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.

Developmental and reproductive toxicity hazard characterization of 2-amino-2-methyl-1-propanol (AMP).

2-Amino-2-methyl-1-propanol (AMP™) is a widely used pH stabilizer in personal care products (PCPs); thus, the safety implications of dermal AMP exposure remain of interest. We have previously reported that exposure to AMP in PCPs when used as intended is not anticipated to result in an increased risk of hepatotoxicity (primarily steatosis and altered phospholipid homeostasis). The current study focuses on AMP in PCP's potential for developmental and reproductive toxicity (DART) in humans, based on data from animal studies. Animal studies suggest that exposure to AMP can result in post-implantation loss. However, such effects occur at maternally toxic doses, posing a challenge for determining appropriate hazard classifications in the context of relevant consumer use scenarios. Our assessment concluded that human exposure to AMP in PCPs is not anticipated to result in DART at non-maternally toxic doses. Further, mode of action (MOA) analysis elucidated the potential biological pathways underlying DART effects observed in high-dose animal studies, such that perturbation of uterine choline synthesis was the most well-supported MOA hypothesis. Downstream uterine effects might reflect choline-dependent changes in epigenetic control of pathways important for implantation maintenance and uterine cell energetics. Since AMP-induced post-implantation loss occurs at doses higher than pathology related to liver toxicity, maintaining AMP exposures from exceeding the onset dose for maternal liver effects will also be protective of DART effects. Furthermore, dermal exposure to AMP expected from the use of PCPs is highly unlikely to result in toxicologically significant systemic AMP concentrations; thus, DART is not anticipated.

In silico occupational exposure banding framework for data poor compounds in biotechnology.

Occupational exposure limits (OELs) and occupational exposure bands (OEBs) provide quantitative benchmarks for worker health protection. If empirical toxicology data are insufficient to derive an OEL, an OEB is often assigned using partial toxicology data along with other relevant hazard information. There is no consensus methodology to assign OEBs for chemicals lacking any empirical toxicology data. Thus, this study developed an in silico framework for OEB assignment of data poor compounds. It relies upon computational tools to evaluate standard toxicological end points and to assign reliability ratings, which are then used to assign Global Harmonization System (GHS) hazard categories. Subsequently, the hazard categories are entered into the National Institute for Occupational Safety and Health (NIOSH) occupational exposure banding tool to assign bands for individual end points as well as an overall OEB. As a proof-of-concept, five compounds with established OELs (i.e., "knowns") were evaluated. The knowns were assigned to overall OEBs C, D, or E, four of which were equal to or lower than the OEBs based on actual harmonized GHS categories as well as established OELs, indicating that the OEBs assigned using this framework are likely to be protective. Subsequently, five compounds with little to no experimental data and no established OELs from any U.S. agency or consensus OEL-setting organizations were evaluated (i.e., "unknowns"). The unknowns were assigned to overall OEBs D or E. It was concluded that the proposed framework can be used to assign protective OEBs to compounds with little to no toxicology testing data. As additional data become available, the compound may be de-risked, and a precautionary OEB (or an OEL) can be assigned. The proposed framework provides an example of a practical methodology to evaluate data poor compounds and shows that the output of this framework is expected to be protective of worker health.

Preliminary human health risk assessment of antibiotic exposures in human waste handling occupations.

