Improvements in quantitative noncancer risk assessment. Sponsored by the Risk Assessment Specialty Section of the Society of Toxicology.
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Animals↗
Biomedical subjects
R B Conolly
Publications and source records attributed to R B Conolly.
Relationship between hepatocyte necrosis, proliferation, and initiation induced by diethylnitrosamine in the male F344 rat.
Diethylnitrosamine (DEN) is commonly used as an initiator in rodent models of multistage carcinogenesis. Because the initiating activity of DEN has been attributed, in part, to its induction of regenerative cell proliferation, the temporal and quantitative relationships among necrosis, replication, and initiation were characterized in livers of male F344 rats subsequent to administration of a single dose of 10 or 150 mg DEN/kg. Following a dose of 150 mg DEN/kg body weight, maximal hepatocellular necrosis was observed 2 days postinjection and amounted to 9% of the hepatic volume being necrotic by light microscopic criteria. Changes in serum levels of alanine and aspartate aminotransferases, indicators of hepatocellular necrosis, paralleled changes in the necrotic volume fraction. Hepatocyte replication was estimated using nuclear labeling with bromodeoxyuridine (BrdU), which was constantly infused for 2 or 7 days by osmotic minipump. BrdU labeling was maximally increased at 4 days with 2-day infusion (26.1% in treated vs 0.5% in controls) and at 7 days with 7-day infusion (46% in treated vs 2% in controls). Initiation was quantitated by enumeration of hepatocytes which stained positive for placental glutathione-S-transferase (GST-P). Increased numbers of GST-P-positive hepatocytes were observed on Day 4 and increased to a maximum of 109/cm2 section area, or 0.077% of all hepatocytes. Thus, the temporal pattern changes following 150 mg DEN/kg body wt are consistent with the attribution of regenerative cell proliferation contributing to the yield of initiated cells. A comparison of the peak BrdU (2-day) labeling index and the peak GST-P staining frequency suggests a rate of initiation of roughly 10(-3)-10(-4)/cell division following 150 mg DEN/kg body wt.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pharmacokinetics of 2-methoxyethanol and 2-methoxyacetic acid in the pregnant mouse: a physiologically based mathematical model.
A physiologically based pharmacokinetic (PBPK) model was created to describe the disposition of 2-methoxyethanol (2-ME) and its teratogenic metabolite, 2-methoxyacetic acid (2-MAA), in the pregnant CD-1 mouse. The model's foundation is a mathematical description of the physiological changes that occur during gestation (O'Flaherty et al., Toxicol. Appl. Pharmacol. 112, 245-256, 1992). The PBPK model was developed and validated with data collected on Gestation Day (GD) 11. Absorption, distribution, and oxidation of 2-ME to 2-MAA and ethylene glycol (EG) were simulated. Flow-limited disposition of 2-ME in maternal tissues was described using in vitro-determined tissue partition coefficients (PCs). The maximum velocity (Vmax) of 2-ME oxidation to 2-MAA was calculated from literature-based in vitro data. Vmax for EG formation, and Michaelis constants for 2-MAA and EG pathways, were estimated from optimized simulations of plasma 2-ME and metabolite levels obtained after intravenous injection of 5-600 mg 2-ME.kg-1.2-MAA disposition and elimination in the dam were described by a nonphysiological one-compartment model, which was linked to the 2-ME model, based on the volume of distribution (0.510 liters.kg-1) and overall elimination rate constant (0.124 hr-1) calculated from iv 2-MAA plasma concentration-time courses. Transfer of 2-MAA between the placenta and conceptus was described as a diffusion-limited process to more accurately simulate the higher concentrations of 2-MAA determined in embryonic compartments compared with maternal plasma levels. Subsequent 2-MAA disposition within the embryo proper and surrounding fluid of the GD 11 conceptus was adequately described using embryo/blood (0.94) and extraembryonic fluid/blood (1.33) PCs. Extension of the PBPK model to oral and subcutaneous 2-ME administrations required optimization of first-order absorption rates; model simulations agreed closely with measured 2-ME/2-MAA levels. With refinements and further validation, the PBPK model of 2-ME/2-MAA disposition should prove helpful for extrapolation throughout gestation and between species.
