An Insight Into Risk Assessment and Reformulation of Drug Products Manufactured Using Benzene Grade Carbomer: A Regulatory Perspective.

Cancer has been an enormous pain point for patients and regulatory bodies across the globe. In Dec. 2023, the US FDA released guidance on benzene-grade carbomer formulations, which triggered pharmaceutical manufacturers to assess risk, test finished products, and reformulate drug products with benzene-grade carbomer. The immediate implementation of the stoppage of finished products with benzene-grade carbomers has threatened pharmaceutical excipients and finished product manufacturers. The gravity of this situation prompted the US Pharmacopeia to extend the deadline for discontinuation from August 1, 2025, to August 1, 2026, allowing manufacturers ample time for reformulation and regulatory compliance.There is an immediate need to understand the guidance and to learn how manufacturers should do the risk assessment and approach reformulation. This review provides an in-depth analysis of the risk assessment and reformulation processes involved in various dosage forms utilizing benzene-grade carbomer, supported by specific case studies.This review offers insights into navigating the USFDA guidelines to ensure formulation safety and compliance, thus enabling pharmaceutical practitioners to uphold the highest standards of patient care and tackle life cycle management challenges.The decision of the USFDA to restrict the usage of high benzene content of carbomer in the formulation is a welcome move. This article has shown a way for researchers to see opportunities in the path and provide best-in-class medicines to patients with a better formulation safety profile.

Benzene Exposure in Workers From a Waste Oil Regeneration Plant During Ordinary Activities by Air and Biological Monitoring.

BACKGROUND: In the regeneration of waste oil, a strategical technological process for the European Union circular economy action plan, exhausted oils are regenerated to produce high performing oil bases. Aim of this work was to assess the exposure to benzene in plant workers during ordinary activities. METHODS: 59 workers, potentially exposed to benzene, and 9 administrative workers from an Italian plant were monitored for the whole work shift with personal air samplers; urinary benzene (BEN-U) and S-phenyl mercapturic acid (SPMA) were measured by mass spectrometry methods in end-shift urine samples. Different job tasks were identified among workers. RESULTS: Median (minimum-maximum) airborne exposures to benzene were <0.9 (<0.9-6.3) and <0.9 (<0.9-0.9) µg/m3, BEN-U and SPMA levels were 0.094 (<0.015-3.095) µg/L and 0.15 (<0.10-9.67) µg/g crt and 0.086 (0.034-0.712) µg/L and <0.10 (<0.10-3.19) µg/g creatinine in workers and administrative workers, respectively. No differences were found among job tasks and between workers and administrative workers, while higher levels were found in smokers than in non-smokers. For all job tasks, the exposure to benzene was always below occupational limit values. CONCLUSIONS: This study has investigated for the first time the exposure to benzene of workers employed in the re-refining of exhaust oil. The results showed that normal production activities in regenerating used oils do not pose a risk of exposure to benzene in workers.

Targeting IGF2BP1 alleviated benzene hematotoxicity by reprogramming BCAA metabolism and fatty acid oxidation.

Benzene is the main environmental pollutant and risk factor of childhood leukemia and chronic benzene poisoning. Benzene exposure leads to hematopoietic stem and progenitor cell (HSPC) dysfunction and abnormal blood cell counts. However, the key regulatory targets and mechanisms of benzene hematotoxicity are unclear. In this study, we constructed a benzene-induced hematopoietic damage mouse model to explore the underlying mechanisms. We identified that Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) was significantly reduced in benzene-exposed mice. Moreover, targeting IGF2BP1 effectively mitigated damages to hematopoietic function and hematopoietic molecule expression caused by benzene in mice. On the mechanics, by metabolomics and transcriptomics, we discovered that branched-chain amino acid (BCAA) metabolism and fatty acid oxidation were key metabolic pathways, and Branched-chain amino acid transaminase 1 (BCAT1) and Carnitine palmitoyltransferase 1a (CPT1A) were critical metabolic enzymes involved in IGF2BP1-mediated hematopoietic injury process. The expression of the above molecules in the benzene exposure population was also examined and consistent with animal experiments. In conclusion, targeting IGF2BP1 alleviated hematopoietic injury caused by benzene exposure, possibly due to the reprogramming of BCAA metabolism and fatty acid oxidation via BCAT1 and CPT1A metabolic enzymes. IGF2BP1 is a potential regulatory and therapeutic target for benzene hematotoxicity.