Exposure to biosolids in human waste handling occupations is associated with a risk for illness due to microbial infections. Although several years of exposure to biosolids might be hypothesized to be a prophylaxis against infection, the risks associated with infections from antibiotic-resistant organisms can also be a potential concern. Therefore, this study aimed to conduct a screening level risk assessment by deriving occupational exposure limits (OELs) characterizing the risks of adverse health effects among workers in human waste handling occupations with a focus on exposure to two pharmaceuticals commonly found in biosolids: ciprofloxacin (CIP) and azithromycin (AZ). Epidemiological and exposure studies of workers exposed to biosolids were identified through searches of major scientific databases. Screening OELs (sOELs) for these antibiotics were derived using a standardized methodology. The airborne concentrations of CIP and AZ antibiotics were determined using an exposure factors approach. The health-based exposure limits (i.e., sOELs) and the acceptable daily exposure (ADE) values for both of these antibiotics were derived as 80 µg/m3 and 12 µg/kg-day, respectively. An exposure factor approach suggested that inhalation route exposures to CIP and AZ are well below the sOELs and ADE daily doses, and likely too low to cause direct adverse health effects through antibiotic inhalation. A critical review of epidemiological studies on different occupations handling biosolids showed that the workers in industries with potential biosolids exposure have experienced an increased incidence of microbial-exposure-related illness. The health effects seen in the workers have been attributed to bacterial, viral, and protozoan infections. To the extent that bacteria are the pathogen of concern, it is not clear whether these bacteria are resistant to antibiotics commonly found in biosolids. It is also unclear whether the presence of antibiotics or antibiotic-resistant bacteria increases the susceptibility of these workers. Additional studies will provide more definitive estimates of inhalation and dermal exposures to CIP and AZ and could verify the exposure estimates in this study based on the literature and common exposure factors.

Estimating inhalation bioavailability for peptides and proteins 1 to 10 kDa in size.

Inhalation is a critical route for occupational exposure. To protect workers from adverse effects, health-based exposure limits (HBELs) are derived using chemical-specific information including inhalation bioavailability. Inhalation bioavailability of large proteins is well studied and generally accepted to be 1% or less. However, the inhalation bioavailability of peptides and proteins 1-10 kDa in size is not well defined. The goal of this study was to expand upon previous analyses and evaluate the inhalation bioavailability of small peptides. Inhalation bioavailability data for 72 peptides and protein samples ranging from 1.1 to 10.9 kDa in size were evaluated. The median inhalation bioavailability was 20%, which is in agreement with previously published analyses. Inhalation bioavailabilities for the vast majority were below 50%. Interestingly, species, peptide size, and peptide identity did not correlate with inhalation bioavailability. Other factors including inhalation dosimetry, peptide degradation, and chemical characteristics also decrease the amount of peptide available for absorption. Together, the median bioavailability of 20% is likely an appropriate estimate of systemic exposure and is sufficiently protective in most cases for the purposes of occupational exposure safety. Thus, in the absence of peptide-specific data or concerns, an inhalation bioavailability default of 20% is recommended for 1-10 kDa peptide and proteins.

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.

Strategies for refinement of occupational inhalation exposure evaluation in the EPA TSCA risk evaluation process.

The focus on occupational exposures in the first published risk evaluations of existing chemicals by the Environmental Protection Agency (EPA) under the amended Toxic Substances Control Act (TSCA) puts a welcome spotlight on protecting the health of workers in the United States. Because new, fit-for-purpose occupational exposure assessment methodologies were developed by EPA, the objective of this analysis was to evaluate these methodologies in light of other existing occupational risk assessment frameworks. We focused our analysis on three chlorinated chemicals (methylene chloride, carbon tetrachloride, perchloroethylene). The EPA's methods were evaluated relative to peer-reviewed and professional organizations' guidelines for conducting site- and facility-based exposure assessment. Analyses of several key phases in the EPA approach were conducted to evaluate the effect of alternative approaches on exposure estimates. The revised exposure estimates using these alternative approaches yielded substantially different exposure estimates from those in the TSCA risk evaluations for these chemicals. The results also demonstrated the importance of utilizing a tiered approach to exposure estimation that includes collecting qualitative data, defining similar exposure groups, and integrating well-parameterized models with empirical data. These approaches aid in preventing mischaracterization of exposures and generating exposure estimates representative of current industrial practices. Collaboration among industry, EPA, and other government agencies to develop a harmonized approach to exposure assessment would improve the methodological rigor of, and increase stakeholder confidence in, the results of TSCA risk evaluations.

Analysis of dermal exposure assessment in the US Environmental Protection Agency Toxic Substances Control Act risk evaluations of chemical manufacturing.

