Harvey J. Clewell

Review and evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry.

In standard risk assessment methods for carcinogenic or noncarcinogenic chemicals, quantitative methods for evaluating interindividual variability are not explicitly considered. These differences are currently considered by the use of statistical confidence limits or default uncertainty factors. This investigation consisted of multiple tasks aimed at making quantitative predictions of interindividual differences in susceptibility by using physiologically based pharmacokinetic (PBPK) models. Initially, a systematic, comprehensive review of the literature was conducted to identify any quantitative information related to gender- or age-specific physiological and biochemical factors that could influence susceptibility to chemical exposure. These data were then organized from a pharmacokinetic perspective by process and by chemical class to identify key factors likely to have a significant impact on susceptibility as it relates to internal target tissue dose. Overall, a large number of age- and gender-specific quantitative differences in pharmacokinetic parameters were identified. The majority of these differences were identified between neonates/children and adults, with fewer differences identified between young adults and the elderly. The next phase of this work consists of using PBPK models to develop examples of approaches through the development of case studies. The goal of the case studies is to continue to develop a methodology that incorporates PBPK modeling to assess the likelihood that a chemical or class of chemicals may present an age- or gender-specific risk. The case studies should also demonstrate practical methods for quantitatively incorporating information on age- and gender-specific pharmacokinetic differences in risk assessments for chemicals.

Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model

Vinyl chloride (VC) is a trans-species carcinogen, producing tumors in a variety of tissues, from both inhalation and oral exposures, across a number of species. In particular, exposure to VC has been associated with a rare tumor, liver angiosarcoma, in a large number of studies in mice, rats, and humans. The mode of action for the carcinogenicity of VC appears to be a relatively straightforward example of DNA adduct formation by a reactive metabolite, leading to mutation, mistranscription, and neoplasia. The objective of the present analysis was to investigate the comparative potency of a classic genotoxic carcinogen across species, by performing a quantitative comparison of the carcinogenic potency of VC using data from inhalation and oral rodent bioassays as well as from human epidemiological studies. A physiologically-based pharmacokinetic (PBPK) model for VC was developed to support the target tissue dosimetry for the cancer risk assessment. Unlike previous models, the initial metabolism of VC was described as occurring via two saturable pathways, one representing low capacity-high affinity oxidation by CYP2E1 and the other (in the rodent) representing higher capacity-lower affinity oxidation by other isozymes of P450, producing in both cases chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) as intermediate reactive products. Depletion of glutathione by reaction with CEO and CAA was also described. Animal-based risk estimates for human inhalation exposure to VC using total metabolism estimates from the PBPK model were consistent with risk estimates based on human epidemiological data, and were lower than those currently used in environmental decision-making by a factor of 80.

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 days 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.

Improving Risk Assessment: Research Opportunities in Dose Response Modeling to Improve Risk Assessment

Substantial improvements in dose response modeling for risk assessment may result from recent and continuing advances in biological research, biochemical techniques, biostatistical/mathematical methods and computational power. This report provides a ranked set of recommendations for proposed research to advance the state of the art in dose response modeling. The report is the result of a meeting of invited workgroup participants charged with identifying five areas of research in dose response modeling that could be incorporated in a national agenda to improve risk assessment methods. Leading topics of emphasis are interindividual variability, injury risk assessment modeling, and procedures to incorporate distributional methods and mechanistic considerations into now-standard methods of deriving a reference dose (RfD), reference concentration (RfC), minimum risk level (MRL) or similar dose-response parameter estimates.

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.

Under What Conditions Is Trichloroethylene Likely To Be a Carcinogen in Humans

This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or use recommendation. Exposures to trichloroethylene (TCE) induce several types of cancer in experimental animals. TCE is metabolized in the body to multiple compounds, several of which are carcinogenic at relatively high doses in rodents. Risk assessments can be pursued with any one of the animal cancer endpoints after consideration of their relevance for humans exposed at low environmental concentrations. Among the TCE metabolites, dichloroacetic acid (DCA), trichloroacetic acid (TCA), chloral hydrate (CHL), and 1,2-dichlorovinylcysteine (DCVC) are each considered carcinogenic in rodents. Two of these, DCA and CHL, are used therapeutically in humans, while a third, TCA, has metabolic effects similar to compounds used therapeutically in humans to reduce lipid concentrations in blood. Each of these three compounds produces biological responses that are expected in humans. However, these biological responses, although they serve as precursors for tumor formation in rodents, are not expected to lead to tumors in humans at any environmentally relevant exposure situations. 1,2-DCVC, formed by a minor pathway of TCE metabolism, is further metabolized in kidney to a reactive thioketene. Of the observed animal carcinogenic responses, only the kidney tumors from the DCVC pathway are considered relevant as predictors of human cancer. Factors that increase TCE metabolism to glutathione conjugates or predispose humans to kidney damage should increase risks posed to workers from high-concentration exposures to TCE. Based on our knowledge of the cytotoxic and mutagenic modes of action expected for these active metabolite (s), a nonlinear cancer risk assessment approach is recommended to be used with the kidney tumor data to assess the human risks of TCE.