Acetates↗
An approach to mechanism-based cancer risk assessment for formaldehyde.
The established carcinogenicity of formaldehyde in the rat and suggestive epidemiological evidence that formaldehyde may be a human carcinogen have led to its regulation by U.S. Federal agencies as a probable human carcinogen. These risk assessments have typically been based on tumor data in F344 rats exposed chronically to formaldehyde by inhalation and used the inhaled concentration as a measure of dose and the linearized multistage model (LMS) for dose-response characterization. Low-dose risks estimated with the LMS are thought to be conservative but are also generally acknowledged to be highly uncertain. In this manuscript, we first consider in generic terms how use of chemical-specific data on mechanisms of target tissue dosimetry and the series of tissue responses to the chemical that culminate in tumor formation can lead to more accurate dose-response characterization. A planned mechanism-based risk assessment for formaldehyde is then described. This risk assessment uses data on target tissue dosimetry, size of the target cell population in the rat nasal epithelium, number and size of putative preneoplastic lesions, and tumor incidence. These data establish parameter values for a biologically based, multistage cancer model that is then used to predict cancer risk at low exposure levels. Such work provides insights into the relative roles of formaldehyde-stimulated cell replication and procarcinogenic mutation in tumor formation. Finally, future directions are outlined for research on tissue dosimetry and scaling of the mechanism-based formaldehyde risk model from rats to people.
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Incorporating biologically based models into assessments of risk from chemical contaminants.
The general approach to assessment of risk from chemical contaminants in drinking water involves three steps: hazard identification, exposure assessment, and dose-response assessment. Traditionally, the risks to humans associated with different levels of a chemical have been derived from the toxic responses observed in animals. It is becoming increasingly clear, however, that further information is needed if risks to humans are to be assessed accurately. Biologically based models help clarify the dose-response relationship and reduce uncertainty.
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Determining health risks associated with disinfectants and disinfection by-products: research needs.
In order to minimize the levels of potentially toxic disinfectants and disinfection by-products in treated water while maintaining adequate protection against microbiological contamination, the total risks associated with disinfection have to be measured and compared with the risks from microbial agents. Because much work has already been carried out on chlorination and its by-products, it is recommended that research focus on major disinfection alternatives, i.e., ozonation, chloramination, carbon dioxidation, and the most practical combinations of these options. The primary research needs are (1) assessment of the relative toxicological hazards of the disinfectants and their by-products and (2) development of biologically based models for the dose-response relationships of these chemicals.
Animals↗
Biologically based modeling in toxicology research.
Biologically based modeling can be described as the process by which the specific mechanistic steps governing tissue disposition and toxic action of chemicals are expressed in quantitative terms by a set of equations leading to prediction of the outcome of specific toxicological experiments by computer simulation. These models are useful in risk assessment because their mechanistic biological basis permits the high-to-low dose, route to route and interspecies extrapolation of the tissue disposition and toxic action of chemicals. By far their greatest utility is not as "finished" risk assessment models, but as research tools that convey a quantitative expression of our hypotheses of tissue disposition and toxic action of a chemical. A structured modeling approach to toxicology problems helps identify the data gaps in the areas of chemical disposition and toxic action, thus prioritizing on-going research to obtain critical information required to conduct quantitative risk assessment. This paper examines progress in developing comprehensive biologically based models for cancer induction by non-genotoxic carcinogens that are cytotoxic in target tissues. The strategies for linking the models on dosimetry, cytotoxicity, and carcinogenicity are described in detail. The basic concepts and approaches discussed here can be applied to many other toxic chemicals and to toxicity endpoints other than cancer.
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Polychlorotrifluoroethylene (PCTFE) oligomer pharmacokinetics in Fischer 344 rats: development of a physiologically based model.
