Noise exposures of sugar cane mill workers in Guatemala.

Objective: To describe personal noise exposure measurements obtained on Guatemala sugar cane mill workers as a function of job category.Design: This is a descriptive evaluation of existing data.Sample: The data set included 51 representative noise dosimetry surveys utilising NIOSH sampling protocol, completed on workers performing 21 jobs in a Guatemalan sugar cane mill. Results: Noise doses ranged from a low of 50.9% to an extreme of 25174%. The highest observed mean noise doses were for evaporator cleaners (15761%) and juice extractors (2047%). Ninety percent of noise dosimetry samples were between 50% to 1200% dose. Annual noise exposures are also reported after considering the 7-month seasonal work schedule.Conclusions: The majority of sugar cane mill workers were exposed to hazardous occupational noise exceeding the Guatemalan permissible exposure limit (GMLSW), which is consistent with U.S. NIOSH recommended exposure limit of 100% noise dose (85 dBA time-weighted average). Consequently, the majority of workers should be enrolled in a hearing conservation programme including engineering noise control in order to prevent long-term adverse effects on workers' hearing.

Assessment of cadmium and lead content in tomatoes and tomato products.

BACKGROUND: Cadmium and lead are completely redundant in the human body and any amount of these elements ingested poses a risk of adverse health effects. In non-occupational exposure the highest amount of xenobiotics enters the body with food. Valued for their taste, universal culinary application and health benefits tomatoes and tomato products are consumed almost every day by a large proportion of society. In order to protect consumers' health it is very important to monitor cadmium and lead content in food products. OBJECTIVE: The aim of the study was the health assessment of cadmium and lead content in tomatoes and tomato products in relation to their acceptable maximum levels in the relevant legislation. MATERIAL AND METHODS: Fresh fruits of the tomato plant and tomato products (juices, purées, concentrates, sauces) were analysed. Heavy metal content (Cd, Pb) was determined by flameless atomic absorption spectrometry (AAS). Before the AAS determination the samples were subjected to pressure mineralisation using microwave energy. RESULTS: Cadmium and lead contents in the studied food products were within the allowed range (the maximum level of cadmium and lead contamination of tomatoes is 0.05 mg/kg and 0.1 mg/kg of fresh mass). The limit for cadmium was exceeded only in a canned tomato concentrate (0.064 mg/kg of fresh mass). The average cadmium content in raw tomatoes and tomato products was: 0.017 mg/kg fresh weight, and lead 0.021 mg/kg fresh weight. CONCLUSIONS: Despite the low cadmium and lead contamination of the study samples of tomatoes and tomato products, it seems desirable to constantly monitor the content of these elements in food due to their ability to accumulate in the body and the risk of adverse health effects developing after many years of exposure, even to small doses.

Lead and cadmium in infant milk and cereal based formulae marketed in Nigeria: a probabilistic non-carcinogenic human health risk assessment.

BACKGROUND: There has been concern on the likelihood of contamination of infant formulae and consequent health risk in children. OBJECTIVE: This study has assessed and compared the lead and cadmium levels in infant formulae commonly consumed in Nigeria with international regulatory limits. It has also compared the estimated daily intake with Joint FAO/WHO Expert Committee on Food Additives (JECFA) and Proposition 65 Provisional Tolerable Daily Intake. MATERIAL AND METHODS: Lead and cadmium levels in 26 different brands of infant formulae purchased from stores in Port-Harcourt, Rivers state, Nigeria in January 2018 were assayed by Atomic Absorption Spectrophotometry. RESULTS: The lead and cadmium levels in milk based infant formulae ranged from 0.61-3.50 mg/kg and 0.01-0.55 mg/kg respectively whereas the range of the lead and cadmium levels in the cereal and cereal mix based were 0.29-1.95 mg/kg and 0.02-0.37 mg/kg, and 0.47-2.34 mg/kg and 0.001-0.46 mg/kg respectively. The mean lead level in the milk-based formulae (1.49 0.89 mg/kg) was slightly higher than other groups of formulae but the difference was not significant (p<0.05). The mean level of cadmium (0.17 mg/kg) in milk-based infant formulae was higher than levels in cereal and cereal mix but there was no significant statistical difference (p<0.05) between the samples. The lead and cadmium level in milk, cereal and cereal mixed based infant formulae were above the food safe limits. CONCLUSIONS: The consumption of infant formulae may add to the body burden of cadmium and lead of children with attendant public health implication. Regular monitoring and safety assessment of metals contamination of these infant formulae is advised.