The United States Environmental Protection Agency (EPA) regulates chemical manufacture, import, processing, distribution, use, and disposal under the 2016 amended Toxic Substances Control Act (TSCA) for the purposes of protecting the public and sensitive populations-including workers-from chemical exposure risk. The publication of several TSCA risk evaluations provided a unique opportunity to evaluate the evolving regulatory approach for assessing the dermal exposure pathway in occupational settings. In this analysis, the occupational dermal exposure assessment methods employed in several TSCA risk evaluations were assessed. Specifically, a methodology review was conducted for the occupational dermal scenarios of manufacturing and feedstock use in the risk evaluations of three chlorinated organic chemicals: trichloroethylene, carbon tetrachloride, and perchloroethylene. Additionally, alternative exposure estimates were generated using the exposure model IH SkinPermTM. The review and alternative exposure analyses indicate that the current TSCA modeling approach may generate total dermal absorbed doses for chlorinated chemical manufacturing and feedstock use scenarios that are 2- to 20-fold higher than those generated by IH SkinPerm. Best-practice recommendations developed in the methodology review support a tiered, integrated approach to dermal exposure assessment that emphasizes collecting qualitative data; employing validated, peer-reviewed models that align with current industrial practices; and gathering empirical sampling data where needed. Collaboration among industry, EPA, and other stakeholders to share information and develop a standard approach to exposure assessment under TSCA would improve the methodological rigor of, and increase confidence in, the risk evaluation results.

Ciprofloxacin- and azithromycin-resistant bacteria in a wastewater treatment plant.

The occurrence of antibiotic-resistant bacteria (ARB) in wastewater treatment plants (WWTPs) has become an occupational and environmental concern. WWTPs are engineered systems that treat wastewater to meet public health standards before release into the environment. The residuals, as either effluent or solids, are then discharged or beneficially recycled into the environment. Since these wastes contain a diverse array of microorganisms, some of which are resistant to commonly used antibiotics, there is a potential for these organisms to spread in the environment via residual recycling and effluent discharge. Human infections with ARB are increasing, and it is not well known how the interaction between humans and the environment plays a role in this process. WWTP workers, who are on the front lines, may come into direct contact with materials containing these microbes. This study aimed to determine the number of ARB present in both air and sewage sludges in a WWTP using nonselective media supplemented with two antibiotics (ciprofloxacin and azithromycin). The densities of total heterotrophic bacteria, ciprofloxacin-resistant bacteria, and azithromycin-resistant bacteria were 7.82 × 105 - 4.7 × 109, 7.87 × 103 - 1.05 × 108, and 2.27 × 105 - 1.16 × 109 CFU/g, respectively. The prevalence [(concentration on medium with antibiotics/concentration on medium without antibiotics) × 100] of ciprofloxacin-resistant bacteria in treated sludge was twice as low as in digested sludge and approximately three times lower than in raw sludge. For azithromycin, the prevalence of resistant bacteria in treated sludge was about the same in digested and nearly twice lower than in raw sludge. Despite a marked reduction in the mean prevalence of resistant bacteria in dewatered treated sludge for both antibiotics, these differences were not significant. The highest prevalence of antibiotic resistance was observed for azithromycin. Similarly, the prevalence of airborne azithromycin-resistant bacteria inside the belt filter press room (BFPR) was nearly seven times higher than the prevalence of airborne ciprofloxacin-resistant bacteria. These concentrations of ARB were not negligible and may represent an exposure pathway for some workers in WWTPs.

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.

The utility of hERG channel inhibition data in the derivation of occupational exposure limits.

Inhibition of the human ether-à-go-go (hERG) channel may lead to QT prolongation and fatal arrhythmia. While pharmaceutical drug candidates that exhibit potent hERG channel inhibition often fail early in development, many drugs with both cardiac and non-cardiac indications proceed to market. In this study, the relationship between in vitro hERG channel inhibition and published occupational exposure limit (OEL) was evaluated. A total of 23 cardiac drugs and 44 drugs with non-cardiac indications with published hERG channel IC50 and published OELs were identified. There was an apparent relationship between hERG IC50 potency and the OEL for cardiac and non-cardiac drugs. Twenty cardiac and non-cardiac drugs were identified that had a potent hERG IC50 (≤25 µM) and a contrastingly large OEL value (≥100 µg/m3). OELs or hazard banding corresponding to ≤100 µg/m3 should be sufficiently protective of effects following occupational exposure to the majority of APIs with hERG IC50 values ≤ 100 µM. It is important to consider hERG IC50 values and possible cardiac effects when deriving OEL values for drugs, regardless of indication. These considerations may be particularly important early in the drug development process for establishing exposure control bands for drugs that do not yet have full clinical safety data.

