Nickel is one of the most commonly known sensitisers and has been classified by the International Agency for Research on Cancer (IARC) as a possible carcinogen to humans (group 2B). Workers at a South African base metal refinery packaging area are potentially exposed to many hazardous chemicals that include nickel. Aims and Objectives: The aim and objectives of this study were to assess dermal and respiratory exposure of workers exposed to nickel in a packaging section at a South African base metal refinery and to assess the change in skin barrier function during a work shift by measuring percentage change in trans epidermal water loss (TEWL), skin hydration and skin surface pH. Skin health was established with a skin questionnaire. Surfaces that workers may come into contact with were also assessed. Method: Respiratory and dermal exposure assessment was done concurrently. Respiratory exposure was assessed and analysed by using the National Institute for Occupational Safety and Health (NIOSH) method 7300. The Institute of Occupational Medicine (IOM) inhalable aerosol sampler was used for personal air sampling. The TEWL index, skin hydration and skin surface pH of the index finger, palm, forearm and forehead were measured before and at the end of the shift with a Derma Measurement Unit, EDS 12 and Skin-pH-Meter® pH 905. These measurements were reported as percentage change in skin barrier function during the shift. Dermal exposure samples were collected with Ghostwipes™ from the index finger and palm of the dominant hand before, during and at the end of the shift, while samples from the forearm and forehead were only collected before and after the shift. Surface sampling was collected and all wipes were analysed for nickel according the NIOSH method 9102, using inductively coupled plasma-atomic emission spectrometry. Results: Respiratory exposure for the whole group of workers in a packaging section was well below the eight hour Time Weighted Average (TWA) respiratory Occupational Exposure Limit (OEL) of 0.5 mg m-3 for nickel. Dermal nickel loading was detected for all the job categories on all the anatomical areas even before the shift had commenced. During the shift more nickel was detected on the index finger and palm of the hand. Levels on the forearm and forehead were much lower in comparison with the index finger and the palm of the hand. Workplace surfaces, which workers may come into contact with on a daily basis, were also contaminated with nickel. Forklift drivers showed high exposure on the index finger and palm of their hands, and this can be attributed to them not wearing any gloves for hand protection. An increase in percentage change for TEWL was seen for most of the job categories on all anatomical areas measured during the shift. Percentage change in skin surface pH and skin hydration varied among job categories. Conclusion: The research addressed the problem statement, with the stated objectives. It was hypothesised that workers at a packaging section of a base metal refinery are exposed to quantifiable levels of nickel through the dermal exposure route. The hypothesis was accepted and control measures together with future studies were recommended. The results confirmed that all workers at a base metal refinery are exposed to quantifiable levels of nickel through the dermal exposure route. Dermal exposure was evident on all anatomical areas for all job categories before the shift had commenced. Personal protective equipment was provided to all employees, but forklift drivers did not wear gloves when operating the forklift. Respirable exposure to nickel was below the OEL. Changes in TEWL and to a lesser extent skin hydration, suggest a deterioration in skin barrier function during the shift. Forklift drivers as well as plate washers may be the highest risk job categories in developing allergic contact dermatitis. Several measures to lower respiratory and dermal exposure to nickel are also recommended. / MSc (Occupational Hygiene), North-West University, Potchefstroom Campus, 2014

Copper exposure is known to be a rare cause of skin irritation and allergic reactions and according to our knowledge occupational dermal exposure to copper sulphate has not yet been characterised. As a result, the objectives of this study were to assess the dermal exposure of workers at a chemical industry to copper sulphate and to characterise the change in the their skin barrier function from before to the end of the work shift, as the skin’s barrier function can greatly influence the permeation of chemical substances. Methods: The change in skin barrier function of reactor workers, crystal and powder packaging workers at the chemical industry were assessed by measuring their dominant hand’s palm, back and wrist as well as their foreheads’ skin hydration, transepidermal water loss (TEWL) and skin surface