Benchmark Dose Risk Assessment for Formaldehyde Using Airflow Modeling and a Single-Compartment, DNA-Protein Cross-Link Dosimetry Model to Estimate Human Equivalent Doses

Formaldehyde induced squamous-cell carcinomas in the nasal passages of F344 rats in two inhalation bioassays at exposure levels of 6 ppm and above. Increases in rates of cell proliferation were measured by T. M. Monticello and colleagues at exposure levels of 0.7 ppm and above in the same tissues from which tumors arose. A risk assessment for formaldehyde was conducted at the CIIT Centers for Health Research, in collaboration with investigators from Toxicological Excellence in Risk Assessment (TERA) and the U.S. Environmental Protection Agency (U.S. EPA) in 1999. Two methods for dose-response assessment were used: a full biologically based modeling approach and a statistically oriented analysis by benchmark dose (BMD) method. This article presents the later approach, the purpose of which is to combine BMD and pharmacokinetic modeling to estimate human cancer risks from formaldehyde exposure. BMD analysis was used to identify points of departure (exposure levels) for low-dose extrapolation in rats for both tumor and the cell proliferation endpoints. The benchmark concentrations for induced cell proliferation were lower than for tumors. These concentrations were extrapolated to humans using two mechanistic models. One model used computational fluid dynamics (CFD) alone to determine rates of delivery of inhaled formaldehyde to the nasal lining. The second model combined the CFD method with a pharmacokinetic model to predict tissue dose with formaldehyde-induced DNA-protein cross-links (DPX) as a dose metric. Both extrapolation methods gave similar results, and the predicted cancer risk in humans at low exposure levels was found to be similar to that from a risk assessment conducted by the U.S. EPA in 1991. Use of the mechanistically based extrapolation models lends greater certainty to these risk estimates than previous approaches and also identifies the uncertainty in the measured dose-response relationship for cell proliferation at low exposure levels, the dose-response relationship for DPX in monkeys, and the choice between linear and nonlinear methods of extrapolation as key remaining sources of uncertainty.     

Cell Proliferation and Formaldehyde-Induced Respiratory Carcinogenesis

Formaldehyde is a nasal carcinogen in the rat but the cancer risk this chemical poses for humans remains to be determined. Formaldehyde induces nonlinear, concentration-dependent increases in nasal epithelial cell proliferation and DNA-protein cross-link formation following short-term exposure. Presented in this review are results from a mechanistically based formaldehyde inhalation study in which an important endpoint was the measurement of cell proliferation indices in target sites for nasal tumor induction. Male Fischer 344 rats were exposed to 0, 0.7, 2, 6, 10, or 15 ppm formaldehyde for up to 2 years (6 hr/day, 5 day/week). Statistically significant increases in cell proliferation were confined to the 10 and 15 ppm groups, which remained elevated throughout the study. The concentration-dependent increases in cell proliferation correlated strongly with the tumor response curve, supporting the proposal that sustained increases in cell proliferation are an important component of formaldehyde carcinogenesis. The nonlinearity observed in formaldehyde-induced rodent nasal cancer is consistent with a high-concentration effect of regenerative cell proliferation of the target organ coupled with the genotoxic effects of formaldehyde. Cell kinetic data from these studies provide important information that may be utilized in the assessment of risk for humans exposed to formaldehyde.     

