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.

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.

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.

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.

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.

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.

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.

Evaluation of the Safety and Efficacy of Hand Sanitizer Products Marketed to Children Available during the COVID-19 Pandemic.

Hand sanitizer use in the United States (U.S.) increased after the SARS-CoV-2 outbreak. The U.S. Food and Drug Administration (FDA) released temporary manufacturer guidance, changing impurity level limits for alcohol-based hand sanitizers (ABHSs). Since the guidance took effect, the FDA has recommended against using these hand sanitizers due to concerns over safety, efficacy, and/or risk of incidental ingestion. To address current gaps in exposure characterization, this study describes a survey of ABHSs marketed to children available in the U.S., as defined by several inclusion criteria. A subset of ABHSs (n = 31) were evaluated for ethanol and organic impurities using a modified FDA method. Products with detectable impurity levels were compared to the FDA's established interim limits. Seven children's products had impurity levels exceeding the FDA's recommended interim limits, including benzene (up to 9.14 ppm), acetaldehyde (up to 134.12 ppm), and acetal (up to 75.60 ppm). The total measured alcohol content ranged from 52% to 98% in all hand sanitizers tested, ranging from 39% below, and up to 31% above, the labeled concentration. Future studies should confirm impurity contamination sources. A risk assessment could determine whether dermal application or incidental ingestion of impurity-containing hand sanitizers pose any consumer risk.

The Long Goodbye: Finally Moving on from the Relative Potency Approach to a Mixtures Approach for Polycyclic Aromatic Hydrocarbons (PAHs).

For the past several decades, a relative potency approach has been used to estimate the human health risks from exposure to polycyclic aromatic hydrocarbon (PAH) mixtures. Risk estimates are derived using potency equivalence factors (PEFs; also called relative potency factors [RPFs]), based on the ratio of selected PAHs to benzo[a]pyrene (BaP), expressed qualitatively by orders of magnitude. To quantify PEFs for 18 selected carcinogenic PAHs, a systematic approach with a priori and dose response criteria was developed, building on draft work by the US EPA in 2010 and its review by US EPA Science Advisory Board (SAB) in 2011. An exhaustive search for carcinogenicity studies that included both target PAHs and BaP with environmentally relevant exposure routes found only 48 animal bioassay datasets (mostly pre-1992 based on skin painting). Only eight datasets provided adequate low-response data, and of these only four datasets were appropriate for modeling to estimate PEFs; only benzo[b]fluoranthene and cyclopenta[c,d]pyrene had a PEF that could be quantified. Thus, current knowledge of PAH carcinogenicity is insufficient to support quantitative PEFs for PAH mixtures. This highlights the long-acknowledged need for an interdisciplinary approach to estimate risks from PAH mixtures. Use of alternative and short-term toxicity testing methods, improved mixture characterization, understanding the fate and bioavailability of PAH mixtures, and understanding exposure route-related differences in carcinogenicity are discussed as ways to improve the understanding of the risks of PAHs.

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.

Using spectrally-selective radiofrequency pulses to enhance lactate signal for diffusion-weighted MRS measurements in vivo.

Measurement of lactate diffusion properties using diffusion-weighted magnetic resonance spectroscopy in vivo may allow elucidating brain lactate cellular compartmentation, which would be of great importance for neuroscience. However, measuring lactate signal is complicated by low signal-to-noise ratio due to low lactate concentration and J-modulation of its 1.3 ppm peak. In this work, we assess the benefits of using a diffusion-weighting spin echo block and spectrally selective refocusing pulses to suppress the effect of J-coupling on the 1.3 ppm lactate resonance, by not refocusing its coupling partner at 4.1 ppm. Two different kinds of spectrally selective pulses, either polychromatic or single-band, are evaluated in the mouse brain at 11.7 T. Almost complete suppression of J-modulation is shown, resulting in an approximately two-fold signal increase as compared to a reference STE-LASER sequence (for the specific diffusion times used in this work). Repeated measurements confirm that lactate diffusion-weighted signal attenuation is measured with an approximately two-fold precision.

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.

Bayesian hierarchical evaluation of dose-response for peanut allergy in clinical trial screening.

