Establishing short-term occupational exposure limits (STELs) for sensory irritants using predictive and in silico respiratory rate depression (RD50) models.

Sensory irritation is a health endpoint that serves as the critical effect basis for many occupational exposure limits (OELs). Schaper 1993 described a significant relationship with high correlation between the measured exposure concentration producing a 50% respiratory rate decrease (RD50) in a standard rodent assay and the American Conference of Governmental Industrial Hygienists (ACGIH®) Threshold Limit Values (TLVs®) as time-weighted averages (TWAs) for airborne chemical irritants. The results demonstrated the potential use of the RD50 values for deriving full-shift TWA OELs protective of irritant responses. However, there remains a need to develop a similar predictive model for deriving workplace short-term exposure limits (STELs) for sensory irritants. The aim of our study was to establish a model capable of correlating the relationship between RD50 values and published STELs to prospectively derive short-term exposure OELs for sensory irritants. A National Toxicology Program (NTP) database that included chemicals with both an RD50 and established STELs was used to fit several linear regression models. A strong correlation between RD50s and STELs was identified, with a predictive equation of ln (STEL) (ppm) = 0.86 * ln (RD50) (ppm) - 2.42 and an R2 value of 0.75. This model supports the use of RD50s to derive STELs for chemicals without existing exposure recommendations. Further, for data-poor sensory irritants, predicted RD50 values from in silico quantitative structure activity relationship (QSAR) models can be used to derive STELs. Hence, in silico methods and statistical modeling can present a path forward for establishing reliable OELs and improving worker safety and health.

Is survival rate lower after breast cancer in deprived women according to disease stage?

BACKGROUND: Socioeconomic deprivation has been associated with lower breast cancer (BC) survival, but the influence of stage at diagnosis on this association merits further study. Our aim was to investigate this association using the Loire-Atlantique/Vendee Cancer Registry (France). METHODS: Twelve-thousand seven-hundred thirty-eight women living in the area covered by the registry and diagnosed with invasive breast carcinoma between 2008 and 2015 were included in the study. They were censored at maximal 6 years. Deprivation was measured by the French European Deprivation Index. Excess hazard and net survival were estimated for deprivation level, stage and age at diagnosis using a flexible excess mortality hazard model. RESULTS: After adjustment by stage, women living in the most deprived areas had a borderline non-significant higher excess mortality hazard (+25% (95% CI: -3%; +62%)) compared to those living in the least deprived areas. Stage-adjusted 5-year net survival differed significantly between these two subgroups (respectively, 88.2% (95% CI:85.2%-90.5%) and 92.5% (95% CI:90.6%-93.9%)). CONCLUSION: BC survival remained lower in deprived areas in France, despite universal access to cancer care. Intensification of prevention measures could help to reduce advanced BC, responsible for the majority of deaths from BC. A better understanding of remaining social disparities is crucial to implement specific interventions.

Cannabidiol safety considerations: Development of a potential acceptable daily intake value and recommended upper intake limits for dietary supplement use.

Consumer use of hemp-derived products continues to rise, underscoring the need to establish evidence-based safety guidance. The present study sought to develop recommendations for oral upper intake limits of cannabidiol (CBD) isolate. Sufficiently robust and reliable data for this purpose were identified from published human clinical trials and guideline-compliant toxicity studies in animal models. Based on the metrics used in this assessment, a potential Acceptable Daily Intake (ADI) value of 0.43 mg/kg-bw/d (e.g., 30 mg/d for 70-kg adult) was determined for the general population based on liver effects in human studies. This value applies to the most sensitive subpopulations, including children, over a lifetime of exposure and from all sources, including food. For dietary supplements with adequate product labeling intended for use by healthy adults only, a potential Upper Intake Limit (UL) of 70 mg/d was determined based on reproductive effects in animals. For healthy adults, except those trying to conceive, or currently pregnant or lactating, a conservative dietary supplement UL of 100 mg/d was identified based on liver effects; however, as the target population excludes individuals at risk for liver injury, an alternative dietary supplement UL of 160 mg/d for this population can also be considered.

