Reducing Transdermal Uptake of Semivolatile Plasticizers from Indoor Environments: A Clothing Intervention.

Models and laboratory studies suggest that everyday clothing influences the transdermal uptake of semivolatile organic compounds, including phthalate plasticizers, from indoor environments. However, this effect has not been documented in environmental exposure settings. In this pilot study, we quantified daily excretion of 17 urinary metabolites (µg/day) for phthalates and phthalate alternatives in nine participants during 5 days. On Day 0, baseline daily excretion was determined in participants' urine. Starting on Day 1, participants refrained from eating phthalate-heavy foods and using personal care products. On Days 3 and 4, participants wore precleaned clothing as an exposure intervention. We observed a reduction in the daily excretion of phthalates during the intervention; mono-n-butyl phthalate, monoisobutyl phthalate (MiBP), and monobenzyl phthalate were significantly reduced by 35, 38, and 56%, respectively. Summed metabolites of di(2-ethylhexyl)phthalate (DEHP) were also reduced (27%; not statistically significant). A similar reduction among phthalate alternatives was not observed. The daily excretion of MiBP during the nonintervention period strongly correlated with indoor air concentrations of diisobutyl phthalate (DiBP), suggesting that inhalation and transdermal uptake of DiBP from the air in homes are dominant exposure pathways. The results indicate that precleaned clothing can significantly reduce environmental exposure to phthalates and phthalate alternatives.

Occupational exposure to PFAS: Research and protection needed.

Per- and polyfluoroalkyl substances (PFAS) have been used in a variety of consumer and industrial applications. PFAS are associated with numerous detrimental health effects, but workplace exposure to PFAS has only been studied in a small number of occupations. More research is needed to fully understand how workers may be exposed to PFAS and what health effects this may cause.

Occupational exposures to airborne per- and polyfluoroalkyl substances (PFAS)-A review.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a group of synthetically-made chemicals with diverse functional properties that have become ubiquitous in our environment because of their widespread use. PFAS exposure has been associated with adverse health effects, and it is therefore vital to know how exposure may occur. Many studies have focused on environmental exposure from drinking water, but there is a paucity of data on inhalation exposure, especially in occupational settings. METHODS: In this study, through a comprehensive literature search, measured airborne (i.e., aerosols, volatiles, and dust) inhalation exposure and area levels were compiled for various occupations to compare reported levels of PFAS exposure. Airborne PFAS levels measured in various occupations such as ski waxing, textile manufacturing, firefighting, and floor waxing were analyzed and compared. RESULTS: Results of this review demonstrate that workers experience varying levels of PFAS exposure contingent on the workplace and industry and the work tasks performed within the workplace. Out of all occupations, ski waxing exhibited the highest total PFAS airborne concentrations when compared to all other reported occupational and residential exposures. CONCLUSIONS: Further research is recommended to estimate the risk of PFAS exposures in the occupations reviewed and to identify other potential occupations at risk of PFAS exposure. In addition, informed recommendations to implement safety measures ought to be developed to protect workers from adverse health effects.

Occupational exposure and serum levels of per- and polyfluoroalkyl substances (PFAS): A review.

BACKGROUND: Per- and polyfluoroalkyl substances, or PFAS, are a class of chemicals used in nearly all sectors of industry and many consumer products. Their resistance to degradation, however, means that PFAS are ubiquitous in the environment and bioaccumulate. PFAS exposure has also been linked to a variety of adverse health effects. Occupational PFAS exposure is of particular concern as research on PFAS exposure in worker populations has historically been limited and generally restricted to fluorochemical plant workers involved in PFAS production. METHODS: A comprehensive review of peer-reviewed scientific literature was conducted to investigate which worker populations may experience occupational exposure to PFAS. Serum PFAS levels reported in various occupations were analyzed and compared to serum PFAS levels published on the general public exposed to PFAS-contaminated drinking water and the study population of the National Health and Nutrition Examination Survey (NHANES). RESULTS: Our analysis indicates that professional ski waxers and firefighters may be exposed to several different PFAS at levels often similar to or higher than levels among fluorochemical plant workers and individuals in communities with PFAS-contaminated drinking water, and higher than levels in the general public. PFAS serum level data on other occupations were largely absent. CONCLUSIONS: Results highlight a need for additional research on occupational PFAS exposures and concomitant environmental exposures in these populations. Research on exposure levels in occupations and industries known or suspected to utilize PFAS is critically needed to foster informed recommendations for exposure mitigation measures to protect workers from adverse health effects of PFAS exposure.

