, in terms of the number of studies showing a correlation between toluene and toxic
effects in these medical categories. Specifically, CNS had 12 more studies supporting its
involvement in toluene-related toxicity than did the liver. All the studies that investigated toluene’s
relationship with toxic effects on the CNS liver showed a correlation with toluene exposure. Also,
out of the four chemicals researched in this study, toluene had the greatest number of studies
published regarding its health hazards.
For benzene, carcinogenesis had the most support and the respiratory system had the least
support, in terms of the number of studies showing a correlation between benzene exposure and
toxic effects in these medical categories. Specifically, carcinogenesis had 18 more studies supporting
its involvement in benzene-related toxicity than did the respiratory system. All the studies that
investigated benzene’s role in carcinogenesis and impact on the respiratory system showed a
correlation between benzene exposure and toxic effects in these categories.
Out of the four chemicals researched in this study, MEKP had the least number of studies
published regarding its effect on health. The skin had the most support and both the gastrointestinal
tract and carcinogenesis had the least support, in terms of the number of studies showing a
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correlation between MEKP and toxic effects in these medical categories. Specifically, the skin had 1
more study supporting its involvement in MEKP-related toxicity than did the gastrointestinal tract or
carcinogenesis. All the studies that investigated MEKP’s role in carcinogenesis and impact on the
skin and gastrointestinal tract showed a correlation between MEKP and toxic effects in these
categories.
There were very few studies that investigated ECH’s health effects. Carcinogenesis had the
most support and all the other categories were equivalent in terms of the number of studies that
demonstrated ECH’s toxic effects on them. Specifically, carcinogenesis had one more study
supporting its involvement in ECH-related toxicity than did the other areas. All studies showed a
correlation between ECH use and toxic effects in the medical categories.
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Figure 1: The number of studies published between the years 2000 to 2010 investigating the ability of each chemical to produce toxic effects in different medical categories. See methods for search protocol. CNS refers to central nervous system. The total number of studies is shown in grey and the number of studies showing a correlation between the chemical and the medical category is shown in black.
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Part 2: Current Research on the Health Effects of Toluene, Benzene, Methyl Ethyl Ketone Peroxide and Epichlorohydrin
Toluene
Toluene is a clear, colourless, flammable liquid at room temperature (Boyes et al. 2007).
Through flow or agitation, toluene can accumulate static charge (Boyes et al. 2007). At high
temperatures, toluene decomposes to release toxic gases (Boyes et al. 2007). This chemical can
accumulate in confined spaces (Boyes et al. 2007). The most common purpose of toluene is to make
benzene (Boyes et al. 2007). Toluene can also be used to produce other chemicals, including toluene
and maleic anhydride (Zhang et al. 2010). In addition, Benzene is generated from petroleum and
coal sources and is present in gasoline in minute amounts (Zhang et al. 2010). Although benzene is
still used as a solvent and reactant in laboratories, it is rarely used a solvent commercially due to its
toxicity (Zhang et al. 2010). One can be exposed to the toxic effects of benzene through inhalation,
ingestion and eye or skin contact (Zhang et al. 2010). Benzene has been found to have carcinogenic,
hematotoxic, immunotoxic and neurotoxic effects (Zhang et al. 2010).
Occupational exposure to benzene has been strongly correlated with cancer. It has been
suggested that carcinogenic effects may begin at 64 mg/m3 as a result of benzene-induced
chromosomal aberrations (Duarte-Davidson et al. 2001). In addition, sister chromatid exchanges,
DNA cross-linking and DNA adduct formation have all been implicated in the mechanisms by which
benzene causes cancer (Troester et al. 2000). Furthermore, the metabolites of benzene, including
catechols, phenol, hydroquinone and benzoquinone have been observed to result in a dose-dependent
increase of the frequency of homologous DNA recombination (Winn 2003). There is growing
support for the hypothesis that oxidative stress plays a key role in establishing the carcinogenic
effects of benzene. For example, in a study by Winn (2003), it was seen that activation of catalase,
an antioxidant enzyme, completely blocked the increased frequency of recombination. In addition,
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benzene exposure was accompanied by increased levels of free reactive oxygen species (Winn
2003). Thus, it is likely that free radical formation, as a result of benzene metabolism, largely
contributes to benzene’s carcinogenic potential (Winn 2003).
