The discussion here is divided into three parts. First there is a generic introduction to variability and uncertainty and a discussion of some underappreciated features of these concepts that have ...nontrivial implications for structuring risk analyses. Next are some suggestions for a way forward to build a better quantitative understanding of relevant variability and uncertainty. The process involves building databases of putative analogous cases to represent the concerns that are now reflected in the various point-estimate "uncertainty factors" or "adjustment factors" in the formulas used to derive current reference doses and reference concentrations (RfDs and RfCs). The use of such databases is illustrated with some limited selections from our own databases where some preliminary comparisons between child and adult population variability in activity and respiratory response parameters are possible. A final section reflects on the current evolution of practice in estimating variability in risk assessments.
Glutathione transferases (GST) catalyze the conjugation of glutathione (GSH) with electrophiles, many of which may otherwise interact with protein or DNA. In select cases such as halogenated ...solvents, GST-mediated conjugation may lead to a more toxic or mutagenic metabolite. Polymorphisms that exert substantial effects on GST function were noted in human populations for several isozymes. This analysis focuses on three well-characterized isozymes, GSTM1, T1, and P1, in which polymorphisms were extensively studied with respect to DNA adducts and cancer in molecular epidemiologic studies. The current review and analysis focused upon how polymorphisms in these GST contributed to population variability in GST function. The first step in developing this review was to characterize the influence of genotype on phenotype (enzyme function) and the frequency of the polymorphisms across major population groups for all three GST. This information was then incorporated into Monte Carlo simulations to develop population distributions of enzyme function. These simulations were run separately for GSTM1, T1, and P1, and also for the combination of these isozymes, to assess the possibility of overlapping substrate specificity. Monte Carlo simulations indicated large interindividual variability for GSTM1 and T1 due to the presence of the null (zero activity) genotype, which is common in all populations studied. Even for GSTM1 or T1 non-null individuals, there was considerable interindividual variability with a bimodal distribution of enzyme activity evident. GSTP1 polymorphisms are associated with somewhat less variability due to the absence of null genotypes. However, in all cases simulated, the estimated variability is sufficiently large to warrant consideration of GST function distributions in assessments involving GST-mediated activation or detoxification of xenobiotics. Ideally, such assessments would involve physiologically based toxicokinetic (PBTK) modeling to assess population variability in internal dose.
N-Acetyltransferases (NAT) are key enzymes in the conjugation of certain drugs and other xenobiotics with an arylamine structure. Polymorphisms in NAT2 have long been recognized to modulate toxicity ...produced by the anti-tubercular drug isoniazid, with molecular epidemiologic studies suggesting a link between acetylator phenotype and increased risk for bladder cancer. Recent evidence indicates that the other major NAT isozyme, NAT1, is also polymorphic. The current analysis characterizes the main polymorphisms in both NAT2 and NAT1 in terms of their effect on enzyme activity and frequency in the population. Multiple NAT2 alleles (NAT2*5, *6, *7, and *14) have substantially decreased acetylation activity and are common in Caucasians and populations of African descent. In these groups, most individuals carry at least one copy of a slow acetylator allele, and less than 10% are homozygous for the wild type (fast acetylator) trait. Incorporation of these data into a Monte Carlo modeling framework led to a population distribution of NAT2 activity that was bimodal and associated with considerable variability in each population assessed. The ratio of the median to the first percentile of NAT2 activity ranged from 7 in Caucasians to 18 in the Chinese population. This variability indicates the need for more quantitative approaches (e.g., physiologically based pharmacokinetic PBPK modeling) to assess the full distribution of internal dose and adverse responses to aromatic amines and other NAT2 substrates. Polymorphisms in NAT1 are generally associated with relatively minor effects on acetylation function, with Monte Carlo analysis indicating less interindividual variability than seen in NAT2 analysis.
Children's risks can differ from those in adults for numerous reasons, one being differences in the pharmacokinetic handling of chemicals. Immature metabolism and a variety of other factors in ...neonates can affect chemical disposition and clearance. These factors can be incorporated into physiologically based pharmacokinetic (PBPK) models that simulate the fate of environmental toxicants in both children and adults. PBPK models are most informative when supported by empirical data, but typically pediatric pharmacokinetic data for toxicants are not available. In contrast, pharmacokinetic data in children are readily available for therapeutic drugs. The current analysis utilizes data for caffeine and theophylline, closely related xanthines that are both cytochrome P-450 (CYP) 1A2 substrates, in developing PBPK models for neonates and adults. Model development involved scale-up of in vitro metabolic parameters to whole liver and adjusting metabolic function for the ontological pattern of CYP1A2 and other CYPs. Model runs were able to simulate the large differences in half-life and clearance between neonates and adults. Further, the models were able to reproduce the faster metabolic clearance of theophylline relative to caffeine in neonates. This differential between xanthines was found to be due primarily to an extra metabolic pathway available to theophylline, back-methylation to caffeine, that is not available to caffeine itself. This pathway is not observed in adults exemplifying the importance of secondary or novel routes of metabolism in the immature liver. Greater CYP2E1 metabolism of theophylline relative to caffeine in neonates also occurs. Neonatal PBPK models developed for these drugs may be adapted to other CYP1A2 substrates (e.g., arylamine toxicants). A stepwise approach for modeling environmental toxicants in children is proposed.