Will worker DNELs derived under the European REACH regulation extend the landscape of occupational exposure guidance values?

Derived no-effect levels for workers (wDNELs) under the European REACH legislation have many aspects in common with occupational exposure limits (OELs). In an attempt to examine under which circumstances wDNELs might be used as exposure guidance outside their intended application, we compared derivation methods, coverage of substances and numerical values of wDNELs against two regulatory OEL lists (European Commission and Sweden) and three sets of recommendations (European SCOEL, German MAK and US ACGIH). Finally, we looked closer at wDNELs where SCOEL concluded that data were insufficient to derive an OEL. Major differences between wDNELs and OELs include regulatory background, intended use, actors involved, substance selection criteria, transparency and procedure of derivation, and operationalisation in terms of risk management measures. As of summer 2018, approximately five times more substances were covered by wDNELs than by the five sets of OELs examined herein. Meanwhile, many occupationally relevant pollutants were not covered by wDNELs, e.g. one-third of Swedish OELs lack corresponding wDNELs. We also note that wDNELs and OELs for the same substance may vary considerably, up to several orders of magnitude. In conclusion, with extensive substance coverage, wDNELs extend the landscape beyond the OELs. That said, important limitations are (1) that many air pollutants relevant for workers' health are not covered by REACH, and (2) concerns for inconsistencies in the derivation of wDNELs and in their level of protection. In particular, that route-to-route extrapolation is a common practice that may be grossly misleading when the effect of concern is local, e.g. sensitisation.

Derivation of a chronic reference dose for perfluorohexane sulfonate (PFHxS) for reproductive toxicity in mice.

Perfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid that was used as an industrial surfactant, but is now found as an environmental contaminant worldwide. In addition to its use as an industrial surfactant, it is a legacy contaminant from the use of aqueous film-forming foams. Despite its widespread occurrence in the environment and evidence of biological activity associated with PFHxS and similar perfluoroalkyl sulfonic acids in rodents, there is no oral toxicity value currently available from the IRIS Database. To derive an oral reference dose (RfD) for PFHxS, available toxicity studies were reviewed using a weight-of-evidence approach. A 42-day mouse reproductive study was chosen as the critical study for the derivation of the oral RfD. Benchmark dose modeling was utilized to derive a point of departure (POD) for a reduction in litter size. A 95% lower confidence limit on the benchmark dose (BMDL) of 13,900 ng/mL (serum PFHxS) was modeled for a reduction in litter size. An oral RfD for PFHxS of 4.0 ng/kg/d was calculated by conversion of the BMDL to a human equivalent oral dose using a human half-life adjusted dosimetric conversion factor and the application of a total uncertainty factor of 300. Additional research is needed to better characterize the toxicity associated with oral exposure to PFHxS and refine the development of toxicity values.

Derivation of an occupational exposure limit for diacetyl using dose-response data from a chronic animal inhalation exposure study.

Occupational exposure limits (OELs) have been previously proposed for diacetyl; however, most of these values are based on worker cohort studies that are known to have several limitations and confounders. In this analysis, an 8 hour time-weighted average (TWA) OEL for diacetyl was derived based on data from a chronic, 2 year animal inhalation study recently released by the US National Toxicology Program. In that study, complete histopathology was conducted on male and female mice and rats exposed to 0, 12.5, 25 or 50 ppm diacetyl. Several responses in the lower respiratory tract of rats (the more sensitive species) were chosen as the critical endpoints of interest. Benchmark concentration (BMC) modeling of these endpoints was used to estimate BMC values associated with a 10% extra risk (BMC10 ) and the associated 95% lower confidence bound (BMCL10 ), which were subsequently converted to human equivalent concentrations (HECs) using a computational fluid dynamics-physiologically based pharmacokinetic (CFD-PBPK) model to account for interspecies dosimetry differences. A composite uncertainty factor of 8.0 was applied to the human equivalent concentration values to yield 8 hour TWA OEL values with a range of 0.16-0.70 ppm. The recommended 8 hour TWA OEL for diacetyl vapor of 0.2 ppm, based on minimal severity of bronchiolar epithelial hyperplasia in the rat, is practical and health-protective.

Cancer mortality and exposure to nickel and chromium compounds in a cohort of Italian electroplaters.