Inorganic Arsenic as an Endocrine Disruptor: Modulation of the Glucocorticoid Receptor Pathway in Placental Cells via CpG Methylation.

Prenatal exposure to inorganic arsenic (iAs) has been associated with adverse developmental and reproductive outcomes. These outcomes may be tied to altered functionality of nuclear transcription factors such as the glucocorticoid receptor (GR) in the placenta and associated gene expression. The GR pathway is integral for proper fetal and placental development, and perturbations in this pathway may underlie observed associations between prenatal iAs exposure and adverse birth outcomes. We therefore set out to investigate whether iAs modulates the GR signaling pathway in placental cells. JEG-3 trophoblasts were exposed to environmentally-relevant doses of iAs, and mRNA expression assessed. To examine the links between iAs exposure, the GR signaling pathway, and epigenetic modification, DNA methylation levels were also quantified. Treatment with iAs altered the expression of 12 GR-genes that play a role in fetal and placental development. Furthermore, at a gene-specific level, mRNA abundance was associated with changes in DNA methylation patterning in JEG-3 cells, suggesting that the effects of iAs are mediated by epigenetic mechanisms. The identified target genes have been associated with prenatal iAs exposure, placental physiology, and fetal development. This study provides further evidence for iAs as an endocrine disruptor and provides insight as to the mechanisms by which prenatal iAs exposure may induce adverse birth outcomes.

Effective Message Elements for Disclosures About Chemicals in Cigarette Smoke.

Introduction: Cigarette smoke contains at least 93 chemicals or "constituents" that the Food and Drug Administration has identified as harmful and potentially harmful constituents to human health. Our study sought to identify which constituent disclosure message elements are most effective in discouraging people from smoking. Methods: Three hundred eighty eight current smokers aged 18 and older completed an online survey in February 2015. We randomized participants to respond to one of two sets of 13 toxic products that contain cigarette constituents and 25 health effects associated with cigarette constituents. Results: Products that elicited the most discouragement were those with lower chances of exposure (e.g., explosives), followed by products with possible exposure (e.g., rat poison), and products with a high likelihood of exposure (e.g., floor cleaner). Awareness of toxic products that constituents are found in (p < .001) and low exposure products (p < .001) were associated with higher discouragement. Health effects that people had heard are caused by cigarette smoke constituents elicited higher discouragement from smoking cigarettes (p < .001). Cancer was associated with higher discouragement relative to respiratory, cardiovascular, and reproductive health effects (all p < .001). Conclusions: Cigarette smoke constituent messages may be more effective at discouraging smoking if they include information about carcinogenic health effects (e.g., mouth cancer and lung tumors) and low exposure toxic products (e.g., explosives and radioactive material) as message elements. Implications: Our study identified health effects and toxic products, especially cancers and rarely encountered toxic products, that may discourage smoking when included in disclosure messages. By constructing messages that communicate the harms associated with tobacco use by contextualizing those harms in terms of specific constituents, tobacco education messaging efforts may be increasingly successful.

Feasibility of Implementing a Total Worker Health® Intervention During the COVID-19 Pandemic in Small and Medium Businesses : Results From the Carolina PROSPER Study.

