Boron tolerable intake

Boron, which is ubiquitous in the environment, causes developmental and reproductive effects in experimental animals. This observation has led to efforts to establish a Tolerable Intake value for boron. Although risk assessors agree on the use of fetal weight decreases observed in rats as an appropriate critical effect, consensus on the adequacy of toxicokinetic data as a basis for replacement of default uncertainty factors remains to be reached. A critical analysis of the existing data on boron toxicokinetics was conducted to clarify the appropriateness of replacing default uncertainty factors (10-fold for interspecies differences and 10-fold for intraspecies differences) with data-derived values. The default uncertainty factor for variability in response from animals to humans of 10-fold (default values of 4-fold for kinetics and 2.5-fold for dynamics) was recommended, since clearance of boron is 3-to 4-fold higher in rats than in humans and data on dynamic differences—in order to modify the default value—are unavailable. A data-derived adjustment of 6-fold (1.8 for kinetics and 3.1 for dynamics) rather than the default uncertainty factor of 10-fold was considered appropriate for intrahuman variability, based on variability in glomerular filtration rate during pregnancy in humans and the lack of available data on dynamic differences. Additional studies to investigate the toxicokinetics of boron in rats would be useful to provide a stronger basis for replacement of default uncertainty factors for interspecies variation.     

Scientific basis for uncertainty factors used to establish occupational exposure limits for pharmaceutical active ingredients

The traditional “safety factor”; method has been used for years to establish occupational exposure limits (OELs) for active ingredients used in drugs. In the past, a single safety factor was used to address all sources of uncertainty in the limit setting process. The traditional 100‐fold safety factor commonly used to derive an acceptable daily intake value incorporates a default factor of 10 each to account for interindividual variability and interspecies extrapolation. Use of these defaults can lead to overly conservative health‐based limits, especially when they are combined with other (up to 10‐fold) factors to adjust for inadequacies in the available database. In recent years, attempts have been made to quantitate individual sources of uncertainty and variability to improve the scientific basis for OELs. In this paper we discuss the science supporting reductions in the traditional default uncertainty factors. A number of workplace‐specific factors also support reductions in these factors. Recently proposed alternative methodologies provide a framework to make maximum use of preclinical and clinical information, e.g., toxicokinetic and toxicodynamic data, to reduce uncertainties when establishing OELs for pharmaceutical active ingredients.     

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.     

Transient coordinated activity within the developing brain��s default network

The concept of a brain default network postulates that specific brain regions are more active when a person is engaged in introspective mental activity. Transient functional coordination between groups of neurons is thought to be necessary for information processing. Since children develop introspection as they mature, regions of the default network may establish increasing functional coordination with age, resulting in fewer fluctuations in synchronization patterns. We investigated the transient coordinated activity in regions of the default network in seventeen children aged 11 months to 17 years of age using EEG recordings while subjects were resting quietly with eyes closed. The temporal and spatial fluctuations in the phase synchrony patterns were estimated across sites associated with the default network pattern and compared to other regions. Lower variability of the spatio-temporal patterns of phase synchronization associated with the default network was observed in the older group as compared to the younger group. This indicates that functional coordination increases among regions of the default network as children develop.     

Relevance of the 10X Uncertainty Factor to the Risk Assessment of Drugs Used by Children and Geriatrics

Conventional risk assessment practices utilize a tenfold uncertainty factor (UF) to extrapolate from the general human population to sensitive subgroups, such as children and geriatrics. This study evaluated whether the tenfold UF can be reduced when pharmacokinetic and pharmacodynamic data for pharmaceuticals used by children and geriatrics are incorporated into the risk assessment for human sensitivity. Composite factors (kinetics X dynamics) were calculated from data-derived values for bumetanide, furosemide, metoprolol, atenolol, naproxen, and ibuprofen. For the compounds examined, all of the composite factors were lower than 10. Furthermore, 8 of the 12 composite factors were less than 5.5. Incorporation of human kinetic and dynamic data into risk assessment can aid in reducing the uncertainties associated with sensitive subgroups and further study is encouraged.     

