A cancer risk assessment for saccharin

The results from a recently completed large experiment with rats exposed to saccharin show that the dose-response function is much steeper than was previously assumed. Based on this observed steepness, any implied cancer risk at the low doses of interest to man is very small.     

A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients

AIMS: This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation. An enzyme turn-over model was also developed to study the time course of cyclophosphamide induction. METHODS: Fourteen patients received a combination of CP (6 g m-2 ), thiotepum (500 mg m-2 ) and carboplatin (800 mg m-2 ) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data using NONMEM. RESULTS: CP plasma concentrations were described by a two-compartment model with a noninducible and an inducible pathway, the latter forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 l h-1 (90% C.I. 0.92-2.58) and 1.14 l h-1 (0.31-1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn-over half-life to be 24 h. CONCLUSIONS: The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.     

Hormesis: implications for cancer risk assessment

Current guidelines for cancer risk assessment emphasize a toxicant's "mode of action", rather than its empirically derived dose-response relationship, for determining whether linear low-dose extrapolation is appropriate. Thus, for reasons of policy, demonstration of hormesis is generally insufficient to justify a non-linear approach, although it may provide important insights into the actions of toxicants. We evaluated dose-response characteristics of four carcinogens reported to have hormetic dose-response curves: cadmium chloride; ionizing radiation; PAHs; and, 2,3,7,8-TCDD. For each, the study that documented hormesis in one organ also provided evidence of non-hormetic dose-responses in other organs or non-hormetic responses for seemingly similar carcinogens in the same species and organs. Such inconsistency suggests toxicologic reasons that the finding of hormesis alone is not sufficient to justify use of non-linear low-dose extrapolations. Moreover, available data in those examples are not sufficient to know whether hormesis is a property of the toxicants, the target organ, or the exposed species. From the perspectives of cancer risk assessment, the greatest informational value of hormesis may be that it provokes mechanistic studies intended to explain why hormesis occurs.     

Development of a physiologically based pharmacokinetic model for risk assessment with 1,4-dioxane

A six compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the disposition of diethylene-1,4-dioxide (dioxane) and its principal metabolite beta-hydroxyethoxyacetic acid in rats, mice, and humans. The model was developed from experimentally measured partition coefficients (reported here for the first time) as well as pharmacokinetic data previously reported. The completed PB-PK model adequately described data from gavage and intravenous studies in rats, as well as inhalation studies in rats and humans. Substantial nonlinearities were observed in the kinetic behavior of dioxane under high exposure conditions (water concentrations greater than 0.1% dioxane and atmospheric concentrations greater than 300 ppm dioxane). The PB-PK model was subsequently used to prepare quantitative estimates of the "plausible upper bounds" on carcinogenic risk for human populations exposed to dioxane in air or water. Based on these quantitative estimates, it appears that human populations continuously exposed to 740-3700 ppb dioxane in air or 20,000-120,000 ppb dioxane in water would be unlikely to experience increased frequencies of tumors.     

Biologically motivated two-stage model for cancer risk assessment

A model for carcinogenesis is presented that incorporates two features: (1) transition of target stem cells into cancer cells via an intermediate stage in two irreversible steps, and (2) growth and differentiation of normal target and intermediate cells. Implications of the model for initiation-promotion and environmental carcinogenesis are considered.     