Setting impurity limits for endogenous substances: Recommendations for a harmonized procedure and an example using fatty acids.

Endogenous substances, such as fatty, amino, and nucleic acids, are often purposefully used in parenterally pharmaceuticals, but may be present as impurities. Currently, no consensus guidance exists on setting impurity limits for these substances. Specific procedures are needed, as the amount and types of toxicity data available for endogenous substances are typically far less than those for other chemical impurities. Additionally, the parenteral route of administration of these substances is inherently non-physiological, resulting in potentially different or increased severity of toxicity. Risk Assessment Process Maps (RAPMAPs) are proposed as a model to facilitate the development of health-based exposure limits (HBELs) for endogenous substances. This yielded a framework that was applied to derive HBELs for several fatty acids commonly used in parenteral pharmaceuticals. This approach was used to derive HBELs with further vetting based on anticipated perturbations in physiological serum levels, impacts of dose-rate, and consideration of intermittent dosing. Parenteral HBELs of 100-500 mg/day were generated for several fatty acids, and a proposed class-based limit of 50 mg/day to be used in the absence of chemical-specific data. This default limit is consistent with the low toxicity of this chemical class and ICH Q3C value for Class 3 solvents.

Dose and exposure route analyses inform relationships between liver steatosis and 2-amino-2-methyl-1-propanol: Implications for hazard characterization.

2-Amino-2-methyl-1-propanol (AMP™) is widely used as a neutralizer/pH stabilizer in personal care products (PCPs); however, the potential health implications of dermal AMP exposure remain to be fully elucidated. Consequently, an in-depth analysis was performed to determine if PCPs containing AMP pose an elevated risk in humans under the intended use conditions. Animal studies have shown that at high doses, oral AMP exposure could lead to liver steatosis; thus, this study focused on hepatotoxicity. Our assessment revealed that the derived margin of exposure (MoE) values for AMP-containing PCPs were above 100, indicating that dermal exposure to AMP is unlikely to present an elevated risk of hepatotoxicity. Further, mode of action (MOA) analysis was conducted to elucidate the potential mechanisms underlying the observed hepatotoxicity in animal studies. Our analysis proposed that AMP interferes with the CDP-choline pathway in hepatocytes via the inhibition of one or more enzymes integral to the pathway and/or the replacement of choline in the assembly of the phospholipid unit. Ultimately, these events halt the lipid export via very low-density lipoproteins, which can subsequently develop into fatty liver accompanied by hepatotoxicity and other pathological changes if AMP exposure persists at sufficiently high doses. MOA analysis corroborated that dermal exposure to AMP expected from use of PCPs is highly unlikely to result in toxicologically significant systemic concentrations of AMP and thus hepatotoxicity. We concluded that dermal exposure to AMP in PCPs is not anticipated to result in an increased risk of hepatotoxicity.

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.

Ventilation and posture effects on inhalation exposures to volatile cleaning ingredients in a simulated domestic worker cleaning environment.

Associations between cleaning chemical exposures and asthma have previously been identified in professional cleaners and healthcare workers. Domestic workers, including housecleaners and caregivers, may receive similar exposures but in residential environments with lower ventilation rates. Study objectives were to compare exposures to occupational exposure limits (OELs), to determine relative contributions from individual cleaning tasks to overall exposure, and to evaluate the effects of ventilation and posture on exposure. Airborne chemical concentrations of sprayed cleaning chemicals (acetic acid or ammonia) were measured during typical cleaning tasks in a simulated residential work environment. Whole-house cleaning exposures (18 cleaning tasks) were measured using integrated personal sampling methods. Individual task exposures were measured with a sampling line attached to subjects' breathing zones, with readings recorded by a ppbRAE monitor, equipped with a photoionization detector calibrated for ammonia and acetic acid measurements. Integrated sampling results indicated no exposures above OELs occurred, but 95th percentile air concentrations would require risk management decisions. Exposure reductions were observed with increased source distance, with lower exposures from mopping floors compared to kneeling. Exposure reductions were also observed for most but not all tasks when ventilation was used, with implications that alternative exposure reduction methods may be needed.