The hydraulic fluid oil polychlorotrifluoroethylene (PCTFE) is hepato- and nephrotoxic in the rat. Male Fischer 344 rats were exposed to PCTFE either for a single 6-hr exposure (0.5 or 0.25 mg/liter) or daily 5 days/week, 6 hr/day, for 13 weeks (0.5, 0.25, or 0.01 mg/liter). Blood, tissue, and urinary PCTFE concentrations measured postexposure were used to develop a physiologically based pharmacokinetic (PB-PK) model. The PCTFE hydraulic fluid used was a mixture of trimeric and tetrameric oligomers with minor amounts of other chain lengths. The PB-PK model was designed to describe the behavior, not of individual oligomers, but of total mass for the trimer and tetramer in each tissue. Partition coefficients were estimated using the model to optimize tissue/blood concentration ratios measured at the end of the 13-week exposure. First-order metabolic rate constants for both trimeric (2.0 hr-1) and tetrameric (1.0 hr-1) portions were estimated by optimization against urinary fluoride data assuming release of 0.77 mole fluoride per mole trimer and 0.844 mole fluoride per mole tetramer metabolized. To obtain accurate simulation of pharmacokinetic data it was necessary to hypothesize two fat compartments with diffusion-limited exchange of PCTFE oligomer with the blood. Relative concentrations of trimer and tetramer in venous blood, liver, and fat after a single 6-hr exposure were proportional to inhaled concentrations. Tetramer accumulated preferentially with multiple exposure. Components of PCTFE were metabolized to carboxylic acids with release of fluoride. Due to their persistence tetrameric oligomers appear to be more important than trimeric oligomers as causative agents of PCTFE hepato- and nephrotoxicity in the rat.
Administration, Inhalation↗
Chemically induced cell proliferation in carcinogenesis.
Carcinogenesis can proceed by a variety of pathways involving the sequential mutation of normal cellular growth control genes and the clonal expansion of the resulting precancerous or cancerous cells. Chemical carcinogens may act by inducing mutations and/or altering cellular growth control. One class of chemical carcinogens are the genotoxicants. These compounds or their metabolites are DNA reactive and directly induce mutations or clastogenic changes. The observation that most mutagens are also carcinogenic is the basis for many current predictive assays and risk assessment models; however, there are different classes of nongenotoxic carcinogens that do not interact with DNA. Mitogens directly induce cell proliferation in the target tissue; cytotoxicants produce cell death followed by regenerative cell proliferation. Differential toxicity and/or growth stimulation induced by mitogens and cytotoxicants may provide a preferential growth advantage to spontaneous or chemically induced precancerous or cancerous cells. Mutagens are much more effective carcinogens at doses that also induce cell proliferation, and mutational activity may occur as an event secondary to cell proliferation. Thus, chemically induced cell proliferation is an important mechanistic consideration for both genotoxic and nongenotoxic carcinogens. The complex quantitative relationships between chemically induced cell proliferation and carcinogenic activity are under study in many laboratories. Such information should be considered in setting doses for cancer bioassays, for classifying chemical carcinogens and in providing more realistic approaches to risk assessment. Of particular concern in extrapolating cancer risk from rodent models to humans are those nongenotoxic agents that exhibit carcinogenic activity only at doses that also produce cytolethality and regenerative cell proliferation in the target organ.
Carcinogens↗
Biologically based pharmacodynamic models: tools for toxicological research and risk assessment.