Some research has also implied that benzene may have carcinogenic effects within the
respiratory system. In a study by Pariselli et al. (2009), human lung cells (A549) exposed to 0.25
ppm of benzene did not experience DNA damage but did experience a decrease in glutathione
(GSH). Reductions in GSH have been linked with early toxicological effects, and thus, it is possible
that the level of DNA damage that had occurred was too low to be detected in this study. Pariselli et
al. (2009) also found that when benzene was combined with toluene at 0.25 ppm, there was a
dramatic increase in DNA damage when compared to the effect of either chemical alone at 0.25 ppm
(Pariselli et al. 2009). This highlights one of the synergistic effects of being exposed to compounds
containing both toluene and benzene.
Benzene also has extensive hematotoxic and immunotoxic effects. While Qu et al. (2002)
found that 0.5 ppm of benzene was sufficient to decrease the number of neutrophils, Schnatter et al.
(2010) suggests that 8 ppm of benzene is required to induce hematotoxic effects. While some studies
have suggested that less than1 ppm of benzene exposure can result in the reduction of almost all
blood cell counts, including red blood cells, white blood cells, granulocytes, lymphocytes and
platelets, others have found that more than 30ppm is required to induce lymphocyte reduction
(Zhang et al. 2010). In addition, in one study, expressions in red blood cells and white blood cells
were significantly different in the lowest exposed group (at 0.25 ppm) compared with the control
group (Qu et al. 2002). Furthermore, the presence of toluene in toluene-benzene mixtures has been
shown to significantly exacerbate the effects of benzene and increase the decrease in lymphocytes
(Schnatter et al. 2010). In addition, Li et al. ( 2009) found that the level of T-cell receptor excision
DNA circles (TRECs) in the peripheral blood mononuclear cells (PBMCs) of all benzene-exposed
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workers in their study were significantly decreased when compared with controls. As a result, the
thymic output function and the T-cell immune function were impaired in workers after benzene
exposure (Li et al. 2009). Another study showed that increased levels of specific Immunoglobulin G
were correlated with benzene exposure in workers (Dimitrova et al. 2005). It is also likely that
benzene metabolites induce the formation of antibodies during benzene exposure (Dimitrova et al.
2005)
Although most of the research on benzene has focused on its hematotoxic, immunotoxic and
carcinogenic effects, a few studies have elucidated its effects on the CNS (Banik et al. 2005). One
such study showed that male swiss mice that were chronically exposed to benzene via drinking water
for one month, experienced significant dose-dependent decreases in serotonin concentration in
serotonergic neuron-rich regions of the brain (Banik et al. 2005). The most affected areas were the
hypothalamus, raphe, and audateputamen (Banik et al. 2005). This was accompanied by a loss in
short term memory, as seen during the passive avoidance test (Banik et al. 2005). Another study
found that individuals who worked with diesel exhaust suffered memory deficits, sensory losses,
equilibrium balances and mood swings (Kilburn 2000; Sydbom et al. 2001). In light of these
findings, it appears that benzene may have been one of the primary causative agents of the memory
loss seen in the study by Banik et al. (2005).
Overall, the studies that have investigated benzene’s relationship to health in the last decade
indicate that benzene is a potent carcinogen and has pervasive effects on the blood, CNS, immune
system, and respiratory system.
MEKP
MEKP is a colourless, high-viscosity, oily, organic peroxide (Hanausek et al. 2004). MEKP
is liquid at room temperature and is combustible (Hanausek et al. 2004). As such, it has a high risk
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of explosion from exposure to shock, friction, flame, or other sources of ignition (Hanausek et al.
2004). MEKP is extremely reactive and may decompose violently (Hanausek et al. 2004). If it
comes into contact with water or moist air, irritating gases are liberated (Hanausek et al. 2004). One
can be exposed to the toxic effects of MEKP through inhalation, ingestion and eye or skin contact
(Hanausek et al. 2004). Due to its ability to produce free radicals, MEKP is used to initiate the
polymerization of polyester resins and acrylic resins (Hanausek et al. 2004). It is also used as a
hardening agent for fiberglass-reinforced plastic. Studies done within the last decade have suggested
that MEKP may be involved in carcinogenic mechanisms, dermatological conditions and
gastrointestinal tract injuries (Hanausek et al. 2004).