A cellulose nanocrystal-based dual response of photonic colors and fluorescence for sensitive benzene gas detection.

Benzene, as a common volatile organic compound, represents serious risk to human health and environment even at low level concentration. There is an urgent concern on visualized, sensitive and real time detection of benzene gases. Herein, by doping Fe3+ and graphene quantum dots (GQDs), a cellulose nanocrystal (CNC) chiral nematic film was designed with dual response of photonic colors and fluorescence to benzene gas. The chiral nematic CNC/Fe/GQDs film could respond to benzene gas changes by reversible motion. Moreover, chiral nematic film also displays reversible responsive to humidity changes. The resulting CNC/Fe/GQDs chiral nematic film showed excellent response performance at benzene gas concentrations of 0-250 mg/m3. The maximal reflection wavelength film red shifted from 576 to 625 nm. Furthermore, structural color of CNC/Fe/GQDs chiral nematic film change at 44 %, 54 %, 76 %, 87 %, and 99 % relative humidity. Interestingly, due to the stability of GQDs to water molecules, CNC/Fe/GQDs chiral nematic film exhibit fluorescence response to benzene gas even in high humidity (RH = 99 %) environment. Besides, we further developed a smartphone-based response network system for quantitively determinization and signal transformation. This work provides a promising routine to realize a new benzene gas response regime and promotes the development of real-time benzene gas detection.

In-situ treatment of gaseous benzene in fixed-bed biofilter with polyurethane foam: Functional population response and benzene transformation pathway.

Volatile organic compounds emitted from landfills posed adverse effect on health. In this study, gaseous benzene was biologically treated using an in-situ biofilter without air pump. Its performance was investigated and the removal efficiency of benzene reached over 90 %. The decrease in the average benzene concentration was consistent with first-order reaction kinetics. Mycolicibacterium dominated the bacterial consortium (41-57 %) throughout the degradation. Annotation of genes by metagenomic analysis helped to deduce the degradation pathways (benzene degradation, catechol ortho-cleavage and meta-cleavage) and to reveal the contribution of different species to the degradation process. In total, 21 kinds of key genes and 13 enzymes were involved in the three modules of benzene transformation. Mycolicibacter icosiumassiliensis and Sphingobium sp. SCG-1 carried multiple functional genes critically involved in benzene biodegradation. These findings provide technical and theoretical support for the in-situ bioremediation of benzene-contaminated soil and waste gas reduction in landfills.

High-performance activation of ozone by sonocavitation for BTEX degradation in water.

This work presents a novel advanced oxidation process (AOP) for degradation of emerging organic pollutants - benzene, toluene, ethylbenzene and xylenes (BTEXs) in water. A comparative study was performed for sonocavitation assisted ozonation under 40-120 kHz and 80-200 kHz dual frequency ultrasounds (DFUS). Based on the obtained results, the combination of 40-120 kHz i.e., low-frequency US (LFDUS) with O3 exhibited excellent oxidation capacity degrading 99.37-99.69% of BTEXs in 40 min, while 86.09-91.76% of BTEX degradation was achieved after 60 min in 80-200 kHz i.e., high-frequency US (HFDUS) combined with O3. The synergistic indexes determined using degradation rate constants were found as 7.86 and 2.9 for LFDUS/O3 and HFDUS/O3 processes, respectively. The higher extend of BTEX degradation in both processes was observed at pH 6.5 and 10. Among the reactive oxygen species (ROSs), hydroxyl radicals (HO•) were found predominant according to scavenging tests, singlet oxygen also importantly contributed in degradation, while O2•- radicals had a minor contribution. Sulfate (SO42-) ions demonstrated higher inhibitory effect compared to chloride (Cl-) and carbonate (CO32-) ions in both processes. Degradation pathways of BTEX was proposed based on the intermediates identified using GC-MS technique.

Analysis of chemical exposures in racial populations in Canada: An investigation based on the Canadian health measures survey.

