The quantitative estimation of toluene skin absorption in man

Summary The absorption of toluene through the skin of the hand and the forearm in men was investigated experimentally. Both the absorption of liquid toluene and the absorption from aqueous solutions were studied using the direct method. It was stated that under the experimental conditions the rate of absorption of liquid toluene was 14–23 mg/cm²/h.In mean concentrations of 180–600 mg/1 the rate of absorption of toluene from aqueous solutions was 160-600 g/cm²/h and increased according to the increase of toluene concentration.     

Skin absorption and per os administration of methanol in men

Summary Methanol absorption rate through the human skin has been examined by the use of a modified direct method, and a value of 0.192 mg/cm²/min was determined. The excretion of unchanged methanol with urine and exhaled air, after the absorption through the skin and administration per os of identical doses, were also examined.     

Urinary chlorophenols in sawmill workers

Summary The concentration of urinary chlorophenol was assayed for 230 sawmill workers. Information on the work tasks was obtained through questionnaires from occupational health centres. The workers were divided into three groups on the basis of the type of exposure: (1) those with skin absorption as the main route, (2) those with skin and respiratory route of equal importance and (3) those with respiratory tract as the main route. The concentrations of urinary chlorophenol were higher in workers with skin absorption as the main route (median concentration: 7.8 mol l^–1; range 0.1 to 210.9 mol l^–1) than in those with both routes of equal importance (1.4 mol l^–1; range 0.1 to 47.8 mol l^–1, P<0.001) or in those with mainly respiratory route (0.9 mol l^–1; range 0.1 to 13.3 mol l^–1, P<0.001). The urinary chlorophenol concentration was below 15 moll^–1 in all workers with the lungs as the main absorption route. In nine out of 112 workers whose main absorption route was the skin, the urinary chlorophenol values were above 50 mol l^–1. Six were loaders when the through-dipping method was used. In two of them urinary chlorophenol concentrations were as high as 170.8 and 210.9 mol l^–1, These results emphasize the need to develop and use simple methods of protection against skin contact with chlorophenols.     

Evaluation of hippuric,phenylglyoxylic and mandelic acids in urine as indices of styrene exposure

Summary In addition to those of phenylglyoxylic and mandelic acids, a distinct increase in hippuric acid level was observed in the urine of factory workers who were exposed to styrene at 50 to 200 ppm for 160 min. Comparison of the postexposure levels with respective non-exposure levels and supplements with rat exposure experiments revealed hippuric acid to be a poor indicator of styrene exposure at a moderate degree, while the other two acids are much more adequate indices. At a higher dose of styrene (e.g., 500 mg/kg i.p. or 100 ppm for 8 hrs for rats), however, the urinary levels of phenylglyoxylic and mandelic acids reach plateaus, while hippuric acid level remained proportional to the amount of styrene given.The biological half-life of styrene in human subjects is approximately 8 hrs as measured by the disappearance of phenylglyoxylic and mandelic acids from urine.This work was supported in part by a grant from the Fujiwara Memorial Foundation     

Percutaneous absorption of m-xylene in man

Summary Percutaneous absorption of m-xylene was studied in volunteer experiments by means of monitoring xylene concentrations in blood and in exhaled air, and urinary methylhippuric acid excretion. Compared to normal working practices a rather extreme skin exposure, i.e. immersion of both hands in liquid xylene resulted in an estimated absorption of 35 mg xylene in 15 min which equals an estimated pulmonary retention within the same time period at TLV air.level of 100 ppm. The observed absorption rate for m-xylene was approximately 2 g/cm²/min. The penetration of xylene was fairly rapid, peak concentrations appearing in the draining venous blood 4–6 min after exposure. Further absorption took place for five hours, however, after the termination of exposure and the removal of the contaminant by alcohol and water rinsing. It was found, as expected, that venous blood from a contaminated area exhibits a much higher concentration of the contaminant than mixed venous blood. To exclude this error in biological monitoring of xylene (and other skin penetrating solvents) exposure, exhaled air determinations are recommended. As a sporadic finding in the investigation, a symptom-free subject with previous history of atopic dermatitis developed toxic eczema of the hands after xylene exposure and exhibited a three times greater absorption of the compound than the average for the rest of the group.     

Assessment of long-term styrene exposure: a comparative study of a logbook method and biological monitoring

In a recent joint European research project Biomonitoring of human populations exposed to genotoxic environmental chemicals: biomonitoring of styrene exposed individuals, a logbook method for assessment of long-term styrene exposure was applied in two Danish factories manufacturing glass fibre-reinforced polyester. The method was based on work process identification, assignment of work process concentrations and logbook keeping. Measures of exposure calculated by this method were compared with results from simultaneous measurements of styrene in blood and the metabolites mandelic acid and phenylglyoxylic acid in urine. Correlations were comparable with those obtained by use of personal samplers as published in the literature. Styrene in blood, however, only correlated with logbook concentrations at the time of sampling. Exposures were moderate to low. Mean personal 8-h time-weighted average concentration (8hTWAC) was 76 mg/m³ styrene (SD 54 mg/m³, range 2–230 mg/m³). The Danish 8hTWAC threshold limit value for styrene in air, 105 mg/m³ (25 ppm), was exceeded on 17% of personal days. The summed urinary metabolites, mandelic acid and phenylglyoxylic acid, had a mean personal value of 138 mg/g creatinine (SD 84 mg/g creatinine) on the day of sampling. Blood styrene mean value was 129 g/l (SD 74 g/l, range 66–358 g/l). It is concluded that the logbook method offers a technique for testing whether measurements are performed on representative days and may be recommended as a tool supplementary to biological monitoring in the assessment of long-term exposure.     