Evaluation of False Positive and False Negative Outcomes in NTP Long-Term Rodent Carcinogenicity Studies

The decision-making process used by the National Toxicology Program (NTP) in its evaluation of long-term rodent carcinogenicity studies was investigated to determine whether or not this procedure resulted in an excessive number of false positive or false negative outcomes. All site-specific tumor incidences that were found to be significantly ( p < 0.05) increased either by a trend test or by pairwise comparisons of each dosed group against the controls in 218 NTP 2-year studies with Fischer 344 rats and/or B6C3F1 mice were tabulated and compared to the number of statistically significant tumor increases expected to occur by chance. Our evaluation suggests that false positive rates are fairly low in NTP long-term studies. Assessing false negative rates is more difficult because of the limited sensitivity of the bioassay for detecting subtle carcinogenic effects. Moreover, reduced body weights frequently occur in dosed animals, and the positive correlation between the incidences of certain site-specific tumors and body weight may mask the detection of carcinogenic effects. Despite these difficulties, our analysis did identify one tumor showing evidence of false negative outcomes: interstitial cell tumors of the testis in male Fischer 344 (F344) rats. This tumor showed considerably more significant ( p > 0.05) increased incidences than expected by chance, yet none were considered to be chemically-related. However, the biological significance of interstitial cell tumor increases in F344 rats is uncertain because of the high background rate of neoplasia (>90%) for this target site.     

Uncertainties in the CIIT Model for Formaldehyde-Induced Carcinogenicity in the Rat: A Limited Sensitivity Analysis–I

Scientists at the CIIT Centers for Health Research (Conolly et al., 2000, 2003; Kimbell et al., 2001a, 2001b) developed a two-stage clonal expansion model of formaldehyde-induced nasal cancers in the F344 rat that made extensive use of mechanistic information. An inference of their modeling approach was that formaldehyde-induced tumorigenicity could be optimally explained without the role of formaldehyde's mutagenic action. In this article, we examine the strength of this result and modify select features to examine the sensitivity of the predicted dose response to select assumptions. We implement solutions to the two-stage cancer model that are valid for nonhomogeneous models (i.e., models with time-dependent parameters), thus accounting for time dependence in variables. In this reimplementation, we examine the sensitivity of model predictions to pooling historical and concurrent control data, and to lumping sacrificed animals in which tumors were discovered incidentally with those in which death was caused by the tumors. We found the CIIT model results were not significantly altered with the nonhomogeneous solutions. Dose-response predictions below the range of exposures where tumors occurred in the bioassays were highly sensitive to the choice of control data. In the range of exposures where tumors were observed, the model attributed up to 74% of the added tumor probability to formaldehyde's mutagenic action when our reanalysis restricted the use of the National Toxicology Program (NTP) historical control data to only those obtained from inhalation exposures. Model results were insensitive to hourly or daily temporal variations in DNA protein cross-link (DPX) concentration, a surrogate for the dose-metric linked to formaldehyde-induced mutations, prompting us to utilize weekly averages for this quantity. Various other biological and mathematical uncertainties in the model have been retained unmodified in this analysis. These include model specification of initiated cell division and death rates, and uncertainty and variability in the dose response for cell replication rates, issues that will be considered in a future paper.     

Carcinogenicity Studies on MTBE: Critical Review and Interpretation

Chronic inhalation of toxic concentrations of MTBE caused renal tubular cell neoplasms in male Fischer 344 rats and hepatocellular adenomas in female CD-1 mice. In Sprague-Dawley rats the oral administration of MTBE was associated with increased incidences of Leydig cell tumors and of lymphomas and leukemias (combined) in males and females, respectively. Neither lymphomas nor leukemias were individually increased in treated females. Leydig cell tumors are common in rats and do not predict human responses to drugs and chemicals. Neither MTBE nor its metabolite, t -butyl alcohol, possess mutagenic potential and a second metabolite, formaldehyde, is mutagenic in vitro but in vivo results are equivocal. MTBE-induced neoplasms are most likely produced through a nongenetic mechanism which requires chronic exposure to toxic doses. Because of the intense odor (and taste) of MTBE, humans will not tolerate either air or water concentrations sufficient to produce the cytotoxic precursors required to promote cellular proliferation.     