Despite demonstrated disparities in environmental chemical exposures by racial identity, no Canadian study has systematically assessed the feasibility of using a nationally representative dataset to examine differences in chemical concentrations by race. We assessed the feasibility and constraints of analysing chemical exposures in racial populations, including visible minorities and populations of Indigenous identity, using biomonitoring data collected through the Canadian Health Measures Survey (CHMS). Our primary objectives were to assess the ability to 1) generate geometric means and percentiles of chemical concentrations for racial populations by age or sex, 2) statistically compare concentrations among racial populations, and 3) calculate time trends of concentrations by race. We conducted these analyses for several priority chemicals: lead, cadmium, benzene, bisphenol A (BPA), and di(2-ethylhexyl) phthalate (DEHP). Survey participants self-identified as one of the following: White, Black, East and Southeast Asian, South Asian, Middle Eastern, Latin American, First Nations, Metis, and Inuit. Analyses were conducted for individual and combined cycles of the CHMS. Using data from the latest CHMS cycle in which each chemical was measured, we observed that sample sizes were sufficient to report geometric mean concentrations for all races except Inuit. Due to privacy considerations associated with small sample sizes, the 5th and 95th percentile concentrations could not be consistently reported for all racial populations in this analysis. While we were able to statistically compare concentrations among racial populations, the analysis was constrained by the limited number of statistical degrees of freedom available in a single CHMS cycle. Both of these constraints were alleviated by combining multiple cycles of data. The analysis of time trends was less subject to privacy and statistical limitations; we were able to calculate time trends of chemical concentrations for all racial populations. Our findings provide an important baseline for follow-up investigations of descriptive and etiological analyses of environmental chemical exposures and race in the CHMS.

ZMAT3 participated in benzene-caused disruption in self-renewal and differentiation of hematopoietic stem cells via TNF-α/NF-κB pathway.

Benzene is a common environmental and occupational pollutant, benzene exposure causes damage to hematopoietic system. ZMAT3 is a zinc finger protein which has important biological functions. In this study, benzene-exposed mouse model and ZMAT3 overexpression and low expression hematopoietic stem cells (HSCs) models were constructed to explore the mechanism of ZMAT3 in benzene-induced hematopoietic toxicity. The results showed that benzene increased the expression of ZMAT3 in mouse bone marrow (BM) cells, HSCs and peripheral blood (PB) leukocyte, and the changes in HSCs were more sensitive than BM and PB cells. In addition, overexpression of ZMAT3 decreased the self-renewal ability of HSCs and reduced the HSCs differentiation into myeloid hematopoietic cells, while low expression has the opposite effect. Besides, over and low expression of ZMAT3 both increased the HSCs differentiation into lymphoid progenitor cells. Moreover, bioinformatics analysis suggested that ZMAT3 was associated with TNF-α signaling pathway, and the correlation was confirmed in mouse model. Meanwhile, the results indicated that ZMAT3 promoted TNF-α mRNA processing by binding to the ARE structural domain on TNF-α and interacting with hnRNP A2/B1 and hnRNP A1 proteins, ultimately activating the NF-κB signaling pathway. This study provides a new mechanism for the study of benzene toxicity.

Study on the ability of indoor plants to absorb and purify benzene pollution.

The ability of indoor plants to purify benzene pollution is the basic basis for the selection of plants for ecological remediation of indoor benzene pollution. In this study, the purification rate and the purification amount per unit leaf area of 13 test plants at three benzene concentrations were determined by indoor fumigation experiments, and the benzene absorption and purification abilityability of indoor plants were comprehensively evaluated. The results showed that (1) there was a significant correlation between benzene concentration and purification rate and purification amount per unit leaf area. (2) At the three concentrations, Spathiphyllum floribundum showed the highest purification rate and Sansevieria trifasciata var. laurentii showed the highest purification per unit leaf area. (3) The combined results showed that Sansevieria trifasciata var. laurentii, Spathiphyllum floribundum and Aloe arborescens were the strongest absorbers and purifiers, while Podocarpus nagi and Anthurium andraeanum 'Pink champin' had the weakest absorption and purification capacity. The results of this study provide a theoretical basis and reference for the selection of plants with strong capacities to adsorb and purify benzene pollution in indoor air.

Sorption and attenuation of petroleum VOCs in five unsaturated soils: Microcosms and column experiments.