OBJECTIVE: In response to the COVID-19 pandemic's disruptive effect on employers and workers, an interdisciplinary team launched the Carolina Promoting Safe Practices for Employees' Return study to assess the feasibility of providing tailored technical assistance to small and medium North Carolina businesses using a Total Worker Health (TWH) ® approach. METHODS: Feasibility of the approach was assessed via surveys and interviews of business representatives from four participating businesses ranging in size from 3 to 110 employees. RESULTS: The TWH approach is feasible, that is, in demand, practical, and acceptable to protect and promote worker safety, health, and well-being. Potential challenges include implementation cost, difficulty engaging all employees, and difficulty accessing tailored health and safety materials in a timely manner. CONCLUSIONS: Additional refinement and testing of the TWH approach postpandemic with more worksites is warranted.

Estimated burden of disease attributable to selected occupational exposures in the United Arab Emirates.

BACKGROUND: As part of an effort to strengthen occupational safety and health programs, the United Arab Emirates (UAE) commissioned a study to estimate the burden of disease attributable to occupational exposure to carcinogens, particulate matter, and noise. METHODS: We developed an innovative simulation model to estimate the occupational disease burden and facilitate future assessments as more field-based quantitative data become available. RESULTS: We determined that, in 2008, an estimated 46 deaths (95% CI: 27-71) and 17,000 health-care facility visits (95% CI: 16,000-18,000), along with 4,500 cases of noise-induced hearing loss, were attributable to the occupational risk factors covered in this study. Lung cancer and leukemia were associated with the highest number of deaths (38), whereas asthma and chronic obstructive pulmonary disease contributed most to the health-care facility visits (nearly 16,900). The highest estimated occupational disease burden is in construction. CONCLUSION: These results will help the UAE to institute new policies for environment, health, and safety management.

Occupational silica exposure and chronic kidney disease.

INTRODUCTION: Occupational exposure to silica may be associated with chronic kidney disease (CKD). Most studies have been conducted in occupational cohorts with high levels of exposure but small numbers of cases. We analyzed data from a population-based case-control study of occupational silica exposure and CKD. METHODS: Cases were hospital patients with newly diagnosed CKD, and community controls were selected using random digit dialing and frequency matched by age, gender, race, and proximity to the hospital. Silica exposure estimates were assigned by industrial hygiene review of lifetime job history data and weighted for certainty and intensity. Conditional logistic regression was used to estimate the odds ratios (ORs) for CKD conditioned on demographic, lifestyle, and clinical variables. RESULTS: The mean age of participants was 63 years (range 30-83 years); 59% were male and 55% were white. Any silica exposure (compared with none) was associated with a 40% increased risk of CKD [OR = 1.40, 95% confidence interval (CI): 1.04, 1.89] in a multivariable adjusted model. The mean cumulative duration of silica exposure was significantly higher in exposed cases than in exposed controls (33.4 vs. 24.8 years, respectively). Overall, compared with nonexposed participants, the ORs (95% CI) for those below and above the median duration of silica exposure were 1.20 (0.77, 1.86) and 1.76 (1.14, 2.71), respectively. CONCLUSIONS: We found a positive relationship between occupational silica exposure and CKD. A dose-response trend of increasing CKD risk with increasing duration of silica exposure was observed and was particularly strong among nonwhites.

Penetration patterns of monomeric and polymeric 1,6-hexamethylene diisocyanate monomer in human skin.