Percutaneous absorption of N,N-dimethylformamide in humans

Summary Skin penetration fo N,N-dimethylformamide (DMF) liquid or vapour was studied in volunteers. Exposure to liquid DMF was performed in two ways: in a dipping experiment, one hand was dipped up to the wrist in DMF for 2–20 min, while in a patch experiment, 2 mmol DMF was applied to the skin and allowed to be absorbed completely. The period of exposure to DMF vapour (50 mg · m^–3) was 4 h. The DMF metabolites N-hydroxymethyl-N-methylformamide (MF), N-hydroxymethylformamide (F), and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) were monitored in the urine. Liquid DMF was absorbed through the skin at a rate of 9.4 mg · cm^–2 · h^–1. Percutaneous absorption of DMF vapour depended strongly on ambient temperature and humidity and accounted for 13%–36% of totally excreted MF. The results suggest that skin absorption of liquid DMF is likely to contribute to occupational exposure substantially more than penetration of DMF vapour. The yield of metabolites after transdermal DMF absorption was only half of that seen after pulmonary absorption. Elimination of MF and F but not that of AMCC was delayed, which supports the contention that AMCC should be used instead of MF as the most suitable biomarker of DMF in cases where percutaneous intake can occur.     

The applicability of the measurement of urinary thioethers

Summary The excretion of thioethers was measured in the urine of 6 volunteers, who were experimentally exposed to styrene, and 18 styrene workers. In addition, 12 clerks (non-smokers) and 12 sheet-metal workers (smokers) served as control groups. Diet was standardized during the experiments. Thioethers were measured by a spectrophotometric method. The volunteers were exposed to styrene, 210 mg/m³, for 2 h at a 50-W workload. An increase in thioether excretion was observed; the largest was in the urine samples collected between 0.5 and 5 h after the end of the exposure. After 43 h the excretion of thioethers was close to the preexposure level (3.5 mmol/mol creatinine). About 1% of the styrene absorbed was detected as thioethers in urine, which is only about 1/10 of the conversion reported for rats. From excretion rate curves a half-life of about 11 h was calculated for styrene thioethers. The styrene workers were employed at two plants. The average exposure to styrene (time-weighted average 8 h) was estimated to be about 115 mg/m3 (smokers in plant A), 55 mg/m³ (non-smokers in plant A) and 10 mg/m³ (non-smokers in plant B). The excretion of thioethers in exposed workers at plant A was higher by 2–4 mmol/mol creatinine than that in non-exposed controls. In plant B, where exposure was lower, an increase in that amount of thioethers excreted in the urine by exposed workers was less pronounced, and was statistically significant only when post-shift samples were compared with pre-shift samples. The results of the present study indicate that control samples should be collected both from non-exposed groups and from the exposed individuals before work shifts, to improve the likelihood of detecting genotoxic exposure in the work environment.     

In vitro percutaneous absorption of cobalt

Objectives To evaluate skin absorption of cobalt powder in an in vitro system. Experiments with volunteers show that cobalt powder can permeate through the skin, but there are no data with regard to the mechanism or the amount of permeation.Methods Skin permeation was calculated by the Franz diffusion cell method with human skin. A physiological solution was used as receiving phase and the cobalt powder was dispersed in synthetic sweat. The amount of metal passing through the skin was analysed by electro-thermal atomic absorption spectrometry (ETAAS). Parallel polarographic analysis (differential pulse polarography—DPP) allowed evaluation of cobalt present as ions (Co²⁺) in donor and receiving phases. Measurements of cobalt skin content were also performed.Results Evaluation of metal in the receiving phase allowed us to demonstrate the permeation of cobalt through the skin. Steady-state flow of percutaneous cobalt permeation was calculated as 0.0123±0.0054 g cm^–2 h^–1, with a lag time of 1.55±0.71 h.Conclusions The experiments show that cobalt powder can pass through the skin when applied as a dispersion in synthetic sweat, oxidising metallic cobalt into ions, which permeate the skin. These experiments show for the first time how cobalt can permeate the skin.     

Occupational exposure to hexahydrophthalic anhydride: air analysis,percutaneous absorption,and biological monitoring

Summary Urinary hexahydrophthalic acid (HHP acid) levels were determined in 20 workers occupationally exposed to hexahydrophthalic anhydride (HHPA) air levels of 11–220g/m³. The levels of HHP acid in urine increased rapidly during exposure and the decreases were also rapid after the end of exposure. The elimination half-time of HHP acid was 5h, which was significantly longer than in experimentally exposed volunteers, possibly indicating distribution to more than one compartment. There was a close correlation between time-weighted average levels of HHPA in air and creatinine-adjusted levels of HHP acid in urine collected during the last 4 h of exposure (r = 0.90), indicating that determination of urinary HHP acid levels is suitable as a method for biological monitoring of HHPA exposure. An air level of 100 g/m³ corresponded to a postshift urinary HHP acid level of ca. 900 nmol/mmol creatinine in subjects performing light work for 8h. Percutaneous absorption of HHPA was studied by application of HHPA in petrolatum to the back skin of three volunteers. The excreted amounts of HHP acid in urine, as a fraction of the totally applied amount of HHPA, were within intervals of 1.4%–4.5%, 0.2%–1.3%, and 0%–0.4% respectively, indicating that the contribution from percutaneous absorption is of minor importance in a method for biological monitoring.     