Active pharmaceutical contaminants in dietary supplements: A tier-based risk assessment approach.

The presence of active pharmaceutical ingredients (APIs) in adulterated or contaminated dietary supplements is a current product safety concern. Since there are limited guidelines, and no published consensus methods, we developed a tier-based framework incorporating typical lines of evidence for determining the human health risk associated with APIs in dietary supplements. Specifically, the tiered approach outlines hazard identification and decision to test for APIs in products based on criteria for likelihood of contamination or adulteration, and evaluation of manufacturer production standards. For products with detectable levels of APIs, a variety of default approaches, including the use of fraction of the therapeutic dose and the threshold of toxicological concern (TTC), as well as health-based exposure limits (HBELs) are applied. In order to demonstrate its practical use, as well as any limitations and/or special considerations, this framework was applied to five dietary supplements (currently available to the public). We found that the detected levels of APIs in some dietary supplements were above the recommended dose of the drugs, and thus, pose a significant health risk to consumers and potentially workers involved in manufacturing of these supplements. The results support the value of increased product quality surveillance and perhaps regulatory activity.

Derivation of an occupational exposure limit for ß-glucans.

ß-Glucans are abundant bacterial, yeast, and fungal cell wall polysaccharides that have been shown to activate the immune system. Establishment of an occupational exposure limit (OEL) for ß-glucan exposure is critical to the protection of worker health, as these exposures have been linked to immunosuppressive and inflammatory reactions and possibly the development of respiratory diseases. Detectable concentrations of ß-glucans have been identified in common occupational inhalation exposure scenarios, such as in the agricultural and waste management sectors. However, no published exposure benchmarks for inhalation of ß-glucans are available for workers or the general population. Thus, a health-based OEL for inhalation exposure of workers to ß-glucans was derived based on consideration of human and non-human effect data for this class of compounds and contemporary risk assessment methods. The weight of the evidence indicated that the available data in humans showed significant methodological limitations, such as lack of a representative study size, appropriate control population, and clear dose-response relationship. Thus, an OEL of 150 ng/m3 was derived for ß-glucans based on the most relevant nonclinical study. This OEL provides an input to the occupational risk assessment process, allows for comparisons to worker exposure, and can guide risk management and exposure control decisions.

Hazard characterization of carcinogenicity, mutagenicity, and reproductive toxicity for short chain primary nitroalkanes.

Nitroalkanes are organic aliphatic hydrocarbon compounds with a nitro moiety that are commonly used as solvents or intermediates to synthesize a variety of organic compounds due to their inherent reactivity. In June 2020, a harmonized classification and labeling (CLH) proposal was submitted to the European Chemicals Agency (ECHA) for the following harmonized carcinogenicity, mutagenicity, and reproductive toxicity ("CMR") classifications for nitromethane (NM), nitroethane (NE), and 1-nitropropane (1-NP): NM Carc. 1B and Repr. 1B; NE Repr. 1B; and 1-NP Repr. 2. In this assessment, a weight of evidence (WoE) evaluation of studies on animal carcinogenicity and reproductive and developmental toxicity, genotoxicity, and mode of action for these three nitroalkanes was performed to critically assess the relevance of the proposed CMR classifications. Overall, the WoE indicates that NM, NE, and 1-NP are not carcinogenic, genotoxic, nor selective reproductive or developmental toxicants. Based on our analysis, classifying NM, NE, and 1-NP as Category 2 reproductive toxicants is most appropriate. Furthermore, not classifying NE and 1-NP with respect to their carcinogenicity is appropriate based on the available studies for this endpoint coupled with negative results in genotoxicity studies, metabolism data, and in silico predictions. We determined that the classification for NM of Carc. 1B is not appropriate, based on the fact that rat mammary and harderian tumors are likely not relevant to humans and lung and liver tumors reported in mice were equivocal in their dose-response and statistical significance.

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.

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.