pH before and at the end of the work shift. Commercial GhostwipesTM were used to collect dermal exposure samples from the same four anatomical areas before and at the end of the shift. Additional dermal exposure samples were collected from the palm and back of hand, prior to breaks 1 and 2. Surface wipe sampling was also conducted at several work and recreational areas of the chemical industry. Wipe samples were analysed by an accredited analytical laboratory, according to NIOSH method 9102 by means of Inductively Coupled Plasma-Atomic Emission Spectrometry. Results: Changes in skin hydration of the workers and anatomical areas at the end of the work shift were highly variable, while in general TEWL increased and skin surface pH decreased. Copper was collected from the skin of all workers before the shift commenced, and dermal exposure increased throughout the work shift. All of the work and recreational areas from which surface samples were taken, were contaminated with copper. Conclusion: As a result of intermittent use of inadequate protective gloves and secondary skin contact with contaminated surfaces and work clothing, workers at the chemical industry are exposed to copper sulphate via the dermal exposure route. The decrease in the workers’ skin barrier function (increased TEWL) and skin surface pH is most likely the result of their dermal exposure to sulphuric acid, and may lead to enhanced dermal penetration. The low account of skin irritation or reaction incidences among these workers is contributed to their ethnicity as well as to the low sensitisation potential of copper. Recommendations on how to lower dermal exposure and improve workers’ skin barrier function are made. / MSc (Occupational Hygiene), North-West University, Potchefstroom Campus, 2014

Nickel is one of the most commonly known sensitisers and has been classified by the International Agency for Research on Cancer (IARC) as a possible carcinogen to humans (group 2B). Workers at a South African base metal refinery packaging area are potentially exposed to many hazardous chemicals that include nickel. Aims and Objectives: The aim and objectives of this study were to assess dermal and respiratory exposure of workers exposed to nickel in a packaging section at a South African base metal refinery and to assess the change in skin barrier function during a work shift by measuring percentage change in trans epidermal water loss (TEWL), skin hydration and skin surface pH. Skin health was established with a skin questionnaire. Surfaces that workers may come into contact with were also assessed. Method: Respiratory and dermal exposure assessment was done concurrently. Respiratory exposure was assessed and analysed by using the National Institute for Occupational Safety and Health (NIOSH) method 7300. The Institute of Occupational Medicine (IOM) inhalable aerosol sampler was used for personal air sampling. The TEWL index, skin hydration and skin surface pH of the index finger, palm, forearm and forehead were measured before and at the end of the shift with a Derma Measurement Unit, EDS 12 and Skin-pH-Meter® pH 905. These measurements were reported as percentage change in skin barrier function during the shift. Dermal exposure samples were collected with Ghostwipes™ from the index finger and palm of the dominant hand before, during and at the end of the shift, while samples from the forearm and forehead were only collected before and after the shift. Surface sampling was collected and all wipes were analysed for nickel according the NIOSH method 9102, using inductively coupled plasma-atomic emission spectrometry. Results: Respiratory exposure for the whole group of workers in a packaging section was well below the eight hour Time Weighted Average (TWA) respiratory Occupational Exposure Limit (OEL) of 0.5 mg m-3 for nickel. Dermal nickel loading was detected for all the job categories on all the anatomical areas even before the shift had commenced. During the shift more nickel was detected on the index finger and palm of the hand. Levels on the forearm and forehead were much lower in comparison with the index finger and the palm of the hand. Workplace surfaces, which workers may come into contact with on a daily basis, were also contaminated with nickel. Forklift drivers showed high exposure on the index finger and palm of their hands, and this can be attributed to them not wearing any gloves for hand protection. An increase in percentage change for TEWL was seen for most of the job categories on all anatomical areas measured during the shift. Percentage change in skin surface pH and skin hydration varied among job categories. Conclusion: The research addressed the problem statement, with the stated objectives. It was hypothesised that workers at a packaging section of a base metal refinery are exposed to quantifiable levels of nickel