BACKGROUND: Nickel and chromium-VI compounds are carcinogens for lung cancer, although it is still debated if there is an increased risk at low levels of exposure and for other cancers. METHODS: In a cohort of 2991 Italian electroplaters, a proportion of whom were exposed to low levels of nickel and/or chromium, cumulative exposure to their compounds was obtained by multiplying average concentrations of the metals in each electroplating tank by duration of employment in the company. The association of exposure to compounds with mortality was assessed by multivariable Cox models. RESULTS: No cancer site was associated with chromium exposure controlling for nickel, whereas exposure to nickel significantly increased mortality from lung, rectal, and kidney cancers, even after adjusting for exposure to chromium. CONCLUSIONS: Study results suggest that exposure to nickel compounds may increase the risk of lung cancer even below its occupational exposure limit and indicate possible associations with other cancer sites.

Quantitative relationships of exposure to chrysotile asbestos and mesothelioma mortality.

BACKGROUND: While asbestos has long been known to cause mesothelioma, quantitative exposure-response data on the relation of mesothelioma risk and exposure to chrysotile asbestos are sparse. METHODS: Quantitative relationships of mortality from mesothelioma and pleural cancer were investigated in an established cohort of 5397 asbestos textile manufacturing workers in North Carolina, USA. Eligible workers were those employed between 1950 and 1973 with mortality follow-up through 2003. Individual exposure to chrysotile fibres was estimated on the basis of 3420 air samples covering the entire study period linked to work history records. Exposure coefficients adjusted for age, race, and time-related covariates were estimated by Poisson regression. RESULTS: Positive, statistically significant associations were observed between mortality from all pleural cancer (including mesothelioma) and time since first exposure (TSFE) to asbestos (rate ratio [RR], 1.19; 95% confidence interval [CI], 1.06-1.34 per year), duration of exposure, and cumulative asbestos fibre exposure (RR, 1.15; 95% CI, 1.04-1.28 per 100 f-years/mL; 10-year lag). Analyses of the shape of exposure-response functions suggested a linear relationship with TSFE and a less-than-linear relationship with cumulative exposure. Restricting the analysis to years when mesothelioma was coded as a unique cause of death yielded stronger but less precise associations. CONCLUSIONS: These observations support with quantitative data the conclusion that chrysotile causes mesothelioma and encourage exposure-response analyses of mesothelioma in other cohorts exposed to chrysotile.

High frequency and severity of pleural changes in former workers exposed to anthophyllite associated with other contaminating amphibole asbestos in Brazil.

OBJECTIVE: To evaluate the frequency and severity of pleuropulmonary alterations in anthophyllite-exposed former workers in Itapira, São Paulo, Brazil. The amphibole anthophyllite, a magnesium-iron silicate, had its mining, marketing, and use forbidden in Brazil in 1995. METHODS: Former workers were followed from 1999 to 2011. All completed chest X-ray interpreted using the International Labour Office (ILO) classification. High-resolution computed tomography was used at the final evaluation. Spirometry assessed forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and FEV1/FVC throughout the follow-up period. Samples from the mined ore were analyzed by X-ray diffraction (XRD) and scanning electron microscopy coupled to energy dispersive spectroscopy (SEM-EDS). RESULTS: XRD and SEM-EDS confirmed the presence in ore of anthophyllite at a concentration of 75%, in addition to tremolite and other amphiboles in lower concentrations. Twenty-eight subjects were evaluated. Median time of exposure was 3 years (minimum = 1; maximum = 18; interquartile interval = 1-4). Twenty cases of pleural abnormalities were diagnosed in 26 evaluated (77%). The average latency time was 25.6 ± 7.4 years. Two individuals (7.7%) showed progressive worsening of diffuse pleural thickening (DPT) and exhibited an annual FVC decrease of 85 mL and 150 mL, respectively. CONCLUSION: This small sample showed a very high index of nonmalignant pleural abnormalities in anthophyllite-exposed workers compared with workers exposed to other kinds of fibers. Rapidly progressive DPT, defined by the severity of pleural compromise, was possibly secondary to the presence of other amphibole types in the inhaled dust. No significant loss of FVC was found in the studied group as a whole. No cases of asbestosis, lung carcinoma, and mesothelioma were diagnosed in this cohort.

Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

The new lens dose limit: implication for occupational radiation protection.