The cancer model contains extensive biological detail, but is not fully validated. It is extremely useful for organizing what is known about malignant transformation, for linking measures of tissue dose with biological processes, and for proposing new experiments. It became very clear, as the cancer model was developed, that we lack an adequate understanding of the details of biochemical mechanisms of carcinogen action linking the target-tissue dose of carcinogen with effects on cell birth, death, and mutation rates as specified by the MVK model. This problem extends to noncarcinogenic toxicants such as methotrexate and the organophosphates. In these cases the biologically based descriptions of toxicity stop at the first interaction of the chemical with tissue. The linkage from the primary interaction to ultimate toxic effect is a "black box" that, at present, can only be described empirically rather than in biologically based terms. The models for dioxin and prednisolone do illustrate how biological events several steps removed from the initial tissue interaction of the toxicant can be described in quantitative, biologically based terms. As such they point the way for future development of more realistic descriptions in which the use of purely empirical linkages is reduced. Rigorous organization of current knowledge and specification of a logical sequence of new experiments encompass the major reasons for developing biologically based (structural) descriptions of any process. It bears emphasis that biologically based tissue response models, for cancer, for chloroform cytotoxicity, for functional impairment following organophosphate exposure, etc, are in reality quantitative formulations of an hypothesis or proposed mechanism incorporating the pharmacokinetics of the chemical and the linkage between target-tissue dose and toxic effect(s). The quantitative model allows us to see if the hypothesis is consistent with pertinent data and aids in designing experiments to define, refute, or bolster the general nature of the proposed linkages between tissue dose, tissue response and the whole organism's response to the chemical exposure. In this sense these biologically based models are quantitative descriptions of the current level of understanding of toxic effects in animals. We began this review article by looking at the literature on empirical tissue-response models to educate ourselves on the history of PD modeling. We rapidly found that the clear distinction between PK and PD models described in the literature blurs when one moves to biologically based modeling of tissue disposition and tissue response. Many articles on physiologically based pharmacokinetics turn out on close scrutiny to be as closely related to tissue response as they are to kinetics.(ABSTRACT TRUNCATED AT 400 WORDS)
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Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling.
A physiologically based pharmacokinetic (PB-PK) model for CHCl3 has been used to prepare estimates of the probability that human populations exposed to low levels of CHCl3 will develop liver tumors similar to those seen in rodent bioassays. The PB-PK model for CHCl3 was based on a model reported earlier by Corley et al. (1990), but this model differed from that of Corley et al. in that it was also capable of describing a pharmacodynamic endpoint: induction of cytotoxicity in the liver of CHCl3-exposed animals produced by reactive metabolites of CHCl3. Pharmacodynamic descriptions in this model were derived from experimental measurements of cell replication ([3H]thymidine incorporation) as well as from quantitative histopathology in the liver of rats and mice. Two different approaches were used for hazard evaluation: (1) a "Safety Factor" approach based on no observed effect levels for liver tumors. and (2) calculation of lower confidence limits on risk-specific doses with the GLOBAL83 computer program. In each case, cytotoxicity produced by reactive CHCl3 metabolites was used as the measure of "dose" to the liver. The Safety Factor approach suggested that continuous exposure of human populations to concentrations of CHCl3 less than 2840 ppb in air or 13,900 ppb in water would not be likely to significantly increase the risk of developing liver tumors. The second approach suggested a "plausible upper 95% confidence limit" of 1 x 10(-5) for lifetime excess cancer risk for human populations continuously exposed to 2200 or 13,100 ppb CHCl3 in air or water, respectively.
Administration, Inhalation↗
Physiologically based pharmacokinetic and pharmacodynamic model for the inhibition of acetylcholinesterase by diisopropylfluorophosphate.
Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair performance of critical tasks. The ability to predict such effects for realistic exposure scenarios would expedite OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed in mammals. DFP tissue:blood partition coefficients, rates of DFP hydrolysis by esterases, and DFP-esterase bimolecular inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard allometric relationships. These DFP-specific parameter values were used with the model to simulate expected in vivo pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain were successfully simulated after a single iv injection (B.R. Martin, 1985, Toxicol. Appl. Pharmacol. 77, 275-284). AChE inhibition and AChE resynthesis data from this study were also simulated. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain (H. Michalek, A. Meneguz, and G.M. Bisso, 1982, Arch. Toxicol., Suppl. 5, 116-119; M.E. Traina and L.A. Serpietri, 1984, Biochem. Pharmacol. 33, 645-653) were also simulated well, but the return of brain AChE activity to basal levels after cessation of repeated dosing was not as well described. The initial model structure returned brain AChE activity to the original level, while in the laboratory studies brain AChE never returned to basal levels, even at 35 days after the last dose. These data suggest modulation of AChE synthesis with prolonged DFP exposure. This study demonstrated the possibility of using a model based on mammalian physiology and biochemistry to simulate in vivo data on DFP pharmacokinetics and AChE inhibition. Scaling of the model between rats and mice was also successful. The approach holds promise for predictive simulation of organophosphate-mediated AChE inhibition in humans.