We investigated penetration patterns of monomeric and polymeric 1,6-hexamethylene diisocyanate (HDI), experimentally and as part of commercial products, in excised full-thickness human skin at 5, 10, 30, or 60 min after exposure. We observed that both monomeric and polymeric HDI were readily absorbed into the skin and that the clearcoat composition affects the penetration rate of the individual isocyanates. The short-term absorption rates for HDI monomer, biuret, and isocyanurate were determined and used to estimate the exposure time required to reach a body burden equal to the American Conference of Governmental Industrial Hygienists (ACGIH) inhalation threshold limit value (TLV) or Oregon State occupational exposure limit (OEL). Oregon is the only government entity in the United States to promulgate a short-term exposure limit (STEL) for HDI-based polyisocyanates biuret and isocyanurate. Based on these absorption rates for a slow-drying clearcoat after 10 min (1.33 µg cm(-2) h(-1)) or 60 min (0.219 µg cm(-2) h(-1)), we calculated that 6.5 and 40 min dermal exposure, respectively, is required to achieve a dose of HDI equivalent to the ACGIH TLV. For biuret, the time to achieve a dose equivalent to the Oregon OEL for slow-drying clearcoat was much shorter (<31 min) than that for fast-drying clearcoat (618 min). Isocyanurate had the shortest skin absorption times regardless of clearcoat formulation (14 s-1.7 min). These results indicate that the dose received through dermal exposure to HDI-containing clearcoats has a significant potential to exceed the dose equivalent to that received through inhalation exposure at established regulatory limits. A critical need exists to monitor dermal exposure quantitatively in exposed workers, to use proper protective equipment to reduce dermal exposure, and to re-evaluate regulatory exposure limits for isocyanates.

Airborne isocyanate exposures in the collision repair industry and a comparison to occupational exposure limits.

Isocyanate exposure was evaluated in 33 spray painters from 25 Washington State autobody shops. Personal breathing zone samples (n = 228) were analyzed for isophorone diisocyanate (IPDI) monomer, 1,6-hexamethylene diisocyanate (HDI) monomer, IPDI polyisocyanate, and three polyisocyanate forms of HDI. The objective was to describe exposures to isocyanates while spray painting, compare them with short-term exposure limits (STELs), and describe the isocyanate composition in the samples. The composition of polyisocyanates (IPDI and HDI) in the samples varied greatly, with maximum amounts ranging from up to 58% for HDI biuret to 96% for HDI isocyanurate. There was a significant inverse relationship between the percentage composition of HDI isocyanurate to IPDI and to HDI uretdione. Two 15-min STELs were compared: (1) Oregon's Occupational Safety and Health Administration (OR-OSHA) STEL of 1000 µg/m(3) for HDI polyisocyanate, and (2) the United Kingdom's Health and Safety Executive (UK-HSE) STEL of 70 µg NCO/m(3) for all isocyanates. Eighty percent of samples containing HDI polyisocyanate exceeded the OR-OSHA STEL while 98% of samples exceeded the UK-HSE STEL. The majority of painters (67%) wore half-face air-purifying respirators while spray painting. Using the OR-OSHA and the UK-HSE STELs as benchmarks, 21% and 67% of painters, respectively, had at least one exposure that exceeded the respirator's OSHA-assigned protection factor. A critical review of the STELs revealed the following limitations: (1) the OR-OSHA STEL does not include all polyisocyanates, and (2) the UK-HSE STEL is derived from monomeric isocyanates, whereas the species present in typical spray coatings are polyisocyanates. In conclusion, the variable mixtures of isocyanates used by autobody painters suggest that an occupational exposure limit is required that includes all polyisocyanates. Despite the limitations of the STELs, we determined that a respirator with an assigned protection factor of 25 or greater is required to protect against isocyanate exposures during spray painting. Consequently, half-face air-purifying respirators, which are most commonly used and have an assigned protection factor of 10, do not afford adequate respiratory protection.

The genetics of occupational asthma development among workers exposed to diisocyanates: A systematic literature review with meta-analysis.