Improving the Development and Use of Biologically Based Dose Response Models (BBDR) in Risk Assessment

Biologically based dose-response (BBDR) models predict health outcomes (response) resulting from the presence of a toxicant at a biological target (dose). The benefits of BBDR models are many, and research programs are increasingly focusing on mechanistic research to support model development; however, progress has been slow. Impediments to progress include the complexity of dose response modeling, the need for a multidisciplinary team and consistent funding support, and difficulty in identifying and extracting the needed data. Of immediate concern is the lack of transparency of published models to the supporting data and literature, difficulty in accessing model code and simulation conditions sufficient to allow independent replication of results, and absence of well-defined quality criteria. Suggestions are presented to improve the development and use of BBDR models in risk assessment and to address the above limitations. Examples from BBDR models for methylmercury neurotoxicity and 5-fluorouracil embryotoxicity are presented to illustrate the suggestions including what kinds of databases are needed to support model development and transparency, quality assurance for modeling, and how the internet can advance database development and collaboration within the biological modeling community.

Mode of Action Studies for Assessing Carcinogenic Risks Posed by Inorganic Arsenic

Publisher Summary Mode of action (MOA) is emphasized as a unifying concept in the new U.S. environmental protection agency carcinogen risk assessment guidelines. Optimally, MOA hypotheses relate carcinogenicity to obligatory precursor effects, link cancer and non-cancer responses through common pathways, and predict dose–response relationships via biologically based dose-response (BBDR) models. Inorganic arsenic (Asi) increases skin lesions cardiovascular disease, and several types of cancers in humans. The MOA or MOAs for Asi toxicity/carcinogenicity is poorly understood. Multiple effects may be idiosyncratic, each with a distinct MOA. Alternatively, only a limited number of precursor steps may be involved in all tissues. This chapter outlines the proposed MOAs of Asi carcinogenesis—impaired DNA repair, altered DNA methylation, increased growth factor synthesis, and increased oxidative stress. Increasingly, MOA hypotheses are suggesting that concentrations of critical gene products, including growth factors, redox-sensitive proteins, and DNA repair/DNA methylating enzymes, may be altered by Asi. These alterations would enhance tumor promotion or progression. A potential MOA for Asi acting as a late-stage tumor progressor is evaluated in relation to specific data needs for an Asi risk assessment and to the development of a BBDR model for Asi-induced internal tumors in humans. MOA studies of transcriptional processes, measurements of Asi dosimetry in humans, and dose–response evaluations for precursor endpoints appear important for supporting public health decisions about the risks posed by human Asi exposures. Studies of the transcriptional/posttranslational activities of arsenite and metabolites are likely to prove especially valuable for both cancer and non-cancer risk assessments.

Physiologically Based Pharmacokinetic Modeling: A Tool for Understanding ADMET Properties and Extrapolating to Human

Physiologically based pharmacokinetic (PBPK) models differ from classical PK models in that they include specific compartments for tissues involved in exposure, toxicity, biotransforma‐ tion and clearance processes connected by blood flow (Figure 1). Compartments and blood flows are described using physiologically meaningful parameters, which allows for interspe‐ cies extrapolation by altering the physiological parameters appropriately [1]. A key benefit to PBPK models is that factors influencing the absorption, distribution, metabolism, and elimi‐ nation of a compound can be incorporated into a PBPK model in a mechanistic, meaningful way, if a mechanism is understood and sufficient data are available. This mechanistic aspect is supported by physiological parameters influencing absorption (e.g., pH values and transit times through various sections of the GI tract), distribution (e.g., tissue volumes and compo‐ sition), metabolism (e.g., expression levels of various hepatic enzymes and transporters involved with metabolic elimination), and elimination (e.g., glomerular filtration rate and expression levels of transporters in the kidneys involved with renal elimination), which can be explicitly incorporated in the PBPK model.

Application of the Risk Assessment Approaches in the USEPA Proposed Cancer Guidelines to Inorganic Arsenic

Publisher Summary There is convincing evidence from a number of epidemiological studies that exposure to inorganic arsenic (Asi) in air or in drinking water has been associated with an increased incidence of cancer in exposed populations. However, there is less agreement on two critical risk assessment issues: quantification of the dose-response for these exposed populations, especially in the low-dose region and extrapolation of that dose-response relationship to current exposures of the public in air and drinking water. Recent evaluations of the biological basis for Asi carcinogenicity have suggested that the mode of action is nonlinear and may even have an effective threshold. Therefore, under the new USEPA proposed cancer guidelines, inorganic As might better be evaluated using the margin of exposure (MOE) approach rather than linear extrapolation as is now used. The purpose of this investigation was to explore the application of the MOE approach to Asi using epidemiological data for both oral and inhalation routes of exposure. Unfortunately, while qualitative data support a nonlinear mode of action for the carcinogenicity of Asi, quantitative data are inadequate to support a determination of the exposure levels at which nonlinearity might occur. On the basis of benchmark analyses of recently published epidemiological data, it would appear that the risk of cancer from lifetime consumption of Asi in drinking water at the current maximum contaminant level (MCL) might be significant. In contrast, current environmental As inhalation exposures appear unlikely to entail significant risks of cancer.