Percutaneous absorption of aromatic amines in rubber industry workers: impact of impaired skin and skin barrier creams

Background

Several aromatic amines (AA) could cause bladder cancer and are an occupational hygiene problem in the workplace. However, little is known about the percutaneous absorption of chemicals via impaired skin and about the efficacy of skin protection measures to reduce internal exposure.

Aims

To determine the impact of skin status and of skin protection measures on the internal exposure to AA in workers manufacturing rubber products.

Methods

51 workers occupationally exposed to aniline and o‐toluidine were examined. The workplace conditions, risk factors for skin and the use of personal protective equipment were assessed by means of a self‐administered questionnaire. The skin of hands and forearms was clinically examined. Exposure to aniline and o‐toluidine was assessed by ambient air and biological monitoring (analyses of urine samples and of haemoglobin adducts).

Results

Haemoglobin‐AA‐adduct levels in workers with erythema (73%) were significantly higher (p<0.04) than in workers with healthy skin (mean values: aniline 1150.4 ng/l vs 951.7 ng/l, o‐toluidine 417.9 ng/l vs 118.3 ng/l). The multiple linear regression analysis showed that wearing gloves significantly reduced the internal exposure. A frequent use of skin barrier creams leads to a higher internal exposure of AA (p<0.03). However, the use of skincare creams at the workplace was associated with a reduced internal exposure (p<0.03). From these findings we assume that internal exposure of the workers resulted primarily from the percutaneous uptake.

Conclusions

The study demonstrates a significantly higher internal exposure to AA in workers with impaired skin compared with workers with healthy skin. Daily wearing of gloves efficiently reduced internal exposure. However, an increased use of skin barrier creams enhances the percutaneous uptake of AA. Skincare creams seem to support skin regeneration and lead to reduced percutaneous uptake.Occupational exposure to aromatic amines (AA) could be a significant cause of ill health. Several AA are well‐known carcinogens to humans and/or animals, and exposure to them in the workplace should be well controlled.¹ Occupational exposure to AA could be the most common source of urinary bladder cancer in Germany, and the number of bladder cancers due to occupational exposure has been increasing in the past decade.^2,3 Replacement of AA and the corresponding intermediates is not possible in some industries. In the rubber industry, AA aniline and o‐toluidine are released from the accelerators di‐ortho‐tolylguanidine and diphenylguanidine, especially during the vulcanisation process of rubber products. In Germany, o‐toluidine is considered to be carcinogenic to humans.¹ The International Agency for Research on Cancer classified o‐toluidine as probably carcinogenic to humans, but could not find sufficient data to classify aniline as a human carcinogen.⁴For some chemicals in the workplace—for example, glycol ethers, percutaneous absorption can be the main route of uptake.^5,6 Several AA can also be absorbed percutaneously.^1,7,8 Percutaneous absorption of AA can result from direct dermal contact, and also from airborne vapour, aerosols and particulates. Little is known about the absorption of workplace chemicals via impaired skin. We have recently demonstrated that over 70% of workers in the printing industry had hands with impaired skin.^9,10 The breakthrough time of aniline through protective gloves is often only few minutes.¹¹ All these factors complicate the provision of effective safety measures to prevent systemic absorption in the workplace. In this study, we determined the impact of skin status and of skin protection measures (among others, gloves, skin barrier and skincare creams) on the internal exposure of AA in workers manufacturing rubber products at a supplier for the automobile industry.     

Skin absorption of some vaporous solvents in volunteers

Objectives: To determine the dermal absorption rates of vaporous 1,1,1-trichloroethane (111TRI), trichloroethene (TRI), tetrachloroethene (TETRA), hexane (HEX), toluene (TOL) and m-xylene (XYL) in humans. The determined absorption data were used for the validation of two published models for prediction of non-steady-state skin absorption. Methods: Five volunteers were dermally exposed on an area of about 1,000 cm² (forearm and hand) for 20 or 30 min. An inhalation exposure with a known dose rate served as a reference. Using the solvent concentrations in exhaled air, measured after both inhalation and dermal exposure, we calculated the maximum absorption rate into the blood, and the average absorption rates into the skin throughout the exposure, using the linear system dynamics method. Results: The absorption rates into the skin, normalised for exposure concentration, amounted to 0.021 cm/h (111TRI), 0.049 cm/h (TRI), 0.054 cm/h (TETRA), 0.013 cm/h (HEX), 0.14 cm/h (TOL), and 0.12 cm/h (XYL). The maximum absorption rates into the blood ranged from 0.005 nmol/h for 111TRI and HEX to 0.050 nmol/hr for TOL. The ratios between the predicted and experimental values of the absorption rates into the skin ranged, for the model of Cleek and Bunge [4], from 0.3 (HEX) to 1.1 (TRI and TETRA), and for the model of Wilschut and Ten Berge [22], from 1.1 (HEX) to 4.7 (XYL). Conclusion: The linear system dynamics method allowed us to calculate not only the total amount absorbed by the skin but also the maximum absorption rate into the blood. The steady-state absorption rate, usually described by a permeability constant, will be below the absorption rate into the skin and above the maximum absorption rate into the blood. The skin absorption rates predicted by the models showed a good agreement with the experimental values. A comparison of the estimated whole-body skin uptake with the inhalatory uptake from the same atmosphere, revealed that the dermal uptake contributed from 0.1% (HEX) to 1% (TOL and XYL) to the total uptake. Received: 27 September 1999 / Accepted: 25 March 2000     

Percutaneous absorption of neat and aqueous solutions of 2-butoxyethanol in volunteers