The fate of volatile organic compounds (VOC) vapors in the unsaturated zone is the basis for evaluating the natural attenuation potential and vapor intrusion risk. Microcosm and column experiments were conducted to study the effects chemical speciation and soil types/properties on the fate of petroleum VOCs in unsaturated zone. The biodegradation and total attenuation rates of the seven VOCs obtained by microcosm experiments in black soil and yellow earth were also generally higher than those in floodplain soil, lateritic red earth, and quartz sand. The VOC vapors in floodplain soil, lateritic red earth, and quartz sand showed slow total attenuation rates (<0.3 d-1). N-pentane, methylcyclopentane, and methylcyclohexane showed lower biodegradation rates than octane and three monoaromatic hydrocarbons. Volatilization into the atmosphere and biodegradation are two important natural attenuation paths for VOCs in unsaturated soil columns. The volatilization loss fractions of different volatile hydrocarbons in all five unsaturated soils were generally in the order: n-pentane (93.5%-97.8%) > methylcyclopentane (77.2%-85.5%) > methylcyclohexane (53.5%-69.2%) > benzene (17.1%-73.3%) > toluene (0-45.7%) > octane (1.9%-34.2%) > m-xylene (0-5.7%). The fractions by volatilization into the atmosphere of all seven hydrocarbons in quartz sand, lateritic red earth, and floodplain soil were close and higher compared to the yellow earth and black soil. Overall, this study illustrated the important roles chemical speciation and soil properties in determining the vapor-phase transport and natural attenuation of VOCs in the unsaturated zone.

A comparison of the performance of bacterial biofilters and fungal-bacterial coupled biofilters in BTEp-X removal.

Background: Conventional biofilters, which rely on bacterial activity, face challenges in eliminating hydrophobic compounds, such as aromatic compounds. This is due to the low solubility of these compounds in water, which makes them difficult to absorb by bacterial biofilms. Furthermore, biofilter operational stability is often hampered by acidification and drying out of the filter bed. Methods: Two bioreactors, a bacterial biofilter (B-BF) and a fungal-bacterial coupled biofilter (F&B-BF) were inoculated with activated sludge from the secondary sedimentation tank of the Sinopec Yangzi Petrochemical Company wastewater treatment plant located in Nanjing, China. For approximately 6 months of operation, a F&B-BF was more effective than a B-BF in eliminating a gas-phase mixture containing benzene, toluene, ethylbenzene, and para-xylene (BTEp-X). Results: After operating for four months, the F&B-BF showed higher removal efficiencies for toluene (T), ethylbenzene (E), benzene (B), and para-X (p-Xylene), at 96.9%, 92.6%, 83.9%, and 83.8%, respectively, compared to those of the B-BF (90.1%, 78.7%, 64.8%, and 59.3%). The degradation activity order for B-BF and F&B-BF was T > E > B > p-X. Similarly, the rates of mineralization for BTEp-X in the F&B-BF were 74.9%, 66.5%, 55.3%, and 45.1%, respectively, which were higher than those in the B-BF (56.5%, 50.8%, 43.8%, and 30.5%). Additionally, the F&B-BF (2 days) exhibited faster recovery rates than the B-BF (5 days). Conclusions: It was found that a starvation protocol was beneficial for the stable operation of both the B-BF and F&B-BF. Community structure analysis showed that the bacterial genus Pseudomonas and the fungal genus Phialophora were both important in the degradation of BTEp-X. The fungal-bacterial consortia can enhance the biofiltration removal of BTEp-X vapors.

Fostering a Holistic Understanding of the Full Volatility Spectrum of Organic Compounds from Benzene Series Precursors through Mechanistic Modeling.

A comprehensive understanding of the full volatility spectrum of organic oxidation products from the benzene series precursors is important to quantify the air quality and climate effects of secondary organic aerosol (SOA) and new particle formation (NPF). However, current models fail to capture the full volatility spectrum due to the absence of important reaction pathways. Here, we develop a novel unified model framework, the integrated two-dimensional volatility basis set (I2D-VBS), to simulate the full volatility spectrum of products from benzene series precursors by simultaneously representing first-generational oxidation, multigenerational aging, autoxidation, dimerization, nitrate formation, etc. The model successfully reproduces the volatility and O/C distributions of oxygenated organic molecules (OOMs) as well as the concentrations and the O/C of SOA over wide-ranging experimental conditions. In typical urban environments, autoxidation and multigenerational oxidation are the two main pathways for the formation of OOMs and SOA with similar contributions, but autoxidation contributes more to low-volatility products. NOx can reduce about two-thirds of OOMs and SOA, and most of the extremely low-volatility products compared to clean conditions, by suppressing dimerization and autoxidation. The I2D-VBS facilitates a holistic understanding of full volatility product formation, which helps fill the large gap in the predictions of organic NPF, particle growth, and SOA formation.