Risk assessment of mechanism-based inactivation in drug-drug interactions

Drug-drug interactions (DDIs) that occur via mechanism-based inactivation of cytochrome P450 are of serious concern. Although several predictive models have been published, early risk assessment of MBIs is still challenging. For reversible inhibitors, the DDI risk categorization using [I]/K(i) ([I], the inhibitor concentration; K(i), the inhibition constant) is widely used in drug discovery and development. Although a simple and reliable methodology such as [I]/K(i) categorization for reversible inhibitors would be useful for mechanism-based inhibitors (MBIs), comprehensive analysis of an analogous measure reflecting in vitro potency for inactivation has not been reported. The aim of this study was to evaluate whether the term λ/k(deg) (λ, first-order inactivation rate at a given MBI concentration; k(deg), enzyme degradation rate constant) would be useful in the prediction of the in vivo DDI risk of MBIs. Twenty-one MBIs with both in vivo area under the curve (AUC) change of marker substrates and in vitro inactivation parameters were identified in the literature and analyzed. The results of this analysis show that in vivo DDIs with >2-fold change of object drug AUC can be identified with the cutoff value of λ/k(deg) = 1, where unbound steady-state C(max) is used for inhibitor concentration. However, the use of total C(max) led to great overprediction of DDI risk. The risk assessment using λ/k(deg) coupled with unbound C(max) can be useful for the DDI risk evaluation of MBIs in drug discovery and development.     

Mutagenicity of bromate: implications for cancer risk assessment

Bromate (BrO3-) is a rodent carcinogen that is formed as a drinking water ozone disinfection by-product and also used in some food and consumer products. Therefore, bromate is subject to assessment for its risk to humans. Because the selection of an appropriate model for conducting quantitative cancer risk assessment is based upon an understanding of the chemical's mode-of-action, it is necessary to determine whether the chemical is a mutagenic carcinogen. We present a review of the available information concerning the weight-of-the-evidence that bromate is a mutagenic carcinogen. The evidence indicates that bromate is mutagenic and that this activity is mediated by the formation of oxidative damage to the DNA, thus resulting in chromosomal damage. Not only does bromate induce genetic damage in vitro, it is also demonstrated to induce mutations in the kidney of exposed rats. This is significant because the rat kidney is one of the target tissues for tumor induction. While it is clear that bromate can cause damage in the target tissue, it is not clear whether bromate is a mutagenic carcinogen, that is, whether the observed tumors result from a mutagenic mode-of-action. Further research is needed to clarify bromate's mode-of-action. However, in the absence of additional information, it is reasonable, based on an extensive database, to assume that bromate induces tumors via oxidative damage that causes chromosomal breakage.     

An evaluation of the carcinogenic hazard of 1,4-dichlorobenzene based on internationally recognized criteria

1,4-Dichlorobenzene (1,4-DCB) was shown to induce the formation of male rat renal tubule tumors and male and female mouse liver tumors when administered in a chronic bioassay. Since the original carcinogenicity findings, an extensive body of mechanistic information has been developed to elucidate the mode of action by which 1,4-DCB induces these effects and to evaluate the human relevance of the observed animal tumors. In addition, some regulatory and authoritative bodies (U.S. EPA and IARC) have developed rigorous scientific criteria for the amount and types of evidence needed to establish that a material causes kidney toxicity and tumors in male rats through a specific mechanism, alpha-2u-globulin nephropathy. This paper summarizes the mechanistic data developed for 1,4-DCB, which affords an understanding of the lack of human relevance of the male rat renal tubule tumors and mouse liver tumors; assesses that mechanistic data set utilizing the defined set of evaluation criteria formulated by U.S. EPA and IARC for alpha-2u-globulin nephropathy; and discusses the predictive power of mechanistic data developed to elucidate the mode of action of 1,4-DCB in inducing mouse liver tumors. Finally, there is a discussion of how some, but not all, regulatory and authoritative bodies have incorporated this substantial mechanistic data set for 1, 4-DCB into their cancer hazard evaluations and concluded that 1, 4-DCB presents little, if any, cancer hazard to humans.     

A proposed methodology of cancer risk assessment modeling using biomarkers

A methodology for cancer risk assessment modeling was developed using a biomarker of DNA adduct, exposure dose, and tumor response. DNA adducts in the blood and lung were measured after single or multiple administration of [3H]benzo[a]pyrene (1 x BaP) in ICR mice. Making the assumption that DNA adducts are formed in a dose-dependent manner as observed in 1 x BaP treatment, kinetics patterns of DNA adducts were predicted at two other hypothetical BaP doses (2 x BaP, 1/2 x BaP) for single and continuous BaP treatments because the difference between the simulated and the experimental kinetic responses only amounted to 5.49-5.86% in terms of the integrated area under the curve. Correlations between the formation of DNA adducts and exposure doses or between blood DNA and lung DNA adducts were determined to be linear. The dose-response relationship between biomarker and exposure dose was further incorporated into a dose-tumor response equation, obtained from 2-yr bioassay, to predict cancer risk. The interrelationships between exposure dose, biomarker, and tumor response allowed the prediction of cancer risk in animals, once the information on biomarker levels was obtained. Moreover, this methodology could be further applied to human cancer risk assessment after appropriate safety factors were employed.     