Early-life exposure to agents that modulate neurologic function can have long-lasting effects well into the geriatric period. Many other factors can affect neurologic function and susceptibility to ...neurotoxicants in elderly individuals. In this review we highlight pharmacokinetic and pharmacodynamic factors that may increase geriatric susceptibility to these agents. There is a decreasing trend in hepatic metabolizing capacity with advancing years that can affect the ability to clear therapeutic drugs and environmental chemicals. This factor combined with decreased renal clearance causes prolonged retention of numerous drugs in elderly individuals. A geriatric pharmacokinetic database was developed to analyze changes in drug clearance with advancing age. This analysis shows that the half-life of drugs processed by hepatic cytochrome P450 enzymes or via renal elimination is typically 50-75% longer in those older than 65 than in young adults. Liver and kidney diseases are more common in elderly individuals and can further decrease the clearance function of these organs. Polypharmacy, the administration of numerous drugs to a single patient, is very common in elderly individuals and increases the risks for drug interaction and side effects. With advancing age the nervous system undergoes a variety of changes, including neuronal loss, altered neurotransmitter and receptor levels, and decreased adaptability to changes induced by xenobiotics. These changes in the central nervous system can make elderly individuals more susceptible to neurologic dysfunction when confronted with single pharmacologic agents, polypharmacy, or environmental toxicants. The many factors that affect elderly responses to neuroactive agents make environmental risk assessment for this age group a special concern and present a unique challenge.
Pharmacokinetics (PK) of xenobiotics can differ widely between children and adults due to physiological differences and the immaturity of enzyme systems and clearance mechanisms. This makes ...extrapolation of adult dosimetry estimates to children uncertain, especially at early postnatal ages. While there is very little PK data for environmental toxicants in children, there is a wealth of such data for therapeutic drugs. Using published literature, a Children's PK Database has been compiled which compares PK parameters between children and adults for 45 drugs. This has enabled comparison of child and adult PK function across a number of cytochrome P450 (CYP) pathways, as well as certain Phase II conjugation reactions and renal elimination. These comparisons indicate that premature and full-term neonates tend to have 3 to 9 times longer half-life than adults for the drugs included in the database. This difference disappears by 2–6 months of age. Beyond this age, half-life can be shorter than in adults for specific drugs and pathways. The range of neonate/adult half-life ratios exceeds the 3.16-fold factor commonly ascribed to interindividual PK variability. Thus, this uncertainty factor may not be adequate for certain chemicals in the early postnatal period. The current findings present a PK developmental profile that is relevant to environmental toxicants metabolized and cleared by the pathways represented in the current database. The manner in which this PK information can be applied to the risk assessment of children includes several different approaches: qualitative (e.g., enhanced discussion of uncertainties), semiquantitative (age group-specific adjustment factors), and quantitative (estimation of internal dosimetry in children via physiologically based PK modeling).
Perceived needs for extensive chemical-specific toxicological information have impeded efforts to assess risks
and evaluate likely public health protection benefits of possible standards for ...hazardous air pollutants (HAPs). This paper
discusses opportunities to use effects of HAPs on early effect biomarkers, such as birth weights, to predict likely changes
in rare quantal effects of concern that would be relevant for the quantification of likely regulatory benefits from exposure
reductions. In the birth weight example, even modest exposures to common air pollutants can be seen as producing a kind
of tax on the limited resources available to the fetus to grow and develop. In contrast to teratogenic effects, dose response
relationships for fetal growth restriction in animals are often nearly linear, suggesting that the developing fetus may not
generally have untapped ”functional reserve capacity“ that is expected to buffer the effects of modest exposures to
toxicants in the traditional toxicological paradigm. Given this mechanistic perspective, supported in part by parallel dose
response relationships between reported cigarette smoking and both birth weight and infant mortality, restriction on fetal
growth can be associated with changes in quantal end effects of concern that are more difficult to assess directly in
epidemiological studies.
Perceived needs for extensive chemical-specific toxicological information have impeded efforts to assess risks and evaluate likely public health protection benefits of possible standards for ...hazardous air pollutants (HAPs). This paper discusses opportunities to use effects of HAPs on early effect biomarkers, such as birth weights, to predict likely changes in rare quantal effects of concern that would be relevant for the quantification of likely regulatory benefits from exposure reductions. In the birth weight example, even modest exposures to common air pollutants can be seen as producing a kind of tax on the limited resources available to the fetus to grow and develop. In contrast to teratogenic effects, dose response relationships for fetal growth restriction in animals are often nearly linear, suggesting that the developing fetus may not generally have untapped "functional reserve capacity" that is expected to buffer the effects of modest exposures to toxicants in the traditional toxicological paradigm. Given this mechanistic perspective, supported in part by parallel dose response relationships between reported cigarette smoking and both birth weight and infant mortality, restriction on fetal growth can be associated with changes in quantal end effects of concern that are more difficult to assess directly in epidemiological studies.
Pharmacology and toxicology share a common interest in pharmacokinetic data, especially as it is available in pediatric populations. These data have been critical to the clinical pharmacologist for ...many years in designing age-specific dosing regimens. Now they are being used increasingly by toxicologists to understand the ontogeny of physiologic parameters that may affect the metabolism and clearance of environmental toxicants. This article reviews a wide range of physiologic and metabolic factors that are present in utero and in early postnatal life and that can affect the internal dose of an absorbed chemical and its metabolites. It also presents a child/adult pharmacokinetic database that includes data for 45 therapeutic drugs organized into specific children's age groupings and clearance pathways. Analysis of these data suggests that substantial child/adult differences in metabolism and clearance are likely for a variety of drugs and environmental chemicals in the early postnatal period. These results are also relevant to in utero exposures, where metabolic systems are even more immature, but exposures are greatly modified by the maternal system and placental metabolism. The implications of these child/adult differences for assessing children's risks from environmental toxicants is discussed with special focus on physiologically based pharmacokinetic modeling strategies that could simulate children's abilities to metabolize and eliminate chemicals at various developmental stages.
Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish ...DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option.
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