Proteomics Study of Benzene Metabolite Hydroquinone Induced Hematotoxicity in K562 Cells.

Objective: Hydroquinone (HQ), one of the phenolic metabolites of benzene, is widely recognized as an important participant in benzene-induced hematotoxicity. However, there are few relevant proteomics in HQ-induced hematotoxicity and the mechanism hasn't been fully understood yet. Methods: In this study, we treated K562 cells with 40 µmol/L HQ for 72 h, examined and validated protein expression changes by Label-free proteomic analysis and Parallel reaction monitoring (PRM), and performed bioinformatics analysis to identify interaction networks. Results: One hundred and eighty-seven upregulated differentially expressed proteins (DEPs) and 279 downregulated DEPs were identified in HQ-exposed K562 cells, which were involved in neutrophil-mediated immunity, blood microparticle, and other GO terms, as well as the lysosome, metabolic, cell cycle, and cellular senescence-related pathways. Focusing on the 23 DEGs and 5 DEPs in erythroid differentiation-related pathways, we constructed the network of protein interactions and determined 6 DEPs (STAT1, STAT3, CASP3, KIT, STAT5B, and VEGFA) as main hub proteins with the most interactions, among which STATs made a central impact and may be potential biomarkers of HQ-induced hematotoxicity. Conclusion: Our work reinforced the use of proteomics and bioinformatic approaches to advance knowledge on molecular mechanisms of HQ-induced hematotoxicity at the protein level and provide a valuable basis for further clarification.

New perspectives on the anaerobic degradation of BTEX: Mechanisms, pathways, and intermediates.

Aromatic hydrocarbons like benzene, toluene, xylene, and ethylbenzene (BTEX) can escape into the environment from oil and gas operations and manufacturing industries posing significant health risks to humans and wildlife. Unlike conventional clean-up methods used, biological approaches such as bioremediation can provide a more energy and labour-efficient and environmentally friendly option for sensitive areas such as nature reserves and cities, protecting biodiversity and public health. BTEX contamination is often concentrated in the subsurface of these locations where oxygen is rapidly depleted, and biodegradation relies on anaerobic processes. Thus, it is critical to understand the anaerobic biodegradation characteristics as it has not been explored to a major extent. This review presents novel insights into the degradation mechanisms under anaerobic conditions and presents a detailed description and interconnection between them. BTEX degradation can follow four activation mechanisms: hydroxylation, carboxylation, methylation, and fumarate addition. Hydroxylation is one of the mechanisms that explains the transformation of benzene into phenol, toluene into benzyl alcohol or p-cresol, and ethylbenzene into 1-phenylethanol. Carboxylation to benzoate is thought to be the primary mechanism of degradation for benzene. Despite being poorly understood, benzene methylation has been also reported. Moreover, fumarate addition is the most widely reported mechanism, present in toluene, ethylbenzene, and xylene degradation. Further research efforts are required to better elucidate new and current alternative catabolic pathways. Likewise, a comprehensive analysis of the enzymes involved as well as the development of advance tools such as omic tools can reveal bottlenecks degradation steps and create more effective on-site strategies to address BTEX pollution.

Occupational exposure to benzene and mortality risk of lymphohaematopoietic cancers in the Swiss National Cohort.