New issues in cancer risk assessment

When a nonlinear dose-response at low doses can be justified, an acceptable daily intake for a carcinogen can be obtained by dividing a benchmark dose, associated with a low incidence of tumors in animals, by uncertainty factors to account for animal-to-human extrapolation, human variability, and risk reduction from a low observed adverse-effect level. This approach can utilize mechanistic information to justify smaller uncertainty factors than typical default values of 10. If a nonlinear dose-response cannot be justified, traditional linear extrapolation from the benchmark dose to zero sometimes gives similar results. This suggests a unified risk-assessment procedure based on uncertainty factors. The issue of cross-species extrapolation based on the risk relative to background risks, rather than excess risk, is examined. The relative risk approach reduces the estimates of cancer risk in humans based on common rodent tumors, such as the liver in some strains of mice.     

Prediction of drug-drug interactions arising from mechanism-based inactivation: key input parameters and impact on risk assessment

As the prevalence of polypharmacy increases with our aging population, the propensity for adverse drug-drug interactions arising from the altered metabolism of co-administered medicines remains an important consideration for drug development. Mechanism-based inactivation (MBI) of the cytochrome P450 enzyme system is responsible for many clinically relevant drug-drug interactions (DDIs) due to the irreversible and long-lasting effects of the enzyme inactivation. Unlike competitive inhibition, MBI persists after the inactivator has been cleared from the system, since de novo enzyme synthesis is required to restore metabolic activity. Recognizing the potential severity of DDIs arising from MBI, there is increasing need for predictive methodologies that can enable prospective risk assessment for the likelihood of a clinical DDI. Steady-state models, which simplify the system to a single inactivator concentration and assume static, equilibrium conditions, are important tools for assessing the potential for DDIs. More sophisticated, physiologically-based models offer advantages over the static models by taking into account changing inactivator concentration over time, in addition to incorporating population variability into the prediction. Despite the differences between the static and dynamic approaches, a key consideration for both is the sensitivity of the models to the input parameters. These inputs include inactivator-specific kinetic parameters describing MBI in terms of potency (K(I)) and inactivation rate (k(inact)), the unbound inactivator concentration (I(u)), and the enzyme degradation rate, (k(deg)). This commentary investigates the impact of the selection of input parameters, and the uncertainty in their assessment, on the prediction for DDIs arising from MBI and the relevance to risk-assessment.     

A biologically based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity.

The 1990 Clean Air Act Amendments require that health risk from exposure to vinyl acetate be assessed. Vinyl acetate is a nasal carcinogen in rats, but not mice, and induces olfactory degeneration in both species. A biologically based approach to extrapolating risks of inhalation exposure from rats to humans was developed, which incorporates critical determinants of interspecies dosimetry. A physiologically based pharmacokinetic (PBPK) model describing uptake and metabolism of vinyl acetate in rat nose was validated against nasal deposition data collected at three airflow rates. The model was also validated against observations of metabolically derived acetaldehyde. Modifying the rat nose model to reflect human anatomy created a PBPK model of the human nose. Metabolic constants from both rats and humans specific for vinyl acetate and acetaldehyde metabolism enabled predictions of various olfactory tissue dosimeters related to the mode of action. Model predictions of these dosimeters in rats corresponded well with observations of vinyl acetate toxicity. Intracellular pH (pHi) of olfactory epithelial cells was predicted to drop significantly at airborne exposure concentrations above the NOAEL of 50 ppm. Benchmark dose methods were used to estimate the ED10 and LED10 for olfactory degeneration, the precursor lesion thought to drive cellular proliferation and eventually tumor development at excess cellular acetaldehyde levels. A concentration x time adjustment was applied to the benchmark dose values. Human-equivalent concentrations were calculated by using the human PBPK model to predict concentrations that yield similar cellular levels of acetic acid, acetaldehyde, and pHi. After the application of appropriate uncertainty factors, an ambient air value of 0.4 to 1.0 ppm was derived. The biologically based approach supports a workplace standard of 10 ppm.     