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.     

An Objective Uncertainty Factor Adjustment for Methyl mercury Pharmacokinetic Variability

While default uncertainty factor (UF) adjustments have been proposed for pharmacokinetic variability in the derivation of Reference Doses (RfDs), few attempts have been made to derive chemical-specific UFs for such variability. In recent epidemiologic data on the neuro-developmental effects of MeHg, Hg concentration in either hair or blood is the point-of-departure for RfD derivation. The application of a pharmacokinetic model to derive an intake dose from the measured biomarker concentration allows examination of the inter-individual variability in the relationship between intake dose and biomarker concentration through specification of the variability in model parameters. Three independent studies of this variability, using different models and/or different parameter values, are compared. While differences in central tendency estimates give different predictions of the intake dose corresponding to a given biomarker concentration, normalization of the central tendency estimate resulted in strong agreement among the studies. Starting with Hg concentration in hair or blood, and dividing a central tendency estimate of the corresponding intake dose by a UF of 2 to 3, accounts for 95 to 99% of the variability in the relationship between intake dose and biomarker concentration. This variability, however, encompasses only a portion of the maternal ingestion-to-fetal brain pathway. It is therefore likely that this UF underestimates the overall pharmacokinetic variability in this pathway.     

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.     

Pathway-Related Factors: The Potential for Human Data to Improve the Scientific Basis of Risk Assessment

The default uncertainty factors used for risk assessment are applied either to allow for different aspects of extrapolation of the dose-response curve or to allow for database deficiencies. Replacement of toxicokinetic or toxicodynamics defaults by chemical-specific data allows the calculation of a chemical-specific “data-derived factor”, which is the product of chemical-specific values and default uncertainty factors. Such chemical-specific composite values will improve the scientific basis of the risk assessment of that chemical, but the necessary chemical-specific data are rarely available. Categorical defaults related to pathways of elimination and mechanisms of toxicity could be used when the overall fate or mechanism is known, but there are no chemical-specific data sufficient to allow replacement of the default, and the development of an overall data-derived factor. The development of pathway-related categorical defaults is being undertaken using data on selected probe substrates for which adequate data are available. The concept and difficulties of this approach are illustrated using data for CYP1A2.     

Case Studies of Categorical Data-Derived Adjustment Factors

Investigations were performed on representative compounds from five different therapeutic classes to evaluate the use of categorical data-derived adjustment factors to account for interindividual variability. The five classes included antidepressants, angiotensin converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDS), cholesterol lowering agents, and antibiotics. Each of the case studies summarized the mode of action of the class responsible for both the therapeutic and adverse effects and the key pharmacodynamic (PD) and pharmacokinetic (PK) parameters that determine the likelihood of these responses for individual compounds in the class. For each class, an attempt was made to identify the key factors that determine interindividual variability and whether there was a common basis to establish a categorical default adjustment factor that could be applied across the class (or at least across specific subclasses within the class). Linking the PK and PD parameters to the critical endpoint used to establish a safe level of exposure was an important underlying theme throughout the investigations. Despite the wealth of PK and PD information in the published literature on the surrogate compounds representing these classes, it was difficult to derive a categorical adjustment factor that could be applied broadly within each class. The amount of information available may have hindered rather than helped the evaluations. Derivation of categorical defaults for different classes of “common” chemicals may be more straightforward if sufficient data are available. In a few cases (e.g., tricyclic antibiotics, ACE inhibitors and selected antiinflammatory agents) categorical defaults could be proposed, although it is unclear whether the reduction in uncertainty resulting from their application would be offset by the additional uncertainties that may have resulted from their application. Residual uncertainties may remain depending on the level of confidence in the underlying assumptions used to support the categorical defaults. Regardless of the conclusions on the utility of categorical defaults, these investigations provided further support for the use of data-derived adjustment factors on a compound-specific basis.     