Risk-based labeling based on the minimal eliciting doses (EDs) in sensitized populations is a potential replacement for precautionary allergen labeling of food allergens. We estimated the dose-response distribution for peanut allergen using data from double-blind placebo-controlled food challenges (DBPCFCs) conducted in the US at multiple sites, testing a population believed to be similar to the general U.S. food allergic population. Our final (placebo-adjusted) dataset included 548 challenges of 481 subjects. Bayesian hierarchical analysis facilitated model fitting, and accounted for variability associated with various levels of data organization. The data are best described using a complex hierarchical structure that accounts for inter-individual variability and variability across study locations or substudies. Bayesian model averaging could simultaneously consider the fit of multiple models, but the Weibull model dominated so strongly that model averaging was not needed. The ED01 and ED05 (and 95% credible intervals) are 0.052 (0.021, 0.13) and 0.49 (0.22, 0.97) mg peanut protein, respectively. Accounting for challenges with severe reactions at the LOAEL, by using the dose prior to the LOAEL as the new LOAEL, the ED01 drops to 0.029 (0.014, 0.074) mg peanut protein. Our results could aid in establishing improved food labeling guidelines in the management of food allergies.

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.

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.

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.

Ethylene Oxide: Cancer Evidence Integration and Dose-Response Implications.

The International Agency for Research on Cancer (IARC) and the United States Environmental Protection Agency (USEPA) classified ethylene oxide (EtO) as a known human carcinogen. Critically, both noted that the epidemiological evidence based on lymphoid and breast cancers was "limited," but that the evidence in animal studies was "sufficient" and "extensive" (respectively) and that EtO is genotoxic. The USEPA derived one of the highest published inhalation unit risk (IUR) values (3 × 10-3 per [µg/m3 EtO]), based on results from 2 epidemiological studies. We performed focused reviews of the epidemiological and toxicological evidence on the carcinogenicity of EtO and considered the USEPA's reliance on a genotoxic mode of action to establish EtO's carcinogenicity and to determine likely dose-response patterns. Higher quality epidemiological studies demonstrated no increased risk of breast cancers or lymphohematopoietic malignancies (LHM). Similarly, toxicological studies and studies of early effect biomarkers in animals and humans provided no strong indication that EtO causes LHM or mammary cancers. Ultimately, animal data are inadequate to define the actual dose-response shape or predict tumor response at very low doses with any confidence. We conclude that the IARC and USEPA classification of EtO as a known human carcinogen overstates the underlying evidence and that the IUR derived by USEPA grossly overestimates risk.

Meta-regression analysis of the effects of dietary cholesterol intake on LDL and HDL cholesterol.

Background: Elevated low-density lipoprotein (LDL) cholesterol is a major risk factor for cardiovascular disease. Dietary guidance recommends reducing saturated fatty acid, trans fatty acid, and cholesterol intakes to reduce circulating LDL cholesterol. Cholesterol intake may also affect high-density lipoprotein (HDL)-cholesterol concentrations, but its impact has not been fully quantified. Objectives: The aims of this study were to investigate the dose-response relation between changes in dietary cholesterol intake and changes in lipoprotein-cholesterol markers for cardiovascular disease risk and to provide a reference for clinicians on how changes in dietary cholesterol intake affect circulating cholesterol concentrations, after accounting for intakes of fatty acids. Methods: We used a Bayesian approach to meta-regression analysis, which uses Markov chain Monte Carlo techniques, to assess the relation between the change in dietary cholesterol (adjusted for dietary fatty acids) and changes in LDL and HDL cholesterol based on the use of data from randomized dietary intervention trials. Results: Fifty-five studies (2652 subjects) were included in the analysis. The nonlinear Michaelis-Menten (MM) and Hill models best described the data across the full spectrum of dietary cholesterol changes studied (0-1500 mg/d). Mean predicted changes in LDL cholesterol for an increase of 100 mg dietary cholesterol/d were 1.90, 4.46, and 4.58 mg/dL for the linear, nonlinear MM, and Hill models, respectively. Conclusions: The change in dietary cholesterol was positively associated with the change in LDL-cholesterol concentration. The linear and MM models indicate that the change in dietary cholesterol is modestly inversely related to the change in circulating HDL-cholesterol concentrations in men but is positively related in women. The clinical implications of HDL-cholesterol changes associated with dietary cholesterol remain uncertain.

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.