A probabilistic framework for non-cancer risk assessment

Risk assessment involves an analysis of the relationship between exposure and health related outcomes to derive an allowable exposure level or to estimate a low-dose risk. Acceptable levels of human exposure for non-cancer effects generally are derived by dividing an experimental no-observed-adverse-effect-level or a lower confidence limit benchmark dose by a product of several uncertainty factors. This paper presents a hierarchical modeling framework for a probabilistic approach to non-cancer risk assessment. The hierarchical model integrates the distributions of uncertainty factors and the distribution of the actual exposure level to construct the dose-response model for the proportion of population at risk and the dose-response model for the expected proportion of population at risk for a given exposure distribution. The proposed approach is based on the use of the BMDL (lower confidence limit on the benchmark dose) as a POD (point of departure) for risk assessment of non-cancer effects.     

Acute toxicity and cancer risk assessment values for tert-butyl acetate

tert-Butyl acetate (TBAc) is an industrial chemical with potential uses as a degreaser and in architectural coatings. Limited chronic toxicity data exist for TBAc. However, acute inhalation exposure data are available for TBAc. Additionally, TBAc has been demonstrated to be substantially metabolized to tert-butanol (TBA) in rats, and a positive TBA genotoxicity study suggests that TBA may cause oxidative DNA damage. TBA has been shown to induce tumors in both rats and mice, and the Office of Environmental Health Hazard Assessment has calculated an oral cancer potency factor (CSF) for TBA of 3 x 10(-3)(mg/kg-day)(-1). Therefore, TBAc should be considered to pose a potential cancer risk to humans because of the metabolic conversion to TBA. An acute 1-h reference exposure level of 1 mg/m3 can be calculated from the extrapolated no observed adverse effect level of 50 mg/m3. A CSF of 0.002(mg/kg-day)(-1) can be derived for TBAc, assuming 100% metabolism of TBAc to TBA. An inhalation unit risk value for TBAc of 4 x 10(-7)(microg/m(3))(-1) can then be derived from the CSF value for TBAc by assuming a human breathing rate of 20 m3/day, 70% fractional absorption, and an average human body weight of 70 kg.     

The real role of risk assessment in cancer risk management

Regulatory actions taken to reduce the risk of harmful effects of exposure to chemicals often are not commensurate with the toxicological risk assessment. A number of factors relating to psychology, sociology, economics and politics rather than science and medicine affect the final decision. Werner Lutz and colleagues illustrate the situation using the leukemia-inducing chemical benzene as an example.     

Toxicogenomics and cancer risk assessment: A framework for key event analysis and dose–response assessment for nongenotoxic carcinogens

In order to determine a threshold for nongenotoxic carcinogens, the traditional risk assessment approach has been to identify a mode of action (MOA) with a nonlinear dose–response. The dose–response for one or more key event(s) linked to the MOA for carcinogenicity allows a point of departure (POD) to be selected from the most sensitive effect dose or no-effect dose. However, this can be challenging because multiple MOAs and key events may exist for carcinogenicity and oftentimes extensive research is required to elucidate the MOA. In the present study, a microarray analysis was conducted to determine if a POD could be identified following short-term oral rat exposure with two nongenotoxic rodent carcinogens, fenofibrate and methapyrilene, using a benchmark dose analysis of genes aggregated in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) biological processes, which likely encompass key event(s) for carcinogenicity. The gene expression response for fenofibrate given to rats for 2 days was consistent with its MOA and known key events linked to PPARα activation. The temporal response from daily dosing with methapyrilene demonstrated biological complexity with waves of pathways/biological processes occurring over 1, 3, and 7 days; nonetheless, the benchmark dose values were consistent over time. When comparing the dose–response of toxicogenomic data to tumorigenesis or precursor events, the toxicogenomics POD was slightly below any effect level. Our results suggest that toxicogenomic analysis using short-term studies can be used to identify a threshold for nongenotoxic carcinogens based on evaluation of potential key event(s) which then can be used within a risk assessment framework.     