Systematic review of the human health hazards of propylene dichloride.

Propylene dichloride (PDC) is a chlorinated substance used primarily as an intermediate in basic organic chemical manufacturing. The United States Environmental Protection Agency (EPA) is currently evaluating PDC as a high-priority substance under the Toxic Substances Control Act (TSCA). We conducted a systematic review of the non-cancer and cancer hazards of PDC using the EPA TSCA and Integrated Risk Information System (IRIS) frameworks. We identified 12 epidemiological, 16 toxicokinetic, 34 experimental animal, and 49 mechanistic studies. Point-of-contact respiratory effects are the most sensitive non-cancer effects after inhalation exposure, and PDC is neither a reproductive nor a developmental toxicant. PDC is not mutagenic in vivo, and while in vitro evidence is mixed, DNA strand breaks consistently occur. Nasal tumors in rats and lung tumors in mice occurred after lifetime high-level inhalation exposure. Cholangiocarcinoma (CCA) was observed in Japanese print workers exposed to high concentrations of PDC. However, co-exposures, as well as liver parasites, hepatitis, and other risk factors, may also have contributed. The cancer mode of action (MOA) analysis revealed that PDC may act through multiple biological pathways occurring sequentially and/or simultaneously, although chronic tissue damage and inflammation likely dominate. Critically, health benchmarks protective of non-cancer effects are expected to protect against cancer in humans.

Quantitative Risk Assessment of Dermal Sensitization Potential Following Use of Shampoo Products Containing the Formaldehyde Releasing Preservative DMDM Hydantoin.

Historically, formaldehyde was used as a preservative in personal care products to extend product shelf-life; however, given its skin sensitization potential it has been phased out of use and replaced with formaldehyde-releasing preservatives, such as Dimethyloldimethyl hydantoin (DMDMH). A relationship has been established between positive patch test results following exposure to DMDMH and previous sensitization to formaldehyde. Upon direct contact with the skin, formaldehyde can react with skin proteins and cause an acute inflammatory reaction, which may progress to skin sensitization following repeated exposure. This quantitative risk assessment (QRA) aimed to assess the risk of skin sensitization induction following use of shampoo products containing the maximum allowable concentrations of DMDMH in formulation (1% w/v), translating to a free formaldehyde concentration of 0.02%. To determine a margin of safety (MOS) for exposure to DMDMH from use of shampoo products, consumer exposure levels (CEL) were estimated based on typical use scenarios and then benchmarked against an acceptable exposure level (AEL). The AEL was derived using a weight of evidence approach where a range of no expected sensitization induction levels (NESILs) was utilized. The MOS values for a shampoo product containing 1% DMDMH (.02% formaldehyde) was above 1 for the typical use scenario indicating a low likelihood of skin sensitization induction among healthy individuals. Thus, it can be concluded that shampoo products containing DMDMH at or below current allowable concentrations are not expected to increase the risk of skin sensitization induction.

Multi-route exposure sampling of quaternary ammonium compounds and ethanol surface disinfectants in a K-8 school.

