Evaluating the 10X Uncertainty Factor for Children and Elderly with Data-Derived Values for Neuromuscular Blocking Agents

Conventional risk assessment process utilizes a 10-fold uncertainty factor (UF) to extrapolate from the general human population to sensitive subgroups, such as children and elderly. The purpose of this investigation was to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharmacody-namic data are incorporated to characterize human sensitivity. An extensive literature search was conducted on seven neuromuscular blocking agents (mivacurium, atracurium, rocuronium, vecuronium, doxacurium, pancuronium, pipecuronium). Composite factors (kinetics × dynamics) were calculated using the highest data-derived kinetic and dynamic values. For the drugs examined, all of the composite factors for the sensitivity of children were lower than 5. In the elderly, all of the composite factors were lower than 10, and five of seven composite factors were less than 5. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce the uncertainties associated with sensitive subgroups.     

A Study of Safety Factors for Risk Assessment of Drugs Used for Treatment of Attention Deficiency Hyperactivity Disorder in Sensitive Populations

The aim of this study was to search the literature through the library and Internet resources from pharmaceutical companies and associations to obtain pharmacoki-netic and pharmacodynamic data for six of the most used drugs for treatment of Attention Deficiency Hyperactivity Disorder (ADHD). The drugs included meth-ylphenidate, pemoline, haloperidol, bupropion, imipramine, and desipramine. The data collected allowed the evaluation of the 10X uncertainty factor, which was related to healthy adults and sensitive populations (children, elderly and health affected). Once the extensive database review was completed, the data were used to calculate a composite factor (kinetics x dynamics) for each drug. Ten of the 12 data-derived composite factors were less than 10. Therefore, incorporation of human kinetic and dynamic data into risk assessment can help to reduce the uncertainties associated with sensitive subgroups.     

Application of Kinetic and Dynamic Data for Antihistamines to Risk Characterization in Sensitive Populations

A major goal of risk assessment is to protect the health of individuals who may be more sensitive than the general population. This study compared human phar-macokinetic and pharmacodynamic data in sensitive groups (i.e., children, the elderly, diseased states, and poor metabolizers) versus young, healthy adults for the antihistamines cetirizine, fexofenadine, loratadine, azelastine, ebastine, chlorpheniramine, and diphenhydramine. The default components (3.16 each for kinetic and dynamic aspects) of the intraspecies uncertainty factor were adjusted with compound specific data for the antihistamines. The majority (16 of 18) of the composite factors (kinetics X dynamics) for the sensitive groups were less than 10. Children had the lowest composite factors for antihistamines, ranging from 1.1 to 6.3. Application of kinetic and dynamic data for antihistamines to the Renwick/International Programme on Chemical Safety (IPCS) scheme can aid in characterizing the extent of variability in sensitive populations, thereby reducing the uncertainty associated with the risk assessment of sensitive populations.     

Intra-Species Extrapolation in Risk Assessment of Different Classes of Antimicrobials

The risk assessment process for non-carcinogens incorporates all available scientific information, including toxicokinetic and toxicodynamic data. A 10-fold uncertainty factor (UF) is most commonly used to account for underlying variability within the human species. The purposes of this investigation are to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharma-codynamic data are incorporated to characterize interindividual variability and whether another UF is needed for the children group. An extensive literature search was conducted on seven antimicrobials in order to incorporate information on kinetics and dynamics to allow extrapolation among susceptible humans. The drugs are cefaclor, cefuroxime, erythromycin, clarithromycin, ampicillin, gentamicin and amikacin. The composite factor was calculated using the highest ratio for appropriate parameters and default subfactor. According to the data, we concluded that when relevant kinetic and dynamic data are available, replacing the default factors with actual data-derived values was possible for the antimicrobials evaluated and that there is no need to add another UF to the children group.     