Uncertainties in Biologically-Based Modeling of Formaldehyde-Induced Respiratory Cancer Risk: Identification of Key Issues

In a series of articles and a health-risk assessment report, scientists at the CIIT Hamner Institutes developed a model (CIIT model) for estimating respiratory cancer risk due to inhaled formaldehyde within a conceptual framework incorporating extensive mechanistic information and advanced computational methods at the toxicokinetic and toxicodynamic levels. Several regulatory bodies have utilized predictions from this model; on the other hand, upon detailed evaluation the California EPA has decided against doing so. In this article, we study the CIIT model to identify key biological and statistical uncertainties that need careful evaluation if such two-stage clonal expansion models are to be used for extrapolation of cancer risk from animal bioassays to human exposure. Broadly, these issues pertain to the use and interpretation of experimental labeling index and tumor data, the evaluation and biological interpretation of estimated parameters, and uncertainties in model specification, in particular that of initiated cells. We also identify key uncertainties in the scale-up of the CIIT model to humans, focusing on assumptions underlying model parameters for cell replication rates and formaldehyde-induced mutation. We discuss uncertainties in identifying parameter values in the model used to estimate and extrapolate DNA protein cross-link levels. The authors of the CIIT modeling endeavor characterized their human risk estimates as "conservative in the face of modeling uncertainties." The uncertainties discussed in this article indicate that such a claim is premature.     

Statistical Modeling of Animal Bioassay Data with Variable Dosing Regimens: Example—Vinyl Chloride

We consider animal bioassay experiments with variable dosing regimens in which groups of animals are dosed beginning at different ages and for varying durations. Two response models are discussed and then applied to data from an experiment on vinyl chloride exposure of F-344 rats, B6C3F1 and Swiss CD-1 mice, and Syrian Golden hamsters. The multistage model of Armitage and Doll, as extended by Whittemore, Day and Brown, and Crump and Howe, is used to estimate the dose effect on the ordered stages of tumor development. The data for all endpoints and species/strains examined consistently indicate a predominant effect on the first stage, suggesting that vinyl chloride is primarily a tumor initiator. This is consistent with evidence from two-stage experiments on this chemical. The second response model, new to this article, adjusts for survival nonparametrically. It is used to test for an age difference in susceptibility, to evaluate alternative exposure durations, and to compare the effectiveness of alternative dosing regimens for detecting carcinogenicity.     

Quantitative Cancer Risk Estimation for Formaldehyde

Of primary concern are irreversible effects, such as cancer induction, that formaldehyde exposure could have on human health. Dose-response data from human exposure situations would provide the most solid foundation for risk assessment, avoiding problematic extrapolations from the health effects seen in nonhuman species. However, epidemiologic studies of human formaldehyde exposure have provided little definitive information regarding dose-response. Reliance must consequently be placed on laboratory animal evidence. An impressive array of data points to significantly nonlinear relationships between rodent tumor incidence and administered dose, and between target tissue dose and administered dose (the latter for both rodents and Rhesus monkeys) following exposure to formaldehyde by inhalation. Disproportionately less formaldehyde binds covalently to the DNA of nasal respiratory epithelium at low than at high airborne concentrations. Use of this internal measure of delivered dose in analyses of rodent bioassay nasal tumor response yields multistage model estimates of low-dose risk, both point and upper bound, that are lower than equivalent estimates based upon airborne formaldehyde concentration. In addition, risk estimates obtained for Rhesus monkeys appear at least 10-fold lower than corresponding estimates for identically exposed Fischer-344 rats.     

Cancer risk estimation for mixtures of coal tars and benzo(a)pyrene.