A framework for using epidemiological data for risk assessment

Data on health effects from human exposure to chemicals provide the most direct information for risk assessment. Despite their clear relevance for risk assessment and despite the frequently made statements by regulatory bodies to use epidemiological data whenever deemed appropriate, they are not always optimally used. In this article, a framework for using epidemiological data in risk assessment is presented. Before using an epidemiologic study as the basis for risk assessment, its quality must be evaluated. The quality criteria for such a study strongly depends on the type of association between the chemical and health effect in terms of its specificity and latency period. The framework is built on the type of health effect under consideration, whether it is a specific or non-specific effect and time window of the effect, whether it is an acute, sub-acute or long-term effect. Specificity and latency are aspects that have a great impact on the choice of research design and quality criteria that must be met in order to produce reliable results appropriate for risk assessment purposes. Although expert judgement will always play an important role, the framework can help to assess if a set of epidemiological data are sufficiently reliable to serve as the basis for the derivation of health-based exposure limits. The limitations and suitability to use for risk assessment of epidemiologic studies is more likely to be the result of poor or insufficient exposure data than of poor or unreliable health effect information. It is concluded that the value of epidemiologic data not only depends on its intrinsic quality, but also on the type of health effects under consideration. In this respect, the specificity and latency play an important role.     

A risk assessment process for allergic contact sensitization

This review describes an approach that has been used to assess the skin sensitization risk of new chemicals and product formulations prior to launching the new chemical or product on the market. The risk assessment process utilizes a comparative toxicological approach, in which data on the inherent toxicity of a material, and the exposure to it through manufacturing or consumer use or foreseeable misuse, are integrated and compared with data generated by 'benchmark' materials of similar chemistry or product application, or both. This approach has been valuable in providing an accurate assessment of the skin sensitization potential for a wide range of consumer products and pharmaceuticals, ranging from products with a very transient skin exposure (e.g. some paper products), to cosmetics, to products whose ingredients may be deposited on fabrics and thus result in chronic skin exposure. The risk assessment process described includes both guinea-pig (Buehler) and human skin sensitization test methodologies to evaluate inherent toxicity under relevant epicutaneous exposure conditions. Alternative guinea-pig test methods have been reported to be more sensitive than the Buehler method, particularly those employing intradermal injection of the test material in Freund's complete adjuvant (e.g. maximization test). However, by bypassing the skin barrier at induction, these methods can overstate the sensitization risk of epicutaneous exposure to weak sensitizers (Andersen and Hamann, 1983 and 1984; Matsushita et al., 1975a,b), and can understate the risk to very strong sensitizers possibly through tolerance induction (Buehler, 1985). In addition, materials are tested and classified at concentrations that may not be relevant to anticipated human exposure. The Buehler guinea-pig test data are important in assessing skin sensitization risk in the early phases of product development, where human exposure can be limited, controlled and monitored (e.g. manufacturing employees). The Buehler test can often define consumer skin sensitization risk; however, the ultimate consumer skin safety assessment should in general be developed through a series of controlled human tests; the human repeat insult patch test and, when necessary, the provocative or extended product use tests. Post-market monitoring of skin-related consumer comments is the final phase of the data gathering process. These results can be used to assess further each product and to provide valuable feedback to confirm the validity of the overall risk assessment process. Risk assessment for skin sensitization potential is seldom a simple process.(ABSTRACT TRUNCATED AT 400 WORDS)