Sequence analysis of the human virome in febrile and afebrile children

Unexplained fever (UF) is a common problem in children under 3 years old. Although virus infection is suspected to be the cause of most of these fevers, a comprehensive analysis of viruses in samples from children with fever and healthy controls is important for establishing a relationship between viruses and UF. We used unbiased, deep sequencing to analyze 176 nasopharyngeal swabs (NP) and plasma samples from children with UF and afebrile controls, generating an average of 4.6 million sequences per sample. An analysis pipeline was developed to detect viral sequences, which resulted in the identification of sequences from 25 viral genera. These genera included expected pathogens, such as adenoviruses, enteroviruses, and roseoloviruses, plus viruses with unknown pathogenicity. Viruses that were unexpected in NP and plasma samples, such as the astrovirus MLB-2, were also detected. Sequencing allowed identification of virus subtype for some viruses, including roseoloviruses. Highly sensitive PCR assays detected low levels of viruses that were not detected in approximately 5 million sequences, but greater sequencing depth improved sensitivity. On average NP and plasma samples from febrile children contained 1.5- to 5-fold more viral sequences, respectively, than samples from afebrile children. Samples from febrile children contained a broader range of viral genera and contained multiple viral genera more frequently than samples from children without fever. Differences between febrile and afebrile groups were most striking in the plasma samples, where detection of viral sequence may be associated with a disseminated infection. These data indicate that virus infection is associated with UF. Further studies are important in order to establish the range of viral pathogens associated with fever and to understand of the role of viral infection in fever. Ultimately these studies may improve the medical treatment of children with UF by helping avoid antibiotic therapy for children with viral infections.     

Determining “safe” levels of exposure: The validity of the use of 10X safety factors

The current guideline for risk assessment of chemicals having a toxic end point routinely uses the reference dose (RfD) approach based on uncertainty factors of 10. With this method the quality of individual risk assessment varies among chemicals, often resulting in either an over‐ or under‐estimation of adverse health risk. The purpose of this investigation is to evaluate whether the magnitude of the 10X uncertainty factors have scientific merit against data from published experimental studies. A compilation and comparison of ratios between LOAEL/NOAEL (Lowest Observed Adverse Effect Level/No Observed Adverse Effect Level), subchronic/chronic, and animal/human values were made. The results of the present investigation revealed that the use of default factors could be over‐conservative or unprotective. More reasonable estimates of the risk to human health would result in a reduction of unnecessary, and expensive over‐regulation. In addition to the LOAEL to NOAEL, and subchronic to chronic ratios, the adequacy of uncertainty factors for animal to human extrapolations were examined. Although a 10‐fold uncertainty factor (UF) is most commonly used in the risk assessment process, an examination of the literature for the compounds presented here suggests that the use of different values is scientifically justifiable.     

The Use of Kinetic and Dynamic Data in Risk Assessment of Drugs

The risk assessment process for non-carcinogens must incorporate all available scientific information, including toxicokinetic and toxicodynamic data. The framework for exposure limit setting proposed by Renwick and the International Programme on Chemical Safety (IPCS) subdivides traditional 10X uncertainty factors (UFs) into separate partial-log default values based on kinetic and dynamic considerations and allows for incorporation of compound-specific data when available. In this investigation, an extensive literature search was conducted on nine pharmaceuticals in order to incorporate information on kinetics and dynamics to allow extrapolation across species and among susceptible humans. The drugs are diazepam, oxazepam, midazolam, buspirone, fluoxetine, venlafaxine, amlodipine, felodipine, and nifedipine. The composite factors were calculated using the highest ratio or the average ratio for appropriate parameters and default subfactor. For the drugs examined, most of the subfactors for kinetics and dynamics were less than the proposed values by Renwick and IPCS, and the composite factors were far less than 100. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce uncertainties associated with interspecies differences and interindividual variability.     