through the dermal exposure route. The hypothesis was accepted and control measures together with future studies were recommended. The results confirmed that all workers at a base metal refinery are exposed to quantifiable levels of nickel through the dermal exposure route. Dermal exposure was evident on all anatomical areas for all job categories before the shift had commenced. Personal protective equipment was provided to all employees, but forklift drivers did not wear gloves when operating the forklift. Respirable exposure to nickel was below the OEL. Changes in TEWL and to a lesser extent skin hydration, suggest a deterioration in skin barrier function during the shift. Forklift drivers as well as plate washers may be the highest risk job categories in developing allergic contact dermatitis. Several measures to lower respiratory and dermal exposure to nickel are also recommended. / MSc (Occupational Hygiene), North-West University, Potchefstroom Campus, 2014

Copper exposure is known to be a rare cause of skin irritation and allergic reactions and according to our knowledge occupational dermal exposure to copper sulphate has not yet been characterised. As a result, the objectives of this study were to assess the dermal exposure of workers at a chemical industry to copper sulphate and to characterise the change in the their skin barrier function from before to the end of the work shift, as the skin’s barrier function can greatly influence the permeation of chemical substances. Methods: The change in skin barrier function of reactor workers, crystal and powder packaging workers at the chemical industry were assessed by measuring their dominant hand’s palm, back and wrist as well as their foreheads’ skin hydration, transepidermal water loss (TEWL) and skin surface pH before and at the end of the work shift. Commercial GhostwipesTM were used to collect dermal exposure samples from the same four anatomical areas before and at the end of the shift. Additional dermal exposure samples were collected from the palm and back of hand, prior to breaks 1 and 2. Surface wipe sampling was also conducted at several work and recreational areas of the chemical industry. Wipe samples were analysed by an accredited analytical laboratory, according to NIOSH method 9102 by means of Inductively Coupled Plasma-Atomic Emission Spectrometry. Results: Changes in skin hydration of the workers and anatomical areas at the end of the work shift were highly variable, while in general TEWL increased and skin surface pH decreased. Copper was collected from the skin of all workers before the shift commenced, and dermal exposure increased throughout the work shift. All of the work and recreational areas from which surface samples were taken, were contaminated with copper. Conclusion: As a result of intermittent use of inadequate protective gloves and secondary skin contact with contaminated surfaces and work clothing, workers at the chemical industry are exposed to copper sulphate via the dermal exposure route. The decrease in the workers’ skin barrier function (increased TEWL) and skin surface pH is most likely the result of their dermal exposure to sulphuric acid, and may lead to enhanced dermal penetration. The low account of skin irritation or reaction incidences among these workers is contributed to their ethnicity as well as to the low sensitisation potential of copper. Recommendations on how to lower dermal exposure and improve workers’ skin barrier function are made. / MSc (Occupational Hygiene), North-West University, Potchefstroom Campus, 2014

Extensive research has already been performed on Aloe vera therefore it is important that researchers include other aloe species, such as Aloe marlothii and Aloe ferox, in studies involving aloe plant materials (Loots et al., 2007:6891). The use of natural products has regained popularity and in recent years the demand for alternative medication has risen considerably (Walji & Wiktorowicz, 2013:86). The hydration state of the human skin is fundamental for its normal functioning (Verdier-Sévrain & Bonté, 2007:75), with healthy skin possessing a water content higher than 10% (w/v) (Blank, 1952:439). This demonstrates the importance of the topical application of skin moisturisers as part of basic skin care regime (Verdier-Sévrain & Bonté, 2007:75). The first part of this project focused on the in vivo skin hydration effects of the precipitated polysaccharide components of A. vera, A. ferox and A. marlothii leaf gel materials (3% (w/v)) after single (30, 90 and 150 min after application) and multiple applications (twice daily application over a period of four weeks) on healthy volunteers, respectively. The anti-erythema effects of these aloe materials on sodium lauryl sulphate irritated skin were also examined. The skin hydration effects of the aloe materials were determined with