Objectives To study the influence of the presence of water on the dermal absorption of 2-butoxyethanol (BE) in volunteers.Methods Six male volunteers were dermally exposed to 50%, 90% or neat w/w BE for 4 h on the volar forearm over an area of 40 cm². An inhalation exposure with a known input rate and duration served as a reference dosage. The dermal absorption parameters were calculated from 24-h excretion of total (free + conjugated) butoxyacetic acid (BAA) in urine and BE in blood, measured after both inhalation and dermal exposure. Results The dermal absorption of BE from aqueous solutions was markedly higher than that of neat BE. The time-weighted average dermal fluxes were calculated from the urine and blood data and expressed in milligrammes per square centimetre per hour. The dermal fluxes obtained from cumulative 24-h excretion of BAA amounted to 1.34±0.49, 0.92±0.60 and 0.26±0.17 mg cm^–2 h^–1 for 50%, 90% and neat BE, respectively. The dermal fluxes calculated from the BE blood data amounted to 0.92±0.34 and 0.74±0.25 mg cm^–2 h^–1 for 50% and 90% BE, respectively. The permeation rates into the blood reached a plateau between 60 and 120 min after the start of exposure, indicating achievement of steady-state permeation. The apparent permeability coefficient K_p, was 1.75±0.53×10^–3 and 0.88±0.42×10^–3 cm h^–1 for 50% and 90% BE, respectively. Conclusion The percutaneous absorption of BE from aqueous solution increased markedly when compared with neat BE. Even water content as low as 10% led to an approximate fourfold increase in the permeation rates. These findings are important for the health risk assessment of occupational exposure to BE, since BE is commonly used in mixtures that contain water. Exposure to aqueous solutions of 50% and 90% of BE may result in substantial skin absorption: if a 60-min skin contact of 1,000 cm² is assumed, dermal uptake would be four-times higher than the pulmonary uptake of an 8-h occupational exposure at a TLV of 100 mg m^–3. This clearly justifies the skin notation for BE. For the purpose of biological monitoring, both BE in blood and BAA in urine were shown to be reliable indicators of exposure.     

Immunological changes among workers occupationally exposed to styrene

The functional status of the immune system was investigated in a group of 71 workers exposed to styrene and in 65 control subjects, recruited according to the same selection criteria and comparable as to sex, age, and confounding variables. Air and biological monitoring were used to characterize styrene exposure (median of the main urinary metabolites in the next-morning spot samples: 106 mg/g creatinine). Phenotypic analysis of peripheral blood lymphocytes (PBL) by automated flow cytometry revealed a reduced proportion of T lymphocyte subsets (CD3⁺, CD4⁺ and CD4⁺45⁺), with no changes in CD8⁺, and a higher proportion of B lymphocytes (CD19⁺) among styrene-exposed workers. The exposed workers showed a higher proportion of activation markers, namely DR and interleukin-2 receptors (CD25). Immunoglobulin subclasses were comparable in the two groups. An increased prevalence of abnormally low values was apparent for CD2⁺, CD3⁺, CD4⁺, CD4⁺45⁺ and CD11b subsets among workers exposed to styrene, whereas CD19⁺, DR⁺ and CD25⁺ showed an increased prevalence of abnormally high values. Natural killer-related phenotypes (CD56⁺, CD56+16⁺, and CD56⁺16^–) were more expressed among styrene workers, with average increase of 30%. However, the frequency distribution of the lytic activity of natural killer cells against K-562 target cells was shifted towards lower values in the exposed workers as compared to control subjects. Dose-response relationships between indices of internal dose and prevalence of abnormal values were detectable for T lymphocyte subsets, NK phenotypes, and activation markers. These findings suggest that moderate exposure to styrene is associated with an altered distribution of lymphocyte subsets. The decreased proportion of T lymphocytes, mainly of T helper-inducer cells, could hamper regulatory functions, thus suggesting a negative modulation by styrene exposure. Since a proper balance between immunocycte subsets is important for immunological responses, such changes should be regarded as adverse effects.     

Effect of ethanol on the urinary excretion of mandelic and phenylglyoxylic acids after human exposure to styrene

Summary Administration of ethanol in several doses during human exposure to styrene can inhibit the urinary mandelic and phenylglyoxylic acid excretion in a way similar to that reported when ethanol was administered as a single dose. Sensitivity to this inhibitory effect has been found to differ with individual subjects. Differences in long-term consumption of ethanol resulting in different induction of the oxidizing enzymes are suggested to account for this finding. Intra-individual variation in the influence of acute ethanol ingestion on the excretion rate of the mentioned acids can also occur. The habit of drinking ethanol might be important, even for partial redirection of the styrene metabolism from styrene glycol oxidation to styrene glycol conjugation with -glucuronic acid and/or sulfate. The consequences of these observations for the occupational hygiene practice are briefly outlined.     

Experimental human exposure to carbon disulfide

Summary Six human volunteers were exposed to 10 and 20 ppm carbon disulfide at rest and to 3 and 10 ppm carbon disulfide under a 50 W level of physical exercise during four consecutive periods of 50 min. At the start of the experiments, at the end of the exposure periods and during the post-exposure period, urine was sampled and the concentration of 2-thiothiazolidine-4-carboxylic acid (TTCA) was determined. It was established that only a small percentage, ranging from 0.7 to 2.2% of the absorbed carbon sulfide was transformed into TTCA. The excretion rate of TTCA (mol TTCA h^–1) was found to be the best parameter in evaluating the respiratory uptake of carbon disulfide over a range of 37.9 to 163.3 mg CS₂ compared to the urinary concentration of TTCA (mole TTCA ml^–1) or the creatinine corrected concentration of TTCA (mmol TTCA mol^–1 creatinine). The total amount of TTCA (mol TTCA) excreted proved to be independent of the urinary flow (ml h^–1), the estimates of the individual fatty tissue content and the urinary pH. No correlation was found between the respiratory uptake of carbon disulfide (mg CS₂) and the excretion rate of TTCA within each exposure condition of 3, 10 or 20 ppm carbon disulfide, respectively.     