Some Comments on the Selection of Human Intraspecies Uncertainty Factors

The Reference Dose (RfD) is used in the risk assessment of non-carcinogenic chemicals. It is derived by dividing a point of departure by the product of the uncertainty (UFs) and modifying factors (MFs). Separate UFs are used for different variables, e.g., intraspecies variation and, in general, each UF is an order of magnitude (10-fold). On the other hand, the MF is usually based on some known variable such as differences in absorption of a chemical from food and water and its default value is one. The USEPA's Integrated Risk Information System (IRIS) has 14 chemicals that have RfDs based on human studies. We examined those IRIS files to determine the rationale for setting human intraspecies uncertainty factors (UF_H). The first consideration was that the chemical had an adequate peer-reviewed human database. Without such, it would not be possible to derive an RfD based on human data. Ten of the 14 chemicals had an UF_H of 1 or 3; four of these were essential trace elements (ETEs). The rationales for using less than a 10-fold UF_H for the ETEs included; 1) nutritional data, 2) large human exposure groups, 3) minimal effect levels and/or 4) several studies with similar effect levels. For the other compounds, reasons included; 1) large human exposure groups, 2) a critical effect that was not adverse (cosmetic), 3) the most sensitive population was exposed, 4) the compound was on the FDA's “generally regarded as safe” (GRAS) list, 5) database uncertainties and 6) less-than-lifetime exposure adjusted for 70 years exposure. It is important to understand the reasons for selecting a UF_H of 1, or 3 as they will apply to future chemicals considered by the USEPA and other agencies.     

A toxicological basis to derive generic interspecies uncertainty factors for application in human and ecological risk assessment

A new method is proposed to derive the size of the interspecies uncertainty factor (UF) that is toxicologically and statistically based. The method is based on the biological/evolutionary assumption that similarity in susceptibility to toxic substances is a function of phylogenetic relatedness. This assumption is assessed via a large and highly structured aquatic database with over 500 agents tested in specific binary toxicity comparison (i.e., when two species have been tested with the same chemical under identical conditions) for dozens of species of wide phylogenetic relatedness. The methodology takes into account the generic need to estimate a response in any species (not just human) and the need to predict responses for new chemical agents. The method involves quantifying interspecies variation in susceptibility to numerous toxic substances via the use of binary interspecies comparisons that are converted to a 95% UF. This interspecies UF represents an estimate of the upper 95% of the population of 95% prediction intervals (PI) for binary interspecies comparisons within four categories of phylogenetic relatedness (species‐within‐genus, genera‐within‐family, families‐within‐order, orders‐within‐class). The 95% interspecies UFs range from a low of 10 for species‐within‐genus up to 65 for orders‐within‐class. Most mammalian toxicology studies involving mice, rats, cats, dogs, gerbils, and rabbits are orders‐within‐class categories for human risk assessment and would be provided a 65‐fold UF. Larger or smaller interspecies UF values could be selected based on the level of protection desired. The procedures described have application to both human and ecological risk assessment.     

The effect of race on the incidence of low birth weight: persistence of effect after controlling for socioeconomic, educational, marital, and risk status

The purpose of this study was to determine whether the elevated risk for low birth weight (LBW) infants among black mothers would persist when biologic, behavioral, and socioeconomic factors (as measured by socioeconomic status, level of education, and marital status) were controlled. It was found that the odds ratios for the risk of LBW for blacks/whites persisted above 1.5, regardless of what subgroups were used and what factors were controlled. The black/white odds ratios were, however, less than 2.0 when cigarette smoking was not a risk factor and higher than 2.0 when it was. In fact, the highest odds ratios, up to 2.65, occurred among the smoking group. These data suggest that smoking may have a more strongly negative effect among black than white pregnant mothers. In general, the effect of race on the LBW risk was much less strong than that of risk factors that can be influenced, such as adverse maternal practices.     

The Use of Epidemiology in Risk Assessment: Challenges and Opportunities

The assessment of risk from environmental and occupational exposures incorporates and synthesizes data from a variety of scientific disciplines including toxicology and epidemiology. Epidemiological data have offered valuable contributions to the identification of human health hazards, estimation of human exposures, quantification of the exposure–response relation, and characterization of risks to specific target populations including sensitive populations. As with any scientific discipline, there are some uncertainties inherent in these data; however, the best human health risk assessments utilize all available information, characterizing strengths and limitations as appropriate. Human health risk assessors evaluating environmental and occupational exposures have raised concerns about the validity of using epidemiological data for risk assessment due to actual or perceived study limitations. This article highlights three concerns commonly raised during the development of human health risk assessments of environmental and occupational exposures: (a) error in the measurement of exposure, (b) potential confounding, and (c) the interpretation of non-linear or non-monotonic exposure–response data. These issues are often the content of scientific disagreement and debate among the human health risk assessment community, and we explore how these concerns may be contextualized, addressed, and often ameliorated.     