The frequency of surface disinfectant use has increased over the last several years in public settings such as schools, especially during the COVID-19 pandemic. Although these products are important for infection control and prevention, their increased use may intensify the exposure to both persons applying the disinfection product as well as bystanders. Safety assessments have demonstrated that these products, when used as intended, are considered safe for use and effective; however, point-of-contact effects (such as respiratory or dermal irritation) may still occur. Additionally, relative exposures may vary significantly due to the wide variation in disinfectant formulation and application methods. Quantitative estimations of exposures to two commonly used active ingredients, quaternary ammonium compounds (QACs) and ethanol, are not well characterized during product use and application scenarios. To assess the potential for health risks attributable to increased use in classroom settings, as well as to quantitatively evaluate the potential exposure to both ethanol and QACs, student and adult bystander surface and air measurements were collected in a K-8 school setting in Ohio, United States, over a three-day period. Direct-reading instruments were utilized to collect real-time air samples that characterized mass fraction concentrations following the use of the QAC- and ethanol-based disinfectants. Furthermore, surface and air sampling of microbial species were conducted to establish the overall bioburden and effectiveness of each disinfectant to inform the comparative risk and health effect impacts from the tested products use scenario. Both tested products were approximately equally effective at reducing bioburdens on desk surfaces. In some classrooms, concentrations of QAC congeners were significantly increased on desk surfaces following the application of the disinfectant spray; however, the magnitude of the change in concentration was small. Ethanol was not measured on surfaces due to its volatility. Airborne concentrations increased immediately following spray of each disinfectant product but rapidly returned to baseline. Each of the QAC congeners listed in the product safety data sheets were detected and measurable on desk surfaces; however, air concentrations were generally below the limit of detection. The 15-min time-weighted averages (TWAs) of both QACs and ethanol in the air were below respective health effects benchmarks, and therefore, the negative impact on health outcomes is considered to be minimal from short-term, repeated use of ethanol- or QAC-based spray products in a school setting when the products are used as directed.

Assessment of ethanol exposure from hand sanitizer use and potential for developmental toxicity in nursing infants.

Ingestion of ethanol during pregnancy is known to have detrimental effects on the fetus. Although the potential developmental effects of maternal ethanol intake during lactation are less well characterized, public health guidelines recommend avoidance of alcohol or, if alcohol is consumed, to allow for 1-2 h to pass before nursing. A proposal to classify ethanol as potentially harmful to breast-fed children warrants an investigation of the potential adverse neurodevelopmental effects of low-dose ethanol exposure during lactation. There currently are no studies that have examined neurodevelopmental outcomes from lactational exposure to ethanol from the use of topical products that contain ethanol, such as alcohol-based hand sanitizers (ABHS). Furthermore, the epidemiological literature of lactational ethanol exposures from maternal alcohol consumption is limited in design, provides equivocal evidence of neurological effects in infants, and is insufficient to characterize a dose-response relationship for developmental effects. Toxicological studies that observed neurodevelopmental effects in pups from ethanol via lactation did so at exceedingly high doses that also caused maternal toxicity. In this investigation, blood ethanol concentrations (BECs) of breastfeeding women following typical-to-intense ABHS use were computationally predicted and compared to health benchmarks to quantify the risk for developmental outcomes. Margins of 2.2 to 1000 exist between BECs associated with ABHS use compared to BECs associated with neurotoxicity adverse effect levels in the toxicology literature or oral ethanol intake per public health guidelines. Neurodevelopmental effects are not likely to occur in infants due to ABHS use by breastfeeding women, even when ABHSs are used at intense frequencies.

Characterizing extracellular diffusion properties using diffusion-weighted MRS of sucrose injected in mouse brain.

Brain water and some critically important energy metabolites, such as lactate or glucose, are present in both intracellular and extracellular spaces (ICS/ECS) at significant levels. This ubiquitous nature makes diffusion MRI/MRS data sometimes difficult to interpret and model. While it is possible to glean information on the diffusion properties in ICS by measuring the diffusion of purely intracellular endogenous metabolites (such as NAA), the absence of endogenous markers specific to ECS hampers similar analyses in this compartment. In past experiments, exogenous probes have therefore been injected into the brain to assess their apparent diffusion coefficient (ADC) and thus estimate tortuosity in ECS. Here, we use a similar approach in mice by injecting sucrose, a well-known ECS marker, in either the lateral ventricles or directly in the prefrontal cortex. For the first time, we propose a thorough characterization of ECS diffusion properties encompassing (1) short-range restriction by looking at signal attenuation at high b values, (2) tortuosity and long-range restriction by measuring ADC time-dependence at long diffusion times and (3) microscopic anisotropy by performing double diffusion encoding (DDE) measurements. Overall, sucrose diffusion behavior is strikingly different from that of intracellular metabolites. Acquisitions at high b values not only reveal faster sucrose diffusion but also some sensitivity to restriction, suggesting that the diffusion in ECS is not fully Gaussian at high b. The time evolution of the ADC at long diffusion times shows that the tortuosity regime is not reached yet in the case of sucrose, while DDE experiments suggest that it is not trapped in elongated structures. No major difference in sucrose diffusion properties is reported between the two investigated routes of injection and brain regions. These original experimental insights should be useful to better interpret and model the diffusion signal of molecules that are distributed between ICS and ECS compartments.