AIM AND OBJECTIVES: The aim of this article was to explore the implications of the new Euratom dose limit for occupational radiation protection in the context of medical occupational radiation exposures. The European Directive 2013/59/Euratom takes into account the new recommendations on reduction in the dose limit for the lens of the eye for planned occupational exposures released in 2012 by the International Commission on Radiological Protection (ICRP 118). MATERIALS AND METHODS: Different dose-monitoring procedures and devices were considered. Occupational eye lens doses reported by previous studies were analyzed, mainly considering workers involved in interventional procedures with X-rays. The current status of eye lens radiation protection and the main methods for dose reduction were investigated. RESULTS: The analysis showed that the workers, potentially exceeding the new limit, are clinical staff performing interventional procedures with a relatively high X-ray dose. Regarding radiological protection issues, the considered literature reports that the proper use of personal protective equipment may reduce the eye lens absorbed dose. CONCLUSION: The evaluation of the occupational eye lens dose is essential to establish which method of personal dose monitoring should be preferred. Furthermore, education and training about the right use of personal protective equipment are important for medical staff working with ionizing radiation.

Clinical Implications of New Drinking Water Regulation for "Forever Chemicals".

This Viewpoint describes new maximum contaminant levels set by the Environmental Protection Agency for specific perfluoroalkyl and polyfluoroalkyl substances (PFASs) and discusses the role clinicians can play in addressing their patients' PFAS health concerns.

Occupational exposure to beryllium in French industries.

Beryllium (Be) is a metal mainly used in the form of alloys, with copper (Cu) and aluminium (Al) in the metal industry. Be is an extremely toxic element which must be handled under strictly controlled conditions to avoid health hazards to workers. Exposure to Be can be responsible for Chronic Beryllium Disease, a pulmonary disease preceded by sensitization to the element, and for lung cancer. The goals of the current study were to investigate Be exposure in France, to determine the airborne Be occupational exposure levels, the associated impregnation of employees through their urinary Be levels and the factors that might affect them, and finally to study a possible relation between biomonitoring and airborne data. Seventy-five volunteer subjects were thus atmospherically and biologically monitored in five French companies involved in Cu or Al casting, Al smelting, CuBe machining or AlBe general mechanical engineering. Airborne exposure was quite low with only 2% of measurements above the current French Occupational Exposure Limit (2 µg/m3); the population potentially most exposed was foundry workers. Impregnation with Be was also low with only 10% of quantified urinary Be measurements above the current German BAR value (0.05 µg/L). Using a Bayesian statistical modelling approach, the mean subject-specific urinary excretion of Be was found to increase significantly with the mean subject-specific exposure to airborne Be. From this relationship, and based on the current French OEL-8 hr, a Biological Limit Value of 0.08 µg/L (= 0.06 µg/g creatinine) could be proposed.

Exposure to airborne nano-titanium dioxide during airless spray painting and sanding.

The objectives of the study were to measure and characterize exposure to airborne nanoscale titanium dioxide during airless spraying and sanding of a nano-enabled paint, and to evaluate the effectiveness of dust capture methods in reducing airborne nanoparticle concentrations. A tradesperson performed the work activities in an environmentally controlled chamber. Samples were collected in the tradesperson's breathing zone and in surrounding areas to assess bystander exposure. Filter-based samples were analyzed using gravimetric methods, scanning electron microscopy, and energy dispersive spectroscopy. Differential particle count data were obtained by means of a scanning mobility particle sizer. Local exhaust ventilation provided statistically significant reductions of airborne nanoparticle concentrations during sanding. Sanding the paint after drying with a handheld power sander generated relatively low levels of airborne titanium dioxide. In contrast, task-based exposure measurements collected during the initial airless spray application of the nano-enabled paint suggested a potential for occupational exposures to exceed the time-weighted average exposure limit for ultrafine titanium dioxide recommended by the National Institute for Occupational Safety and Health. Painters applying nano-enabled coatings may have little recourse but to rely, in some instances, on lower tiers of the hierarchy of controls, such as personal protective equipment. In light of these findings, employers and industrial hygienists should characterize exposures and implement the hierarchy of controls to ensure painters are sufficiently protected.

Hydrogeochemical characterization and evaluation of groundwater quality in Kangayam taluk, Tirupur district, Tamil Nadu, India, using GIS techniques.