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Development of a physiologically based pharmacokinetic model for chloroform.
A physiologically based pharmacokinetic model describing the disposition of chloroform in mice, rats, and humans was developed. This model was designed to facilitate extrapolations from high doses, such as those used in chronic rodent studies, to low doses that humans may be exposed to in the workplace or the environment. Kinetic constants for mice and rats were derived from in vivo experiments. Enzymatic studies conducted with samples of rodent and human tissues provided a rational basis for estimating human in vivo metabolic rate constants. Incorporation of physiological descriptions of the processes of absorption, distribution, metabolism, and excretion allowed extrapolation between different routes of exposure as well. The model was validated by comparing model predictions with experimental data gathered in mice, rats, and humans after inhalation, oral, or intraperitoneal administration of chloroform. Consistent with previous reports, the metabolic activation of chloroform to toxic intermediates was shown to occur most rapidly in the mouse, less rapidly in the rat, and most slowly in humans. Estimates of the "delivered dose" of chloroform metabolites to internal organs sensitive to chloroform toxicity were calculated. This model may be used to develop refined dose estimates for human populations exposed to low levels of chloroform in the environment.
Administration, Inhalation↗
Pretreatment of primary rat cutaneous epidermal keratinocyte culture with a low concentration of MNNG: effect on DNA cross-linking measured in situ after challenge with bis-2-chloroethyl sulfide.
Bis-2-chloroethyl sulfide- (BCES-) induced DNA cross-links in confluent, primary cultures of newborn rat cutaneous epidermal keratinocytes were detected using an assay that includes in situ unwinding of the DNA followed by separation of single-stranded DNA and double-stranded DNA (DSDNA) with hydroxylapatite. DNA cross-links in BCES-challenged cultures were inferred from increases in the percentage of DNA that remained double-stranded, compared with control cultures, after a 60-min alkaline unwinding incubation. The amount of DNA cross-linking after 5 or 10 microM BCES was increased when keratinocytes were first pretreated with 0.05 microM MNNG for 1 h at 8 a.m., 2 p.m., and 8 p.m. for two consecutive days and challenged with BCES the following morning. This increase was statistically significant (p less than .05, by ANOVA). For example, after 5 microM BCES challenge, cultures not pretreated with MNNG had 114.14% control DSDNA, whereas MNNG pretreated cultures had 122.78% control DSDNA. The level of BCES-induced cross-linking was maximal immediately after 30-min challenge and decreased during postchallenge incubation. At 24 and 48 h post 5, 10, or 20 microM BCES challenge, the level of DSDNA was actually depressed below unchallenged levels. This postchallenge decrease in the level of DSDNA, indicative of SSB in DNA, suggests repair activity by glycosylases and endonucleases. However, completion of repair (i.e., a return to control levels of DSDNA) was not seen in these experiments. The activity that resulted in decreases in the level of DSDNA during postchallenge incubation response was unaffected by MNNG pretreatment.
Animals↗
Dose-response hearing loss for white noise in the Sprague-Dawley rat.