The legacy of weapons grade plutonium production: Health status of Hanford complex workers who manage the waste.

The extent and etiology of health effects in workers who maintain underground storage tanks at the Hanford Nuclear Reservation (Hanford) have been subjects of controversy and concern for several decades. Hanford is a decommissioned nuclear production complex managed by the US Department of Energy in southeast Washington State. This integration-of-evidence review evaluates the relationship between exposure to vapors from mixed chemical and radioactive waste stored in underground storage tanks at Hanford and worker health. Hanford workers' health information was gathered from technical reports, media reports, and published literature, including the systematic search of seven databases. This review describes the health status and health concerns of Hanford tank farm workers based on the integration of the available health effects data from disparate sources. In interviews with external groups, Hanford workers reported both irritant-type symptoms and diseases that they believe are attributable to tank farm vapors. However, the results of this integration-of-evidence review indicated that no pervasive pattern of occupational disease was identified that can be associated with exposure to tank farm vapors. Inhalation exposure to asbestos and beryllium is associated with lung disease from various types of nuclear industry work but not from work on tank farms. This review concluded that while irritant-type symptoms and isolated cases of occupational disease are plausible under certain conditions, the currently available data do not support a pervasive pattern of occupational disease associated with vapor exposure.

Revisiting double diffusion encoding MRS in the mouse brain at 11.7T: Which microstructural features are we sensitive to?

Brain metabolites, such as N-acetylaspartate or myo-inositol, are constantly probing their local cellular environment under the effect of diffusion. Diffusion-weighted NMR spectroscopy therefore presents unparalleled potential to yield cell-type specific microstructural information. Double diffusion encoding (DDE) consists in applying two diffusion blocks, where gradient's direction in the second block is varied during the course of the experiment. Unlike single diffusion encoding, DDE measurements at long mixing time display some angular modulation of the signal amplitude which reflects microscopic anisotropy (µA), while requiring relatively low gradient strength. This angular dependence has been formerly used to quantify cell fiber diameter using a model of isotropically oriented infinite cylinders. However, how additional features of the cell microstructure (such as cell body diameter, fiber length and branching) may also influence the DDE signal has been little explored. Here, we used a cryoprobe as well as state-of-the-art post-processing to perform DDE acquisitions with high accuracy and precision in the mouse brain at 11.7 â€‹T. We then compared our results to simulated DDE datasets obtained in various 3D cell models in order to pinpoint which features of cell morphology may influence the most the angular dependence of the DDE signal. While the infinite cylinder model poorly fits our experimental data, we show that incorporating branched fiber structure in our model allows more realistic interpretation of the DDE signal. Lastly, data acquired in the short mixing time regime suggest that some sensitivity to cell body diameter might be retrieved, although additional experiments would be required to further support this statement.

Derivation of cancer no significant risk levels and screening safety assessment for 2-nitropropane in spray products.