Metabolic interferences in subjects occupationally exposed to binary styrene-acetone mixtures

Objective: To investigate the excretion of styrene metabolites (mandelic acid, MA, and phenylglyoxylic acid, PGA) in workers employed in plastic manufacturing to verify the possible influence of coexposure to acetone on styrene metabolism. Methods: This study was carried out on 50 workers employed in 3 factories producing polyester buttons. The workers were divided into three groups according to three different levels of acetone exposure. The trend of excretion for metabolites was examined during and after work shifts. Styrene and acetone were monitored on Thursday during the entire work shift by passive dosimeters placed on the lapel of the workers' uniforms, desorbed by carbon disulfide, and analyzed by gas chromatography. Biological monitoring was performed by determination of the urinary metabolites of styrene in urine samples collected on Thursday at the middle and the end of the work shift. MA and PGA were determined by a high-pressure liquid chromatographic method. Results: The styrene concentrations ranged between 16 and 439 mg/m³, and in ten samples they exceeded the TLV-TWA (213 mg/m³). The acetone concentration ranged between 15 and 700 mg/m³ (TLV-TWA 1780 mg/m³), with the mean value being 208 mg/m³. During cleaning operations higher exposures to acetone demonstrated, with concentrations ranging between 500 and 3400 mg/m³. The amounts of MA and PGA determined at the end of workshifts did not significantly differ between the groups with different levels of acetone coexposure. Analysis of variance (ANOVA) between the groups confirmed that MA and PGA excretion did not significantly differ, although the metabolite values measured on the “morning of the day after” appeared higher in those groups with high levels of acetone exposure and were related to the average airborne concentrations of the solvent. In addition, the range and degree of correlation between styrene in air and biological levels of metabolites were modified by coexposure to acetone. Conclusions: Our data demonstrate that amounts of MA and PGA did not differ in groups with different levels of acetone exposure, but when the acetone air concentration increased the degree of correlation between styrene and MA and PGA decreased. Furthermore, coexposure to acetone levels similar to those described herein may hamper the use of urinary metabolites for the assessment of exposure to styrene, especially on an individual basis. Received: 23 January 1998 / Accepted: 29 May 1998     

Effects of exercise intensity on circulating leukocyte subpopulations

Objectives The purpose of this study was to examine the relation between exercise intensity and immune function. Methods Ten healthy young males underwent a constant work rate exercise of three levels, 90%, 80% and 70% ventilatory threshold (VT) work rate, for 20 min on a bicycle ergometer. These work rates were calculated for each individual based on his VT work rate obtained by the incremental exercise tests. Blood samples were collected before and after the exercise, and immune function indices were measured. Results Compared with the obtained at in the incremental test, the with the exercise of 70% VT work rate was at a similar level and the one with the exercise of 90% or 80% VT work rate had a significantly greater value. The numbers of leukocytes and neutrophils significantly increased in the 90% and 70% VT work rate groups. In 80% VT work rate group, the CD4/CD8 ratio was significantly depressed. The CD16⁺CD57⁻ (%), natural killer cell populations, had a tendency to increase at 80% VT work rate, and also the CD16⁺CD57⁻ (%) had a similar tendency at 90% or 80% VT work rate. Conclusions This study shows that moderate exercise reaching or exceeding the VT level acutely affects T cell and NK cell subsets.     

A comparative study of the kinetics and bioavailability of pure and soil-adsorbed naphthalene in dermally exposed male rats

The aim of this study was to utilize pharmacokinetic techniques to assess the bioavailability of sandy or clay soil-adsorbed naphthalene vs chemical alone following dermal treatment of male rats. Animals were exposed to 43 g total of ¹⁴C-naphthalene (pure or adsorbed to one of two soils) introduced into a shallow glass cap covering a 13-cm² area on the skin of each rat. While both soils delayed the time to reach maximum plasma concentration of radioactivity and significantly increased the half-life of plasma absorption, only sandy soil significantly decreased the peak plasma concentration of radioactivity versus the pure compound. Within 12 h after dermal application, approximately 50% of the naphthalene dose was excreted in the urine of the pure and clay soil-adsorbed groups. However, when naphthalene was adsorbed to sandy soil, the percentages of the initial dose excreted in the urine collected between 0–12 h and 12–24 h were nearly equal (33–39%). Furthermore, sandy soil adsorption shifted the secondary excretion route from expired air to feces and significantly lowered the amount of radioactivity in expired air relative to naphthalene alone. In the presence of sandy soil, a significantly larger amount of radioactivity washed off of the skin application sites. In all groups the predominant urinary metabolites determined by high performance liquid chromatography were 2,7- and 1,2-dihydroxynaphthalenes.     