Diisocyanates are widely used compounds that pose a safety concern for workers in occupations within the spray-paint, spray-foam insulation, and furniture varnish industries. Epidemiological studies show that only a subset of workers exposed to diisocyanates develop diisocyanate-induced occupational asthma (diisocyanate asthma, DA), indicating that genetic susceptibility may play a role. The purpose of this systematic literature review was to compile and meta-analyze the reported data on genetic susceptibility markers for DA. Three databases (Embase, Pubmed, and Scopus) were searched and 169 non-duplicate publications were identified, of which 22 relevant occupational studies were included in this review. Researchers reported prevalence odds ratios (PORs) for 943 comparisons in 82 different genes/serotypes. Protein network functions for the DA-associated genes from this review include: antigen processing, lymphocyte activation, cytokine production regulation, and response to oxidative stress. Meta-analysis of comparisons between workers with DA and controls was conducted for 23 genetic markers within: CTNNA3, GSTM1, GSTP1, GSTT1, HLA-C, HLA-DQB1, HLA-DR1, HLA-DR3, HLA-DR4, HLA-DR7, and HLA-DR8. These genes code for proteins that are involved in cell-cell adhesions (CTNNA3), glutathione conjugation for xenobiotic metabolism (GST gene family), and immune system response (HLA gene family). The most compelling pooled PORs were for two studies on CTNNA3 (increased DA risk: rs10762058 GG, rs7088181 GG, rs4378283 TT; PORs 4.38-4.97) and three studies on HLA-DR1 (decreased DA risk, POR 0.24). Bioinformatics of the predicted protein pathways for DA shows overlap with biomarker-associated pathways in workers before development of asthma, suggesting overlap in toxicokinetic and toxicodynamic pathways of diisocyanates. The control groups were also compared against each other and differences were negligible. Suggestions for improving future research are also presented. Of the highest importance, the literature was found to be profoundly publication-biased, in which researchers need to report the data for all studied markers regardless of the statistical significance level. We demonstrate the utility of evaluating the overlap in predicted protein pathway functions for identifying more consistency across the reported literature including for asthma research, biomarker research, and in vitro studies. This will serve as an important resource for researchers to use when generating new hypothesis-driven research about diisocyanate toxicology.

Hemoglobin adducts in workers exposed to 1,6-hexamethylene diisocyanate.

We investigated the utility of 1,6-hexamethylene diamine (HDA) hemoglobin adducts as biomarkers of exposure to 1,6-hexamethylene diisocyanate (HDI) monomer. Blood samples from 15 spray painters applying HDI-containing paint were analyzed for hemoglobin HDA (HDA-Hb) and N-acetyl-1,6-hexamethylene diamine (monoacetyl-HDA-Hb) by GC-MS. HDA-Hb was detected in the majority of workers (≤1.2-37 ng/g Hb), whereas monoacetyl-HDA-Hb was detected in one worker (0.06 ng/g Hb). The stronger, positive association between HDA-Hb and cumulative HDI exposure (r(2) = 0.3, p < 0.06) than same day exposure (p ≥ 0.13) indicates long-term elimination kinetics for HDA-Hb adducts. This association demonstrates the suitability of HDA-Hb adducts for further validation as a biomarker of HDI exposure.

The utility of naphthyl-keratin adducts as biomarkers for jet-fuel exposure.

We investigated the association between biomarkers of dermal exposure, naphthyl-keratin adducts (NKA), and urine naphthalene biomarker levels in 105 workers routinely exposed to jet-fuel. A moderate correlation was observed between NKA and urine naphthalene levels (p = 0.061). The NKA, post-exposure breath naphthalene, and male gender were associated with an increase, while CYP2E1*6 DD and GSTT1-plus (++/+-) genotypes were associated with a decrease in urine naphthalene level (p < 0.0001). The NKA show great promise as biomarkers for dermal exposure to naphthalene. Further studies are warranted to characterize the relationship between NKA, other exposure biomarkers, and/or biomarkers of biological effects due to naphthalene and/or PAH exposure.

Factors affecting variability in the urinary biomarker 1,6-hexamethylene diamine in workers exposed to 1,6-hexamethylene diisocyanate.