Differential Sensitivity of Children and Adults to Chemical Toxicity

Children, particularly neonates, can be biologically more sensitive to the same toxicant on a body weight basis than adults. Current understanding of the rates of maturation of metabolism and evidence from case studies indicate that human infants up to 6 months of age typically lack the capacity to detoxify and eliminate substances as readily as adults. For most chemicals, the infant physiologic systems usually produce higher blood levels for longer periods. The newborn's metabolic capacity rapidly matures and, by 6 months of age, children are usually not more sensitive than adults based on their pharmacokinetic competence. Whether children are at greater risk from chemical exposures is another question. Drawing conclusions about the ability of the U.S. Environmental Protection Agency's intraspecies (UF_H) and database (UF_D) uncertainty factors to protect children on the basis of the modest data available is challenging. However, virtually all studies available suggest that a high percentage of the population, including children, is protected by using a 10-fold UF_H or by using a 3.16-fold factor each for toxicokinetic and toxicodynamic variability. Based on specific comparisons for newborns, infants, children, adults and those with severe disease, the population protected is between 60% and 100%, with the studies in larger populations that include sensitive individuals suggesting that the value is closer to 100%. UF_D is likewise protective when used with databases that are missing substantive studies.     

Subdivision of Uncertainty Factors to Allow for Toxicokinetics and Toxicodynamics

Tenfold uncertainty factors have been used in risk assessment for about 40 years to allow for species differences and inter-individual variability. Each factor has to allow for toxicokinetic and toxicodynamic differences. Subdividing the 10-fold factors into kinetic and dynamic defaults, which when multiplied give a product of 10, offers a number of advantages. A major advantage is that chemical-specific data can be introduced to replace one or more of the default subfactors, hence contributing to a chemical-related overall factor. Subdivision of the 10-fold factors also facilitates analysis of the appropriateness of the overall 10-fold defaults, and the development of a more refined approach to the use of uncertainty factors.     

Hollow-fiber ultrafiltration for simultaneous recovery of viruses, bacteria and parasites from reclaimed water

Hollow-fiber ultrafiltration (UF) is a technique that has been reported to be effective for recovering a diverse array of microbes from water, and may also be potentially useful for microbial monitoring of effluent from water reclamation facilities. However, few data are available to indicate the potential limitations and efficacy of the UF technique for treated wastewater. In this study, recovery efficiencies were determined for various options available for performing the tangential-flow UF technique, including hollow-fiber ultrafilter (i.e., dialyzer) type, ultrafilter pre-treatment (i.e., blocking), and elution. MS2 and ΦX174 bacteriophages, Clostridium perfringens spores, Escherichia coli, and Cryptosporidium parvum oocysts were seeded into 10-L reclaimed water samples to evaluate UF options. Then a single UF protocol was established and studied using seeded and non-seeded 100-L samples from two water reclamation facilities in Georgia, USA. Baxter Exeltra Plus 210 and Fresenius F200NR dialyzers were found to provide significantly higher microbial recovery than Minntech HPH 1400 hemoconcentrators. The selected final UF method incorporated use of a non-blocked ultrafilter for UF followed by elution using a surfactant-based solution. For 10-L samples, this method achieved recovery efficiencies of greater than 50% recovery of seeded viruses, bacteria, and parasites. There was no significant difference in overall microbial recovery efficiency when the method was applied to 10- and 100-L samples. In addition, detection levels for pathogens in seeded 100-L reclaimed water samples were 1000 PFU HAV, 10,000 GI norovirus particles, < 500 Salmonella and < 200 Cryptosporidium oocysts. These data demonstrate that UF can be an effective technique for recovering diverse microbes in reclaimed water to monitor and improve effluent water quality in wastewater treatment plants.     