Cancer Research Center Hotline: “Sun Safe Kids,” Implementing a Low Cost,School-based Public Policy to Protect Hawai‘i's Children from Skin Cancer Risks

The rates of melanomas and skin cancers are increasing in the United States. Children attending elementary schools are in the most danger of acquiring these diseases later in life, and elementary school children in Hawai‘i have the greatest risk of all children in the United States. The parents and educators of Hawai‘i''s elementary school age children are unaware of the potential risks for cancer that young children experience every day at school. Effective sun protection policies have been implemented in other jurisdictions, including Australia, that have similar risks for over-exposure to solar ultraviolet radiation in children. These proven policy models can inform sun protection practices in Hawai‘i. A simple policy whereby public elementary schools require that children wear ordinary long sleeves shirts and hats during the school''s outdoor activities will protect Hawai‘i''s children from overexposure to sun''s ultraviolet radiation. Establishment of a state law codifying the implementation of this simple, yet scientifically proven strategy into the policies of Hawai‘i''s public elementary schools can significantly reduce the incidence and deaths from melanoma and skin cancer in the state.The rates of melanomas and skin cancers are increasing in the United States.^1,2 Children attending elementary schools are in the most danger of acquiring these diseases later in life, and elementary school children in Hawai‘i have the greatest risk of all children in the United States.^3,4 The parents and educators of Hawai‘i''s elementary school age children are unaware of the potential risks for cancer that young children experience every day at school.⁴ Public elementary schools can simply require that elementary school age children wear ordinary long sleeves shirts and hats during the school''s outdoor activities, applying a “No Hat, No Shirt, No Play” school uniform requirement policy, to protect these children from overexposure to sun''s ultraviolet radiation.^3–5 Establishment of a state law codifying the implementation of this simple, yet scientifically proven strategy into the policies of all of Hawai‘i''s public elementary schools can significantly reduce the incidence and deaths from melanoma and skin cancer in the state.Skin cancers are the most preventable type of cancer.^4,6 Over the past 10 years, the number of deaths from most other types of cancer in the United States, and Hawai‘i have dropped significantly.⁷ A large portion of this reduction in cancer death rates is attributed to improved primary prevention practices.⁸ However, despite improvements in the management of other cancer types, the incidence and death rates from melanoma and skin cancers continue to rise at an alarming rate.⁹ There were an estimated 1.4 million new cases of skin cancer diagnosed in the United States, in 2008, accounting for nearly half of all cancer incidence.¹⁰ In Hawai‘i, it is estimated that over 5,000 people will be diagnosed and treated for skin cancer this year.⁷ The depletion of the earth''s ozone layer, that provides our planet with protection against solar UV radiation, is a major factor contributing to the increasing rates of skin cancer.¹¹ Hawai‘i''s proximity to the equator where the sun rays are more direct, add to this enhanced risk of skin cancer for the local residents and visitors.⁴ Efforts to reduce exposure to ultraviolet radiation, particularly in Hawai‘i will reduce the burden of this disease.There are two types of skin cancers, non-melanoma skin cancers, and melanomas. Both are attributable to overexposure to UV radiation, particularly during childhood.⁵ Fifty to 80% of a person''s lifetime cumulative exposures to the sun''s UV radiation occur before age 18.⁴ Non-melanoma skin cancers, called basal and squamous cell skin cancers occur in the surface layers of the skin. Although these types of skin cancers are often not fatal, they do account for significant morbidity and malaise associated with the excision of a patients'' sun exposed areas, including the skin of the hands, legs, neck, and face.¹⁰ Children who experience severe blistering sunburns are at increased risk for melanomas.⁹ Melanomas arise in the skin pigmentation cells, presenting common risks for melanomas in people with dark completions as those with lighter completions.⁴ Melanomas are a less common skin cancer type but they are the most deadly type, accounting for 75% of all deaths related to skin cancer.⁴ Parents are legally and morally responsible for the safety and welfare of their young children. Public school teachers, school administrators, and by extension the state governments who manage, fund, and establish policies for public schools, assume this parental responsibility while children attend. In Hawai‘i, 97% of children, ages 3 to 14, or about 179,475 students attend elementary schools, and 63% of these students attend public elementary schools in the state.¹² In Hawai‘i''s tropical climate, schools are traditionally built with open architectural features and campus layouts to facilitate natural structural cooling by mountain trade winds.⁴ These design features of Hawai‘i''s schools expose students to direct sunlight while walking between class, during physical education athletic activities, during recesses, and during lunch periods while at school.⁴ Hawai‘i''s parents and educators unwittingly expose young children to dangerous levels of UV radiation while at school, and establish schools as a primary risk setting for the development of skin cancer in adults. The use of sun protection strategies in elementary school children is estimated to have the potential to reduce the risk of developing skin cancer by 78%.⁴Educators in both the United States and Hawai‘i are receptive and willing to implement sun protection policies for primary school children when the risks are made clear to the school administrators, faculty, and teachers. A study conducted by Buller et al (2002) was designed to assess sun protection policies in the United States. The researchers surveyed 1000 public elementary schools. The study found that only 3.4% of the schools had sun protection policies for children, although 84% reported that the students were outdoors during peak periods of the day for UV exposures.¹³ Most of the administrators, about 72.8%, were willing to adopt sun exposure mitigation policies; however the majorreported barriers were lack of awareness of the risks and organizational barriers in school districts.¹³ A similar study conducted in Hawai‘i by Eakin, et al (2004) found that 99% of the schools in Hawai‘i scheduled outdoors activities during the midday peak UV radiation, and that few schools had sun protection uniform policies.⁴ Among the primary school educators surveyed in Hawai‘i, 78% believed that excessive sun exposure was an important childhood risk for skin cancers, and over a third were in favor of a statewide policy to prevent skin cancer risks in their children.