Two-year chronic bioassays were conducted by using B6C3F1 female mice fed several concentrations of two different mixtures of coal tars from manufactured gas waste sites or benzo(a)pyrene (BaP). The purpose of the study was to obtain estimates of cancer potency of coal tar mixtures, by using conventional regulatory methods, for use in manufactured gas waste site remediation. A secondary purpose was to investigate the validity of using the concentration of a single potent carcinogen, in this case benzo(a)pyrene, to estimate the relative risk for a coal tar mixture. The study has shown that BaP dominates the cancer risk when its concentration is greater than 6,300 ppm in the coal tar mixture. In this case the most sensitive tissue site is the forestomach. Using low-dose linear extrapolation, the lifetime cancer risk for humans is estimated to be: Risk < 1.03 x 10(-4) (ppm coal tar in total diet) + 240 x 10(-4) (ppm BaP in total diet), based on forestomach tumors. If the BaP concentration in the coal tar mixture is less than 6,300 ppm, the more likely case, then lung tumors provide the largest estimated upper limit of risk, Risk < 2.55 x 10(-4) (ppm coal tar in total diet), with no contribution of BaP to lung tumors. The upper limit of the cancer potency (slope factor) for lifetime oral exposure to benzo(a)pyrene is 1.2 x 10(-3) per microgram per kg body weight per day from this Good Laboratory Practice (GLP) study compared with the current value of 7.3 x 10(-3) per microgram per kg body weight per day listed in the U.S. EPA Integrated Risk Information System.     

Use of a Chemical Probe to Increase Safety for Human Volunteers in Toxicokinetic Studies

To avoid interspecies extrapolation in toxicokinetics and drug development, it is convenient to directly develop human data. In that case, exposure dose should pose null or negligible risk to the exposed individual, but still be sufficiently high to allow quantification. We propose to reduce the dose received by human volunteers during exposure, and to compensate for loss of information by exposing the same volunteers to a nontoxic agent. This method was applied to develop 1,3-butadiene (BD) exposure protocols for humans. To study the potential of such a procedure, we worked with simulated data. Three exposure times (20, 10, and 5 minutes) and four exposure concentrations (2, 1, 0.8, and 0.5 ppm) were used to define 12 inhalation exposure scenarios for BD. Isoflurane was used as a probe, with simulated exposure of 20 subjects to 20 ppm isoflurane during 15 minutes. Isoflurane or BD-exhaled air concentrations were supposed to be measured 10 times. A three-compartment physiological toxicokinetic model was used to jointly describe BD and isoflurane data. For each subject, BD data were analyzed, in a Bayesian framework, either alone or together with the isoflurane data. The precision of BD metabolic rate constant or fraction metabolized was increased, and bias reduced, when BD and probe data were considered jointly. An exposure to 10 ppm x min BD and 300 ppm x min isoflurane gave equivalent precision and bias as a unique exposure to 40 ppm x min BD. The BD dose received by volunteers could therefore be at least quartered if BD exposure was supplemented with that of a probe.     

Cancer Risk Estimation for Mixtures of Coal Tars

Two-year chronic bioassays were conducted by using B6C3F1 female mice fed several concentrations of two different mixtures of coal tars from manufactured gas waste sites or benzo(a)pyrene (BaP). The purpose of the study was to obtain estimates of cancer potency of coal tar mixtures, by using conventional regulatory methods, for use in manufactured gas waste site remediation. A secondary purpose was to investigate the validity of using the concentration of a single potent carcinogen, in this case benzo(a)pyrene, to estimate the relative risk for a coal tar mixture. The study has shown that BaP dominates the cancer risk when its concentration is greater than 6,300 ppm in the coal tar mixture. In this case the most sensitive tissue site is the forestomach. Using low-dose linear extrapolation, the lifetime cancer risk for humans is estimated to be: Risk < 1.03 × 10⁻⁴ (ppm coal tar in total diet) + 240 × 10⁻⁴ (ppm BaP in total diet), based on forestomach tumors. If the BaP concentration in the coal tar mixture is less than 6,300 ppm, the more likely case, then lung tumors provide the largest estimated upper limit of risk, Risk < 2.55 × 10⁻⁴ (ppm coal tar in total diet), with no contribution of BaP to lung tumors. The upper limit of the cancer potency (slope factor) for lifetime oral exposure to benzo(a)pyrene is 1.2 × 10⁻³ per μg per kg body weight per day from this Good Laboratory Practice (GLP) study compared with the current value of 7.3 × 10⁻³ per μg per kg body weight per day listed in the U.S. EPA Integrated Risk Information System.     