OBJECTIVES: Previous studies established a causal relationship between occupational benzene exposure and acute myeloid leukemia (AML). However, mixed results have been reported for associations between benzene exposure and other myeloid and lymphoid malignancies. Our work examined whether occupational benzene exposure is associated with increased mortality from overall lymphohaematopoietic (LH) cancer and major subtypes. METHODS: Mortality records were linked to a Swiss census-based cohort from two national censuses in 1990 and 2000. Cases were defined as having any LH cancers registered in death certificates. We assessed occupational exposure by applying a quantitative benzene job-exposure matrix (BEN-JEM) to census-reported occupations. Exposure was calculated as the products of exposure proportions and levels (P × L). Cox proportional hazards models were used to calculate LH cancer death hazard ratios (HR) and 95% confidence intervals (CI) associated with benzene exposure, continuously and in ordinal categories. RESULTS: Our study included approximately 2.97 million persons and 13 415 LH cancer cases, including 3055 cases with benzene exposure. We observed increased mortality risks per unit (P × L) increase in continuous benzene exposure for AML (HR 1.03, 95% CI 1.00-1.06) and diffuse large B-cell lymphoma (HR 1.09, 95% CI 1.04-1.14). When exposure was assessed categorically, increasing trends in risks were observed with increasing benzene exposure for AML (P=0.04), diffuse large B-cell lymphoma (P=0.02), and follicular lymphoma (P=0.05). CONCLUSION: In a national cohort from Switzerland, we found that occupational exposure to benzene is associated with elevated mortality risks for AML, diffuse large B-cell lymphoma, and possibly follicular lymphoma.

Occupational benzene exposure and colorectal cancer: A systematic review and meta-analysis.

Recent reports suggest that benzene exposure may be associated with solid cancers, such as lung and bladder cancers. Instead, evidence on the association between benzene and colorectal cancer (CRC) is sparse. Thus, we aimed to summarize current literature on the association between occupational benzene exposure and CRC. We searched Pubmed, Embase (through Ovid), and Scopus to retrieve cohort and nested case-control studies on the association between occupational benzene exposure and solid cancers. The search was initially completed in December 2022 and later updated in April 2024. We assessed quality of included studies using a modified version of Newcastle-Ottawa Scale. We computed pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) of CRC according to occupational benzene exposure, using the Paule-Mandel method. Twenty-eight studies were included in the meta-analysis. Most of them were conducted in Europe or North America (82.1%) and were industry-based (89.3%). Pooled RRs comparing workers exposed to benzene with those who were unexposed for incidence and mortality were 1.10 (95% CI: 1.06, 1.15) and 1.04 (95% CI: 0.97, 1.11) for CRC, 1.12 (95% CI: 1.01, 1.24) and 1.08 (95% CI: 0.99, 1.19) for colon cancer, and 1.04 (95% CI: 0.94, 1.14) and 1.05 (95% CI: 0.92, 1.19) for rectal cancer, respectively. Only one study supported the occurrence of a dose-response relationship between occupational benzene exposure and CRC, while others found no increase in risk according to dose of exposure or duration of employment. Our findings suggest that occupational benzene exposure may be associated with CRC. Further research with detailed assessment of individual-level exposure is warranted to confirm our results.

The microRNA miR-152 can mitigate and prevent the toxic effect of benzene on porcine ovarian cells.

Epigenetic methods to prevent the reproductive toxicity of oil-related environmental contaminants are currently unavailable. The present study aimed to examine the ability of the microRNA miR-152 to mitigate the effects of benzene on ovarian cells. Porcine ovarian granulosa cells transfected or not transfected with miR-152 mimics were cultured with or without benzene (0, 10 and 100 ng/ml). The expression of miR-152; viability; proliferation (cell proliferation and expression of mRNAs and accumulation of PCNA and cyclin B1); apoptosis (expression of mRNAs and accumulation of bax and caspase 3; and the proportion of cells with fragmented DNA); and release of progesterone, estradiol and IGF-I were analyzed via RT-qPCR; the Trypan blue exclusion test; quantitative immunocytochemistry; BrdU; XTT; TUNEL assays; and ELISA. Administration of benzene promoted the expression of apoptosis markers and reduced cell viability, all measured markers of proliferation, the release of steroid hormones and IGF-I. Overexpression of miR-152 was associated with increased cell viability, proliferation, progesterone and IGF-I release and reduced apoptosis and estradiol output. Moreover, miR-152 mitigated or prevented the effects of benzene on all the measured parameters in addition to estradiol release. The present observations suggest the toxic effect of benzene and the stimulatory influence of miR-152 on ovarian cell functions. Moreover, this is the first demonstration of the ability of miRNAs to mitigate and prevent the reproductive toxicity of benzene.