The main objective of the present study is to evaluate the hydrogeochemical characteristics of groundwater and its suitability for drinking water supply in Kangayam taluk, Tirupur district, Tamil Nadu, India. To achieve this objective, seventy-eight groundwater samples were collected from the wells spread over the study area during December 2016. The collected groundwater samples were tested in the laboratory for various hydrogeochemical parameters such as hydrogen ion concentration (pH), electrical conductivity, total dissolved solids, total hardness, calcium, magnesium, sodium, potassium, chloride, bicarbonate, carbonate, nitrate, sulphate and fluoride. The analytical results were compared with WHO drinking water standards to assess the suitability of groundwater for drinking purposes. To understand the spatial variation of hydrogeochemical parameters over the study area, choropleth (zonation) maps were prepared using geographical information system (GIS). Overall groundwater quality zones were demarcated by overlaying and integrating all the spatial plots using GIS. Three groundwater quality zones such as (1) most desirable, (2) maximum allowable and (3) not permissible were demarcated based on the limits prescribed by the WHO for drinking purposes. This study indicates that 49% of the study area does not possess potable groundwater. About 21% of the area represents "most desirable" category, and the remaining 30% area represents "maximum allowable" category for drinking purposes. The Piper's trilinear diagram indicates that groundwater of this region is Mixed CaMgCl type. As the groundwater quality is poor nearly 49% of the total area, it is necessary to go for treatment before drinking water supply. It is also essential to recharge the aquifer artificially to improve the quantity and quality of groundwater.

Food as a source of exposure to nickel

According to the European Food Safety Authority (EFSA), food is the main source of nickel intake by the general population. Based on the risk assessment, EFSA determined the tolerable daily intake of this element (TDI) from all sources at the level of 2.8 µg/kg body weight, which is for an adult 196 µg, while for a child 56 µg. The Benchmark Dose Lower Confidence Limit (BMDL10) associated with dermatitis at 1.1 µg/kg body weight was also determined as well as the Margin of Exposure (MOE). Nickel intake in the Member States varies and depends on consumption habits. CONTAM Panel of EFSA considered the unlikely possibility of developing cancers related to the intake of nickel with food. According to experts, other harmful effects on the human body are more often identified. An additional aspect requiring further investigations that will allow an actual estimation of exposure associated with intake of this element by various groups of population is the issue of nickel absorption in the human body. The review of the EFSA opinion on the request of the European Commission planned in the near future based on the collected data as part of the action of the Commission Recommendation (EU) 2016/1111 on monitoring the presence of nickel in food will contribute to taking appropriate actions related to consumer protection, including the most vulnerable groups of population.

Estimating the Impact of Changes to Occupational Standards for Silica Exposure on Lung Cancer Mortality.

BACKGROUND: Respiratory exposure to silica is associated with the risk of death owing to malignant and nonmalignant disease. 2.3 million US workers are exposed to silica. Occupational exposure limits for silica are derived from a number of lines of evidence, including observational studies. Observational studies may be subject to healthy worker survivor bias, which could result in underestimates of silica's impact on worker mortality and, in turn, bias risk estimates for occupational exposure limits. METHODS: Using data on 65,999 workers pooled across multiple industries, we estimate the impacts of several hypothetical occupational exposure limits on silica exposure on lung cancer and all-cause mortality. We use the parametric g-formula, which can account for healthy worker survivor bias. RESULTS: Assuming we could eliminate occupational exposure, we estimate that there would be 20.7 fewer deaths per 1,000 workers in our pooled study by age 80 (95% confidence interval = 14.5, 26.8), including 3.91 fewer deaths owing to lung cancer (95% CI = 1.53, 6.30). Less restrictive interventions demonstrated smaller but still substantial risk reductions. CONCLUSIONS: Our results suggest that occupational exposure limits for silica can be further strengthened to reduce silica-associated mortality and illustrate how current risk analysis for occupational limits can be improved.

Characterizing risk assessments for the development of occupational exposure limits for engineered nanomaterials.