Although urinary 1,6-hexamethylene diamine (HDA) is a useful biomarker of exposure to 1,6-hexamethylene diisocyanate (HDI), a large degree of unexplained intra- and inter-individual variability exists between estimated HDI exposure and urine HDA levels. We investigated the effect of individual and workplace factors on urine HDA levels using quantitative dermal and inhalation exposure data derived from a survey of automotive spray painters exposed to HDI. Painters' dermal and breathing-zone HDI-exposures were monitored over an entire workday for up to three separate workdays, spaced approximately one month apart. One urine sample was collected before the start of work with HDI-containing paints, and multiple samples were collected throughout the workday. Using mixed effects multiple linear regression modeling, coverall use resulted in significantly lower HDA levels (p = 0.12), and weekday contributed to significant variability in HDA levels (p = 0.056). We also investigated differences in urine HDA levels stratified by dichotomous and classification covariates using analysis of variance. Use of coveralls (p = 0.05), respirator type worn (p = 0.06), smoker status (p = 0.12), paint-booth type (p = 0.02), and more than one painter at the shop (p = 0.10) were all found to significantly affect urine HDA levels adjusted for creatinine concentration. Coverall use remained significant (p = 0.10), even after adjusting for respirator type. These results indicate that the variation in urine HDA level is mainly due to workplace factors and that appropriate dermal and inhalation protection is required to prevent HDI exposure.

Development of a sampling patch to measure dermal exposures to monomeric and polymeric 1,6-hexamethylene diisocyanate: a pilot study.

The purpose of this study was to develop and evaluate a patch sampler to monitor dermal exposures to monomeric and polymeric 1,6-hexamethylene diisocyanate (HDI) in the automotive refinishing industry. Different patch materials were used to construct the patches, and patches impregnated with a derivatizing solution were compared with those that were not impregnated. We observed that impregnated felt patches measured significantly more HDI monomer (p = 0.04) than non-impregnated patches in a controlled experiment. Both impregnated and non-impregnated patches were compared with the tape-strip method by monitoring three spray painters' dermal exposure to monomeric and polymeric HDI. Isocyanurate was the predominant species measured by all three sampler types with detectable levels in >86% of samples. Overall, tape-strips of exposed skin measured lower levels of monomeric and polymeric HDI than impregnated patch samplers at the same sampling site on the skin. Unlike tape-strips, impregnated patches are not as prone to evaporative or reactive losses or losses due to rapid penetration into the skin. Further investigations are warranted to evaluate these and other methods to measure dermal exposure to workers under occupational conditions to better understand the relationship between dermal exposure and internal dose.

Field comparison of air sampling methods for monomeric and polymeric 1,6-hexamethylene diisocyanate.

This study was to critically compared 13 different air samplers for their ability to monitor air exposures to monomeric and polymeric 1,6-hexamethylene diisocyanate (HDI) in the automotive refinishing industry. Using both fast- and slow-drying clearcoat, we tested the following types of samplers: single- and dual-stage 37-mm polypropylene (PP) and polystyrene (PS) samplers (open- and closed-face), IOM (with plastic and stainless steel inserts), OSHA42, IsoChek, and WA-DOSH samplers. Midget impingers with frit were used as reference samplers. We observed the PP, PS, and IOM samplers to measure greater levels of HDI monomer and biuret when a fast-drying clearcoat was applied compared with a slow-drying clearcoat. When a slow-drying clearcoat was applied, the open-face PP and PS samplers measured significantly more monomeric and polymeric HDI (2-fold; p < 0.003) than the closed-face PP and PS samplers. We determined that significantly more monomeric and polymeric HDI were measured by impingers (1.3-1.9-fold) compared with single-stage PP/PS (N = 59), dual-stage PP/PS (N = 59), or IOM (N = 24) samplers. However, when stratified by cassette characteristics, the open-face single-stage PP and PS samplers performed equally to the impingers for HDI monomer when a fast-drying clearcoat was applied, and for all analytes when a slow-drying clearcoat was applied. Significantly higher HDI monomer concentrations (1.2-3.1-fold; p = 0.001) were measured with OSHA42 compared with the impinger. The IsoChek did not detect HDI monomer, and of the three samplers analyzed by laboratories other than UNC (i.e., OSHA42, IsoChek, and WA-DOSH), the WA-DOSH was in the best agreement with the impingers. The influence of clearcoat drying time on the sampler's ability to measure monomeric and polymeric HDI emphasizes the importance of the speciation of diisocyanates in chemical analysis and the careful consideration for the selection of the air sampler to be used when measuring exposures during automotive spray painting.