⁴In the US Center for Disease Control and Prevention''s “Guide to Community Preventive Services” (a compendium of all the empirically tested research on methods to reduce the burden of common diseases in the United States), there are only two interventions recommended to be proven effective methods to prevent skin cancers and melanomas in young people.¹⁴ The first method is the promotion of covering up behavior, including wearing long-sleeved clothing and hats. The second is providing policy changes and education in elementary school settings.¹⁴ These two specific interventions by the CDC are the result of the agency''s systematic review of over 159 studies, considering interventions'' scientific merit, barriers to implementation, overall costs, and cost effectiveness. Several types of prevention strategies were rigorously evaluated to identify the best population-based skin cancer prevention programs. A “No Hat, No Shirt, No Play” policy was recommended as the intervention strategy for primary schools.The CDC examined studies using various types of interventions, including the development and promotion of public media education campaigns about risk, promoting the use of sunscreen, and enhancing access to and utilization of clinical and self-administered skin cancer screenings. These methods were not found to be as effective, efficacious, or cost-effective as simply having primary school children wear a hat and long sleeves during participation in outdoor activities at school.¹⁴ The development of a “No Hat, No Shirt, No Play” policy in Hawai‘i''s public schools offers the application of the best science to prevent skin cancer, and is proven to be an acceptable prevention method for children, their parents, and educators.³There are several examples of school-based policies that have been adopted that can be used as a model to create state legislation designed to curb the epidemic rise in skin cancer rates in Hawai‘i. In Australia, a country that shares similar proximity to the earth''s equator as Hawai‘i, the implementation of a “No Hat, No Shirt, No Play” school policy was evaluated in a study entitled “Kidskin.”⁵ This randomized and controlled community trial utilized objective observational assessments of adherence to a “No Hat, No Shirt, No Play” policy by primary school children, parents, and educators in a range of primary schools in Australia.⁵ The researchers found that even in schools that did not receive the complementary education program about sun protection behaviors and strategies, there was a 76% adherence to the “No Hat, No Shirt, No Play” policy by the school children. Also described in the “Kidskin” research, the intervention schools, where a full complement of sun protection education was delivered, the students, the parents, and school educators'' adherence rates to the “No Hat, No Shirt, No Play” policy ranged from 85% to 100%. These adherence measures were obtained during unannounced videotaping of these primary school students during their outdoor, lunch, and recess activities. No other skin cancer prevention policy measures implemented by the “Kid-skin” program in Australian schools, including the establishment of increased shade structures in the children''s outdoor play areas, matched the effectiveness of the children and the schools in the “No Hat, No Shirt, No Play” policy.⁵Despite the overwhelming adherence of Australian children to Kidskin''s “No Hat, No Shirt, No Play” policy, there were barriers to implementation. These barriers may represent a challenge to Hawai‘i state legislation for a statewide “No Hat, No Shirt, No Play” policy in Hawai‘i''s schools. In the Kidskin study, parental support to enforce their children''s wearing of the program''s recommended “Gold Standard” hat was challenging. The researchers hypothesize that additional parental education may reduce the effect of this parental barrier to the policy.⁵ This barrier also underscores the importance of the additional inclusion of adult education about the risks of sun protection in children, combined with the mandatory “No Hat, No Shirt, No Play” policy. These two components can serve to reinforce the adherence to the program.It is not clear from the Kidskin study whether clothing costs were also a factor associated with preventing parent''s adoption of the “No Hat, No Shirt, No Play” policy. There will be always be parents who are not financially able to meet the “No Hat, No Shirt, No Play” policy program''s requirement to provide a long sleeve shirt and hat for their child. A support program for parents who are unable to provide these apparel resources could be established, and based upon parental income eligibility requirements. Income data from the Hawai‘i Department of Business Economic Development and Tourism can be used to determine the cost of such a program. It is estimated that there are about 13% of individuals with children under the age of 18, or about 38,000 people who have incomes that are below state poverty levels.¹⁵ Applying this data, it is estimated that approximately 5,000 children in Hawai‘i would need financial support to meet the requirements of a statewide “No Hat, No Shirt, No Play” policy program.¹⁵The adoption of a support program for low income families to adhere to a Hawai‘i primary school “No Hat, No Shirt, No Play” policy may not require the use of any public funding. As part of the state''s, “No Hat, No Shirt, No Play” policy program, an information list of preferred hat and long sleeve shirt vendors could be included as a resource for parents to obtain the suitable clothing needed to meet the program''s requirements. Clothing vendors, as a benefit for being placed on this vendor resource list, would agree to donate 10% of their expected sales profits in merchandise, and this merchandise would in turn be made available to parents who are unable to meet the “No Hat, No Shirt, No Play” policy program''s uniform requirement for their children.It is expected that the increased vendor sales revenue realized by requiring parents to include a long sleeve shirt and hat as part of a outdoor school uniform would generate about 3.8 million dollars in new spending if only 85% of the 96,108 public school primary students and their parents adhere to the program by buying shirts and hats at the retail price which will cost about $40.00 (Deputla, personal communication, 2009). Shirt and hat clothing vendors typically make a minimum of about $2 to $4 in profit per item (Deputla, personal communication, 2009). Adding a 10% allocation from vendors would generate about $40,000 in funds towards the support of the expected 5,000 families needing help. This allocation could still provide the vendors with a minimum of $345,988 in annual net profits to share.There are additional challenges to the implementation of a “No Hat, No Shirt, No Play” policy in Hawai‘i primary schools. The implementation of this policy, and the requirements for adherence, could dissuade public schools from promoting outdoor activities and seriously curb support of the state''s primary schools already tenuous budgets for athletic programs. The reality of reducing support for primary school physical activity for students could also contribute to the increasing obesity rates in young people.