The commercialization of engineered nanomaterials (ENMs) began in the early 2000's. Since then the number of commercial products and the number of workers potentially exposed to ENMs is growing, as is the need to evaluate and manage the potential health risks. Occupational exposure limits (OELs) have been developed for some of the first generation of ENMs. These OELs have been based on risk assessments that progressed from qualitative to quantitative as nanotoxicology data became available. In this paper, that progression is characterized. It traces OEL development through the qualitative approach of general groups of ENMs based primarily on read-across with other materials to quantitative risk assessments for nanoscale particles including titanium dioxide, carbon nanotubes and nanofibers, silver nanoparticles, and cellulose nanocrystals. These represent prototypic approaches to risk assessment and OEL development for ENMs. Such substance-by-substance efforts are not practical given the insufficient data for many ENMs that are currently being used or potentially entering commerce. Consequently, categorical approaches are emerging to group and rank ENMs by hazard and potential health risk. The strengths and limitations of these approaches are described, and future derivations and research needs are discussed. Critical needs in moving forward with understanding the health effects of the numerous EMNs include more standardized and accessible quantitative data on the toxicity and physicochemical properties of ENMs.

Bioavailability of protein therapeutics in rats following inhalation exposure: Relevance to occupational exposure limit calculations.

Protein therapeutics represent a rapidly growing proportion of new medicines being developed by the pharmaceutical industry. As with any new drug, an Occupational Exposure Limit (OEL) should be developed to ensure worker safety. Part of the OEL determination addresses bioavailability (BA) after inhalation, which is poorly understood for protein therapeutics. To explore this, male Sprague-Dawley rats were exposed intravenously or by nose-only inhalation to one of five test proteins of varying molecular size (10-150 kDa), including a polyethylene glycol-conjugated protein. Blood, lung tissue and bronchoalveolar lavage (BAL) fluid were collected over various time-points depending on the expected test protein clearance (8 minutes-56 days), and analyzed to determine the pharmacokinetic profiles. Since the BAL half-life of the test proteins was observed to be > 4.5 h after an inhalation exposure, accumulation and direct lung effects should be considered in the hazard assessment for protein therapeutics with lung-specific targets. The key finding was the low systemic bioavailability after inhalation exposure for all test proteins (∼≤1%) which did not appear molecular weight-dependent. Given that this study examined the inhalation of typical protein therapeutics in a manner mimicking worker exposure, a default 1% BA assumption is reasonable to utilize when calculating OELs for protein therapeutics.

Estimations of Retinal Blue-Light Irradiance Values and Melatonin Suppression Indices Through Clear and Yellow-Tinted Intraocular Lenses.

Spectral transmittance values in the wavelength range of 300 to 800 nanometers were measured using a spectrophotometer for 18 intraocular lenses (IOLs) including clear (ZCB00) and yellow-tinted (ZCB00V, both from AMO Japan) IOLs with three different lens powers. Also measured were the blue-light irradiance (BLI) values, which might reflect retinal damage caused by sunlight, and the melatonin suppression indices (MSIs), which might reflect the nonvisual photoreception function, through these IOLs. The BLIs (in mWcm-2) calculated were 7.62, 7.50, and 7.46 for the +10-diopter (D), +20-D, and +30-D ZCB00 IOLs, respectively; 4.10, 3.92, and 4.00 for the +10-D, +20-D, and +30-D ZCB00V IOLs, respectively; 5.76 for phakic eyes; and 15.00 for aphakic eyes. The MSIs (in mWcm-2sr-1) calculated were 1.18, 1.19, and 1.18 for the +10-D, +20-D, and +30-D ZCB00 IOLs, respectively; 0.98, 0.94, and 0.95 for the +10-D, +20-D, and +30-D ZCB00V IOLs, respectively; 1.03 for phakic eyes; and 1.21 for aphakic eyes. The data from the six clear IOLs (SA60AT, Alcon Japan; VA-60BBR, Hoya; AU6 K, Kowa, N4-18B, Nidek; X-60, Santen; KS-3Ai, Staar Japan) and seven yellow-tinted IOLs (SN60AT; YA-60BBR, Hoya; AU6N, Kowa; N4-18YG, Nidek; NX-60, Santen; KS-AiN, Staar Japan; XY-1, Hoya) reported previously also were discussed. Compared to aphakic eyes, ZCB00 and ZCB00V IOLs reduce the BLI values by 49-50% and 73-74%, respectively; and currently available ultraviolet-blocking clear and yellow-tinted IOLs reduce the BLI values by 43-82%, respectively. Yellow-tinted IOLs absorb more circadian rhythm-associated light than clear IOLs. Although the data presented in this study cannot be applied directly to IOL implanted in patients, the balance between photoprotection and photoreception must be considered when using IOLs in a clinical setting.