Survey of dermal protection in Washington State collision repair industry.

Substantial exposure to isocyanates may occur during spray painting in autobody shops, yet information is lacking on the efficacy of the protective clothing used during spray painting. We investigated the personal and workplace factors associated with painters' dermal protection use during a large-scale exposure assessment study. Survey data indicated that 69% of painters always used gloves, with latex gloves (47%) and nitrile gloves (34%) used most frequently. Among latex glove users, 53% used thin latex (0.05-0.13 mm), 6% used medium latex (0.15-0.20 mm), and 12% used thick latex (> 0.20 mm). Among nitrile glove users, 27% used thin nitrile and 45% used medium nitrile. Sixty-three percent of painters always used coveralls, 44% preferring one particular brand. Although overspray presents an opportunity for dermal exposure to the neck and face, only 19% of painters protected these areas with personal protective equipment. Painters who always used coveralls were more likely to use gloves (odds ratio = 7.9, p = 0.061). Painters who reported ever having smoked cigarettes used gloves (p = 0.05) and coveralls (p = 0.04) more frequently. Painters who sprayed more than 34 clear coat jobs per month used coveralls most frequently (p = 0.038). Exact logistic regressions along with random sample calculations indicated that the survey results were independent of the shops. Because of the small sample size in this study, future research is warranted to corroborate these results. Studying the effectiveness of gloves and coveralls against polyurethane paints and understanding the underlying motivators and preferences for painters and business owners is needed for the development of best practices for the selection and use of dermal protection.

Viability of cultured human skin cells treated with 1,6-hexamethylene diisocyanate monomer and its oligomer isocyanurate in different culture media.

The isocyanate monomer 1,6-hexamethylene diisocyanate (HDI) and one of its trimers, HDI isocyanurate, are airway and skin sensitizers contained in polyurethane paint. The toxic response of cultured skin cells to these compounds was measured by evaluating the isocyanate concentrations at which 50% of the cells die (i.e., lethal concentration 50%, LC50) because the relative toxicity of each form of HDI should be considered when exposure limits of HDI-based paints are set. By using a luminescent ATP-viability assay, we compared the cytotoxic effects of HDI monomer and HDI isocyanurate on cultured human skin cells (keratinocytes, fibroblasts, and melanocytes) after 4-h isocyanate exposures using culture media with varying levels of nutrients in order to also determine the effects of media composition on isocyanate toxicity. Before analysis, experimental wells were normalized to controls containing cells that were cultured with the same vehicle and media. The measured mean LC50 values ranged from 5 to 200 µM across the experimental conditions, in which HDI isocyanurate in protein-devoid media was the most toxic to cells, producing the lowest LC50 values. For HDI monomer, keratinocytes were the most resistant to its toxicity and melanocytes were the most susceptible. However, when exposed to HDI isocyanurate, the opposite was observed, with melanocytes being the most resilient and the keratinocytes and fibroblasts were more susceptible. Depending on the type of skin cells, dose-response data indicated that HDI isocyanurate was 2-6 times more toxic than HDI monomer when using protein-devoid media whereas HDI isocyanurate was 4-13 times more toxic than HDI monomer when protein-rich media was used. Therefore, if the protein-devoid saline medium alone were used for these experiments, then a significant under-estimation of their relative toxicities in protein-rich environments would have resulted. This difference is because HDI monomer toxicity was more attenuated by the presence of protein in the culture media than HDI isocyanurate toxicity. Thus, conclusions based on comparative toxicity studies and consequent inference applied to potential human toxicity can be affected by in vitro culture media conditions. The physiochemical difference in reactivity of the two forms of HDI to biological molecules most likely explains the observed toxicity differences and may have implications for skin penetration, adverse effects like skin sensitization, and systemic responses like asthma. Future studies are warranted to investigate differences in the biological availability, cellular toxicity, and immunologic sensitization mechanisms for HDI monomer and HDI isocyanurate.