Bayesian Estimation of Pharmacokinetic and Pharmacodynamic Parameters in a Mode-of-Action-Based Cancer Risk Assessment for Chloroform

Chloroform is a carcinogen in rodents and its carcinogenicity is secondary to events associated with cytotoxicity and regenerative cell proliferation. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that links the processes of chloroform metabolism, reparable cell damage, cell death, and regenerative cellular proliferation was developed to support a new cancer dose-response assessment for chloroform. Model parameters were estimated using Markov Chain Monte Carlo (MCMC) analysis in a two-step approach: (1) metabolism parameters for male and female mice and rats were estimated against available closed chamber gas uptake data; and (2) PD parameters for each of the four rodent groups were estimated from hepatic and renal labeling index data following inhalation exposures. Subsequently, the resulting rodent PD parameters together with literature values for human age-dependent physiological and metabolism parameters were used to scale up the rodent model to a human model. The human model was used to predict exposure conditions under which chloroform-mediated cytolethality is expected to occur in liver and kidney of adults and children. Using the human model, inhalation Reference Concentrations (RfCs) and oral Reference Doses (RfDs) were derived using an uncertainty factor of 10. Based on liver and kidney dose metrics, the respective RfCs were 0.9 and 0.09 ppm; and the respective RfDs were 0.4 and 3 mg/kg/day.     

Methyl tert Butyl Ether Systemic Toxicity

In male F344 rats exposed in a chronic inhalation study to methyl tertiary butyl ether (MTBE) a treatment related increase in severity of chronic nephropathy and mortality and an increase in hyaline droplets in the kidney were noted. Liver weights were increased in both rats and mice but no histological lesions other than hypertrophy are seen. Transient CNS effects but no indications of permanent nervous system effects were noted. MTBE is not a reproductive or developmental hazard. MTBE is rapidly absorbed. MTBE with some metabolite, tertiary butyl alcohol (TBA) and a little CO₂, are excreted in the air. The urinary excretion products in animals are TBA metabolites, while in humans the urinary excretion products are MTBE and TBA. A comparison of the systemic responses of the possible metabolites TBA and formaldehyde indicate that they are not responsible for toxicity associated with MTBE, except that TBA may be partially responsible for the kidney effects reported. Animals and humans are similar in the uptake and excretion though with some differences in metabolism of MTBE. This supports the use of the animal data as a surrogate for humans.     

A Health Risk Benchmark for the Neurologic Effects of Styrene: Comparison with NOAEL/LOAEL Approach

Benchmark dose (BMD) analysis was used to estimate an inhalation benchmark concentration for styrene neurotoxicity. Quantal data on neuropsychologic test results from styrene-exposed workers [Mutti et al. (1984). American Journal of Industrial Medicine, 5, 275-286] were used to quantify neurotoxicity, defined as the percent of tested workers who responded abnormally to > or = 1, > or = 2, or > or = 3 out of a battery of eight tests. Exposure was based on previously published results on mean urinary mandelic- and phenylglyoxylic acid levels in the workers, converted to air styrene levels (15, 44, 74, or 115 ppm). Nonstyrene-exposed workers from the same region served as a control group. Maximum-likelihood estimates (MLEs) and BMDs at 5 and 10% response levels of the exposed population were obtained from log-normal analysis of the quantal data. The highest MLE was 9 ppm (BMD = 4 ppm) styrene and represents abnormal responses to > or = 3 tests by 10% of the exposed population. The most health-protective MLE was 2 ppm styrene (BMD = 0.3 ppm) and represents abnormal responses to > or = 1 test by 5% of the exposed population. A no observed adverse effect level/lowest observed adverse effect level (NOAEL/LOAEL) analysis of the same quantal data showed workers in all styrene exposure groups responded abnormally to > or = 1, > or = 2, or > or = 3 tests, compared to controls, and the LOAEL was 15 ppm. A comparison of the BMD and NOAEL/LOAEL analyses suggests that at air styrene levels below the LOAEL, a segment of the worker population may be adversely affected. The benchmark approach will be useful for styrene noncancer risk assessment purposes by providing a more accurate estimate of potential risk that should, in turn, help to reduce the uncertainty that is a common problem in setting exposure levels.     