In the last decade, there has been only one study that has investigated the carcinogenic effects
of MEKP. When SENCAR mice were exposed to MEKP topically for 4 weeks, epidermal
hyperplasia was increased significantly (Hanausek et al. 2004). Since epidermal hyperplasia is a
biomarker of tumour production, MEKP was thought to have tumour- promoting activity (Hanausek
et al. 2004). In addition to carcinogenic effects, this study also illustrated the ability of MEKP to
cause skin damage. Similarly, an investigation by Minamoto et al. (2002) found that of the 22
fibreglass-reinforced plastics factory workers they studied, all had experienced skin problems after
beginning their job, and four showed positive skin reactions to MEKP. These workers had been
exposed to MEKP by working with the hardeners at this factory (Minamoto et al. 2002). This study
has established a correlation between MEKP and irritant contact dermatitis (Minamoto et al. 2002).
MEKP has also been seen to cause upper gastrointestinal tract injuries. A previously healthy
53 year old who had ingested MEKP died 6 hours after its ingestion (Moon et al. 2010). On simple
radiography, it was seen that the patient had diffuse gastric emphysema (Moon et al. 2010). This was
likely due to the upper gastrointestinal tract pressure that occurred (Moon et al. 2010). Corrosives
significantly damage the esophagogastric mucosa, and this in turn increases gastrointestinal tract
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pressure (Moon et al. 2010). MEKP’s corrosive power can be attributed to its free radical production
and lipid peroxidation ability (Moon et al. 2010). Lipid peroxidation has also been the suspected
mechanism by which MEKP results in liver necrosis (Moon et al. 2010). Liver necrosis has been
observed in both adult and pediatric patients who have experienced chronic exposure to MEKP
(Enckevort et al. 2008; Bates et al. 2001).
Overall, these studies indicate that MEKP has substantial damaging effects on the skin,
gastrointestinal tract and liver and that MEKP can cause cancer. The findings from this review need
to be considered in view of the fact that very few studies have investigated the effect of MEKP on
health.
ECH
ECH, an aliphatic epoxide, is a colorless liquid that is employed in manufacturing epoxy
resins, glycerin, coatings, adhesives, paints, varnishes, insecticides, and many other products (Shin et
al. 2010). It is commercially synthesized from allyl chloride, allyl alcohol, dichlorohydrin glycerin,
or propylene (Shin et al. 2010). ECH exposure can occur via inhalation, ingestion, and eye or skin
contact (Shin et al. 2010). Rapid absorption occurs following any of the aforementioned exposure
routes (Shin et al. 2010). In the last 10 years, research on ECH has shown that it may be
carcinogenic and exert negative effects on the respiratory tract, heart, kidney, liver and reproductive
system (Shin et al. 2010).
One major study has suggested that epichlorohydrin (ECH) may be carcinogenic. Bukvic et
al. (2000) looked at the effect of ECH on the blood of 4 healthy non-smoking and 3 smoking males.
They found that ECH increased the amount of sister chromatid exchanges and cell frequencies in the
lymphocyte cultures of all subjects (Bukvic et al. 2000). Interestingly, the effects of ECH were
observed to be comparable in lymphocyte cultures from non-smoker and smoker subjects (Bukvic et
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al. 2000). Since greater frequency of cells and sister chromatid exchanges have been related to the
formation of tumours (Bukvic et al. 2000), it is likely that ECH is a carcinogen. Most importantly,
this study implies that when cancer arises in smokers who have been exposed to ECH, it is important
not to assume that smoking is the underlying cause of the cancer and to seriously explore the effect
ECH might have had in contributing to the cancer. Since epoxides themselves are alkylating agents
in vivo and can react with different nucleophilic centers of cellular macromolecules including
proteins and DNA, another way that ECH may be carcinogenic is through forming DNA adducts
(Koskinen et al. 2000). Many studies have shown that DNA adducts are formed upon ECH exposure
(Koskinen et al. 2000). DNA adducts, in turn, have been correlated with carcinogenic processes
(Koskinen et al. 2000). However, this correlation is not a strong one as DNA adduct formation from
epoxides could also be due to other chemicals within the expoxides.
ECH has also been suggested to be substantially damaging to the respiratory system. One
study investigated the effect of ECH on the respiratory tract of 167 workers in a factory (Luo et al.
2003). 66 air samples of the workers’ environments were taken to determine areas of high and low
ECH (Luo et al. 2003). The prevalence of obstructive lung function abnormalities and small airway
lung dysfunction were significantly higher in the ECH workers than in the control group (Luo et al.