Two proposition 65 no-significant-risk level (NSRL)-type values were derived for 2-nitropropane (2-NP), in the absence of a Californian published NSRL. In addition, a safety assessment was performed based on estimated typical consumer inhalation and dermal exposure to 2-NP during indoor application of paint from a spray can containing the solvent 1-nitropropane. For the NSRL derivation, benchmark dose (BMD) modeling was performed using hepatocellular carcinoma incidence data from 2-NP single exposure inhalation studies in Sprague-Dawley rats. Several BMD models provided an acceptable fit for the male rat hepatocellular carcinoma incidence data (gamma, log-probit, log-logistic and multistage); therefore, the mean of the BMD lower limits from each model were used as the point of departure to derive the inhalation cancer potency. The oral human cancer potency was derived from the inhalation human cancer potency based on the ratio of the uptake factors for inhalation vs. oral routes. The derived inhalation and oral NSRLs are 67 µg/day and 32 µg/day, respectively. For the inhalation and dermal exposure assessment, three key factors were analyzed: the 2-NP residual concentration in the spray paint product, the mass of spray paint used and the frequency of use. Based on the screening exposure assessment, potential consumer inhalation and dermal exposure to 2-NP from indoor application of paint from a spray can does not exceed our proposed NSRLs, and a warning label is therefore not required for spray can products containing the solvent 1-nitropropane where 2-NP is a minor contaminant.

Benchmark dose (BMD) modeling: current practice, issues, and challenges.

Benchmark dose (BMD) modeling is now the state of the science for determining the point of departure for risk assessment. Key advantages include the fact that the modeling takes account of all of the data for a particular effect from a particular experiment, increased consistency, and better accounting for statistical uncertainties. Despite these strong advantages, disagreements remain as to several specific aspects of the modeling, including differences in the recommendations of the US Environmental Protection Agency (US EPA) and the European Food Safety Authority (EFSA). Differences exist in the choice of the benchmark response (BMR) for continuous data, the use of unrestricted models, and the mathematical models used; these can lead to differences in the final BMDL. It is important to take confidence in the model into account in choosing the BMDL, rather than simply choosing the lowest value. The field is moving in the direction of model averaging, which will avoid many of the challenges of choosing a single best model when the underlying biology does not suggest one, but additional research would be useful into methods of incorporating biological considerations into the weights used in the averaging. Additional research is also needed regarding the interplay between the BMR and the UF to ensure appropriate use for studies supporting a lower BMR than default values, such as for epidemiology data. Addressing these issues will aid in harmonizing methods and moving the field of risk assessment forward.

Derivation of a no-significant-risk-level for tetrabromobisphenol A based on a threshold non-mutagenic cancer mode of action.

A no-significant-risk-level of 20 mg day-1 was derived for tetrabromobisphenol A (TBBPA). Uterine tumors (adenomas, adenocarcinomas, and malignant mixed Müllerian) observed in female Wistar Han rats from a National Toxicology Program 2-year cancer bioassay were identified as the critical effect. Studies suggest that TBBPA is acting through a non-mutagenic mode of action. Thus, the most appropriate approach to derivation of a cancer risk value based on US Environmental Protection Agency guidelines is a threshold approach, akin to a cancer safe dose (RfDcancer ). Using the National Toxicology Program data, we utilized Benchmark dose software to derive a benchmark dose lower limit (BMDL10 ) as the point of departure (POD) of 103 mg kg-1  day-1 . The POD was adjusted to a human equivalent dose of 25.6 mg kg-1  day-1 using allometric scaling. We applied a composite adjustment factor of 100 to the POD to derive an RfDcancer of 0.26 mg kg-1  day-1 . Based on a human body weight of 70 kg, the RfDcancer was adjusted to a no-significant-risk-level of 20 mg day-1 . This was compared to other available non-cancer and cancer risk values, and aligns well with our understanding of the underlying biology based on the toxicology data. Overall, the weight of evidence from animal studies indicates that TBBPA has low toxicity and suggests that high doses over long exposure durations are needed to induce uterine tumor formation. Future research needs include a thorough and detailed vetting of the proposed adverse outcome pathway, including further support for key events leading to uterine tumor formation and a quantitative weight of evidence analysis.

Cleaning and asthma: A systematic review and approach for effective safety assessment.