Human health risk assessment and sources analysis of nitrate in shallow groundwater of the Liujiang basin,China

High levels of nitrates in groundwater pose a risk to human health. Hence, groundwater-human health risk assessment and sources analysis are essential. The article aims to assess risk level and identify sources of nitrate in shallow groundwater of the Liujiang basin by using a human health risk assessment (HHRA) model, Factor analysis (FA) and GIS spatial analysis. The results indicated that the most serious pollution was distributed in southern region of the basin; about 60% of the samples exceeded the recommended limit of nitrate as per the World Health Organization limit. Moreover, ingants' health risk were greater than those of adults and children, and about 56% of the groundwater samples will put the infants at risk of health. FA was used to identify various underlying natural and anthropogenic processes that created these distinct risk levels. The FA results can be categorized by two major factors: (1) Organic fertilizers and sewage discharge contamination in central region. (2) Blocking effect of granite and redox conditions in southern parts. This study demonstrates that the great variation of nitrate risk levels in the basin should be attributed to both natural and anthropogenic processes.     

Estimation of Toxicity Equivalency and Probabilistic Health Risk on Lifetime Daily Intake of Polycyclic Aromatic Hydrocarbons from Urban Residential Soils

In this study, toxicity equivalents and health risks, based on concentration of 16 priority polycyclic aromatic hydrocarbons (PAHs) in urban residential soils were estimated for the human population in Gwalior, India. Benzo(a)pyrene total potency equivalents (BaP TPE) were estimated for assessment of human health risk from direct contact with PAH-contaminated soil. Potential risk to contaminated groundwater from leaching of carcinogenic PAHs was assessed by estimating the index of additive cancer risk (IACR). On the basis of lifetime average daily intake of 16 PAHs through ingestion of PAH-contaminated soils, lifetime cancer risk to human adults and children was estimated. The concentration of probable human carcinogenic PAHs in soils accounted for 38% of ∑16PAHs. BaP TPE and index of additive cancer risk (IACR) were lower than guideline values of 0.6 mg kg^?1 and <1, respectively. Estimated lifetime average daily intakes of PAHs via soil ingestion were lower than recommended dose. However, the ILCR for human adults was within acceptable limits recommended by regulatory agencies, but may need action for children in Gwalior, India.     

Valoración del estado nutricional en Geriatría: declaración de consenso del Grupo de Nutrición de la Sociedad Española de Geriatría y Gerontología

Ongoing population ageing is one of the factors influencing the increase in the prevalence of undernutrition, as elderly people are a vulnerable group due to their biological, psychological and social characteristics.Despite its high prevalence, undernutrition is underdiagnosed in the geriatric sphere. For this reason, the aim of this consensus document is to devise a protocol for geriatric nutritional assessment. A multidisciplinary team has been set up within the Spanish Society of Geriatrics and Gerontology (in Spanish Sociedad Española de Geriatría y Gerontología [SEGG]) in order to address undernutrition and risk of undernutrition so that they can be diagnosed and treated in an effective manner.The MNA-SF is a practical tool amongst the many validated methods for nutritional screening. Following suspicion of undernutrition, or after establishing the presence of undernutrition, a full assessment will include a detailed nutritional history of the patient. The compilation of clinical-nutritional and dietetic histories is intended to help in identifying the possible risk factors at the root of a patient's undernutrition. Following this, an anthropometric assessment, combined with laboratory data, will describe the patient's physical and metabolic changes associated to undernutrition. Currently, the tendency is for further nutritional assessment through the use of non-invasive techniques to study body composition in association with functional status. The latter is an indirect index for nutritional status, which is very interesting from a geriatrician's point of view. To conclude, correct nutritional screening is the fundamental basis for an early undernutrition diagnosis and to assess the need for nutritional treatment. In order to achieve this, it is fundamental to foster research in the field of nutritional geriatrics, in order to expand our knowledge base and to increasingly practice evidence-based geriatrics.     