Worker Exposure Standard for Phosphine Gas

The 1998 U.S. Environmental Protection Agency Office of Pesticide Programs (OPP) re-registration eligibility decision (RED) for phosphine fumigants has generated much interest in defining safe levels of exposure for workers and worker bystanders. This report summarizes the pertinent literature on phosphine toxicity, including animal inhalation studies and human epidemiology studies, and also describes a margin-of-exposure (MOE) analysis based on available worker exposure data. In addition, a safe occupational exposure limit is estimated using typical OPP assumptions, after determination of appropriate uncertainty factors, based on quality of data in the principal study and pharmacokinetic considerations. While a conservative 8-hour time-weighted average (TWA) of 0.1 ppm was calculated, the overall weight of evidence, from a risk-management perspective, supports a conclusion that an occupational TWA of 0.3 ppm provides adequate health protection. In addition, a 15-minute short-term exposure limit (STEL) of 3 ppm was estimated. Finally, in contrast to the MOE analysis described in the OPP's phosphine RED, the MOE analysis described herein does not indicate that fumigation workers are currently being exposed to unacceptable levels of phosphine. Collectively, these findings support the occupational exposure limits of 0.3 ppm (8-hour TWA) and 1 ppm (STEL) established in the updated applicator's manuals for phosphine-generating products, which recently received approval from OPP.     

Using Physiologically-Based Pharmacokinetic Modeling to Address Nonlinear Kinetics and Changes in Rodent Physiology and Metabolism Due to Aging and Adaptation in Deriving Reference Values for Propylene Glycol Methyl Ether and Propylene Glycol Methyl Ether Acetate

Reference values, including an oral reference dose (RfD) and an inhalation reference concentration (RfC), were derived for propylene glycol methyl ether (PGME), and an oral RfD was derived for its acetate (PGMEA). These values were based on transient sedation observed in F344 rats and B6C3F1 mice during a two‐year inhalation study. The dose‐response relationship for sedation was characterized using internal dose measures as predicted by a physiologically‐based pharmacokinetic (PBPK) model for PGME and its acetate. PBPK modeling was used to account for changes in rodent physiology and metabolism due to aging and adaptation, based on data collected during Weeks 1, 2, 26, 52, and 78 of a chronic inhalation study. The peak concentration of PGME in richly perfused tissues (i.e., brain) was selected as the most appropriate internal dose measure based on a consideration of the mode of action for sedation and similarities in tissue partitioning between brain and other richly perfused tissues. Internal doses (peak tissue concentrations of PGME) were designated as either no‐observed‐adverse‐effect levels (NOAELs) or lowest‐observed‐adverse‐effect levels (LOAELs) based on the presence or the absence of sedation at each time point, species, and sex in the two‐year study. Distributions of the NOAEL and LOAEL values expressed in terms of internal dose were characterized using an arithmetic mean and standard deviation, with the mean internal NOAEL serving as the basis for the reference values, which was then divided by appropriate uncertainty factors. Where data were permitting, chemical‐specific adjustment factors were derived to replace default uncertainty factor values of 10. Nonlinear kinetics, which was predicted by the model in all species at PGME concentrations exceeding 100 ppm, complicate interspecies, and low‐dose extrapolations. To address this complication, reference values were derived using two approaches that differ with respect to the order in which these extrapolations were performed: (1) default approach of interspecies extrapolation to determine the human equivalent concentration (PBPK modeling) followed by uncertainty factor application, and (2) uncertainty factor application followed by interspecies extrapolation (PBPK modeling). The resulting reference values for these two approaches are substantially different, with values from the latter approach being seven‐fold higher than those from the former approach. Such a striking difference between the two approaches reveals an underlying issue that has received little attention in the literature regarding the application of uncertainty factors and interspecies extrapolations to compounds where saturable kinetics occur in the range of the NOAEL. Until such discussions have taken place, reference values based on the former approach are recommended for risk assessments involving human exposures to PGME and PGMEA.     