Research indicates a correlative relationship between asthma and use of consumer cleaning products. We conduct a systematic review of epidemiological literature on persons who use or are exposed to cleaning products, both in occupational and domestic settings, and risk of asthma or asthma-like symptoms to improve understanding of the causal relationship between exposure and asthma. A scoring method for assessing study reliability is presented. Although research indicates an association between asthma and the use of cleaning products, no study robustly investigates exposure to cleaning products or ingredients along with asthma risk. This limits determination of causal relationships between asthma and specific products or ingredients in chemical safety assessment. These limitations, and a lack of robust animal models for toxicological assessment of asthma, create the need for a weight-of-evidence (WoE) approach to examine an ingredient or product's asthmatic potential. This proposed WoE method organizes diverse lines of data (i.e., asthma, sensitization, and irritation information) through a systematic, hierarchical framework that provides qualitatively categorized conclusions using hazard bands to predict a specific product or ingredient's potential for asthma induction. This work provides a method for prioritizing chemicals as a first step for quantitative and scenario-specific safety assessments based on their potential for inducing asthmatic effects. Acetic acid is used as a case study to test this framework.

Chemical-induced asthma and the role of clinical, toxicological, exposure and epidemiological research in regulatory and hazard characterization approaches.

Uncertainties in understanding all potential modes-of-action for asthma induction and elicitation hinders design of hazard characterization and risk assessment methods that adequately screen and protect against hazardous chemical exposures. To address this challenge and identify current research needs, the University of Cincinnati and the American Cleaning Institute hosted a webinar series to discuss the current state-of-science regarding chemical-induced asthma. The general consensus is that the available database, comprised of data collected from routine clinical and validated toxicological tests, is inadequate for predicting or determining causal relationships between exposures and asthma induction for most allergens. More research is needed to understand the mechanism of asthma induction and elicitation in the context of specific chemical exposures and exposure patterns, and the impact of population variability and patient phenotypes. Validated tools to predict respiratory sensitization and to translate irritancy assays to asthma potency are needed, in addition to diagnostic biomarkers that assess and differentiate allergy versus irritant-based asthmatic responses. Diagnostic methods that encompass the diverse etiologies of asthmatic responses and incorporate robust exposure measurements capable of capturing different temporal patterns of complex chemical mixtures are needed. In the absence of ideal tools, risk assessors apply hazard-based safety assessment methods, in conjunction with active risk management, to limit potential asthma concerns, proactively identify new concerns, and ensure deployment of approaches to mitigate asthma-related risks.

Derivation of an oral toxicity reference value for nickel.

Nickel (Ni) is in the earth's crust and can be found in environmental compartments such as water, soil, and air, as well as food. This paper presents an assessment of the oral nickel toxicity data in support of non-cancer health-based oral exposure limits or toxicity reference values (TRVs). This paper derives TRVs for three populations of interest: adults, toddlers, and people who have been dermally sensitized to nickel. The adult/lifetime TRV of 20 µg Ni/kg-day is based on post-implantation loss/perinatal mortality in a 2-generation reproductive study in rats. Several recent assessments by regulatory agencies have used the same study and endpoint, but the dose-response modeling conducted here was more appropriate for the study design. Toxicokinetic data from rats and humans indicate that the applied uncertainty factors are very conservative. Because the endpoint relates to fetal exposure and is not relevant to toddlers, a toddler TRV was derived based on decreased body weight in young rats; this TRV was also 20 µg Ni/kg-day. A separate TRV of 4 µg Ni/kg in addition to Ni in food was derived for protection of nickel-sensitized populations from flare-up of dermatitis, based on studies of single exposures in humans under conditions that maximize oral absorption.

A tiered asthma hazard characterization and exposure assessment approach for evaluation of consumer product ingredients.