³ To minimize the potential for the “No Hat, No Shirt, No Play” policy to reduce physical activity in schools, the program can incorporate the use of policy champions. Policy champions could be comprised of prominent athletic figures in Hawai‘i''s culture, including use of University of Hawai‘i sport figures or other well-known local athletes. These champions would serve to extol the benefits of physical activity while simultaneously modeling use of the sun protection apparel used in conjunction with the “No Hat, No Shirt, No Play” policy for schools. Adding the use of these athletic figures or champions is a program component suggested by the Kidskin researchers, and could be part of the program''s educational campaign for schools administrators, parents, and students.⁵There is a perceived concern by the public, promoted through popular media about the potential for skin cancer prevention strategies to cause a reduced absorption of vitamin D in primary school children, a primary metabolic process enhanced through exposure to sunlight. Researchers in Australia noted that there were public misconceptions arising from these media reports about the benefits of sunlight exposure for the enhancement of natural absorption of vitamin D.¹⁶ Australia''s media reports about vitamin D served to reduce adherence to the established sun protection programs and policies recently developed in this country. This effect was significant despite the lack of empirical evidence that sun prevention activities presented little risk of vitamin D deficiencies in populations.⁸ Current research is now being conducted to clarify the role of vitamin D absorption, and identify if there is a relationship between vitamin D consumption and cancer prevention.⁸ However, until definitive conclusions are made about the possible harm presented by reduced vitamin D absorption caused by skin cancer prevention programs, there remains a consistent and clear link between skin cancer including melanomas and overexposure to the sun in children.¹⁶ Additionally in the United States most milk and other food products in the United States provide sufficient supplementation of vitamin D for children and adults.⁸ The mixed messages about vitamin D deficiencies and sun exposure prevention remain inaccurate and unfounded.Beyond the subsequent suffering and death in adulthood that will result from failure to implement primary skin cancer prevention policies, there is a great potential for these diseases to present a tremendous and avoidable financial load on Hawai‘i''s healthcare systems. In 1997, the annual cost of treating the estimated 40,000 melanoma cases in the United States was about 567 million dollars, or an average of about $14,000 per patient per year.¹⁷ However, the annual costs per patient are disproportionately spread among the range of patients, with the cost being $1,310 for patients who are diagnosed with early stage disease, versus $42,000 for patients with later stage cancers.¹⁷ These costs do not include indirect costs, incorporating the loss of earnings and other expenses associated with the disease.The total financial burden of melanoma in the United States is estimated at 1 billion dollars annually.¹⁷ Additionally, these are the costs estimated for the least common type of skin cancer, melanoma. Consider this, cost estimates can be made to include the more common basal and squamous cell skin cancers, and use a treatmentcost model comprised of only excision ($275/pt/yr). Applying this minimum per-person medical cost to the 1.35 million expected new basal and squamous skin cancer cases in the United States, and the 4, 950 expected new cases in Hawai‘i, the annual skin cancer treatment costs amount to nearly $39 billion for the United States, and $1,475,000 for Hawai‘i using 1997 dollars. Finally, the incidence of skin cancers and melanomas becomes more prevalent and frequent after age 50, so that this preventable medical and financial burden will most likely be supported through government Medicare disbursements for people who are older.¹⁰There are models of effective sun protection policies that have been successfully adopted in Hawai‘i''s private primary schools. Research conducted by a Hawai‘i dermatologist, Dr. Nip-Sakamoto at Punahou and Iolani Schools in 2000, pilot tested the efficacy of sun protection education for students, educators, and parents, combined with school policies requiring primary school children to wear sun protection gear including hats (Nip-Sakamoto, personal communication, 2009). Currently, nine years after the initial pilot projects were completed in these schools, both Punahou and Iolani School have instituted broad skin cancer prevention policies that include use of sun protection clothing, education for students, faculty, and parents, and also the new construction and use of sun protective structures in their outdoor sports and recreational facilities (Nip-Sackmoto, personal communication, 2009).Finally, in Hawai‘i there are models for the legislation that support a requirement for parents to provide disease prevention interventions for their children. Since 2002, State Department of Health''s Administrative Rules support legislation for the “Vax-to-School” program that has successfully demonstrated use of a statewide policy to encourage health promotion in primary school students.¹⁸ The program requires that primary school children, and children in other age groups be administered vaccines for many common diseases including chicken pox, rubella, measles, mumps, hepatitis B, diphtheria, tetanus, and pertussis.¹⁹ This program has supported the vaccination of primary school children through the use of over 260 medical providers. The CDC estimates that the program supports Hawai‘i''s 90% immunization rate for children entering elementary schools.²⁰ Funding for the program is provided by allocations from the CDC, in conjunction with the Hawai‘i State Medicaid program.^19,20 The programmatic policy standards of the “Vax to School” program can be successfully adapted for “No Hat, No Shirt, No Play” legislation.Although there are several barriers that can contribute to the implementation of a mandated statewide “No Hat, No Shirt, No Play” policy for primary school children, there is overwhelming evidence that this type of intervention may be a feasible and an effective method to promote the health and safety of our children. The potential costs of not implementing this simple strategy can be considered using various measures including the potential treatment cost for skin cancer, the personal disfigurements created by these treatments, or the number of deaths that will eventually result from overexposure to the sun. Currently there are few options to prevent cancers. There has been great success in changing social norms concerning tobacco use in young people, subsequently reducing mortality rates from this disease. Overexposure to the sun represents the new paradigm in cancer prevention for our children. We can implement changes now that can assure our children a more healthy future.