Uncertainty/Safety Factors in Health Risk Assessment: Opportunities for Improvement

This paper presents the results of deliberations from participants who met on the second day of the Fourth Annual Workshop on the Evaluation of Uncertainty/Safety Factors in Health Risk Assessment. The group reviewed the previous day's presentations and implications for improvement in risk assessment. After much discussion, the group concluded that, in the short term, significant improvements could be made in the pharmacokinetic component of the inter-species uncertainty factor and developed a series of default options for this factor. These defaults consider route of exposure (oral or inhalation), and the form of the active compound (parent, metabolite, or very reactive metabolite). Several assumptions are key to this approach, such as a similar oral or inhalation bioavailability across species. We believe this method represents a useful default approach until more compound-specific information is available.     

Rationale for the Chemical-Specific Adjustment Factors Used to Derive an Occupational Exposure Limit for Timolol Maleate

Timolol maleate is a non-selective beta-adrenergic blocking agent currently used primarily to reduce intraocular pressure in the treatment of glaucoma. It also produces effects on the heart and bronchial smooth muscle and all of these effects are of potential concern in workers handling this active pharmaceutical ingredient. The disposition of timolol maleate is influenced by a polymorphism in oxidative metabolism by CYP2D6 and two distinct phenotypes have been identified (i.e., poor and extensive metabolizers). These properties of timolol maleate provided an opportunity to use the compound as a case study to demonstrate the derivation of chemical-specific adjustment factors for pharmacokinetics and pharmacodynamics to replace the default uncertainty factor for interindividual variability. Overall, the available data on the pharmacodynamic endpoints showed very little variability and most pharmacokinetic studies failed to discern significant differences in relatively small groups of healthy volunteers or patients. Reports of bradycardia and bronchoconstriction in patients receiving therapeutic doses are relatively rare. In one study, there was a significant reduction in heart rate 24 hours post-dose that was associated with elevated area under the curve (AUC) values. A chemical-specific adjustment factor (CSAF) for kinetics of 9.8 based on these AUC data was combined with a CSAF for dynamics of 1.2 and applied to the extrapolated no-effect level for clinically significant cardiovascular effects (with correction for oral bioavailability) to establish an occupational exposure limit (OEL) for timolol maleate which is expected to be protective of workers that may be poor metabolizers or asthmatics.     

Inter- and Intra-Species Extrapolation in Risk Assessment of Different Classes of Pesticides

Risk assessors routinely use the reference dose (RfD) approach for non-cancer risk assessment. In this approach, No-Observed-Adverse-Effect-Level (NOAEL) is divided by the product of uncertainty factors (UFs) and, occasionally, an additional modifying factor (MF), each usually employed by default as factors of 10. In the present investigation, kinetic and dynamic data have been used in order to reduce uncertainties when establishing exposure guidelines for examples of chemicals representing four classes of pesticides (warfarin, lindane, carbaryl and parathion). An intensive search of databases was conducted for these pesticides, and toxicokinetic and toxicodynamic parameters in inter- and intra-species were evaluated. The kinetic and dynamic subfactors were less than the proposed values of Renwick and the International Programme on Chemical Safety (IPCS). The composite factors for all the examined pesticides were less than 100. The present study indicated that in setting exposure levels it is important to incorporate kinetic and dynamic data, as they become available, rather than rely on default uncertainty factors, which are imprecise in many cases.     

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.     

Evaluating the Evidence for Hormesis: A Statistical Perspective

It is possible to account for hormesis under current regulatory guidelines by invoking criteria for departure from default risk assessment procedures. However, past experience suggests that it will be difficult to amass enough evidence for hormesis in an individual case to permit departure from default procedures. Accordingly, hormesis is likely to be important in agency risk assessments only if guidelines are modified to incorporate hormesis as a default assumption. This could be appropriate if hormesis is determined to be a universal or near-universal phenomenon. Although there is ample evidence that hormesis occurs in many specific situations, the overall prevalence of hormesis is very difficult to evaluate based on currently available data. The lack of a valid statistical test for hormesis is a major limitation when evaluating evidence for hormesis. The attempts at estimating the prevalence of hormesis reviewed herein did not adequately control for false positives and/or may have had inadequate power to detect hormesis. Some suggestions are made for constructing a database and analyzing the data therein that would provide more readily interpretable information on the prevalence of hormesis.     

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.