Determination of Leukemogenic Benzene Exposure Concentrations: Refined Analyses of the Pliofilm Cohort

Biologic data on benzene metabolite doses, cytotoxicity, and genotoxicity often show that these effects do not vary directly with cumulative benzene exposure (i.e., concentration times time, or c × t ). To examine the effect of an alternate exposure metric, we analyzed cell-type specific leukemia mortality in Pliofilm workers. The work history of each Pliofilm worker was used to define each worker's maximally exposed job/department combination over time and the associated long-term average concentration associated with the maximally exposed job (LTA-MEJ). Using this measure, in conjunction with four job exposure estimates, we calculated SMRs for groups of workers with increasing LTA-MEJs. The analyses suggest that a critical concentration of benzene exposure must be reached in order for the risk of leukemia or, more specifically, AMML to be expressed. The minimum concentration is between 20 and 60 ppm depending on the exposure estimate and endpoint (all leukemias or AMMLs only). We believe these analyses are a useful adjunct to previous analyses of the Pliofilm data. They suggests that (a) AMML risk is shown only above a critical concentration of benzene exposure, measured as a long-term average and experienced for years, (b) the critical concentration is between 50 and 60 ppm when using a median exposure estimate derived from three previous exposure assessments, and is between 20 and 25 ppm using the lowest exposure estimates, and (c) risks for total leukemia are driven by risks for AMML, suggesting that AMML is the cell type related to benzene exposure.     

Lactational Transfer of Tetrachloroethylene in Rats

Tetrachloroethylene (PCE) is a commonly used organic solvent and a suspected human carcinogen, reportedly transferred to human breast milk following inhalation exposure. Transfer of PCE to milk may represent a threat to the nursing infant. A physiologically based pharmacokinetic (PBPK) model was developed to quantitatively assess the transfer of inhaled PCE into breast milk and the consequent exposure of the nursing infant. The model was validated in lactating rats. Lactating Sprague-Dawley female rats were exposed via inhalation to PCE at concentrations ranging from 20-1000 ppm, and then returned to their nursing, 10- to 11-day-old pups. Tetrachloroethylene concentrations in the air, blood, milk, and tissue were determined by gas chromatography and compared to model predictions. The model described the distribution of inhaled PCE in maternal blood and milk, as well as the nursed pup's gastrointestinal tract, blood, and tissue. Several computer simulations of PCE distribution kinetics in exhaled air, blood, and milk of exposed human subjects were run and compared with limited human data available from the literature. It is concluded that the PBPK model successfully described the concentration of PCE in both lactating rats and humans. Although predictions vs. observations were good, the model slightly underpredicted the peak whole pup PCE concentration and underpredicted systemic clearance of PCE from the pup.     

Use of Biological Markers in Risk Assessment1

Measurements of intermediate end points in the carcinogenic process may reduce uncertainty in human risk assessment from bioassay data, by identifying sources of interspecies variation and dose nonlinearity. This paper describes desirable properties of such markers: persistence, predictive power, temporal relevance, and consistency across dose rate and species. We illustrate these properties by evaluating markers for squamous cell nasal carcinoma in rodents exposed to formaldehyde. We also discuss design issues for bioassays that evaluate markers and tumors simultaneously at necropsy.