The effect of noise exposure on the inner ear is well documented. However, the sensitivity to noise-induced damage varies with animal species. The purpose of this investigation was to generate a hearing loss dose-response curve for a 20-day white noise exposure in the Sprague-Dawley rat. Eight male rats were exposed to 110, 100, 95 or 85 dB sound pressure level (SPL) for 6 hr/day, 5 days/week for 4 weeks in a sound-attenuated chamber fitted with a bank of overhead speakers. Controls were placed in an identical chamber without speakers. Four weeks after the exposure period ended, brainstem auditory evoked response (BAER) thresholds were recorded in all rats at 32, 16, 8, 4, 2, 1, and 0.5 kHz. Rats were then killed and cochlear tissues were processed for surface preparation. Hair cells were counted. Outer hair cell loss in the organ of Corti was observed in rats exposed to 95, 100, and 110 dB. Summary cytocochleograms were prepared for each rat by graphing the percentage of all hair cells remaining vs the percentage of distance along the basilar membrane as measured from the apex. The summary cytocochleograms were averaged and the area above this curve, corresponding to hair cell loss, was calculated. BAER threshold elevations (dB) were converted into percentage loss overall hearing function. Noise exposure level (dB) and (1) percentage area above the group average summary cytocochleogram and (2) percentage hearing loss were plotted as dose-response curves. Log-probit analysis was used to calculate ED50 noise exposure levels of 117 and 104 dB (SPL), (1), and (2), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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Pharmacokinetics, biochemical mechanism and mutation accumulation: a comprehensive model of chemical carcinogenesis.
Chemical carcinogenesis is a process beginning with carcinogen absorption and ending with development of a malignant tumor. Individual elements of this process have been studied intensively but no comprehensive model has been developed. This report describes a comprehensive model which incorporates carcinogen pharmacokinetics, biochemical mechanism of action, and the resultant mutation of normal cells to malignancy. Model parameters correspond to specific physiological and biochemical structures and processes. The model was encoded in a simulation language and used to examined biochemical and cellular effects of exposure to an initiator and a promoter. With laboratory validation, the model should be useful for interpretation and design of studies on carcinogenic mechanisms and for risk assessment.
Carcinogens↗
Comparison of blood toluene levels after inhalation and oral administration.
The purpose of this investigation was to compare blood toluene levels in Sprague-Dawley rats after oral and inhalation administration. Groups of 30 rats were dosed by gavage with 86.7, 217, 433, or 867 mg toluene/kg body wt or exposed for up to 6 hr, 5 rats per exposure, to an atmosphere of either 200 or 1000 ppm toluene. Blood was sampled by cardiac puncture from 5 rats in each of the six dose groups at 0.5, 1.0, 2.0, 4.0, 6.0, and 24.0 hr after gavage dosing or the beginning of the inhalation exposure. Blood toluene levels were analyzed. A four-parameter model was fitted to the blood toluene levels of the orally dosed rats. The area under the curve generated by this model, representing total blood toluene concentration over 6 hr, was calculated and compared to the area under the blood toluene curve for the 6-hr inhalation exposure. Integrated areas from the two routes of exposure were used for direct comparison of oral and inhalation exposures. The data demonstrate that gavage dosing can be used to approximate inhalation exposure to toluene.
Administration, Inhalation↗
Comparative ototoxicity of gentamicin in the guinea pig and two strains of rats.
Gentamicin ototoxicity and nephrotoxicity were compared in two strains of rats, Sprague-Dawley and Fisher-344, and in the Hartley albino guinea pig. Treatment groups consisting of 8 male rats of each strain and four male guinea pigs were dosed subcutaneously for 14 days with either 80 or 100 mg/kg of gentamicin sulfate in saline. Brainstem auditory evoked response (BAER) thresholds were recorded from each animal in each group on day 11 post-administration. Blood urea-nitrogen and serum creatinine were measured in blood obtained on day 11 post-administration as measures of nephrotoxicity. Kidney weight/body weight ratios were also determined. Loss of sensory hair cells was observed in the basal region of the organ of Corti from all animals treated with 100 mg/kg of gentamicin. The hair cell loss and BAER threshold elevations were greatest in the guinea pigs. Fisher-344 rats showed more extensive hair loss and greater BAER threshold elevations than Sprague-Dawley rats. The Fisher-344 rats exhibited increased blood urea-nitrogen and kidney weight/body weight ratios. Sprague-Dawleys did not suffer any nephrotoxic effects. These data indicate that the Fisher-344 rat is useful animal in which to study aminoglycoside ototoxicity as it exhibits both functional and morphological changes after gentamicin administration.
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