Asthma is a complex syndrome with significant consequences for those affected. The number of individuals affected is growing, although the reasons for the increase are uncertain. Ensuring the effective management of potential exposures follows from substantial evidence that exposure to some chemicals can increase the likelihood of asthma responses. We have developed a safety assessment approach tailored to the screening of asthma risks from residential consumer product ingredients as a proactive risk management tool. Several key features of the proposed approach advance the assessment resources often used for asthma issues. First, a quantitative health benchmark for asthma or related endpoints (irritation and sensitization) is provided that extends qualitative hazard classification methods. Second, a parallel structure is employed to include dose-response methods for asthma endpoints and methods for scenario specific exposure estimation. The two parallel tracks are integrated in a risk characterization step. Third, a tiered assessment structure is provided to accommodate different amounts of data for both the dose-response assessment (i.e., use of existing benchmarks, hazard banding, or the threshold of toxicological concern) and exposure estimation (i.e., use of empirical data, model estimates, or exposure categories). Tools building from traditional methods and resources have been adapted to address specific issues pertinent to asthma toxicology (e.g., mode-of-action and dose-response features) and the nature of residential consumer product use scenarios (e.g., product use patterns and exposure durations). A case study for acetic acid as used in various sentinel products and residential cleaning scenarios was developed to test the safety assessment methodology. In particular, the results were used to refine and verify relationships among tiered approaches such that each lower data tier in the approach provides a similar or greater margin of safety for a given scenario.

Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment.

1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05mg/kgday is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350µg/L is proposed using a default relative source contribution for water of 20%.

Micro-environmental factors impact breathing zone exposures: A simulated petrochemical manufacturing facility task.

This study investigates the impact of micro-environmental factors on worker breathing zone exposure levels in petrochemical facilities. A laboratory simulation study evaluated near-field exposure to methane for a typical maintenance task. Individual and combinations of micro-environmental factors significantly affected methane exposure. Airflow direction and speed were significant determinants of exposure concentration reduction. A side airflow direction at medium to high speed produced the lowest gas concentration in the breathing zone. Worker body orientation relative to the methane emission point was also a critical factor affecting gas concentration in the worker's breathing zone. The study provides insights into how variations in airflow and small changes in position impact near-field exposures for petrochemical tasks, guiding industrial hygiene professionals' training on qualitative exposure estimation and providing input for near-field exposure modeling to guide quantitative exposure and risk assessment.

Assessment of associations between inhaled formaldehyde and lymphohematopoietic cancer through the integration of epidemiological and toxicological evidence with biological plausibility.

Formaldehyde is recognized as carcinogenic for the portal of entry sites, though conclusions are mixed regarding lymphohematopoietic (LHP) cancers. This systematic review assesses the likelihood of a causal relationship between formaldehyde and LHP cancers by integrating components recommended by NASEM. Four experimental rodent bioassays and 16 observational studies in humans were included following the implementation of the a priori protocol. All studies were assessed for risk of bias (RoB), and meta-analyses were conducted on epidemiological studies, followed by a structured assessment of causation based on GRADE and Bradford Hill. RoB analysis identified systemic limitations precluding confidence in the epidemiological evidence due to inadequate characterization of formaldehyde exposure and a failure to adequately adjust for confounders or effect modifiers, thus suggesting that effect estimates are likely to be impacted by systemic bias. Mixed findings were reported in individual studies; meta-analyses did not identify significant associations between formaldehyde inhalation (when measured as ever/never exposure) and LHP outcomes, with meta-SMRs ranging from 0.50 to 1.51, depending on LHP subtype. No associations with LHP-related lesions were reported in reliable animal bioassays. No biologically plausible explanation linking the inhalation of FA and LHP was identified, supported primarily by the lack of systemic distribution and in vivo genotoxicity. In conclusion, the inconsistent associations reported in a subset of the evidence were not considered causal when integrated with the totality of the epidemiological evidence, toxicological data, and considerations of biological plausibility. The impact of systemic biases identified herein could be quantitatively assessed to better inform causality and use in risk assessment.