Health risk assessment of fluoride in water distribution network of Mashhad,Iran

High and low levels of fluoride in drinking waters have been considered as a major public health issue in recent years. This cross-sectional study was conducted over five consecutive years (from 2012 to 2016) in the water distribution network of Mashhad city, Iran with the objectives of determining levels of fluoride and to perform health risk assessment among residents in the study area. Water samples were taken from 30 stations and were analyzed using UV-visible spectrophotometer. The mean annual concentrations of fluoride in all stations during five years of consecutive study were lower than the respective maximum permissible limits (1.5 mg/L) in water as regulated by the WHO. The human health risk assessment was performed by calculating the chronic daily intake and hazard quotient (HQ) of fluoride through human oral intake for adults (men and women) and children for each year during a five-year study. Health risk analysis in this study presented that the non-carcinogenic risk associated with fluoride exposure through drinking water in Mashhad was mostly acceptable because the mean HQ values of fluoride were lower than 1.     

Machine learning-based risk factor analysis and prevalence prediction of intestinal parasitic infections using epidemiological survey data

BackgroundPrevious epidemiological studies have examined the prevalence and risk factors for a variety of parasitic illnesses, including protozoan and soil-transmitted helminth (STH, e.g., hookworms and roundworms) infections. Despite advancements in machine learning for data analysis, the majority of these studies use traditional logistic regression to identify significant risk factors.MethodsIn this study, we used data from a survey of 54 risk factors for intestinal parasitosis in 954 Ethiopian school children. We investigated whether machine learning approaches can supplement traditional logistic regression in identifying intestinal parasite infection risk factors. We used feature selection methods such as InfoGain (IG), ReliefF (ReF), Joint Mutual Information (JMI), and Minimum Redundancy Maximum Relevance (MRMR). Additionally, we predicted children’s parasitic infection status using classifiers such as Logistic Regression (LR), Support Vector Machines (SVM), Random Forests (RF) and XGBoost (XGB), and compared their accuracy and area under the receiver operating characteristic curve (AUROC) scores. For optimal model training, we performed tenfold cross-validation and tuned the classifier hyperparameters. We balanced our dataset using the Synthetic Minority Oversampling (SMOTE) method. Additionally, we used association rule learning to establish a link between risk factors and parasitic infections.Key findingsOur study demonstrated that machine learning could be used in conjunction with logistic regression. Using machine learning, we developed models that accurately predicted four parasitic infections: any parasitic infection at 79.9% accuracy, helminth infection at 84.9%, any STH infection at 95.9%, and protozoan infection at 94.2%. The Random Forests (RF) and Support Vector Machines (SVM) classifiers achieved the highest accuracy when top 20 risk factors were considered using Joint Mutual Information (JMI) or all features were used. The best predictors of infection were socioeconomic, demographic, and hematological characteristics.ConclusionsWe demonstrated that feature selection and association rule learning are useful strategies for detecting risk factors for parasite infection. Additionally, we showed that advanced classifiers might be utilized to predict children’s parasitic infection status. When combined with standard logistic regression models, machine learning techniques can identify novel risk factors and predict infection risk.     

Clinic-based primary care of frail older patients in California.

We surveyed medical directors of primary care clinics in California to learn how those clinics cared for their frail older patients. Of 143 questionnaires sent, 127 (89%) were returned. A median of 30% of all patient encounters were with persons aged 65 or older, and a median of 20% of older patients were considered frail. A total of 20% of the clinics routinely provided house calls to homebound elderly patients. Of clinics involved in training medical students of physicians (teaching clinics), 70% had at least one physician with an interest in geriatrics, compared with 42% of nonteaching clinics (P less than .005). For frail patients, 40% of the clinics routinely performed functional assessment, while 20% routinely did an interdisciplinary evaluation. Continuing education in geriatrics emerged as a significant independent correlate of both functional assessment and interdisciplinary evaluation. Among the 94 clinics with a standard appointment length for the history and physical examination, only 11 (12%) allotted more than 60 minutes for frail patients. The data suggest that certain geriatric approaches are being incorporated into clinic-based primary care in California but do not provide insight into their content or clinical effects.     