Interventional probability of causation (IPoC) with epidemiological and partial mechanistic evidence: benzene vs. formaldehyde and acute myeloid leukemia (AML).

INTRODUCTION: Causal epidemiology for regulatory risk analysis seeks to evaluate how removing or reducing exposures would change disease occurrence rates. We define interventional probability of causation (IPoC) as the change in probability of a disease (or other harm) occurring over a lifetime or other specified time interval that would be caused by a specified change in exposure, as predicted by a fully specified causal model. We define the closely related concept of causal assigned share (CAS) as the predicted fraction of disease risk that would be removed or prevented by a specified reduction in exposure, holding other variables fixed. Traditional approaches used to evaluate the preventable risk implications of epidemiological associations, including population attributable fraction (PAF) and the Bradford Hill considerations, cannot reveal whether removing a risk factor would reduce disease incidence. We argue that modern formal causal models coupled with causal artificial intelligence (CAI) and realistically partial and imperfect knowledge of underlying disease mechanisms, show great promise for determining and quantifying IPoC and CAS for exposures and diseases of practical interest. METHODS: We briefly review key CAI concepts and terms and then apply them to define IPoC and CAS. We present steps to quantify IPoC using a fully specified causal Bayesian network (BN) model. Useful bounds for quantitative IPoC and CAS calculations are derived for a two-stage clonal expansion (TSCE) model for carcinogenesis and illustrated by applying them to benzene and formaldehyde based on available epidemiological and partial mechanistic evidence. RESULTS: Causal BN models for benzene and risk of acute myeloid leukemia (AML) incorporating mechanistic, toxicological and epidemiological findings show that prolonged high-intensity exposure to benzene can increase risk of AML (IPoC of up to 7e-5, CAS of up to 54%). By contrast, no causal pathway leading from formaldehyde exposure to increased risk of AML was identified, consistent with much previous mechanistic, toxicological and epidemiological evidence; therefore, the IPoC and CAS for formaldehyde-induced AML are likely to be zero. CONCLUSION: We conclude that the IPoC approach can differentiate between likely and unlikely causal factors and can provide useful upper bounds for IPoC and CAS for some exposures and diseases of practical importance. For causal factors, IPoC can help to estimate the quantitative impacts on health risks of reducing exposures, even in situations where mechanistic evidence is realistically incomplete and individual-level exposure-response parameters are uncertain. This illustrates the strength that can be gained for causal inference by using causal models to generate testable hypotheses and then obtaining toxicological data to test the hypotheses implied by the models-and, where necessary, refine the models. This virtuous cycle provides additional insight into causal determinations that may not be available from weight-of-evidence considerations alone.

Leukemia risk assessment of exposure to low-levels of benzene based on the linearized multistage model.

Objectives: To assess leukemia risk in occupational populations exposed to low levels of benzene. Methods: Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m3·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model. Results: The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10-4, respectively; Ptrend < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary t, t-MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m3·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m3·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10-6. Conclusion: This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m3·year.

Insight into hematological parameters of petrol station workers.

OBJECTIVE: Benzene is one of the major carcinogenic factors that can affect liver, kidneys, and lungs. Chronic inhalation of benzene vapor by petrol stations workers has been shown to have an impact on hematological parameters; thus, the present study aimed to investigate the effect of benzene exposure on petrol station workers. SUBJECTS AND METHODS: The study involved 99 participants, 50 of whom have been exposed to benzene and 49 of whom have not (control). A 5 ml blood sample in an ethylenediaminetetraacetic acid (EDTA) anticoagulant tube was collected from each subject, and a complete blood count test was used to test hematological parameters. RESULTS: The current study showed a significant decrease in red blood cells, packed cell volume, and hemoglobin in the exposed group compared to the control group. However, the amount of white blood cells was significantly increased (p < 0.0001) in the exposed group compared to the control group. Notably, there was no significant difference in platelet counts between the two groups. In terms of exposure time, subjects who have been exposed to benzene for more than a year and fewer than 10 years showed a significant decrease (p < 0.05) in RBCs indices and a significant increase (p < 0.0001) in WBCs compared to those in the control group CONCLUSIONS: Thus, the findings indicated that significant differences in hematological parameters were found in workers who were exposed to benzene compared to those who had not been exposed.