the Corneometer® CM 825 and Visioscan® VC 98 during the short term study (single application) and longer term study (multiple applications). In addition, as an indirect measurement of skin hydration, the Cutometer® dual MPA 580 was used to measure skin elasticity during the longer term study. To determine the anti-erythema effects of the aloe materials when applied to irritated skin areas, the haemoglobin content of the skin was measured with a Mexameter® MX 18. The results from the in vivo study indicated that A. ferox gel material dehydrated the skin, whereas A. vera and A. marlothii gel materials hydrated the skin during the short term study. Results from the longer term study showed that all the aloe leaf materials have skin dehydration effects, probably due to the aloe absorbing moisture from the skin into the applied gel layer upon drying. From the anti-erythema study, it was seen that A. vera and A. ferox materials had the potential to reduce erythema on the skin similar to that of the positive control group (i.e. hydrocortisone gel) after six days of treatment. The skin possesses exceptional barrier properties which can mostly be ascribed to the outermost layer of the skin, the stratum corneum (SC). Due to the physical barrier the skin has against drug permeation, the delivery of drug molecules into and across the skin continues to be challenging (Lane, 2013:13) and to overcome this barrier, penetration enhancers can be used to efficiently deliver drugs across the skin (Barry, 2002:522). The aim of the second part of this project was to determine the skin penetration enhancing effects of the gel and whole leaf materials of A. vera, A. marlothii and A. ferox. Ketoprofen was used as the marker compound and a high performance liquid chromatography (HPLC) method was developed and validated to determine the amount of ketoprofen present in the samples. Prior to the skin diffusion studies, membrane release studies were performed to test whether the solutions containing different concentrations of the aloe leaf materials (i.e. 3.00%, 1.50% and 0.75% (w/v)) released ketoprofen from their gel-like structures. From these studies, it was evident the 0.75% (w/v) concentration had the highest average percentage ketoprofen release, which was subsequently chosen as the concentration for the aloe leaf materials tested in the transdermal skin diffusion studies. The in vitro permeation study was conducted across dermatomed (400 μm thick) skin in Franz diffusion cells. Tape stripping was performed after completion of the diffusion studies to determine the concentration ketoprofen present in the SC-epidermis and epidermis-dermis layers of the skin. Results from the in vitro permeation study showed that A. vera gel enhanced the flux of ketoprofen to the highest extent (20.464 μg/cm2.h) when compared to the control group (8.020 μg/cm2.h). Aloe marlothii gel (12.756 μg/cm2.h) and A. ferox whole leaf material (12.187 μg/cm2.h) also enhanced the permeation of ketoprofen across the skin compared to the control group. A. vera gel material was the most efficient transdermal drug penetration enhancer of the selected aloe species investigated. In order to determine by which mechanism the aloe leaf materials enhanced the skin permeation of ketoprofen (Hadgraft et al., 2003:141), the permeation profiles were analysed using a non-linear curve-fitting procedure (Díez-Sales et al., 1991:3) to obtain α, β and kp values. A change in the α-value indicated the aloe leaf material influenced the partition coefficient (K), whereas a change in β indicated the aloe leaf material influenced the diffusivity (D) (with the assumption that h, the diffusional path length is constant) (Otto et al., 2010:278). The calculated α-values indicated the drug permeation enhancing effect of A. vera gel can be ascribed to an increased partitioning of the drug into the skin. The calculated β-values showed A. ferox whole leaf altered the diffusion characteristics of the skin for ketoprofen. The tape stripping results showed A. marlothii whole leaf delivered the highest concentration of the ketoprofen into the SC-epidermis and epidermis-dermis layers of the skin. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Extensive research has already been performed on Aloe vera therefore it is important that researchers include other aloe species, such as Aloe marlothii and Aloe ferox, in studies involving aloe plant materials (Loots et al., 2007:6891). The use of natural products has regained popularity and in recent years the demand for alternative medication has risen considerably (Walji & Wiktorowicz, 2013:86). The hydration state of the human skin is fundamental for its normal functioning (Verdier-Sévrain & Bonté, 2007:75), with healthy skin possessing a water content higher than 10% (w/v) (Blank, 1952:439). This demonstrates the importance of the topical application of skin moisturisers as part of basic skin care regime (Verdier-Sévrain & Bonté, 2007:75). The first part of this project focused on the in vivo skin hydration effects of the precipitated polysaccharide components of A. vera, A. ferox and A. marlothii leaf gel materials (3% (w/v)) after single (30, 90 and 150 min after application) and multiple applications (twice daily application over a period of four weeks) on healthy volunteers, respectively. The anti-erythema effects of these aloe materials on sodium lauryl sulphate irritated skin were also examined. The skin hydration effects of the aloe materials were determined with the Corneometer® CM 825 and Visioscan® VC 98 during the short term study (single application) and longer term study (multiple applications). In addition, as an indirect measurement of skin hydration, the Cutometer® dual MPA 580 was used to measure skin elasticity during the longer term study. To determine the anti-erythema effects of the aloe materials when applied to irritated skin areas, the haemoglobin content of the skin was measured with a Mexameter® MX 18. The results from the in vivo study indicated that A. ferox gel material dehydrated the skin, whereas A. vera and A. marlothii gel materials hydrated the skin during the short term study. Results from the longer term study showed that all the aloe leaf materials have skin dehydration effects, probably due to the aloe absorbing moisture from the skin into the applied gel layer upon drying. From the anti-erythema study, it was seen that A. vera and A. ferox materials had the potential to reduce erythema on the skin similar to that of the positive control group (i.e. hydrocortisone gel) after six days of treatment. The skin possesses exceptional barrier properties which can mostly be ascribed to the outermost layer of the skin, the stratum corneum (SC). Due to the physical barrier the skin has against drug permeation, the delivery of drug molecules into and across the skin continues to be challenging (Lane, 2013:13) and to overcome this barrier, penetration enhancers can be used to efficiently deliver drugs across the skin (Barry, 2002:522). The aim of the second part of this project was to determine the skin penetration enhancing effects of the gel and whole leaf materials of A. vera, A. marlothii and A. ferox. Ketoprofen was used as the marker compound and a high performance liquid chromatography (HPLC) method was developed and validated to determine the amount of ketoprofen present in the samples. Prior to the skin diffusion studies, membrane release studies were performed to test whether the solutions containing different concentrations of the aloe leaf materials (i.e. 3.00%, 1.50% and 0.75% (w/v)) released ketoprofen from their gel-like structures. From these studies, it was evident the 0.75% (w/v) concentration had the highest average percentage ketoprofen release, which was subsequently chosen as the concentration for the aloe leaf materials tested in the transdermal skin diffusion studies. The in vitro permeation study was conducted across dermatomed (400 μm thick) skin in Franz diffusion cells. Tape stripping was performed after completion of the diffusion studies to determine the concentration ketoprofen present in the SC-epidermis and epidermis-dermis layers of the skin. Results from the in vitro permeation study showed that A. vera gel enhanced the flux of ketoprofen to the highest extent (20.464 μg/cm2.h) when compared to the control group (8.020 μg/cm2.h). Aloe marlothii gel (12.756 μg/cm2.h) and A. ferox whole leaf material (12.187 μg/cm2.h) also enhanced the permeation of ketoprofen across the skin compared to the control group. A. vera gel material was the most efficient transdermal drug penetration enhancer of the selected aloe species investigated. In order to determine by which mechanism the aloe leaf materials enhanced the skin permeation of ketoprofen (Hadgraft et al., 2003:141), the permeation profiles were analysed using a non-linear curve-fitting procedure (Díez-Sales et al., 1991:3) to obtain α, β and kp values. A change in the α-value indicated the aloe leaf material influenced the partition coefficient (K), whereas a change in β indicated the aloe leaf material influenced the diffusivity (D) (with the assumption that h, the diffusional path length is constant) (Otto et al., 2010:278). The calculated α-values indicated the drug permeation enhancing effect of A. vera gel can be ascribed to an increased partitioning of the drug into the skin. The calculated β-values showed A. ferox whole leaf altered the diffusion characteristics of the skin for ketoprofen. The tape stripping results showed A. marlothii whole leaf delivered the highest concentration of the ketoprofen into the SC-epidermis and epidermis-dermis layers of the skin. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014