2003). While the prevalence of small airway abnormalities was not significantly different between
the low and high ECH groups, that of obstructive lung function abnormalities was (Luo et al. 2003).
Thus, this study indicates that low concentrations of ECH (less than 0.2 ppm) is sufficient to result in
small airway abnormalities, but that higher ECH concentrations are required to produce obstructive
lung function aberrations (Luo et al. 2003). The results of this study also indicate that very low
concentrations of ECH cause a significantly high occurrence of respiratory tract irritation symptoms
(cough, phlegm, chest tightness, dyspnea) (Luo et al. 2003).
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In addition to respiratory function, ECH has also been suggested to have significant effects
in other areas of the body. In a study of 24 female and male rats that were given ECH through daily
gavage for 10 weeks, it was seen that the lowest observed level of ECH required to produce illness
was 3.3mg/kg/day (Shin et al. 2010). At this level of ECH, there was a reduction in the male fertility
index (Shin et al. 2010). In addition, at 30 mg/kg/day, an increase in the incidence of clinical signs,
such as nasal discharge, soft feces, depression, and piloerection were seen (Shin et al. 2010). As
well, cystic pustules of the epididymis and enlargement of the kidneys occurred (Shin et al. 2010).
This was accompanied by an increase in the weights of the heart, liver, epididymis, and a decrease in
male fertility (Shin et al. 2010). 30mg/kg/day of ECH also caused the following effects: spermatic
granulomas, cell debris in the ducts, desquamation of the epithelial cells, vacuolization of the
epithelial cells, oligospermia in the epididymis, atrophy and exfoliation of germ cells in the testis,
and focal necrosis/degeneration, cast formation, vacuolization of renal tubular cells, renal tubular
regeneration, renal tubular dilation, inflammatory cell infiltration, and congestion/hemorrhage in the
kidney (Shin et al. 2010). The increase in the incidence and severity of these results with increasing
dose of ECH indicates that it is likely that these findings were directly due to ECH exposure. In
addition, at 10mg/kg, a reduction in male fertility, elevation in kidney weight and histopathological
changes of the epididymis were found (Shin et al. 2010).
Overall, in the last decade, the studies that have investigated ECH’s relationship to health
indicate that ECH is a potential carcinogen and has pervasive effects on the cardiovascular system,
kidney, liver, reproductive system and the respiratory system. The findings from this review need to
be considered in view of the fact that very few studies have investigated the effect of ECH on health.
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Conclusion
In reviewing the findings of studies published between the years 2000 to 2010 on the health
effects of toluene, benzene, MEKP and ECH, it is apparent that there are many gaps within the
literature that need to be investigated in future studies. The effects of MEKP and ECH have only
been researched in a limited number of studies, and as such, establishing strong conclusions
regarding their health effects is not possible; however, the evidence reviewed here indicates that
these are potentially significant hazards that warrant more research. In addition, most studies have
focused on non-human animal models, and findings from these studies need to be supplemented by
more studies on human cell lines. As well, studies that quantify how far these chemicals can be
transmitted through workplace air and the extent of their potency when indirect exposure is taking
place are required. Moreover, the standard levels of exposure required to develop toxic effects in
each medical category for each chemical needs to be determined and communicated to workplaces
and workers. Currently, the amount of exposure required to result in acute and chronic effects have
not been established (Berenguer et al. 2004). In addition, more multi-generational studies are
necessary to further investigate the chronic health effects of these chemicals as chronic effects are
most likely to significantly reduce a worker’s quality of life. Such multi- generational studies would
also allow researchers to assess potential differences between the generations, both in terms of the
types of effects observed and in terms of the required doses. Also, in future reviews, more synonyms
for each keyword should be entered into the search field to maximize the number of results obtained.
This review suggests that since toluene and benzene have received a great deal more attention in the
literature than MEKP and ECH, their health effects may be more significant or they may be more
used more commonly in workplaces. Although it is important to identify gaps in the literature
reviewed in this study, it is equally important to acknowledge that this study strongly suggests that
toluene, benzene, MEKP and ECH have far-reaching effects on workers’ health that need to be
23
seriously considered and addressed in workplaces where workers, indirectly or directly, interact with
these chemicals.
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* These are the studies that were cited in-text in part 2 of this report