A review of the use of uncertainty factors in the health risk assessment of some metals

Because metals can produce health risks, standards for regulating metal exposure are necessary. The purpose of this chapter is to review the application of uncertainty factors to mercury, arsenic, and cadmium. By the conventional method, uncertainty factors are often applied to animal studies to establish the reference dose (RfD) in humans. However, with the availability of a better database from improved study designs, it was demonstrated that uncertainty factors can be decreased. Incorporation of more pharmacokinetic and mechanistic data into the risk assessment process, as well as discussions between risk assessors and the research community to identify research needs are essential in reducing uncertainty factors.     

Establishing Data-Derived Adjustment Factors from Published Pharmaceutical Clinical Trial Data

In non-cancer risk assessment the goal traditionally has been to protect the majority of people by setting limits that account for interindividual variability in the human population. The Environmental Protection Agency (EPA) has assigned a default uncertainty factor (?UF) of 10 to account for interindividual variability in response to toxic agents in the general population. Previous studies have suggested that it is appropriate to equally divide this factor into sub-factors of 3.2 each for variability in human pharmacokinetics (PK) and pharmacodynamics (PD). As an extension of this model, one can envision using scientific data from the literature to modify the default sub-factors with compound-specific adjustment factors (AFs) and to create new and more scientifically based defaults. In this paper, data from published clinical trials on six pharmaceutical compounds were used to further illustrate how to calculate and interpret data-derived AFs. The clinical trial data were analyzed for content and the reported mean and standard deviation values for two key PK parameters, area under the curve of blood concentration by time (AUC) and peak plasma concentration (C_max), were evaluated. The mean PK values for each study were subsequently analyzed for variability within the population (unimodal distributions) and for the presence of potentially susceptible sub-populations (bimodal distributions). A method based on the proportion of the population covered was applied and data-derived AFs were calculated for these six compounds. Our results showed that, of the 15 possible data-derived AFs calculated using unimodal and bimodal distributions, only three exceeded a value of 3.2. This study further illustrates the value of calculating data-derived values when sufficient PK data are available.     

Efficiency of ultrafiltration/diafiltration in removing organic and elemental process equipment related leachables from biological therapeutics

In the production of biological therapeutics such as monoclonal antibodies (mAbs), ultrafiltration and diafiltration (UF/DF) are widely regarded as effective downstream processing steps capable of removing process equipment related leachables (PERLs) introduced upstream of the UF/DF step. However, clearance data available in the literature are limited to species with low partition coefficients (log P) such as buffer ions, hydrophilic organic compounds, and some metal ions. Additional data for a wide range of PERLs including hydrophobic compounds and elemental impurities are needed to establish meaningful, comprehensive safety risk assessments. Herein, we report the results from studies investigating the clearance of seven different organic PERLs representing a wide range of characteristics (i.e., log P (−0.3 to 18)), and four model elements with different chemical properties spiked into a mAb formulation at 10 ppm and analyzed during clearance using gas chromatography–mass spectrometry (GC–MS), liquid chromatography-photodiode-array-mass spectrometry (LC-PDA-MS), and inductively coupled plasma mass spectrometry (ICP-MS). The clearance data showed ideal clearance and sieving of spiked organic PERLs with log P < 4, partial clearance of PERLs with 4 < log P < 9, and poor clearance of highly hydrophobic PERLs (log P > 9) after nine diafiltration volumes (DVs). Supplemental clearance studies on seven additional PERLs present at much lower concentration levels (0.1–1.5 ppm) in the mAb formulation upstream of UF/DF and three PERLs associated with the tangential flow filtration (TFF) equipment also demonstrated the similar correlations between log P and % clearance. For model elements, the findings suggest that UF/DF in general provides ideal clearance for elements. Evidence showed that the UF/DF process does not only help mitigate leachables risk from PERLs introduced upstream of UF/DF, but also from the TFF operation itself as all three TFF-related PERLs were effectively cleared. Overall, the UF/DF clearance presented in this work demonstrated whereas highly hydrophobic PERLs and elements that exist as charged species, particularly transition metal ions, may not be as effectively cleared and thus warrant further risk assessment; hydrophilic and some hydrophobic PERLs (log P < 4) are indeed well-cleared and thus present a lower overall safety risk.